J Endocrinol Invest DOI 10.1007/s40618-014-0202-6

CONSENSUS STATEMENT

Rare diseases in clinical endocrinology: a taxonomic classification system G. Marcucci • L. Cianferotti • P. Beck-Peccoz • M. Capezzone • F. Cetani • A. Colao • M. V. Davı` • E. degli Uberti • S. Del Prato • R. Elisei • A. Faggiano • D. Ferone • C. Foresta • L. Fugazzola • E. Ghigo • G. Giacchetti • F. Giorgino • A. Lenzi • P. Malandrino • M. Mannelli • C. Marcocci • L. Masi • F. Pacini • G. Opocher • A. Radicioni • M. Tonacchera • R. Vigneri • M. C. Zatelli • M. L. Brandi

Received: 19 August 2014 / Accepted: 17 October 2014 Ó Italian Society of Endocrinology (SIE) 2014

Abstract Purpose Rare endocrine–metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of

basic and clinical scientists, a document on the taxonomy of REMD has been produced. Methods and results This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. Conclusions This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning

G. Marcucci (&)  L. Cianferotti  M. L. Brandi Head, Bone Metablic Diseases Unit, Department of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy e-mail: [email protected]

M. V. Davı` Section D, Department of Medicine, Clinic of Internal Medicine, University of Verona, Verona, Italy

M. L. Brandi e-mail: [email protected] P. Beck-Peccoz  L. Fugazzola Department of Clinical Sciences and Community Health, University of Milan and Endocrine Unit, Fondazione IRCCS Ca’ Granda, Milan, Italy M. Capezzone Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy F. Cetani  R. Elisei  M. Tonacchera Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy A. Colao  A. Faggiano Dipartimento di Medicina Clinica e Chirurgia, Universita` Federico II di Napoli, Naples, Italy

E. degli Uberti  M. C. Zatelli Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy S. Del Prato Section of Metabolic Diseases and Diabetes, Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy D. Ferone Endocrinology, Department of Internal Medicine and Medical Specialties and Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy C. Foresta Department of Medicine and Centre for Human Reproduction Pathology, University of Padova, Padua, Italy E. Ghigo Division of Endocrinology, Diabetology and Metabolism Department of Medical Sciences, University Hospital Citta` Salute e Scienza, Turin, Italy

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and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment. Keywords Taxonomy  Endocrinopathy  Orphan disease  Endocrine glands  Neuroendocrine tumors Abbreviations ACA Abs AFP ALP Apo B AVP BAP BB-CK b-HCG Ca cAMP CaSR CEA CgA CK DDAVP DHEA DHEA-s DHT DIT DOC

Adrenal cortex antibodies Alpha fetoprotein Alkaline phosphatase Apolipoprotein B Arginine vasopressin Bone alkaline phosphatase Brain-specific creatine kinase isoenzyme b-Human chorionic gonadotropin Calcium Cyclic adenosine monophosphate Calcium-sensing receptor Carcino-embryonic antigen Chromogranin A Creatin kinase Desmopressin Dehydroepiandrosterone Dehydroepiandrosterone-sulfate Dihydrotestosterone Di-iodinated tyrosine Deoxycorticosterone

G. Giacchetti Division of Endocrinology, Azienda Ospedaliero-Universitaria, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Universita` Politecnica delle Marche, Ancona, Italy F. Giorgino Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy A. Lenzi Chair of Endocrinology, Section Medical Pathophysiology, Food Science and Endocrinology, Department Exp. Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy P. Malandrino Endocrinology, Department of Clinical and Molecular Biomedicine, Garibaldi-Nesima Medical Center, University of Catania, Catania, Italy M. Mannelli Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy C. Marcocci Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy

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FGF23 FPG GAD Abs GIST Gs hCG HDL 5-HIAA 5-HT IA2 Abs IDL IGF-1 K LDL LPL Mg MIT MPC Abs Na NSE 21OH Abs 17-OHP 17a-OH Abs P PCA Abs PP PRL PTHrP SCC Abs

Fibroblast growth factor 23 Fasting plasma glucose Glutamic acid decarboxylase antibodies Gastro-intestinal stromal tumors G-protein alpha subunit Human chorionic gonadotropin High-density lipoprotein 5-Hydroxyindoleacetic acid 5-Hydroxytryptophan Tyrosine phosphatase antibodies Intermediate-density lipoprotein Insulin-like growth factor Potassium Low-density lipoprotein Lipoprotein lipase Magnesium Mono-iodinated tyrosine Melanin-producing cells antibodies Sodium Neuron-specific enolase 21 hydroxylase antibodies 17 OH progesterone 17 alpha-hydroxylase antibodies Phosphorus Parietal cell antibodies Pancreatic polypeptide Prolactin Parathyroid hormone-related protein Side-chain cleavage enzyme antibodies

L. Masi Department of Orthopedic, Metabolic Bone Diseases Unit AOUC-Careggi Hospital, Largo Palagi, 1, Florence, Italy F. Pacini Section of Endocrinology and Metabolism, University of Siena, Siena, Italy G. Opocher Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padua, Italy G. Opocher Department of Medicine DIMED, University of Padova, Padova, Italy A. Radicioni Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy R. Vigneri Department of Clinical and Molecular Biomedicine, University of Catania, and Humanitas Catania Center of Oncology, Catania, Italy

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SS StCA Abs TmP/GFR tTGA Abs TPO Abs UFC Ur. Ca Ur. K Ur. Na Ur. P VIP VLCFA

Somatostatin Steroid-producing cell antibodies Renal tubular reabsorption of phosphate Tissue transglutaminase antibodies Thyroid peroxidase antibodies Urinary free cortisol Urinary calcium Urinary potassium Urinary sodium Urinary phosphorus Vasoactive intestinal polypeptide Very long chain fatty acids

Introduction Rare endocrine–metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology and constitute a major challenge for the clinical endocrinologist. Indeed, adult endocrinologists have to constantly face and/or rule out rare diseases in the differential diagnoses of clinical endocrine disorders more than any other medical specialist outside the pediatric field. The rare diseases of interest to endocrinologists involve all fields of endocrinology, encompassing those of the pituitary, thyroid, and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands. The estimated total average prevalence of rare endocrine diseases in a million inhabitants is around 20–50/1,000,000. To date REMD are not organized into an itemized taxonomy. There is no single, widely accepted definition for rare disease. In general, a rare disease, also referred to as ‘‘orphan disease’’, is any disorder whose prevalence is lower than a given cutoff encoded by the legislation of each country. In the United States, a 1984 amendment to the 1983 Orphan Drug Act (a USA law designed to facilitate the development and commercialization of drugs to treat rare diseases) defines rare disease as ‘‘any disease or condition that affects\200,000 people at any given time in the United States’’ or any disease whose prevalence is \7.5/ 100,000 [1]. This definition is also included in the 2002 Rare Disease Act, which established the Office of Rare Disease as the coordinating federal authority on this matter [2, reviewed in 3]. The European Commission on Public Health, which officially addressed this issue in 1999 in the view of ‘‘adopting a programme of Community action on rare diseases’’, defines these disorders as ‘‘life-threatening or chronically debilitating diseases which are of such low

prevalence that special combined efforts are needed to address them’’, along with a prevalence of \5/10,000 [4]. This definition has been recently confirmed in the Report on the State of the Art of Rare Disease in Europe in 2013 [5]. The European Organization for rare diseases (EURORDIS) estimates that as many as 5,000–7,000 distinct rare diseases exist, and as much as 6–8 % of the population of the European Union is affected by at least one [6]. Only about 400 rare diseases have targeted therapies. About 80 % have a genetic component, according to the Rare Genomics Institute. Therefore, despite the low prevalence of each rare disease, the total number of people affected by rare diseases in the EU is estimated to be between 27 and 36 million [5, 7, 8]. Among these, the majority suffer from even more uncommon diseases with a prevalence of B1/ 100,000 [8]. Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true for genetic diseases, for which the founder effect can result in a disease that is very rare worldwide being prevalent within a smaller community. The geographic dispersion of a relatively small number of patients affected by rare diseases leads to many unique and complicated issues that are exclusive to these groups. These include difficulties in finding providers with the appropriate knowledge of the disorder to be able to plan proper diagnostic algorithms and procedures, and to prescribe safe and effective treatments. Funding to conduct investigations to assess the natural history, etiology (including genetic testing), and effectiveness of pharmacological therapies is also an important issue [9, 10]. Although a rare disease affects no more than 200,000 persons, many of them share similar symptoms and take advantage of the same treatments. Indeed, a critical component of advancing rare disease research centers relies on the establishment of disease registries and associated data [11–14]. EURORDIS estimates that at least 80 % of rare diseases have a genetic origin [6, 15]. Symptoms of some rare disorders may be revealed at birth or in childhood, whereas others only appear later in life, up to the fourth or fifth decade. Rare diseases require early diagnosis, and frequently, a multifaceted approach and follow-up by expert medical teams. Many rare diseases are complex, chronic, severe, and disabling, leading to reduced quality of life and life expectancy. In addition, these patients are often particularly isolated and vulnerable. The lack of specific health policies for rare diseases and the scarcity of expertise translate into delayed diagnoses and difficult access to care [9]. Misdiagnosis and non-diagnosis are the main hurdles that must be overcome to improve the quality of

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life for thousands of rare disease patients. A translational approach characterized by scientific cooperation between clinicians and researchers is mandatory to increase knowledge about rare diseases and plan screening and management protocols. For many, rare disease treatment poses a challenge due to limited scientific data and poor commercial interest on behalf of pharmaceutical industries [16]. For these reasons, today rare diseases are a priority area for action in public health programs. In 2010 the 5th European Conference on rare diseases (ECRD) focused on the state-of-art health policies relevant to rare diseases, and released recommendations on: national plans and strategies for rare diseases, European reference networks and centers of expertise for rare disease, science from the bench to the bedside, medicine for people living with a rare disease and information, help lines, empowerment, and medical education [17]. Several Countries endorse and support specific plans to overcome these issues. In Europe and North America, several projects on rare diseases are ongoing, and thematic networks have been created with new calls that are launched yearly [18, 19]. In 2011, a joint consortium between the USA and Europe, the International Rare Diseases Research Consortium (IRDiRC, http://www.irdirc. org), initiated and endorsed by the European Commission and the US National Institute of Health Research, was launched to foster collaboration in this field. The ambitious goal of this consortium is to develop a diagnostic tool for every known rare disease and to deliver at least 200 new therapies for these disorders by 2020. The consortium acknowledges that correct classification of rare diseases is of preliminary importance to this purpose. Awareness and empowerment of patients with rare diseases are crucial [17]. Thus, non-profit national and international organizations and related coalitions, often supported by related foundations, have been created for rare diseases as a whole, as well as for specific disorders. Cooperation between researchers/clinicians and patients, endorsed and pursued by specific organizations such as the National Organization for Rare Disorders (NORD, https:// www.rarediseases.org) in North America, is critical to better address the everyday challenges of these patients through the development of specific approaches. On the other hand, scientific societies can support these efforts beginning with the categorization and classification of diseases. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology (SIE), including basic and clinical scientists, a document on the taxonomy of REMD of the adult has been produced. This extensive and as complete as possible document has been designed to include mainly REMDs which manifest or persist into adulthood. Although this instrument is addressed primarily to clinical endocrinologists to serve as

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a tool for use in clinical practice for an improved categorization of patients, it is advisable that in the future it could also be used for specific drug development and policymaking in public health [20].

Materials and methods The taxonomy of REMD has been built taking advantage of evidence based on the available literature and position statements. Main reviews and reference papers have been included. For genetically determined disorders, the Online Mendelian Inheritance in Men (OMIM, http://www.omim.org) database has been used, retrieving phenotype numbers and gene/locus numbers [21]. The nomenclature for disease acronyms used is the one approved by the Gene Nomenclature Committee belonging to the Human Genome Organization (HUGO-HGNC) [22]. For non-genetically determined REMD, Orphanet nomenclature has been used [23]. The results have been summarized in 11 tables, divided according to endocrine gland or metabolic disorder (pituitary, thyroid gland, bone and mineral metabolism, axis PTH/PTHrP–PTHR1, glucose and lipids metabolism, metabolism of water, adrenal glands and paraganglia, ovary, testis, rare diseases with possible involvement of multiple endocrine glands, and neuroendocrine tumors). For each disease, the following have been specified: disease name and related acronym, OMIM phenotype number, mutated gene(s) and OMIM gene/locus number (related genes), phenotypic traits, typical metabolic biomarkers, incidence, prevalence, age range of expression, and the most significant references, where available. These essential data are sufficient to frame a rare endocrine disease by clinical endocrinologists. Since the specific purpose of this taxonomic study is to classify REMD, we refer to further literature for general and specific descriptions of the different disorders and related therapy.

Results and discussion The taxonomy of REMD of the adult comprises a total of 169 main disorders and 346 with all variants and subtypes, distributed in 11 tables: 90 % are genetically determined. Among these, in 93 % of the cases the specific gene/locus has been identified. For the remaining 10 % a monogenic cause has not been established. REMD (main disorders, with all variants and subtypes) have been subdivided as follows: (Table 1) 24 rare pituitary diseases, (Table 2) 24 rare thyroid diseases, (Table 3)

OMIM phenotype number

# 102200



# 219090





Disorder

1) Pituitary adenoma, GHsecreting

2) Pituitary adenoma, TSHsecreting

3) Pituitary adenoma, ACTHsecreting

4) Pituitary adenoma, LHsecreting

5) Pituitary adenoma, FSHsecreting

Table 1 Rare pituitary diseases









(605555)

AIP

OMIM gene/ locus number

Pituitary adenoma

Pituitary adenoma

Moon face, buffalo hump, obesity, skin thinning, large and purple abdominal striae, ecchymotic lesions or purpura, lower limb edema, muscle atrophy, osteoporosis, hypertension and cardiovascular complications, hirsutism, gonadal dysfunction, psychic disturbances

Cushing’s syndrome:

Hyperthyroidism, goiter

The excessive secretion of GH and IGF1 leads to severe complications in the cardiovascular, respiratory, metabolic, skeletal, and integumentary systems

Other manifestations: Increased sweating, goiter, joint involvement, carpal tunnel syndrome, visual abnormalities, headache, colon polyps, sleep apnea, reproductive disorders

Coarsened facial appearance, acral enlargement, increased skin thickness and soft tissue hyperplasia

Gigantism in juveniles or acromegaly in adults

Phenotype

High FSH levels

High LH levels

High ACTH, and UFC levels

High TSH, FT3, and FT4 levels

The standard method for diagnosing acromegaly is the measurement of the GH nadir during an oral glucose tolerance test, which is undetectable in normal individuals, while acromegalics fail to suppress GH levels

High GH and IGF-1 levels

Typical metabolic biomarkers

Unknown

Unknown

1–3/ 1,000,000

Unknown

3–4/ 1,000,000

Incidence

Unknown

Unknown

40/ 1,000,000

Unknown

40–130/ 1,000,000

Prevalence

Variable

Variable

Variable

Variable

Variable

Age range of expression

[28]

[27]

[26]

[25]

[24]

References

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123

# 308700

# 147950

# 244200

# 612370

7a) Hypogonadotropic hypogonadism 1 with or without anosmia; HH1

7b) Hypogonadotropic hypogonadism 2 with or without anosmia; HH2

7c) Hypogonadotropic hypogonadism 3 with or without anosmia; HH3

7d) Hypogonadotropic hypogonadism 5 with or without anosmia; HH5 (608892)

CHD7

(607123)

PROKR2

(136350)

FGFR1

KAL 1 (300836)

Invasive and somatostatin analogs— resistant

(605555)

7) Congenital hypopituitarism

Macroadenomas:

AIP

# 102200

Hypogonadotropic hypogonadism, anosmia, cleft palate, and sensorineural hearing loss

Hypogonadotropic hypogonadism, anosmia, midline, cranial fusion defect, cleft lip, cleft palate, hypotelorism, unilateral renal agenesis

Hypogonadotropic hypogonadism, anosmia, midline cranial anomalies, cleft lip, cleft palate and imperfect fusion

Anosmia due to agenesis of the olfactory lobes, hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone. Transmitting females have partial or complete anosmia. Renal agenesis, bimanual synkinesia, pes cavus, high-arched palate, and cerebellar ataxia

Acromegaly, gigantism





Phenotype

6) Familial isolated pituitary adenomas (FIPA), Familial isolated somatotropinoma (IFS)

OMIM gene/ locus number

OMIM phenotype number

Disorder

Table 1 continued

Low FSH, LH, T, 17b-estradiol levels

Low FSH, LH, T, 17b-estradiol levels

Low FSH, LH, T, 17b-estradiol levels

Low FSH, LH, T, 17b-estradiol levels

IFS: High GH and IGF-1 levels

FIPA: high GH and IGF1 levels or high PRL levels or high ACTH and cortisol levels

Typical metabolic biomarkers

Unkonwn

Unkonwn

Unkonwn

1/ 10,000–1/ 86,000

Unknown

Incidence

Male: 1/8,000 Female: 1/40,000

Male: 1/8,000 Female: 1/40,000

Male: 1/8,000 Female: 1/40,000

Male: 1/8,000 Female: 1/40,000

IFS: Unknown

FIPA: 5 % di PA

Pituitary adenomas (PA): 1/1,000

Prevalence

Adolescence

Adolescence

Adolescence

[30]

[30]

[30]

[30]

[29]

\18–40 years

Adolescence

References

Age range of expression

J Endocrinol Invest

OMIM phenotype number

# 614838

# 614839

# 614841

# 614842

# 245800

#176270

Disorder

7e) Hypogonadotropic hypogonadism 9 with or without anosmia; HH9

7f) Hypogonadotropic hypogonadism 10 with or without anosmia; HH10

7g) Hypogonadotropic hypogonadism 12 with or without anosmia; HH12

7h) Hypogonadotropic hypogonadism 13 with or without anosmia; HH13

7i) Laurence–Moon syndrome

7l) Prader–Willi syndrome; PWS

Table 1 continued

(182279)

SNRPN

(602117)

NDN



(603286)

KiSS1

(152760)

GnRH1

(162330)

TAC3

(608137)

NSMF

OMIM gene/ locus number

Reduced fetal movement, hypotonia, feeding difficulties, intellectual delay, hyperphagia, cryptorchidism, GH deficiency, mixed hypogonadism, delayed puberty, behavioral problems, dysmetabolism, osteoporosis

Oftalmologic signs: retinitis pigmentosa and blindness. Endocrinological signs: hypogonadotropic hypogonadism with hypogenitalism, obesity and growth delay. Polydactyly, renal dysfunction

Neurological symptoms: cognitive impairment, ataxia, progressive spastic paraplegia

Hypogonadotropic hypogonadism, anosmia, cleft palate, and sensorineural hearing loss

Hypogonadotropic hypogonadism, anosmia, cleft palate, and sensorineural hearing loss

Hypogonadotropic hypogonadism, anosmia, cleft palate, and sensorineural hearing loss

Hypogonadotropic hypogonadism, anosmia, cleft palate, and sensorineural hearing loss

Phenotype

Low FSH, LH, T, 17b-estradiol, GH, IGF-1 levels, high LDL levels, low HDL levels, normal levels of triglicerides, no insulin resistance

Low FSH, LH, T, 17b-estradiol levels, dyslipoproteinemia, hyperglycemia

Low FSH, LH, T, 17b-estradiol levels

Low FSH, LH, T, 17b-estradiol levels

Low FSH, LH, T, 17b-estradiol levels

Low FSH, LH, T, 17b-estradiol levels

Typical metabolic biomarkers

1/ 25,000–1/ 10,000

Unknown

Unkonwn

Unkonwn

Unkonwn

Unkonwn

Incidence

1–9/100,000

Unknown

Male: 1/8,000 Female: 1/40,000

Male: 1/8,000 Female: 1/40,000

Male: 1/8,000 Female: 1/40,000

Male: 1/8,000 Female: 1/40,000

Prevalence

Variable

Variable

Adolescence

Adolescence

Adolescence

Adolescence

Age range of expression

[32]

[31]

[30]

[30]

[30]

[30]

References

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123 ALMS1

#203800

7m) Alstrom syndrome; ALMS

# 613038

# 262600

# 221750

# 262700

# 182230

8a) Pituitary hormone deficiency, combined 1; CPHD1

8b) Pituitary hormone deficiency, combined 2; CPHD2

8c) Pituitary hormone deficiency, combined 3; CPHD3

8d) Pituitary hormone deficiency, combined 4; CPHD4

8e) Pituitary hormone deficiency, combined 5; CPHD5 (Septooptic dysplasia) (601802)

HESX1

(602146)

LHX4

(600577)

LHX3

(601538)

PROP1

(173110)

POU1F1

8) Pituitary hormone deficiency, combined

(606844)

OMIM gene/ locus number

OMIM phenotype number

Disorder

Table 1 continued

Optic nerve hypoplasia, pituitary gland hypoplasia, midline abnormalities of the brain, absence of the corpus callosum and septum pellucidum

Poorly developed sella turcica with PRL, TSH and GH. Deficiency corpus callosum, hypoplasia ectopic neurohypophysis

Rigidity of the cervical spine, mild sensorineural hearing loss, deficiency of all anterior pituitary hormones except ACTH, with consequent clinical manifestations

Growth failure, failure to thrive, hypothyroidism, incomplete secondary sexual development, infertility, small penis, ACTH deficiency (less common)

Severe growth deficiency, hypothyroidism, prominent forehead, marked midfacial, hypoplasia, severe mental retardation, preserved production of FSH, LH and ACTH

Obesity, nystagmus, photodysphoria, blindness in adulthood, bilateral sensorineural hearing loss throughout childhood. Dilated cardiomyopathy, renal, pulmonary and hepatic disturbances. Diabetes mellitus Type 2, hypothyroidism, GH deficiency, primary hypogonadism in males, hyperandrogenism in females

Phenotype

Low GH, ACTH, TSH, FT3, FT4, FSH, LH, IGF1, T, 17b-estradiol, levels. Neonatal hypoglycemia

Low GH, IGF-1, TSH, FT3, FT4 and PRL levels

Low GH, IGF-1, IGF-I binding protein3, TSH, FT4, LH, FSH, testosterone, 17b-estradiol and PRL levels

Low GH, IGF-1, TSH, FT3, FT4, LH, FSH, T, 17b-estradiol, PRL, ACTH, cortisol levels

Low GH, PRL TSH, FT3 and FT4 levels. Normal ACTH, LH and FSH levels

Hyperinsulinemia, hypertriglicerydemia, hyperuricemia, hypotiroidism, low FSH, LH, T, 17bestradiol, GH, IGF-1 levels

Typical metabolic biomarkers

1/10,000

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

\1/ 1,000,000

\1/ 1,000,000

Unknown

Unknown

1–9/ 1,000,000

Prevalence

Variable

Variable

Variable

Variable

Variable

Variable

Age range of expression

[38]

[37]

[36]

[35]

[34]

[33]

References

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# 262400

#160980

9) Isolated growth hormone deficiency, type 1a; IGHD1A

10) Pituitary tumors (Carney complex, type 1)



1) Sporadic medullary thyroid carcinoma (MTC)

# 155240

# 171400

2a) Familial medullary thyroid carcinoma (MTC)

2b) Familial medullary thyroid carcinoma (multiple endocrine neoplasie: MEN2A)

2) Familial medullary thyroid carcinoma

OMIM phenotype number

(164761)

RET

(191315)

NTRK1

(164761)

RET

(164761)

RET

Medullary thyroid carcinoma, pheochromocytoma, parathyroid adenomas. Associated characteristic features: cutaneous lichen amyloidosis, Hischprung’s disease rarely prominent corneal nerves

Thyroid nodules with possible lymph node or distant metastases, diarrhea. Four or more family members across at least two or more generations have isolated medullary thyroid carcinoma

High serum basal levels and stimulated calcitonin, elevated catecholamines and catecholamine metabolites, high serum Ca and PTH levels

High CEA and calcitonin levels

High CEA and calcitonin levels

Typical metabolic biomarkers

Unknown

Unknown

Incidence

Unknown

Unknown

0.5 of all thyroid cancers

Incidence

Variable, 20–30 % hypercortisolism with low ACTH levels, less frequently high levels of PRL, GH or IGF-1, or high levels of T, high serum FT4, FT3 levels, low TSH level

Low GH and IGF1 levels, fasting hypoglycemia, high cholesterol levels

Typical metabolic biomarkers

Thyroid nodules with possible lymph node or distant metastases, diarrhea

Phenotype

Spotty skin, cardiac myxomas, pigmentation, precocious puberty, Cushing’s syndrome, caused by primary pigmented nodular adrenal dysplasia, skin pigmented lesions, pituitary tumors precocious, thyroid and testes tumors, other myxoid tumors

Proportionate short stature, decreased growth velocity, micropenis, fasting hypoglycemia, truncal obesity, highpitched voice, pubertal delay (gonadotropin independent)

Phenotype

OMIM gene/locus number

(188830)

PRKAR1A

(139250)

GH1

OMIM gene/ locus number

Disorder

Table 2 Rare thyroid diseases

OMIM phenotype number

Disorder

Table 1 continued

1/30,000

Unknown

1–9/100,000

3–25 years

Adulthood (if no screened)

Adulthood

Age range of expression

Neonatal/ infancy

\1/ 1,000,000

Prevalence

Since the second/ third year of life

Age range of expression

Unknown

Prevalence

[42]

[42]

[41]

References

[40]

[39]

References

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123



3) Anaplastic thyroid carcinoma

# 160980

# 158350

# 175100

# 188550

# 188455

4a) Familial differentiated thyroid cancer (Carney complex, type 1)

4b) Familial differentiated thyroid cancer (Cowden syndrome 1)

4c) Familial differentiated thyroid cancer (Gardner syndrome)

5) Familial nonmedullary thyroid cancer, papillary

6) Thyroglossal duct cyst, familial

4) Familial differentiated thyroid cancer

OMIM phenotype number

Disorder

Table 2 continued



(606918)

GOLGA5

CCDC6 (601985)

(601984)

NCOA4

(600299)

PCM1

(603406)

TRIM24

(605769)

TRIM33

(611731)

APC

(601728)

PTEN

(188830)

PRKAR1A



OMIM gene/locus number

Growing thyroid mass in the median region of the neck

Thyroid nodule, usually single, fixed, freely moveable. Hoarseness, dysphagia, cough and dyspnea are signs of the advanced stages of the disease. Two or more family members across at least 2 or more generations have isolated papillary thyroid cancer

Patients may begin to develop multiple polyps in the colon. Unless the colon is removed, these polyps will become malignant (cancerous)

Multiple hamartomas in the skin, breast, thyroid, digestive tract, endometrium and the brain, high risk of malignant tumors (breast, endometrium and follicular thryoid cancer)

Spotty skin pigmentation, cardiac myxomas, endocrine overactivity, acromegaly, Cushing’s syndrome, caused by primary pigmented nodular adrenal dysplasia, pituitary tumors and thyroid and testes tumors, other myxoid tumors

Rapidly growing thyroid mass invading surrounding structures with compressive symptoms. Cervical lymph nodes enlargement and distant metastases frequently

Phenotype

None

None

None

None

None

None

Typical metabolic biomarkers

Unknown

Unknown

1/8,300

Unknown

Unknown

Unknown

Incidence

Unknown

Unknown

1/ 11,300–37,600

1/200,000

Unknown

1–9/1,000,000

Prevalence

Variable

Variable

Second decade of life

Neonatal/ infancy

Neonatal/ infancy

Adulthood ([60 years)

Age range of expression

[49]

[48]

[47]

[46]

[45]

[44]

References

J Endocrinol Invest

# 188570

# 614450

7) Thyroid hormone resistance, generalized, autosomal dominant; GRT

8) Hypothyroidism, Congenital, Nongoitrous, 6; CHNG6

# 300523

# 241850

# 275200

# 274600

# 218700

# 610978



9a) Permanent congenital hypothyroidism (Allan–Herndon– Dudley syndrome; AHDS)

9b) Permanent congenital hypothyroidism (Hypothyroidism, athyroidal, with spiky hair and cleft palate)

9c) Hypothyroidism, congenital, nongoitrous, 1; CHNG1 (TSH resistance)

9d) Pendred syndrome; PDS

9e) Hypothyroidism, congenital, nongoitrous, 2; CHNG2

9f) Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction; CAHTP

10) Inherited Thyroxinebinding globulin deficiency

9) Permanent congenital hypothyroidism

OMIM phenotype number

Disorder

Table 2 continued

(314200)

SERPINA7

(600635)

NKX2–1

PAX 8 (167415)

(605646)

SLC26A4

(603372)

TSHR

(602617)

FOXE1

(300095)

SLC16A2

THRA

(190160)

THRB

OMIM gene/locus number

Clinically euthyroid individuals with partial to complete TBG deficiency

Hypothyroidism with thyroid agenesis, hypoplasia, normal sized thyroid gland, respiratory distress, neurological disorders (choreoathetosis)

Hypothyroidism with thyroid agenesis, hypoplastic, ectopy, normal sized thyroid gland

Bilateral sensorineural hearing loss (with variable degree), euthyroid goiter

Rare hypoparathyroidism, hypoplastic thyroid glands

Athyroidal hypothyroidism cleft palate, spiky hair, choanal atresia, bifid epiglottis

Mental retardation, congenital hypotonia, generalized muscle weakness

Growth retardation, delayed mental and bone development, and constipation

Goiter, clinically euthyroid, delayed speech development, childhood attention-deficit/hyperactivity disorder

Phenotype

Low total FT4 levels, normal TSH and FT4 levels, low to undetectable TBG levels

Low FT4 and FT3 levels, high TSH levels

Low FT4 and FT3 levels, high TSH levels

None

High TSH levels, low FT4 levels

High FT3 levels, low to below normal FT4 levels and TSH levels within the range

High FT3 levels, low to below normal FT4 levels and levels of TSH within the range

Normal TSH levels, low-normal FT4 and high normal FT3 levels

High FT3 and FT4 levels, inappropriate secretion of TSH

Typical metabolic biomarkers

1:5,000 newborns (1:2,800 in males)

Unknown

Unknown

Unknown

Unknown

Unknown

1/4,000

Unknown

1/50,000

Incidence

1–5/100,000

Unknown

2/100,000

1–9/100,000

Unknown

\1/1,000,000

\1/1,000,000

Unknown

Unknown

Prevalence

Variable

Neonatal

Neonatal

Neonatal/ Infancy

Neonatal

Neonatal

Neonatal

Neonatal/ infancy

Neonatal/ infancy

Age range of expression

[58]

[57]

[56]

[55]

[54]

[53]

[52]

[51]

[50]

References

J Endocrinol Invest

123

123

OMIM phenotype number

# 274500

# 274700

# 274800

# 607200

11b) Thyroid dyshormonogenesis 2A; TDH2A

11c) Thyroid Dyshormonogenesis 3; TDH3

11d) Thyroid dyshormonogenesis 4; TDH4

11e) Thyroid dyshormonogenesis 6; TDH6

OMIM phenotype number

# 166200

# 259420

1a) Osteogenesis imperfecta type 1

1b) Osteogenesis Imperfecta type 3

1) Osteogenesis imperfecta; OI

Disorder

(606759)

DUOX2

(612025)

IYD

(188450)

TG

(606765)

TPO

SLC5A5 (601843)

OMIM gene/locus number

Risk of perinatal lethality, multiple long bone deformities, fractures at birth (over 50 % are wheelchair dependent at an early stage, very short stature with adult height ranging from 90 to 120 cm, possible respiratory compromise), blue or grey sclera, severe dentinogenesis imperfecta and triangular faces

(120160)

COL1A2

The most severe form

(120150)

Blue sclera, no dentinogenesis imperfecta, minimal bony deformity, risk of vertebral and long bone fractures, normal height, minimal functional limitations

COL1A1

Mild form

None

None

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

1/100,000

1/66,000

Unknown

Prevalence

Unknown

The overall prevalence of OI is estimated at between 1/10,000 and 1/20,000, but the prevalence of type I is unknown

Prevalence

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

Incidence

Normal or low FT4 and FT3 levels, high TSH levels

Low FT4 and FT3 levels, high TSH levels, urinary excretion of MIT and DIT

Low FT4 and FT3 levels, high TSH levels, urinary excretion of iodopeptides

Low FT4 and FT3 levels, high TSH levels

Low FT4 and FT3 levels, high TSH levels, low saliva/plasma (123)I ratio

Typical metabolic biomarkers

(120150)

Phenotype

Permanent or transient hypothyroidism with normal sized thyroid gland or goiter

Permanent hypothyroidism with goiter

Hypothyroidism with diffuse or nodular goiter

Hypothyroidism with diffuse or nodular goiter

Hypothyroidism with diffuse or nodular goiter

Phenotype

COL1A1

OMIM gene/locus number

Table 3 Rare mineral and bone diseases

# 274400

11a) Thyroid dyshormonogenesis 1; TDH1

11) Thyroid dyshormonogenesis

Disorder

Table 2 continued

Neonatal/ infancy

Childhood

Age range of expression

Neonatal

Neonatal

Variable

Neonatal

Variable

Age range of expression

[64]

[64]

References

[63]

[62]

[61]

[60]

[59]

References

J Endocrinol Invest

OMIM phenotype number

# 166220

# 610967

# 613982



Disorder

1c) Osteogenesis Imperfecta type 4

1d) Osteogenesis Imperfecta type 5

1e) Osteogenesis Imperfecta type 6

2) Cystic angiomatosis of bone

Table 3 continued



(172860)

SERPINF1

(614757)

IFITM5

(120160)

COL1A2

(120150)

COL1A1

OMIM gene/locus number

Disseminated multifocal hemangiomatous and/or lymphangiomatous lesions of the skeleton, in both the axial and appendicular skeleton, with possible visceral organ involvement. The process can be monostotic or polyostotic, isolated skeletal involvement is very rare

Moderate to severe skeletal deformity and fragility. Bone biopsy specimens: fish scale-like appearance of the bone lamellae and the presence of excessive osteoid. No blue sclera or dentinogenesis imperfecta Laboratory findings are unremarkable, although increases in ALP activity have been noted

None

None

None

Moderate severity. The patients range from being fully mobile to completely wheelchair dependent. Scoliosis, severe osteoporosis, ligament laxity, blue sclera at a young age and white in adults, no dentinogenesis imperfecta, triangular faces Distinctive phenotype with moderate to severe bone fragility. Hypertrophic callus formation and early calcification of the interosseous membrane between the bones of the forearm. Limits of pronation and supination, radial head dislocation. The lamellar organization of the bone: irregular mesh-like appearance. No blue sclera and dentinogenesis imperfecta

Typical metabolic biomarkers

Phenotype

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

Unknown

\1/1,000,000

Unknown

Prevalence

The first decade of life, it is usually manifested by the age of puberty, with a range extending to the third decade

Neonatal/ Infancy

Neonatal/ infancy

Neonatal/ infancy

Age range of expression

[65]

[64]

[64]

[64]

References

J Endocrinol Invest

123

123

# 123880

3) Cystic angiomatosis of bone, diffuse; GSD –

OMIM gene/locus number

# 264700

# 600081

# 277440

4a) Vitamin d hydroxylationdeficient rickets, type 1a; VDDR1A

4b) Vitamin d hydroxylationdeficient rickets, type 1b; VDDR1B

4c) Vitamin d-dependent rickets, type 2a;VDDR2A

VDR (601769)

(608713)

CYP2R1

(609506)

CYP27B1

4) Vitamin d hydroxylation-deficient rickets

OMIM phenotype number

Disorder

Table 3 continued

Growth retardation, muscle weakness, convulsion for hypocalcemia, bone pain at the lower extremities that delays their development of walking, fracture and pseudo-fractures, fracture and pseudofractures sparse bone trabeculae thin bony cortex, delayed opacification of the epiphyses, subperiosteal erosions due to secondary hyperparathyroidism dental caries or hypoplasia of the teeth, scalp and body alopecia

Curvatures of the femur, tibia, fibula, enlargement of the wrists, enlargement of the ankles

Hypotonia, muscle weakness, difficulty in walking, difficulty in standing, rickets, increased fractures, bone pain, sparse bone trabeculae, thin bony cortex, delayed opacification of the epiphyses, widened, distorted epiphyses, frayed, irregular metaphyses, lower limb deformities, bowing of the legs

Rickets, tetany, convulsions, seizures, muscle weakness, and poor growth. Enamel hypoplasia is occasionally observed

The most severe form of cystic angiomatosis of bone. Severe debilitation, resorption of most or all of a bone associated with a proliferation of vascular channels. Histologically compared to cystic angiomatosis of bone, it produces significantly more destruction with osteolysis and tends to involve one bone only

Phenotype

Low serum Ca and P levels, high 1–25 OH2 D3 levels, normal 25 OH D3 levels, markedly high PTH and BAP levels

Low serum Ca and P levels, high 1–25 OH2 D3 levels, normal 25 OH D3 levels, markedly high PTH and BAP levels

high BAP levels

Low serum Ca levels, very low/ undetectable 1–25 OH2 D3 levels, normal 25 OH D3 levels, slightly high PTH levels,

Laboratory findings are unremarkable, although increases in ALP have been noted

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

Rare in other countries

1/2,358, in the Saguenay-Lac-SaintJean region of Quebec province

Rare in other countries

1/2,700 in Quebec

Unknown

Prevalence

First 6 months of life

Infancy

Soon after birth

Variable

Age range of expression

[69]

[68]

[67]

[66]

References

J Endocrinol Invest

# 211900

# 610455

# 307800

# 193100

5b) Tumoral calcinosis, normophosphatemic, familial; NFTC

6) Hypophosphatemic rickets, X-linked dominant; XLHR

7) Hypophosphatemic rickets, autosomal dominant; ADHR

OMIM phenotype number

5a) Tumoral calcinosis, hyperphosphatemic, familial; HFTC

5) Tumoral calcinosis

Disorder

Table 3 continued

(605380)

FGF23

(300550)

PHEX

SMAD9 (610456)

(604824)

KL

(605380)

FGF23

(601756)

GALNT3

OMIM gene/locus number

Rickets/osteomalacia, short stature, fatigue and weakness

Rickets/osteomalacia short stature, late dentition, tooth abscesses

Reddish to hyperpigmented skin lesions, soft tissue masses at the extremities, severe conjunctivitis, and severe gingivitis

Altered skeletal mineralization, ectopic calcifications around large joints, soft tissue masses around the hips, the shoulders and the elbows

Phenotype

High Ur. P levels, low serum P and renal TmP/GFR levels, normal serum Ca levels, low Ur. Ca levels, normal PTH and 25 OH D3 levels, inappropriately low or normal 1–25 OH2 D3 levels, high BAP intact FGF23 levels

High Ur. P levels, low serum P and renal TmP/GFR levels, normal serum Ca levels, low Ur. Ca levels, normal PTH and 25 OH D3 levels, inappropriately low or normal 1–25 OH2 D3 levels, high BAP intact FGF23 levels, low serum GH (not always)

Normal Ur. P and serum P levels

Low Ur. P levels, high serum P levels and TmP/GFR, normal serum Ca, Ur. Ca, PTH, and 25 OH D3 levels, inappropriately high 1–25 OH2 D3, low intact serum FGF23 levels

Typical metabolic biomarkers

1–3 years

\1/1,000,000 Unknown

Within 1 year of life

1–9/100,000

1/25,000

Unknown

Unknown

Age range of expression

Unknown

1/20,000

Prevalence

Unknown

Unknown

Incidence

[73]

[72]

[71]

[70]

References

J Endocrinol Invest

123

OMIM phenotype number

# 241530

# 166250

# 241520

# 612286

Disorder

8) Hypophosphatemic rickets with hypercalciuria, hereditary; HHRH

9) Osteoglophonic dysplasia; OGD

10) Hypophosphatemic rickets, autosomal recessive; ARHR1

11) Nephrolithiasis/ osteoporosis, hypophosphatemic, 1; NPHLOP1

Table 3 continued

123 (182309)

SLC34A1

(600980)

DMP1

(136350)

FGFR1

(609826)

SLC34A3

OMIM gene/locus number

Kidney stones, nephrocalcinosis, osteoporosis

High bone density at the base of skull, clavicles and ribs anomalies, enthesopathies, short stature, limited movement of spine and hip, calcification of the ligaments at the bony insertions sites

Rickets/osteomalacia, severe craniofacial abnormalities, bone dysplasia, macroglossia, and hypertrophy of the gums, severe dwarfism, mandibular prognathism, frontal bossing, and proptosis

Rickets/osteomalacia, kidney stone, nephrocalcinosis

Phenotype

High Ur. P levels, low serum P and renal TmP/GFR levels, high Ur. Ca levels, normal serum Ca, PTH levels, high 1–25 OH2D3 levels, low/normal high serum intact FGF23 levels

High Ur. P levels, low serum P and renal TmP/GFR levels, low Ur. Ca levels, normal serum Ca, PTH levels, high BAP, extremely high intact serum FGF23 levels

High Ur. P levels, low serum P and renal TmP/GFR, normal Ur. Ca, serum Ca, PTH, 25 OH D3 levels, normal/low 1–25 OH2 D3 levels, high serum intact FGF23 levels

High Ur. P levels, low serum P levels, low Renal TmP/GFR, high Ur.Ca levels, normal/high serum Ca levels, high 1–25 OH2 D3 levels, normal 25 OH D3 and PTH levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Incidence

\1/1,000,000

Unknown

Variable

1–3 years

Newborns

1–3 years

\1/1,000,000

Unknown

Age range of expression

Prevalence

[72]

[72]

[74]

[72]

References

J Endocrinol Invest

% 612089

12) Hypophosphatemic rickets and hyperparathyroidism

# 259700

# 259710

13a) Osteopetrosis, autosomal recessive 1; OPTB1

13b) Osteopetrosis, autosomal recessive 2; OPTB2

13) Osteopetrosis

OMIM phenotype number

Disorder

Table 3 continued

(602642)

TNFSF11

(604592)

TCIRG1



OMIM gene/locus number

Hearing loss, blindness (retinal degeneration or increase of intracranical pressure), sometime hydrocephalus, hypersplenism, dental problems, osteomyelitis of the mandible, generalized high bone mass, sclerotic cranial base, loss of trabecular structure, poor definition between cortical and medullary bone, short stature, macrocephaly, frontal bossing, genus valgum

Hearing loss, blindness (retinal degeneration or increase of intracranical pressure), sometimes hydrocephalus, hypersplenism, dental problems, osteomyelitis of the mandible, generalized high bone mass, sclerotic cranial base, loss of trabecular structure, poor definition between cortical and medullary bone, short stature, macrocephaly, frontal bossing, genus valgum, ‘‘rugger-Jersey’’ spine (vertebral endplate thickening)

Rickets, kidney stones

Phenotype

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, and acid phosphatase levels, anemia

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, and acid phosphatase levels, anemia

High Ur.P, low levels renal TmP/GFR, and serum P levels, high serum Ca levels, inappropriately normal 1–25 OH2D3 levels, high PTH, serum intact FGF23, and serum a-Klotho levels

Typical metabolic biomarkers

1/200,000 live births

1/200,000 live births

Unknown

Incidence

1–9/1,000,000

1–9/1,000,000

Unknown

Prevalence

Neonatal/ infancy

Neonatal/ infancy

10 years

Age range of expression

[76]

[76]

[75]

References

J Endocrinol Invest

123

OMIM phenotype number

# 259730

# 611490

# 259720

Disorder

13c) Osteopetrosis, autosomal recessive 3; OPTB3

13d) Osteopetrosis, autosomal recessive 4; OPTB4

13e) Osteopetrosis, autosomal recessive 5; OPTB5

Table 3 continued

123 (607649)

OSTM1

(602727)

CLCN7

(611492)

CA2

OMIM gene/locus number

Hearing loss, blindness (retinal degeneration or increase of intracranical pressure), sometime hydrocephalus, hypersplenism, dental problems, osteomyelitis of the mandible, generalized high bone mass, sclerotic cranial base, loss of trabecular structure, poor definition between cortical and medullary bone, short stature, macrocephaly, frontal bossing, genus valgum, ‘‘rugger-Jersey’’ spine (vertebral endplate thickening)

Hearing loss, blindness (retinal degeneration or increase of intracranical pressure), sometime hydrocephalus, hypersplenism, dental problems, osteomyelitis of the mandible, generalized high bone mass, sclerotic cranial base, loss of trabecular structure, poor definition between cortical and medullary bone, short stature, macrocephaly, frontal bossing, genus valgum, ‘‘rugger-Jersey’’ spine (vertebral endplate thickening)

Hearing loss, blindness (retinal degeneration or increase of intracranical pressure), sometime hydrocephalus, hypersplenism, dental problems, osteomyelitis of the mandible, cerebral calcification, mental retardation, generalized high bone mass, sclerotic cranial base, loss of trabecular structure, poor definition between cortical and medullary bone, short stature, macrocephaly, frontal bossing, genus valgum, fractures very common

Phenotype

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, acid phosphatase levels, anemia

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, acid phosphatase levels, anemia

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, acid phosphatase levels, immunodeficiency, anemia, tubular renal acidosis

Typical metabolic biomarkers

Unknown

1/200,000 live births

Unknown

Incidence

Neonatal/ infancy

Neonatal/ Infancy

\1/1,000,000

Neonatal/ infancy

\1/1,000,000

1–9/1,000,000

Age range of expression

Prevalence

[76]

[76]

[76]

References

J Endocrinol Invest

OMIM phenotype number

# 611497

# 612301

# 607634

# 166600

Disorder

13f) Osteopetrosis, autosomal recessive 6; OPTB6

13g) Osteopetrosis, autosomal recessive 7; OPTB7

13h) Osteopetrosis, autosomal dominant 1; OPTA1

13i) Osteopetrosis, autosomal dominant 2; OPTA2

Table 3 continued

(602727)

CLCN7

(603506)

LRP5

(603499)

TNFRSF11A

(611466)

PLEKHM1

OMIM gene/locus number

The typical radiographic sign is ‘‘sandwich vertebrae’’ (dense bands of sclerosis parallel to the vertebral endplates). The main complications are confined to the skeleton, including fractures, scoliosis, hip osteoarthritis and osteomyelitis, particularly affecting the mandible in association with dental abscess or caries. Cranial nerve compression is a rare but important complication, with hearing and visual loss affecting around 5 % of individuals

Hearing loss, blindness (retinal degeneration or increase of intracranical pressure), sometime hydrocephalus, hypersplenism, dental problems, osteomyelitis of the mandible generalized high bone mass, sclerotic cranial base, loss of trabecular structure, poor definition between cortical and medullary bone, short stature, macrocephaly, frontal bossing, genus valgum Increase in bone density that affects mainly the cranial vault, chronic skeletal pain and disorders of the cranial nerves (trigeminal neuralgia, facial paralysis, deafness)

Hearing loss, blindness (retinal degeneration or increase of intracranical pressure), sometime hydrocephalus, hypersplenism, dental problems, osteomyelitis of the mandible, facial palsy due to cranial nerve VII compression, bone marrow failure (in some patients), generalized high bone mass, sclerotic cranial base, loss of trabecular structure, poor definition between cortical and medullary bone, short stature, macrocephaly, frontal bossing, genus valgum, ‘‘rugger-Jersey’’ spine (vertebral endplate thickening), hip osteoarthritis

Phenotype

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, acid phosphatase levels, anemia

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, acid phosphatase levels, anemia

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, acid phosphatase levels, anemia

Low serum Ca levels, high PTH, 1–25 OH2 D3, BB-CK, acid phosphatase levels, anemia

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Incidence

1–9/100,000

\1/1,000,000

\1/1,000,000

Unknown

Prevalence

Childhood

Adolescence/ young adulthood

Unknown

Childhood

Age range of expression

[78]

[77]

[76]

[76]

References

J Endocrinol Invest

123

123

# 265800

# 166700

14) Pycnodysostosis

15) Osteopoikilosis

# 239100

# 144750

16a) Hyperostosis corticalis generalisata

16b) Hyperostosis corticalis generalisata, benign form of worth, with torus palatinus

16) Endosteal hyperostosis

OMIM phenotype number

Disorder

Table 3 continued

(603506)

LRP5

(605740)

SOST

(607844)

LEMD3

(601105)

CTSK

OMIM gene/locus number

There is a homogenous increase in bone mass without sclerotic bands, and the cranial vault rather than the basis is dense. Fractures are unusual

The clinical manifestations and the radiological signs, including wide mandibular bone, can be identical to Van Buchem disease and sclerostenosis. The absence of fractures, increased thickness of the cortices of the long bones, and increased density of the axial skeleton. Metamorphosis of the face occurs during adolescence as the forehead flattens, the mandibules become elongated and the gonial angle decreases. Taurus palatinus (osseous prominance of the palate vault)

Progressive asymmetrical enlargement of the jaw that occurs during puberty. The adult mandible is markedly thickened with a wide angle, dental malocclusion is uncommon. Recurrent facial nerve palsy, deafness and optic atrophy from narrowing of cranial foramina are common and can begin as early as infancy. Long bones may become painful with applied pressure, but there are no fractures

(juvenile elastoma) and collagen-type nevi (dermatofibrosis lenticularis disseminate), osteosclerotic foci in epimethaphysal regions of long bones

Disseminate connective tissue nevi with both elastic-type nevi

Dolichocephaly, open fontanel, generalized high bone mass, bone fragility, short stature, clavicular dysplasia, obtuse angle of mandible, short terminal phalanges

Phenotype

ALP activity in serum may be increased

ALP activity in serum may be increased

Unknown

Low GH and IGF-I levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

Unknown

1/50,000

1–1.7/1,000,000

Prevalence

Variable

Variable

Childhood/ adulthood

Infancy/early childhood

Age range of expression

[80]

[80]

[76]

[79]

References

J Endocrinol Invest

# 131300

# 123000

% 155950

17) Camurati– Engelmann disease; CAEND

18) Craniometaphyseal dysplasia, autosomal dominant; CMDD

19) Melorheostosis

# 241500

# 241500

20a) Hypophosphatasia perinatal

20b) Hypophosphatasia infantile

20) Hypophosphatasia:

OMIM phenotype number

Disorder

Table 3 continued

(171760)

ALPL

(171760)

ALPL

LEMD3 (607844)

(605145)

ANKH

(190180)

TGFb1

OMIM gene/locus number

Rickets, skeletal demineralization with fracture and thoracic deformity, inadeguate weight gain, hypotonia, seizures, nephrocalcinosis

Extreme skeletal demineralization, irritability, periodic apnea with cyanosis, bradycardia, fever, myelophthisic anemia, intracranical hemorrhage

Sporadically joint contractures, sclerodermatous skin lesions, muscle atrophy, hemangiomas, lymphedema, linear hyperostosis of the cortex of long bones reminiscent of dripping candle wax

Impaired vision, hearing loss, facial nerve paralysis, metaphyseal flaring, hyperostosis and sclerosis of the cranial bones, thick bony wedge over the bridge of the nose and glabella (first signs)

Leg pain, muscular weakness, diaphyseal dysplasia, hyperostosis of the skull base, cortical bone thickening and sclerosis of the diaphysis of the long tubular bones by both endosteal and periosteal bone proliferation

Phenotype

High serum Ca levels, high Ur. Ca levels, low PTH, 1–25 OH2 D3, ALP levels, high serum pyridoxal-50 phosphate monohydrate levels

High serum Ca levels, low PTH, 1–25 OH2 D3, and ALP levels, high serum pyridoxal-50 phosphate monohydrate levels

There is no definitive diagnostic laboratory test for melorheostosis and the results of complete blood count, as well as serum P and ALP tests are typically normal

Unknown

Anemia

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

Unknown

\1/1,000,000

\1/1,000,000

Unknown

Prevalence

Postnatally but before 6 months

In utero

Variable

Childhood

Childhood

Age range of expression

[83]

[83]

[82]

[81]

[80]

References

J Endocrinol Invest

123

123

# 241510

# 146300

# 174810

20c) Hypophosphatasia childhood

20d) Hypophosphatasia adult

21) Familial expansile osteolysis; FEO (603499)

TNFRSF11A

(171760)

ALPL

(171760)

ALPL

OMIM gene/locus number

Progressive osteoclastic resorption accompanied by medullary expansion led to severe, painful, disabling deformity and a tendency to pathologic fracture, associated deafness and loss of dentition

Focal skeletal changes, with predominantly peripheral distribution

Recurrent metatarsal fractures, femoral pseudo-fractures, osteopenia, chondrocalcinosis

Rickets, progressive premature loss of teeth (before 5 years), premature fusion of cranial sutures with craniosinostosis, short stature, waddling gait

Phenotype

# 239300

# 614749

22a) Hyperphosphatasia with mental retardation syndrome type 1; HPMRS1

22b) Hyperphosphatasia with mental retardation syndrome type 2; HPMRS2 (614730)

PIGO

(610274)

PIGV

Moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, additional features, such as cardiac septal defects or seizures

Mental retardation, various neurologic abnormalities such as seizures and hypotonia, hyperphosphatemia, facial dysmorphism, variable degrees of brachytelephalangy

22) Hyperphosphatasia with mental retardation syndrome

OMIM phenotype number

Disorder

Table 3 continued

High serum ALP levels

High serum ALP levels

Serum ALP and urinary hydroxyproline are elevated to a variable degree, possible high serum Ca levels

Normal serum Ca levels, normal Ur. Ca levels, high serum P levels (in 50 % of patients), high TmP/GFR levels, low ALP levels, high serum pyridoxal-50 phosphate monohydrate levels

Normal serum Ca levels; normal Ur. Ca levels, high serum P levels (in 50 % of patients), high TmP/GFR, low ALP levels, high serum pyridoxal-50 phosphate monohydrate levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

\1/1,000,000

Unknown

Unknown

Unknown

Prevalence

Neonatal/ infancy

Neonatal/ infancy

Childhood/ second decade

Adulthood

After 6 months

Age range of expression

[86]

[85]

[84]

[83]

[83]

References

J Endocrinol Invest

# 239000

# 174800

23) Paget disease, juvenile

24) McCune–Albright syndrome; MAS

25b) Exostoses multiple type 2

25a) Exostoses multiple type1

# 133701

# 133700

# 614207

22c) Hyperphosphatasia with mental retardation syndrome type 3; HPMRS3

25) Exostoses multiple

OMIM phenotype number

Disorder

Table 3 continued

(608210)

EXT2

(608177)

EXT1

(139320)

GNAS

(602643)

TNFRSF11B

(615187)

PGAP2

OMIM gene/locus number

Malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma

Multiple outgrowing cartilage-capped bony protuberances, mostly located in the metaphyseal and juxta-metaphyseal regions of long bones. Osteochondromas, which can be asymptomatic or result in pain, compression of peripheral nerves or vessels, bony deformity, restricted range of joint movement, and short stature

Cranial foramen impingement, craniofacial hyperostosis, facial asymmetry, deafness, blindness, gastrointestinal polyps, polyostotic fibrous dysplasia, pathologic fracture, large cafe au lait spots with irregular margins, pituitary adenoma hyperthyroidism, hyperparathyroidism, Cushing syndrome, precocious puberty, acromegaly, hyperprolactinemia

Retinal degeneration, premature loss of teeth and dwarfism mentally retardation

Osteoporosis, expanded long bones, bowed long bones, and coarse trabeculations, calvaria markedly thickened with islands of increased bone density, muscular weakness may be striking

Mild to severe mental retardation, hypotonia with very poor motor development, sensorineural hearing, loss seizures, poor speech, mild microcephaly, disordered sleep pattern

Phenotype

Unknown

Unknown

High GH levels and PRL excess, hypercortisolism, suppressed levels of TSH and elevated FT3, high serum estradiol in female, excess of T in male, renal P wasting, with or without hypophosphatemia

High acid and ALP levels, high leucine aminopeptidase, and hydroxyproline in blood and urine levels, high uric acid, high serum osteocalcin and urinary hydroxyproline and pyridinoline: deoxypyridinoline levels

High serum ALP levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Rare

Unknown

Incidence

1–9/100,000

1–9/100,000

Childhood

Childhood

Chilhood

Childhood

\1/1,000,000

1–9/1,000,000

Neonatal/ infancy

Age range of expression

Unknown

Prevalence

[91]

[90]

[89]

[88]

[87]

References

J Endocrinol Invest

123

123

# 135100

26) Fibrodysplasia ossificans progressiva; FOP (102576)

ACVR1

OMIM gene/locus number Intermittently progressive ectopic ossification and malformed big toes, which are often monophalangic (hallux valgus, malformed first metatarsal, and/ or monophalangism). Sporadic episodes of painful soft tissue swellings, occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. Atypical features (e.g. intercurrent aplastic anemia, craniopharyngioma, childhood glaucoma or growth retardation)

Phenotype

OMIM phenotype number

OMIM gene/locus number

% 610071

1b) Hyperparathyroidism type 3; HRPT3



(607393)

CDC73

2a) Hyperparathyroidism familial not isolated (MEN1)

# 131100 (613733)

MEN1

2) Hyperparathyroidism familial not isolated:

# 145000

1a) Hyperparathyroidism type 1; HRPT1

1) Hyperparathyroidism familial isolated:

Disorder

Parathyroid adenoma/hyperplasia, entero-pancreatic tumor (gastrinoma, insulinoma, non-functioning neuroendocrine tumor, glucagonoma, VIP-oma, somatostatinoma), Foregut carcinoid, thymic carcinoid, bronchial carcinoid, gastric enterochromaffin-like non-functioning tumors, anterior pituitary tumor (PRL, GH ? PRL, GH, nonfunctioning, ACTH, TSH), adrenal cortex nonfunctioning tumors, pheochromocytoma, lipomas, facial angiofibromas, collagenomas

Parathyroid adenoma, hyperplasia

Parathyroid adenoma, hyperplasia

Phenotype

Table 4 Rare diseases of the PTH/PTHR1 and PTHrP receptors

OMIM phenotype number

Disorder

Table 3 continued

High levels of one or more of the following markers: PRL, IGF-1, gastrin, Fasting glucose, insulin, PP, glucagon, VIP, CgA, Ca, PTH

High PTH and serum Ca levels, low serum P levels

High PTH and serum Ca levels, low serum P levels

Typical metabolic biomarkers

Unknown

Typical metabolic biomarkers

1–3.3/100,000

Unknown

Unknown

5–81 years

Variable

Variable

Age range of expression

Childhood

\1/1,000,000

Prevalence

Age range of expression

Prevalence

0.2–2/100,000

Unknown

Unknown

Incidence

Unknown

Incidence

[95]

[94]

[93]

References

[92]

References

J Endocrinol Invest

#145001

2d) Hyperparathyroidism 2; HRPT2 (Hyperparathy -roidism-jaw tumor syndrome) (607393)

CDC73

(600778)

CDKN1B

Parathyroid adenoma/hyperplasia, renal tumors (Wilm tumors, polycystic kidney disease or renal harmartomas) and fibro-osseous tumors of the jaw

Intermediate features between MEN1 and MEN2 with presence of neoplasms in at least 2 endocrine glands

Associated characteristic physical features: full lips, thickened eyelids, high-arched palate, marfanoid habitus

MEN2B: Aggressive medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and thickened corneal nerves

Associated characteristic features: cutaneous lichen amyloidosis, Hischprung’s Disease rarely prominent corneal nerves

MEN2A: Medullary thyroid carcinoma, pheochromocytoma, parathyroid adenomas

Phenotype

# 131100

# 610755

3a) Primary hyperparathyroidism due to somatic mutations (MEN1)

3b) Primary hyperparathyroidism due to somatic mutations (MEN4) (600778)

CDKN1B

(613733)

MEN1

Intermediate features between MEN1 and MEN2 with presence of neoplasms in at least 2 endocrine glands

Tumors of parathyroids, weakness, fatigue, depression, bone pain, muscle soreness, decreased appetite, feelings of nausea and vomiting, constipation, polyuria, polydipsia, cognitive impairment, kidney stones and osteoporosis

3) Primary hyperparathyroidism due to somatic mutations

# 610755

(164761)

# 162300

2c) Hyperparathyroidism familial not isolated (MEN4)

RET

# 171400

2b) Hyperparathyroidism familial not isolated (MEN2A-2B)

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 4 continued

High serum Ca, calcitonin, CEA, PTH, gastrin, insulin, VIP, PP, somatostatin, CgA, PRL, GH, IGF1, ACTH, UFC, serum and urinary catecholamines levels. High or low glycemia, low serum P levels

High serum Ca, PTH, and Ur. Ca levels, low serum P levels

High PTH and serum Ca levels, low serum P levels

Unknown

Unknown

Unknown

Unknown

4/100,000

4/100,000

Unknown

4/100,000

MEN2B: \1/ 100,000

MEN2B: \1/ 500,000

High serum Ca, calcitonin, CEA, PTH, gastrin, insulin, VIP, PP, somatostatin, CgA, PRL, GH, IGF1, ACTH, UFC, serum, and urinary catecholamines levels. High or low glycemia, low serum P levels

MEN2A:1/30,000

MEN2A: Unknown

High serum basal levels and stimulated calcitonin, elevated catecholamines and catecholamine metabolites, high serum Ca and PTH levels

Prevalence

Incidence

Typical metabolic biomarkers

50–55 years

50–55 years

Variable

50–55 years

(earlier onset in first years of life)

MEN2B: Childhood

MEN2A:3–25 years

Age range of expression

[99]

[98]

[97]

[96]

[42, 43]

References

J Endocrinol Invest

123

123

#193300

# 145001

# 239200

# 608266

3c) Primary hyperparathyroidism due to somatic mutations (modifier of von Hippel–Lindau syndrome)

3d) Primary hyperparathyroidism due to somatic mutations (Hyperparathyroidism-jaw tumor syndrome)

4) Hyperparathyroidism, neonatal severe; NSHPT

5) Parathyroid cancer (607393)

CDC73

(601199)

CASR

(607393)

CDC73

(168461)

CCND1

OMIM gene/locus number

6a) Hypocalciuric hypercalcemia, familial type 1; HHC1

# 145980

Mild symptoms: easy fatigue, weakness, polydipsia Little or no increase parathyroids, persistent after subtotal parathyroidectomy

Rare pancreatitis and chondrocalcinosis

Hypercalcemia at birth, generally asymptomatic

(601199)

Typical signs and symptoms of marked hypercalcemia and high PTH levels: bone pain, fractures, kidney stone, fatigue, weakness, weight loss, anorexia, nausea, vomiting, polyuria, and polydipsia, palpable mass in neck [3 cm (30–70 %)

Urgent total parathyroidectomy

Hypercalcemia at birth, rib fractures, hypotonia, respiratory distress, massive increase parathyroids

Adrenal pheochromocytoma, retinal angioma, hemangioblastoma of the central nervous system, endolymphatic sac tumor, pancreatic endocrine tumor, clear cell renal cancer

Adrenal pheochromocytoma, retinal angioma, hemangioblastoma of the central nervous system, endolymphatic sac tumor, pancreatic endocrine tumor, clear cell renal cancer

Phenotype

CASR

6) Hypocalciuric hypercalcemia, familial

OMIM phenotype number

Disorder

Table 4 continued

Mild-moderate hypercalcemia, normal serum Mg levels or modestly elevated, relative hypocalciuria, ratio of renal calcium clearance to creatinine clearance below 0.01, PTH normal or modestly elevated (5–10 %), normal 1–25 OH2 D3 levels

Abnormally elevated serum and urinary levels of hCG and its malignant hyperglycosilated isoform

Secretion in some patients of N-terminal PTH fragment

High serum Ca levels ([14–15 mg/dl), high serum PTH (3–10 times above the upper limit of normal range) levels

1/10,000–1/100,000

\1/100

Unknown

Unknown

High metanephrine, normetanephrine, three metossithyramine levels

Marked high serum Ca levels ([16 mg/dl), relative hypocalciuria, very high PTH, and serum Mg levels

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma)

Incidence

High metanephrine, normetanephrine, 3 metossi-thyramine levels

Typical metabolic biomarkers

2 % of primary hyperparathy -roidism

Unknown

Unknown

Unknown

Unknown

Prevalence

At birth

50 years

At birth

50–55 years

4–60 years

Age range of expression

[104]

[103]

[102]

[101]

[100]

References

J Endocrinol Invest









AIRE

# 600740













6c) Hypocalciuric hypercalcemia, familial type 3; HHC3

7) Hypercalcemia hypocalciuric acquired

8) Ectopic hyperparathyroidism associated to a clear cell carcinoma of the ovary

9) Ectopic hyperparathyroidism associated to small cell lung carcinoma

10) Ectopic hyperparathyroidism associated to thymoma

11) Autoimmune isolated hypoparathyroidism

12) Hypoparathyroidism polyendocrine syndrome (607358)

Ab anti CASR gene

AP2S1

(139313)

GNA11

# 145981

6b) Hypocalciuric hypercalcemia, familial type 2; HHC2

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 4 continued

Candidiasis, hypocorticosurrenalism, hypoparathyroidism (±other autoimmune diseases)

Hypocalcemia

Thymoma, hypercalcemia

Small cell lung carcinoma, hypercalcemia

Cell carcinoma of the ovary, hypercalcemia

Hypercalcemia

Hypercalcemia, osteomalacia (after the age of 30 years)

Hypercalcemia at birth, generally asymptomatic

Phenotype

Low serum Ca and PTH levels, high serum P and ACTH levels

Low serum Ca and PTH levels, high serum P levels, CaSR antibodies and NALP5 antibodies

High serum Ca and renal tubular reabsorption levels, low P levels, maximal tubular reabsorption of P, and high serum PTH levels

High serum Ca and PTH levels

High serum Ca and PTHrP levels

Hypercalcemia and inappropriately low urine calcium excretion

High serum Ca levels and inappropriately low Ur Ca excretion, mild hypophosphatemia, modestly high serum PTH levels

High serum Ca levels and inappropriately low Ur Ca excretion, normal or modestly elevated serum Mg, normal P/Ca clearance to creatinine clearance below 0.01 (in some cases 0.010–0.011) normal or modestly high serum PTH levels

Typical metabolic biomarkers

1/14,000–1/80,000

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Prevalence

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

20–30 years

20–30 years

Variable

Variable

Variable

Unknown

Unknown

Unknown

Age range of expression

[112]

[111]

[110]

[109]

[108]

[107]

[106]

[105]

References

J Endocrinol Invest

123

123

# 146200

13) Hypoparathyroidism, familial isolated; FIH

# 615361

# 307700

# 188400

# 146255

14b) Hypocalcemia, autosomal dominant 2; HYPOC2

15) X-linked hypoparathyroidism; HYPX

16) DiGeorge syndrome; DGS

17) Hypoparathyroidism, sensorineural deafness, and renal disease; HDR

# 127000

# 241410

18b) Kenny–Caffey syndrome, Type 2; KCS2

19) Hypoparathyroidism– retardation– dysmorphism syndrome; HRD

20a) Kearns–Sayre syndrome; KSS

# 530000

20) Mitochondrial diseases

# 244460

18a) Kenny–Caffey syndrome, Type 1; KCS1

18) Kenny–Caffey syndrome

# 601198

14a) Hypocalcemia, autosomal dominant 1; HYPOC1

14) Hypocalcemia, autosomal dominant

OMIM phenotype number

Disorder

Table 4 continued



Mitochondrial DNA

(604934)

TBCE

(615292)

FAM111A

(604934)

TBCE

(131320)

GATA3

(602054)

TBX1

Hypocalcemia, ophthalmoplegia, pigmentary retinal de generation, cardiomyopathy

Hypocalcemia, mental retardation, dysmorphism

Hypocalcemia, bone dysplasia, short stature, dental abnormalities

Hypocalcemia, bone dysplasia, short stature, dental abnormalities

Hypocalcemia, bilateral deafness, renal dysplasia

Abnormal faces, immunodeficiency, cardiac defects, ectodermal abnormalities

(only males)

Epilepsy, hypocalcemia

(asymptomatic in some patients)



Mild hypocalcemia, hypercalciuria

(139313)

(asymptomatic in some patients)

GNA11

Mild hypocalcemia, hypercalciuria

(601199)

Severe hypocalcemia

Phenotype

CASR

(603716)

GCM2

(168450)

PTH

OMIM gene/locus number

Low serum Ca and PTH levels, high serum P levels

Low serum Ca and PTH levels

Low serum Ca and PTH levels, high serum P levels

Low serum Ca and PTH levels, high serum P levels

Low serum Ca and PTH levels, high serum P levels

Very low serum Ca and PTH levels, high serum P levels

Low serum Ca and PTH levels

Low serum Ca and Mg levels and low/normal PTH levels, normal/ high serum P levels

Low serum Ca and Mg levels and low/normal PTH levels, normal/ high serum P levels

Extremely low serum Ca levels and low undetectable PTH levels, and high serum P levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

\1/1,000,000

\1/1,000,000

\1/1,000,000

\1/1,000,000

1/2,000–1/4000

Unknown

Unknown

First decade

First decade

First decade

First decade

First decade

10–40 years

Infantile onset

Variable

20–40 years

First decade

\1/1,000,000

\1/70,000

Age range of expression

Prevalence

[120]

[119]

[118]

[118]

[117]

[116]

[115]

[114]

[114]

[113]

References

J Endocrinol Invest

# 540000

# 609015

# 201450

20b) Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MELAS

20c) Trifunctional protein deficiency

20d) Deficiency of Acyl-coa dehydrogenase, medium-chain; ACADMD

# 103580

# 603233

% 203330

# 612463

21a) Pseudohypoparathyroidism type 1A; PHP1A

21b) Pseudohypoparathyroidism type 1B; PHP1B

21c) Pseudohypoparathyroidism type 2; PHP2

22) Pseudopseudo hypoparathyroidism; PPHP

21) Pseudohypoparathyroidism

OMIM phenotype number

Disorder

Table 4 continued

(139320)

GNAS

(139320)

Short stature, obesity, round faces, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation

Isolated renal PTH resistance and lack the features of AHO

No clinical features of Albright hereditary osteodystrophy (AHO)

GNAS

Renal PTH resistance

(139320)

Multiple hormone resistance, short stature, obesity, round faces, subcutaneous ossifications, brachydactyly, and other skeletal anomalies

Myopathy

Myopathy

Myopathy, encephalopathy, stroke-like episodes

Phenotype

GNAS

(139320)

GNAS

(607008)

ACADM

(143450)

HADHB

(600890)

HADHA



Mitochondrial DNA

OMIM gene/locus number

Abnormally high basal urinary excretion of cAMP and a normal increase in urinary cAMP after PTH infusion

Normal erythrocyte Gs activity and a normal cAMP response to PTH infusion; the phosphaturic effect of PTH is deficient, low serum Ca levels, high serum P levels, and increased PTH levels

Decreased cAMP response to PTH infusion, normal erythrocyte Gs activity, low serum Ca levels, high serum P levels

Decreased cellular cAMP response to PTH infusion, decreased erythrocyte Gs activity, low serum Ca levels, high serum P levels

None

None

None

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Prevalence

Childhood

Childhood

Variable

Childhood

Unknown

Unknown

Infancy

Age range of expression

[127]

[126]

[125]

[124]

[123]

[122]

[121]

References

J Endocrinol Invest

123

OMIM phenotype number

# 156400

# 600002

% 166000

Disorder

23) Metaphyseal chondrodysplasia, Jansen type

24) Eiken skeletal dysplasia

25) Enchondromatosis, multiple, Ollier type

Table 4 continued

123 (168468)

PTH1R

(168468)

PTH1R

(168468)

PTH1R

OMIM gene/locus number

Soft tissues hemangiomas (Maffucci Syndrome), multiple enchondromas with skeletal deformities and potential risk for malignant change to chondrosarcoma

Multiple epiphyseal dysplasia

Late adolescence cartilaginous tissue in the metaphysis disappears, sclerosis and thickening of the base of skull with cranial auditory and optical nerve compression

At the puberty partially calcified cartilage that protrude into diaphysis

In younger patients: Enlargement of metaphysis with a wide zone of irregular calcifications (lesions similar to rickets)

Short legs and relatively long arms

Hyphoscoliosis with bell-shaped thorax and widened costochondral junctions, metaphyseal enlargement of the joints, frontonasal hyperplasia

High skull vault, flattening of the nose and forehead, low-set ears, hypertelorism, high-arched palate, micrognathia, retrognathia

Phenotype

Slightly high PTH levels

None

High serum Ca, Ur. Ca. and Ur. P. levels, high Ur. cAMP levels, undetectable/low PTH levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Incidence

1–9/100,000

Childhood

Neonatal/ infancy

Neonatal/ infancy

\1/1,000,000

\1/1,000,000

Age range of expression

Prevalence

[130]

[129]

[128]

References

J Endocrinol Invest

# 520000

? 107741

# 201475

4) Diabetes and deafness, maternally inherited; MIDD

5) Apolipoprotein e, deficiency or defect of, included

6) Acyl-coa dehydrogenase deficiency; ACADVLD

# 201450

# 248370

# 613327

# 612526

# 269700

# 608594

# 615238

# 613877

3) Mandibuloacral dysplasia with type a lipodystrophy; MADA

2) Lipodystrophy, congenital generalized; CGL

# 151660

1) Lipodystrophy, familial partial; FPLD

# 604367

OMIM phenotype number

Disorder

Very long chain, deficiency ACADVL (609575) Medium chain, deficiency ACADM (607008)

Liver (Reye syndrome), heart (hypertrophic or dilated cardiomyopathy acute or chronic) and muscle (moderate or severe hypotonia or recurrent rhabdomyolysis); hypoglycemia, neuropathy, and pigmentary retinopathy

Palmar xanthomas and manifestations of coronary and peripheral atherosclerosis

Onset of sensorineural hearing loss and diabetes in adulthood. Some patients may have additional features observed in mitochondrial disorders, including pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, renal problems, and neuropsychiatric symptoms

MT-TL1 (590050) MT-TE (590025) MT-TK (590060)

Homozygous or compound heterozygous for apoE2 (–)

Growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. The lipodystrophy is characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue in the neck and trunk. Some patients may show progeroid features. Metabolic complications can arise due to insulin resistance and diabetes

Absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia

Abnormal subcutaneous adipose tissue distribution, metabolic abnormalities include insulinresistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently

Phenotype

Type A: LMNA (150330) Type B: ZMPSTE24 (606480)

Type 1: AGPAT2 (603100) Type 2: BSCL2 (606158) Type 3: CAV1 (601047) Type 4: PTRF (603198)

Type 2: LMNA (150330) Type 3: PPARG (601487) PPP1R3A (600917) Type 4: PLIN1 (170290) Type 5: CIDEC (612120)

OMIM gene/locus number

Table 5 Rare metabolic diseases of glucose, lipids, and mucopolysaccharides

Low total plasma carnitine levels

High cholesterol, triglycerides, and IDL lipoprotein levels

Hyperglycemia

Hyperglycemia and hyperinsulinemia

Hyperglycemia and hypertriglyceridemia

Hypertriglyceridemia

Typical metabolic biomarkers

Unknown

Unknown

MIDD accounts for 0.5–3 % of diabetes mellitus

Unknown

Unknown

Unknown

Incidence

Unknown

0.02/100

1–9/1,000,000

\1/1,000,000

1–9/1,000,000

Unknown

Prevalence

Childhood/ adulthood

Childhood

Adulthood

Neonatal/ infancy

Neonatal/ infancy

Late childhood/ early adult life

Age range of expression

[136]

[135]

[134]

[133]

[132]

[131]

References

J Endocrinol Invest

123

123

# 255110

# 212140

# 255120

7) Carnitine palmitoyltransferase 2 deficiency, late-onset

8) Carnitine deficiency, systemic primary; CDSP

9) Carnitine palmitoyltransferase deficiency

# 201470

# 609015

# 200100

10) Deficiency of Acyl-Coa dehydrogenase, shortchain; ACADSD

11) Trifunctional protein deficiency

12) Abetalipoproteinemia; ABL

# 600649

OMIM phenotype number

Disorder

Table 5 continued

MTTP (157147)

HADHA (600890) HADHB (143450)

CTP1B (601987)

Type 1: CTP1A (600528) Type 2: CPT2 (600650)

SLC22A5 (603377)

CPT2 (600650)

OMIM gene/locus number

Hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy, and coagulopathy. Hepatic steatosis is also common

Classic trifunctional protein deficiency can be classified into three main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death, infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy

Clinical features are variable: a severe form of the disorder can cause infantile onset of acidosis and neurologic impairment, whereas some patients develop only myopathy. With the advent of screening for inborn errors of metabolism, patients with putative pathogenic mutations but who remain asymptomatic have also been identified

Severe episodes of hypoketotic hypoglycemia usually occurring after fasting or illness

Defect in the high-affinity carnitine transporter expressed in muscle, heart, kidney, lymphoblasts, and fibroblasts. This results in impaired fatty acid oxidation in skeletal and heart muscle. In addition, renal wasting of carnitine results in low serum levels and diminished hepatic uptake of carnitine by passive diffusion, which impairs ketogenesis

Inherited disorder of mitochondrial long-chain fatty acid oxidation. Recurrent episodes of rhabdomyolysis triggered by prolonged exercise, fasting, or febrile illness

Phenotype

Hypocholesterolemia, low vitamins A, D, E and K levels

None

None

Hypoglycemia usually occurring after fasting or illness

Low serum carnitine levels

High serum muscle enzymes and myoglobinuria levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Childhood

Neonatal/ infancy

Neonatal/ infancy

\1/1,000,000

\1/1,000,000

Infancy/early childhood

\1/1,000,000

Unknown

Neonatal/ infancy

Adolescence/ young adulthood

Age range of expression

1–9/100,000

Unknown

Unknown

Unknown

Prevalence

Incidence

[141]

[122]

[140]

[139]

[138]

[137]

References

J Endocrinol Invest

# 238600

# 230800

14) Hyperlipoproteinemia type 1

15) Gaucher Disease

16) Glycogen storage disease; GSD

# 301500

13) Fabry disease

# 613507

# 612934

# 612932

# 611881

# 612933

# 261670

# 613027

# 261750

# 306000

# 232800

# 306000

# 232700

# 232800

# 232600

#232400

# 232300

# 232220

# 232200

# 610539

# 231005

# 231000

OMIM phenotype number

Disorder

Table 5 continued

Type1a: G6PC (613742) Type1b: SLC37A4 (602671) Type2: GAA (606800) Type3a, b, c, d: AGL (610860) Type4: GBE 1 (607839) Type5: PYGM (608455) Type6: PYGL (613741) Type9a: PYGL (613741) Type7: PFKM (610681) Type9 (9a, 9b, 9c): PHKA2 (306000) PHKB (172490) PHKG2 (172471) Type10: PGAM2 (612931) Type11: LDHA (150000) Type12: ALDOA (103850) Type13: ENO3 (131370) Type14: PGM1 (171900) Type15: GYG1 (603942)

Type 1, 3, 3a, 3c, Perinatal lethal: GBA (606463) Gaucher disease, atypical, due to saposin c deficiency: PSAP (176801)

LPL (609708)

GLA (300644)

OMIM gene/locus number

Affected tissue liver and muscle, severe hypoglycemia and hepatomegaly, growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia

Clinical severity, ranging from affected infants to asymptomatic adults

Intracellular accumulation of glucosylceramide in most tissue, ‘Gaucher cells’; hepatosplenomegaly, pancytopenia. Type 3: central nervous system involvement and neurologic manifestations; ocular pingueculae, dermal hyperpigmentation

Hyperchylomicronemia, pancreatitis, hepatosplenomegaly, eruptive xanthomas, and lactescence of the plasma (severe phenotype), diabetes mellitus

The disorder is a systemic disease, manifests as progressive renal failure, cardiac disease, cerebrovascular disease, smallfiber peripheral neuropathy, and skin lesions, among other abnormalities

Phenotype

Markedly high triglycerides levels, myoglobinuria in GSD V, high serum lactate, pyruvate, and creatine kinase levels, with myoglobinuria in GSD type 11

Deficient activity of betaglucocerebrosidase; chitotriosidase deficiency

Extreme concentrations of circulating large chylomicrons (chylomicronemia), low or absent LPL activity in post-heparin plasma

Determination of the enzyme alphaGalactosidse A activity

Typical metabolic biomarkers

Type 1 is the most common (25 % of all GSDs), 1/20,000–43,000

1/100,000–1/300,000

1/60,000

Unknown

1/40,000

Unknown

1–5/10,000

1/55,000

1/1,000,000

Prevalence

Incidence

Infancy

Infancy/ adulthood

Infancy/ childhood

Childhood

Age range of expression

[145]

[144]

[143]

[142]

References

J Endocrinol Invest

123

123 Type 2: KCNJ11 (600937) Type 3: GCK (138079) Type 4: HADH (601609) Type 5: INSR (147670) Type 6: GLUD1 (138130) SLC16A1 (600682)

# 601820

# 143890

# 144010

# 603813

19) Hypercholesterolemia, familial

20) Hypercholesterolemia, autosomal dominant, type b

21) Hypercholesterolemia, autosomal recessive; ARH

# 610021

# 606762

# 609968

# 609975

# 602485

Type 1: ABCC8 (600509)

# 256450

18) Hyperinsulinemic hypoglycemia, familial; HHF

LDLRAP1 (605747)

APOB (107730)

LDLR (606945) GSBS (604088) ITIH4 (600564) APOB (107730) PCSK9 (607786)



% 151900

17) Lipomatosis, multiple

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 5 continued

Homozygotes, including severely elevated plasma low LDL, tuberous and tendon xanthomata, and premature atherosclerosis

The phenotype can be altered by a SNP in the modifier genes (APOA2, EPHX2, GHR)

Tendinous xanthomas, corneal arcus, and coronary artery disease

Homozygotes, including severely elevated plasma low LDL, tuberous and tendon xanthomata, and premature atherosclerosis

The phenotype can be altered by a SNP in the modifier genes (APOA2, EPHX2, GHR)

Tendinous xanthomas, corneal arcus, and coronary artery disease

Homozygotes, including severely elevated plasma low LDL, tuberous and tendon xanthomata, and premature atherosclerosis

The phenotype can be altered by a single nucleotide polymorphism (SNP) in the modifier genes (APOA2, EPHX2, GHR)

Tendinous xanthomas, corneal arcus, and coronary artery disease

Severe hyperinsulinemic hypoglycemia, neoformation of islets of Langerhans from pancreatic duct epithelium, b-cell hypertrophy and b-cell hyperplasia, brain damage

Numerous encapsulated lipomas on the trunk and extremities

Phenotype

HDL C 330 mg/dl

LDL [ 500 mg/dl

HDL C 330 mg/dl

LDL [ 500 mg/dl

HDL C 330 mg/dl

LDL [ 500 mg/dl

High ammonium and insulin levels

None

Typical metabolic biomarkers

Homozygous familial hypercholesterolemia is estimated to be 1/1,000,000, where the heterozygous familial hypercholesterolemia is estimated at 1/500

Homozygous familial hypercholesterolemia is estimated to be 1/1,000,000, where the heterozygous familial hypercholesterolemia is estimated at 1/500

Homozygous familial hypercholesterolemia is estimated to be 1/1,000,000, where the heterozygous familial hypercholesterolemia is estimated at 1/500

1/5,000 births (for the sporadic form), but may be as high as 1/2,500 births (in societies with high rates of consanguinity, especially in the Arabian Peninsula)

0.002/100

Incidence

Homozygous FH is greater in specific regions presumably due to founder effects and isolation of a population

The prevalence is variable

Homozygous FH is greater in specific regions presumably due to founder effects and isolation of a population

The prevalence is variable

Homozygous FH is greater in specific regions presumably due to founder effects and isolation of a population

The prevalence is variable

Unknown

Unknown

Prevalence

Birth/early childhood

Birth/early childhood

Birth/early childhood

Birth/infancy

Third or fourth decade

Age range of expression

[148]

[148]

[148]

[147]

[146]

References

J Endocrinol Invest

# 607016

22) Mucopolysaccharidosis; MPS

# 222300

# 304800

2) Wolfram syndrome 1; WFS1

3) Diabetes insipidus, nephrogenic

(192340)

# 304900

(300538)

AVPR2

(606201)

WFS1

(304900)

X-linked recessive

AVP

# 125700

1) Diabetes insipidus, neurohypophyseal

OMIM gene/locus number

OMIM phenotype number

Disorder

Polyuria and polydipsia. Episodes of hypernatremic dehydration during the first 1 or 2 years of life. Sometimes low intelligence quotient

Polyuria and polydipsia

Plasma osmolality [300 mOsm/kg. Urinary osmolality \300 mOsm/kg, urinary osmolality does not increase after fluid restriction and DDAVP

Plasma osmolality [300 mOsm/kg. Urinary osmolality \300 mOsm/kg, urine osmolality does not increase after fluid restriction but increases [50 % after DDAVP

Unknown

Unknown

Unknown

Plasma osmolality [300 mOsm/kg. Urinary osmolality \300 mOsm/kg, urine osmolality does not increase after fluid restriction but increases [50 % after DDAVP

Polyuria and polydipsia

1/100,000

Incidence

Incidence

Urinary excretion of glycosaminoglycans

Typical metabolic biomarkers

Typical biomarkers

Airway obstruction, skeletal deformities, cardiomyopathy, and in most patients, neurologic decline

Accumulation of glycosaminoglycans in nearly all cell types, tissues, and organs that lead to organ failure, cognitive impairment and reduced life expectancy. Corneal clouding, mental retardation, hernias, dysostosis multiplex, and hepatosplenomegaly

Phenotype

Phenotype

Hurler–Scheie syndrome: IDUA (252800) MPS, type 2: IDS (300823) MPS type 3a, b, c, d San Filippo Syndrome a, b, c, d: SGSH (605270) NAGLU (609701) HGSNAT (610453) GNS (60766) AR-MPS type 4a and I4b Morquio Syndrome A and B: GALNS (612222) GLB1 (611458) MPS type 6: B ARSB (611542) MPS type 7: GUSB (611499) MPS type 9: HYAL1 (607071)

OMIM gene/locus number

Table 6 Rare water metabolism diseases

# 601492

# 253220

# 253200

# 253010

# 253000

#252940

#252930

#252920

#252900

# 309900

OMIM phenotype number

Disorder

Table 5 continued

1–2/ 1,000,000

Unknown

1/25,000

Prevalence

Early childhood

Age range of expression

At birth

Childhood

About a year and a half

Age range of expression

Variable

Prevalence

[153]

[152]

[150, 151]

References

[149]

References

J Endocrinol Invest

123

123

# 125800

# 300539

4) Diabetes insipidus, nephrogenic, autosomal

5) Nephrogenic syndrome of inappropriate antidiuresis; NSIAD (300538)

AVPR2

(107777)

AQP2

OMIM gene/locus number

The main clinical features, seizure or irritability, appeared to be linked to the severe hyponatremia

Hypotonic euvolemic hyponatremia

Polyuria and polydipsia. Episodes of hypernatremic dehydration during the first 1 or 2 years of life. Sometimes low intelligence quotient

Phenotype

OMIM phenotype number

1c) Hyperaldosteronism, familial, type 3

# 613677

1) Familial hyperaldosteronism 1a) Glucocorticoid# 103900 remediable aldosteronism; GRA (hyperaldosteronism, familial, type 1) 1b) Hyperaldosteronism, % 605635 familial, type 2

Disorder

Early onset and sometimes severe and resistant hypertension, polyuria, polydipsia, non-specific symptoms of hypokaliemia (weakness, fatigue, myalgia, constipation, headache)

Early onset and sometimes severe and resistant, hypertension, polyuria, polydipsia, non-specific symptoms of hypokaliemia (weakness, fatigue, myalgia, constipation, headache)



KCNJ5 (600734)

Heterogeneous phenotype: Early severe resistant hypertension, or normotension

Phenotype

Biological markers of primary hyperaldosteronism of variable intensity, abnormal elevated urinary levels of 18-oxo and 18 hydroxycortisol. High level of plasmatic aldosterone suppressed plasma renin activity, low or normal serum K levels, metabolic alkalosis, high hybrid steroids 18-oxo and 18-hydroxycortisol levels High serum aldosterone levels, suppressed plasma renin activity, low or normal K levels, metabolic alkalosis, high hybrid steroids 18-oxo and 18-hydroxycortisol levels

Typical metabolic biomarkers

Undetectable levels of AVP

1–2/ 1,000,000

Prevalence

Unknown

Unknown

Unknown

Incidence

Variable

Infancy

\1/1,000,000

Variable

Age range of expression

Infancy/adulthood, but most diagnoses were made during the first 2 years of life

At birth

Age range of expression

Unknown

Unknown

Prevalence

\1/ \1/ 1,000,000 1,000,000

Unknown

Plasma osmolality [300 mOsm/kg. Urinary osmolality \300 mOsm/kg, urinary osmolality does not increase after fluid restriction and DDAVP Plasma osmolality \275 mOsm/kg; urinary osmolality [100 mOsm/kg; urinary sodium [30 mmol/l

Incidence

Typical biomarkers

CYP11B1 (610613)

OMIM gene/locus number

Table 7 Rare adrenal glands and paraganglia diseases

OMIM phenotype number

Disorder

Table 6 continued

[158]

[157]

[156]

References

[155]

[154]

References

J Endocrinol Invest

OMIM phenotype number

# 263800

# 601678

# 607364

# 602522

# 613090

# 177200

% 145260

Disorder

2) Gitelman syndrome

3) Bartter syndrome 3a) Bartter syndrome, antenatal, type 1

3c) Bartter syndrome type 3

3d) Bartter Syndrome type 4A

3e) Bartter syndrome type 4B

4) Liddle Syndrome

5) Pseudohypoaldosteronism, type 2a; PHA2A

Table 7 continued



SCNN1B (600760) SCNN1G (600761)

CLCNKA (602024) CLCNKB (602023)

BSND (606412)

CLCNKB (602023)

SLC12A1 (600839)

SLC12A3 (600968)

OMIM gene/locus number

Constitutive activation of the renal epithelial sodium channel Children: asymptomatic, detection of early and severe hypertension Young adult: aspecific symptoms of hypokaliemia (weakness, fatigue, myalgia, constipation) Hypertension, delayed growth, weakness, periodic paralysis

Short stature, normal blood pressure, hyperplasia, and hypertrophy of the juxtaglomerular cells

Short stature, normal blood pressure, hyperplasia and hypertrophy of the juxtaglomerular cells

Antenatal: fetal polyuria, polyhydramnios (between 24 and 30 weeks of gestation), premature delivery Neonates/infancy: hyposthenuria, several salt wasting failure to thrive, hypotension, nephrocalcinosis, osteopenia Short stature, normal blood pressure, hyperplasia and hypertrophy of the juxtaglomerular cells

Asymptomatic or transient period of muscle weakness, tetany, vomiting, abdominal pains chondrocalcinosis (swelling, local heat, tenderness over the affected joint), tendency of low blood pressure, sometimes delayed growth

Phenotype

High serum K levels, low plasma renin activity, normal or elevated level of aldosterone, hyperchloremic metabolic acidosis

Hypokaliemic metabolic alkalosis, high Ur. Ca levels secondary hyperaldosteronism, increased renal prostaglandin production, occasionally, low serum Mg levels, high serum Na and excretion of Ur. K Hypokaliemic metabolic alkalosis, high Ur. Ca levels secondary hyperaldosteronism, increased renal prostaglandin production, occasionally, low serum Mg levels, high serum Na and excretion of Ur. K Hypokaliemic metabolic alkalosis, high Ur. Ca levels secondary hyperaldosteronism, increased renal prostaglandin production, occasionally, low Mg levels, high serum Na and excretion of Ur. K Low serum K levels, metabolic alkalosis, high serum Na levels, low rates of Ur. Na, high rates of Ur. K, low plasma renin activity, suppressed aldosterone secretion

Moderate hypokaliemic metabolic alkalosis, high Ur. Ca levels, high plasma renin activity, high aldosterone levels, high excretion of Ur. Na

Low serum Mg levels, hypokaliemic alkalosis, low Ur. Ca excretion secondary hyperaldosteronism

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Incidence

Variable

Infancy/young adulthood (\35 years)

\1/1,000,000

Unknown

Infancy/ adolescence/ adulthood

Infancy/ adolescence/ adulthood

Infancy/ adolescence/ adulthood

Unknown

Unknown

Unknown

Antenatal/infancy

Infancy (above 6-year old)/ adolescence/ adulthood

\1/40,000

Unknown

Age range of expression

Prevalence

[165]

[164]

[162]

[163]

[162]

[161]

[159]

References

J Endocrinol Invest

123

123

# 218030



6) Apparent mineralocorticoid excess; AME

7) Sporadic pheochromocytoma

10) Paragangliomas

9b) Familial pheochromocytoma type 2 (Pheochromocytoma)

# 171300

MAX (154950)

TMEM127 (613403)

NF1 (613113)

# 162200

8c) Familial pheochromocytoma (neurofibromatosis, type 1)

9) Familial pheochromocytoma: 9a) Familial # 171300 pheochromocytoma type 1 (Pheochromocytoma)

VHL (608537)

# 193300

RET (164761)



HSD11B2 (614232)

OMIM gene/locus number

8b) Familial pheochromocytoma (von Hippel–Lindau; VHL)

8) Familial pheochromocytoma: 8a) Familial # 171400 pheochromocytoma # 162300 (MEN2A-2B)

OMIM phenotype number

Disorder

Table 7 continued

Adrenal pheochromocytoma, sympathetic paraganglioma

Adrenal pheochromocytoma

MEN2A: Medullary thyroid carcinoma, pheochromocytoma, parathyroid adenomas Associated characteristic features: cutaneous lichen amyloidosis, Hischprung’s Disease rarely prominent corneal nerves MEN2B: Aggressive medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and thickened corneal nerves Associated characteristic physical features: full lips, thickened eyelids, high-arched palate, marfanoid habitus Adrenal pheochromocytoma, retinal angioma, hemangioblastoma of the central nervous system, endolymphatic sac tumor, pancreatic endocrine tumor, clear cell renal cancer Adrenal pheochromocytoma, Lysch nodules, caffe-au lat spots, cutaneous neurofibromas, neural crest-derived tumors, gastrointestinal stromal tumor (GIST)

Congenital defect in 11-betadehydrogenase type II Early onset and severe hypertension, polyuria, polydipsia, failure to thrive Adrenal pheochromocytoma, extraadrenal paraganglioma

Phenotype

High metanephrine, normetanephrine, 3 metossithyramine levels

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma) 0.8/100,000 (for all types of pheocromocytoma/ paraganglioma)

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma)

High metanephrine, normetanephrine, 3 metossithyramine levels

High metanephrine, normetanephrine, 3 metossithyramine levels

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma)

Unknown

Unknown

Unknown

Unknown

MEN2A:1/ 30,000 MEN2B: \1/ 100,000

13–80 years

21–72 years

4–84 years

4–60 years

MEN2A:3–25 years MEN2B: Childhood (earlier onset in first years of life)

[170]

[169]

[168]

[100]

[42, 43]

[167]

4–84 years

0.2 % of hypertensive population

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma) MEN2A: Unknown MEN2B: \1/ 500,000

[166]

Neonatal/infancy (first year of life)

\1/1,000,000

Unknown

References

Age range of expression

Prevalence

Incidence

High metanephrine, normetanephrine, 3 metossithyramine levels

High serum basal levels and stimulated calcitonin, elevated catecholamines and catecholamine metabolites, high serum Ca and PTH levels

High metanephrine, normetanephrine, 3 metossithyramine levels

Low serum K levels, metabolic alkalosis, high serum Na levels, low plasma renin activity, low levels of aldosterone

Typical metabolic biomarkers

J Endocrinol Invest

# 614165

10e) Paragangliomas 5; PGL5

# 604287

12b) Adrenal hyperplasia, congenital, due to steroid 11-beta-hydroxylase deficiency

# 202010

12) Adrenal hyperplasia, congenital 12a) Adrenal hyperplasia, # 201910 congenital, due to 21-hydroxylase deficiency

11b) Paraganglioma (Carney Triad)

# 606864

# 115310

10d) Paragangliomas 4; PGL4

11) Other paraganglioma 11a) Paraganglioma and gastric stromal sarcoma

SDHC (602413)

# 605373

10c) Paragangliomas 3; PGL3

CYP11B1 (610613)

CYP21A2 (613815)

SDHB (185470) SDHC (602413) SDHD (602690) –

SDHA (600857)

SDHB (185470)

SDHAF2 (613019)

SDHD (602690)

OMIM gene/locus number

# 601650

# 168000

OMIM phenotype number

10b) Paragangliomas 2; PGL2

10a) Paragangliomas 1; PGL1

Disorder

Table 7 continued

11b-Hydroxylase deficiency: Virilization, sexual ambiguity, hypertension

Classic salt wasting: females prenatal virilized Simple virilizing: females prenatal virilized Nonclassic: postnatally hyperandrogenism

Paraganglioma, GIST, pulmonary amartocondroma

Paraganglioma, gastrointestinal stromal tumor

Sympathetic paraganglioma, head and neck parasympathetic paraganglioma, renal clear cell carcinoma Sympathetic paraganglioma, head and neck parasympathetic paraganglioma

Head and neck paragangliomas, adrenal pheochromocytoma

Head and neck parasympathetic paraganglioma

Head and neck parasympathetic paraganglioma, adrenal pheochromocytoma, sympathetic paraganglioma, pituitary adenoma

Phenotype

High DOC and 11-deoxycortisol levels

High 17-OHP, DHEA and androstenedione levels

High metanephrine, normetanephrine, 3 metossithyramine levels

High metanephrine, normetanephrine, 3 metossithyramine levels

High metanephrine, normetanephrine, 3 metossithyramine levels

High metanephrine, normetanephrine, 3 metossithyramine levels High metanephrine, normetanephrine, 3 metossithyramine levels

None

High metanephrine, normetanephrine, 3 metossithyramine levels

Typical metabolic biomarkers

1/100,000

1–9/1,000,000

1–9/100,000

Unknown

Unknown

Classic salt wasting 1/20,000 Simple virilizing 1/60,000 Nonclassic 1/1,000

12 % of pediatric GISTs (1–5/ 10 000)

Unknown

Unknown

Classic salt wasting: newborn to 6 months Simple virilizing: newborn/2 years (female), 2–4 years (male) Nonclassic: Childhood/ adulthood Newborn/adulthood

Unknown

Unknown

Unknown

5–65 years

Childhood

Unknown

Unknown

Unknown

5–65 years

Age range of expression

Unknown

Prevalence

Unknown

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma) 0.8/100,000 (for all types of pheocromocytoma/ paraganglioma)

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma) 0.8/100,000 (for all types of pheocromocytoma/ paraganglioma) Unknown

Incidence

[177]

[176]

[175]

[174]

[167]

[167]

[173]

[172]

[171]

References

J Endocrinol Invest

123

123

14) Hereditary Cushing 14a) Hereditary Cushing (Carney Complex variant/type 1)

# 608837 # 160980

MYH8 (160741) PRKAR1A (188830)

AIP (605555) GNAS (139320)

# 219090

13) Cushing syndrome (Pituitary adenoma, ACTH-secreting)

STAR (600617)

# 201710

CYP11A1 (118485)

POR (124015)

# 613571

12e) Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency 12f) Lipoid congenital adrenal hyperplasia; LCAH

# 613743

HSD3B2 (613890)

# 201810

12d) Deficiency of 3-betahydroxysteroid dehydrogenase, type 2

12g) Adrenal insufficiency, congenital, with 46, xy sex reversal, partial or complete

CYP17A1 (609300)

# 202110

12c) Adrenal hyperplasia, congenital, due to 17-alpha-hydroxylase deficiency

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 7 continued

Cardiac, endocrine, cutaneous, and neural myxomatous tumors, pigmented lesions of the skin and mucosae

StAR deficiency: Lipoid adrenal hyperplasia, impaired adrenal and gonadal steroidogenesis with no sexual development, salt wasting P450 Side-chain Cleavage deficiency: Depending on the impairment of CYP11A1 and ranging from severe adrenal deficiency to mild disorder of sex development Truncal and facial obesity, signs of hypercatabolism (thinned skin, purple striae, ecchymosis, bruising with no obvious trauma, proximal muscle weakness with amyotrophy, unexplained osteoporosis), weight gain with decreasing growth velocity. Other less specific features: fatigue, high blood pressure, glucose intolerance, hypokalemia, acne, hirsutism, menstrual irregularity, diminished libido, erectile dysfunction, and neuropsychological disturbances

17a-Hydroxilase deficiency: Impaired adrenal and gonadal steroidogenesis (disorder of sex development); hypokalemic hypertension 3b-HSD type 2 deficiency: Impaired adrenal and gonadal steroidogenesis (ambiguous genitalia in male; mild virilization in female), salt wasting P450 Oxidoreductase deficiency: Disorder of sex development, skeletal malformations

Phenotype

High cortisol, GH and IGF-1 levels, subtle hyperprolactinemia

High UFC and late night salivary cortisol, absent cortical suppression to 1 mg overnight or 48 h: 2 mg dexamethasone test, abnormal response to desmopressin test or even CRH test

Low steroid values and elevated plasma renin activity

Low steroid values and elevated plasma renin activity

High pregnenolone, progesterone and 17-OHP levels

High 17-OH-pregnenolone and DHEA levels

Hypergonadotropic hypogonadism, high DOC and 11-deoxycortisol levels

Typical metabolic biomarkers

Unknown

1/400,000

Unknown

Unknown

1/150,000

Unknown

Unknown

Incidence

\1/1,000,000

1–9/100 000

Unknown

Unknown

Variable (it most commonly presents in the teen years and early adulthood)

Variable (peak incidence at 25–40 years)

Newborn to childhood

Newborn

Puberty

Early infancy

\1/1,000,000

Unknown

Adolescence

Age range of expression

1/1,000,000

Prevalence

[184]

[183]

[182]

[181]

[180]

[179]

[178]

References

J Endocrinol Invest

# 131100

# 610475

14b) Hereditary Cushing (MEN1)

14c) Hereditary Cushing (Pigmented nodular adrenocortical disease, primary, PPNAD 2)

15b) Li–Fraumeni syndrome 1; LFS1

# 151623

15) Familial adrenocortical tumors 15a) Familial # 131100 adrenocortical tumors (MEN1)

OMIM phenotype number

Disorder

Table 7 continued

TP53 (191170)

MEN (613733)

PDE11A (604961)

MEN (613733)

OMIM gene/locus number

Parathyroid adenoma/hyperplasia, entero-pancreatic tumor (gastrinoma, insulinoma, nonfunctioning neuroendocrine tumor, glucagonoma, VIP-oma, somatostatinoma), Foregut carcinoid, thymic carcinoid, bronchial carcinoid, gastric enterochromaffin-like nonfunctioning tumors, anterior pituitary tumor (PRL, GH ? PRL, GH, non-functioning, ACTH, TSH), adrenal cortex non-functioning tumors, pheochromocytoma, lipomas, facial angiofibromas, collagenomas Breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, acute leukemia, adrenocortical Carcinomas, lung adenocarcinoma, colon cancer, pancreatic cancer, prostate cancer, Wilms tumor, phyllodes tumor

Parathyroid adenoma/hyperplasia, entero-pancreatic tumor (gastrinoma, insulinoma, nonfunctioning neuroendocrine tumor, glucagonoma, VIP-oma, somatostatinoma), Foregut carcinoid, thymic carcinoid, bronchial carcinoid, gastric enterochromaffin-like nonfunctioning tumors, anterior pituitary tumor (PRL, GH ? PRL, GH, non-functioning, ACTH, TSH), adrenal cortex non-functioning tumors, pheochromocytoma, lipomas, facial angiofibromas, collagenomas See Cushing syndrome Associated with Carney Complex and PPNAD: PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation

Phenotype

0.2–2/100,000

Unknown

High b-Hcg, alpha-fetoprotein, 17-OHP, T, DHEA-s, and androstenedione levels High complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase

Unknown

0.2–2/100,000

Incidence

High levels of one or more of the following markers: PRL, IGF-1, gastrin, fasting glucose, insulin, PP, glucagon, VIP, CgA, Ca, PTH

High cortisol, GH, IGF-1 levels, subtle hyperprolactinemia

High levels of one or more of the following markers: PRL, IGF-1, gastrin, fasting glucose, insulin, PP, glucagon, VIP, CgA, Ca, PTH

Typical metabolic biomarkers

Unknown

1–3.3/100,000

Unknown

1–3.3/100,000

Prevalence

Adulthood

5–81 years

Variable (most commonly in early adulthood)

5–81 years

Age range of expression

[186]

[95]

[185]

[95]

References

J Endocrinol Invest

123

123 DAX1 (300473)

# 219080

# 610489

# 103230

# 300200

16) ACTH-independent macronodular adrenal hyperplasia; AIMAH

17) Pigmented nodular adrenocortical disease, primary, 1; PPNAD1

18) Adrenocortical hypofunction, chronic primary congenital 19) Adrenal hypoplasia, congenital

# 300100



# 130650

15e) Hereditary Cushing (Beckwith–Wiedemann syndrome)

20) Adrenomyeloneuropathy, included; ALD

CDKN1C (600856) KCNQ1O T1 (604115) H19 (103280) NSD1 (606681) GNAS (139320) ARMC5 (615549) PRKAR1A (188830)

% 609266

15d) Li–Fraumeni syndrome 3; LFS3

ABCD1



CHEK2 (604373)

# 609265

15c) Li–Fraumeni syndrome 2; LFS2

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 7 continued

Adrenal hypoplasia congenita: disorders of adrenal cortex, gonads, and hypothalamus Adrenoleukodystrophy: adrenal deficiency combined with demyelination within the nervous system

Skin hyperpigmentation, weight loss, hypotension, fatigue, nausea

An endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands Clinical features of adrenal Cushing syndrome, including hypertension

Breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, acute leukemia, adrenocortical Carcinomas, lung adenocarcinoma, colon cancer, pancreatic cancer, prostate cancer, Wilms tumor, phyllodes tumor Breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, acute leukemia, adrenocortical Carcinomas, lung adenocarcinoma, colon cancer, pancreatic cancer, prostate cancer, Wilms tumor, phyllodes tumor Abdominal wall defects (omphalocele, umbilical hernia, and diastasis recti), visceromegaly involving liver, spleen, pancreas, kidneys, or adrenals, fetal adrenocortical cytomegaly, renal anomalies: primary malformations, renal medullary dysplasia, nephrocalcinosis, and nephrolithiasis, predisposition to embryonal malignancies

Phenotype

Unknown

High b-Hcg, alpha-fetoprotein, 17-OHP, T, DHEA-s, and androstenedione levels High complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase

Mineral and glucocorticoid deficiency, electrolyte disorders (hyponatremia, hyperkalemia) Mineral and glucocorticoid deficiency combined with hypogonadotropic hypogonadism Mineral and glucocorticoid deficiency

Mildly or clearly high cortisol level, low ACTH level

High cortisol level, low ACTH level

1/20,000

0.8/100,000 (70–80 % autoimmune adrenalitis) Rare

Unknown

Unknown

Unknown

Unknown

High b-Hcg, alpha-fetoprotein, 17-OHP, T, DHEA-s, and androstenedione levels High complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase

Low glycemia levels

Incidence

Typical metabolic biomarkers

1–9/100,000

Unknown

Childhood/ adulthood

[194]

[193]

[192]

Childhood/ adulthood Puberty

[191]

[190]

[189]

[188]

[187]

References

12–21 years

The fifth and sixth decades of life

\1/1,000,000

Unknown but less 2/1,000,000 persons per year 4–11/100,000

Neonatal/infancy

Adulthood

Adulthood

Age range of expression

1–5/10,000

Unknown

Unknown

Prevalence

J Endocrinol Invest

# 202300

22) Adrenocortical carcinoma, hereditary; ADCC

OMIM phenotype number

1a) Turner syndrome



Monosomy x/partial deletion of chromosome X

1) Congenital hypogonadism hypergonadotropic (female)

Disorder

TP53 (191170)

MC2R (607397) MRAP (609196)

OMIM gene/locus number

OMIM gene/locus number

# 202200

21) Glucocorticoid deficiency 1; GCCD1

Table 8 Rare ovarian diseases

OMIM phenotype number

Disorder

Table 7 continued

Short stature, delayed puberty, primary amenorrhea, or premature ovarian failure, hypoplastic left heart, coarctation of the aorta, low hairline, low-set ears, small mandible, multiple pigmented nevi, cubitus valgus, nail hypoplasia, hyperconvex uplifted nails, characteristic faces, shortening of the fourth metacarpal, high-arched palate, recurrent otitis media, and neurosensory hearing loss

Phenotype

Familial glucocorticoid deficiency (unresponsiveness to ACTH) Tall stature, failure to thrive, hyperpigmentation skin, seizures, coma, recurrent hypoglycemic episodes, frequent, severe infections Adrenal mass with metastatic spread at diagnosis in up to 75 % of cases, virilism

Phenotype

Markedly high FSH level

Typical metabolic biomarkers

1/1,000,000

Unknown

Incidence

Unknown

Incidence

High glucocorticoids alone (35 %), glucocorticoids and androgens (35 %), androgens alone (10 %), aldosterone (\1 %) levels

Low cortisol and normal plasma renin

Typical metabolic biomarkers

1–5/ 10,000

Prevalence

Birth

Age rangeof expression

3–5 years

Childhood

\1/1,000,000

1–9/1,000,000

Age range of expression

Prevalence

[197]

References

[196]

[195]

References

J Endocrinol Invest

123

123

2) Premature ovarian failure; POF

Type 3:

KRAS

(190070)

# 611553

# 613224

# 613706

FMR1

(309550)

Type 2a:

DIAPH2

(300108)

Type 2b:

# 300511

# 300604

# 608996

# 611548

# 612310

# 612964

(184757)

NR5A1

Type 7:

(608697)

FIGLA

Type 6:

(610934)

NOBOX

Type 5:

(605597)

FOXL2

Type 3:

(300603)

FLJ22792

Type 1:

# 311360

(164757)

BRAF

Type 7:

(164790)

NRAS

Type 6:

(164760)

RAF1

Type 5:

(182530)

SOS1

High FSH level

(176876)

# 610733

Primary amenorrhea, or oligo/ amenorrhea (lasting 4 months), polymenorrhea, or dysfunctional uterine bleeding after having attained normal puberty and having established regular menstrual cycles

PTPN11

# 609942

Type 4:

Normal GH level, but sometimes high IGF-1 level, elevated FSH level

Short stature, facial dysmorphism, a wide spectrum of congenital heart defects, multiple skeletal defects, webbed neck, mental retardation, bleeding diathesis, lymphatic dysplasia

Type 1:

# 163950

1b) Noonan syndrome

Typical metabolic biomarkers

Phenotype

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 8 continued

1/10,000 (by 20 years), 1/1,000 (by 30 years), 1/100 (by 40 years)

1/1,000–1/2,500

Incidence

[1/1,000

Unknown

Prevalence

\40 years

Variable

Age rangeof expression

[199]

[198]

References

J Endocrinol Invest





# 603737

5) Granulosa cell tumor of the ovary

6) Ovarian germ cell cancer







(608665)

PSMC3IP

Type 3:

(300247)

BMP15

Ovarian cancer

Hyperestrinism and various menstrual abnormalities, in postmenopausal patients, postmenopausal bleeding

either multilocular or unilocular

hemorrhage within cysts, solid and yellow, or cystic,

A solid and cystic tumor with

Ovarian tumor. Many tumors have foci that are of intermediate differentiation and other areas that are poorly differentiated tumors. Welldifferentiated tumors are almost always pure without heterologous or retiform components, hyperandrogenism with virilizing features or hirsutism

Unknown

0.4–1.7/100,000

High 17b-estradiol level

None

Unknown

Unknown

Incidence

High androgen level

(136435)

# 614324

4) Ovarian Sertoli– Leydig cell tumors

FSHR

# 300510

Type 2:

High FSH and LH level

Hypergonadotropic ovarian failure, streak gonads

Type 1:

# 233300

3) Ovarian dysgenesis

Typical metabolic biomarkers

Phenotype

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 8 continued

Unknown

Unknown

Unknown

1–9/ 100,000

Prevalence

Variable

Variable

Variable (peak 30 years of age)

Age rangeof expression

[203]

[202]

[201]

[200]

References

J Endocrinol Invest

123

123

OMIM phenotype number

OMIM gene/locus number

# 400045

# 160900

# 238320



1a) 46, XX sex reversal 1; SRXX1

1b) Myotonic dystrophy 1; DM1

1c) Leydig cell hypoplasia, type 1

1d) FSH resistance (136435)

FSHR

(152790)

LHCGR

(605377)

DMPK (CTG repeat)

(480000) (about 80 % are SRY positive, 20 % SRY negative)

SRY

1) Congenital hypergonadotropic hypogonadism

Disorder

Table 9 Rare testicular diseases

Infertility, small testes

Severe forms caused by complete inactivation of LHCGR are characterized by complete 46, XY male pseudohermaphroditism, lack of breast development, and absent development of secondary male sex characteristics. Milder forms caused by partial inactivation of the gene display a broader range of phenotypic expression ranging from micropenis to severe hypospadias

Multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The phenotypes span a continuum from mild to severe forms (mild, classic, congenital). Mild DM is characterized by cataract and mild myotonia. Classic DM is characterized by muscle weakness and wasting, myotonia, cataract, and often cardiac conduction abnormalities; adults may become physically disabled and may have a shortened life span. Congenital DM is characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common

Male external genitalia ranging from normal to ambiguous, two testicles, azoospermia; and absence of Mu¨llerian structures. Approximately 80 % of individuals with 46, XX testicular Disorders of Sex Development (DSD) present after puberty with normal pubic hair and normal penile size, but small testes, gynecomastia, and azoospermia. Approximately 20 % present at birth with ambiguous genitalia. If untreated, males with 46, XX testicular DSD experience the consequences of testosterone deficiency

Phenotype

High FSH levels

Hypergonadotropic hypogonadism secondary to LH resistance. Lack of responsiveness to hCG challenge

Hypergonadotropic hypogonadism secondary to testicular failure

High CK levels

Hypergonadotropic hypogonadism secondary to testicular failure

Typical metabolic biomarkers

Unknown

Unknown

5/100,000

5/100,000

Incidence

Unknown

Unknown

1/20,000

1/20,000

Prevalence

Adulthood

Birth

10–30 years (classic forms). 20–70 years (mild forms)

Birth: 10 years (congenital forms)

Mid puberty/adulthood (infertility)

Birth (ambiguous genitalia)

Age range of expression

[207]

[206]

[205]

[204]

References

J Endocrinol Invest

OMIM phenotype number

# 300100

%273250

# 415000

Disorder

1e) Adrenoleukodystrophy; ALD

1f) Testicular regression syndrome; TRS

1g) Spermatogenic failure, Y-linked, 2; SPGFY2

Table 9 continued



AZF regions



(300371)

ABCD1

OMIM gene/locus number

Infertility with non-obstructive azoospermia or severe oligozoospermia

Regression of testis development between 8 and 14 weeks of gestation. The phenotype of patients varies depending on the timing and extent the fetal testicular regression and ranges from a female to anorchic male phenotype among patients with a 46, XY karyotype. If fetal testicular regression occurs between 8 and 10 weeks of gestation, patients may have female external genitalia with or without ambiguity, associated with lack of gonads, hypoplastic uterus, and rudimentary genital ducts. Regression of the testes after 12–14 weeks results in phenotypic males with anorchia or streak gonads (rudimentary testes). Intermediary phenotypes occur with sexual ambiguity associated with variable degrees of genital duct, urogenital sinus, and external genitalia differentiation anomalies. Patients have either absent or streak gonads

Wide range of phenotypes. Many individuals remain asymptomatic until middle age or even later. Childhood cerebral forms (*35 % of affected individuals): it initially resembles attention-deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within 2 years. Adrenomyeloneuropathy (*40–45 % of affected individuals): progressive stiffness and weakness in the legs, abnormalities of sphincter control, and sexual dysfunction. All symptoms are progressive over decades. Addison disease only (*10 % of affected individuals): signs of adrenal insufficiency, including increased skin pigmentation

Phenotype

Azoospermia or severe oligozoospermia

Hypergonadotropic hypogonadism secondary to absent testes

High VLCFA levels

Typical metabolic biomarkers

50/100,000

1–9/ 100,000

5/100,000

Incidence

5–10 % of azoospermia and severe oligozoospermia

1–9/100,000

1/20,000–1/ 50,000

Prevalence

Variable

Birth

2–20 (Addison disease only)

20–40 years (adrenomyeloneuropathy)

4–8 years (childhood cerebral forms)

Age range of expression

[210]

[209]

[208]

References

J Endocrinol Invest

123

123

OMIM phenotype number

OMIM gene/locus number

# 238320

# 270400

# 201710

# 613743

# 201810

# 264300

2a) Leydig cell hypoplasia, type 1

2b) Smith–Lemli–Opitz syndrome; SLOS

2c) Lipoid congenital adrenal hyperplasia; LCAH

2d) Adrenal insufficiency, congenital, with 46, XY sex reversal, partial or complete

2e) Deficiency of 3-betahydroxysteroid dehydrogenase, type 2

2f) Deficiency of 17-Beta hydroxysteroid dehydrogenase 3 (605573)

HSD17B3

(613890)

HSD3B2

(118485)

CYP11A1

(600617)

STAR

(602858)

DHCR7

(152790)

LHCGR

2) Hypogonadism due to reduced testosterone synthesis or action

Disorder

Table 9 continued

Ambiguous external genitalia or complete female external genitalia at birth. These children are raised as female, and their diagnosis is often discovered when there is absence of menarche (and frequent finding of inguinal testes in these cases)

Salt wasting and non-salt wasting forms with a wide variety of symptoms, including glucocorticoid deficiency and male undervirilization manifesting as a micropenis to severe perineoscrotal hypospadias

Acute adrenal insufficiency in infancy or childhood. Female external genitalia. Milder forms with only clitoromegaly and late-onset adrenal failure

Affected individuals are phenotypic females with a severe salt-losing syndrome (mineralocorticoid deficiency) that is fatal if not treated in early infancy. Severe deficiency of adrenal and gonadal steroids

Prenatal and postnatal growth retardation, microcephaly, moderate to severe intellectual disability, and multiple major and minor malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, hypospadias, postaxial polydactyly, and 2–3 syndactyly of the toes. The clinical spectrum is wide and individuals have been described with normal development and only minor malformations

Two types of Leydig cell hypoplasia have been defined. Type 1, a severe form caused by complete inactivation of LHCGR, is characterized by complete 46, XY male pseudohermaphroditism, lack of breast development, and absent development of secondary male sex characteristics. Type 2, a milder form caused by partial inactivation of the gene, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias

Phenotype

Low T levels and high androstenedione levels

Mineralocorticoid and glucocorticoid primary deficiency

Mineralocorticoid and glucocorticoid primary deficiency

Mineralocorticoid and glucocorticoid primary deficiency

High 7-dehydrocholesterol level and low cholesterol levels

Low T levels, high LH levels, lack of responsiveness to LH/CG challenge

Typical metabolic biomarkers

0.5–1/ 100,000

\1/ 1,000,000

\1/ 1,000,000

Unknown

2–5/ 100,000

Unknown

Incidence

1–9/1,000,000

\1/1,000,000

\1/1,000,000

Unknown

1/20,000–1/ 40,000

Unknown

Prevalence

Birth/puberty

Variable

Variable

Birth–3 months

Birth–puberty

Childhood/adolescence

Age range of expression

[216]

[215]

[214]

[213]

[212]

[211]

References

J Endocrinol Invest

# 264600

# 300068

# 312300

# 313200

2g) Pseudovaginal perineoscrotal hypospadias; PPSH

2h) Androgen insensitivity syndrome; AIS

2i) Partial androgen insensitivity syndrome; PAIS

2l) Spinal and bulbar muscular atrophy, x-linked 1; SMAX1

# 400044

# 612965

# 233420

# 114290

3a) 46, XY Sex reversal 1; SRXY1

3b) 46, XY Sex reversal 3; SRXY3

3c) 46, XY Sex reversal 7; SRXY7

3c) Campomelic dysplasia

3) Other 46, XY DSD

OMIM phenotype number

Disorder

Table 9 continued

(608160)

SOX9

(605423) (50 % of complete gonadal dysgenesis)

DHH

(184757) (13 % of complete gonadal dysgenesis)

NR5A1

(480000) (15 % of complete gonadal dysgenesis)

SRY

AR (CAG repeat) (313700)

(313700)

AR

(313700)

AR

(607306)

SRD5A2

OMIM gene/locus number

Ambiguous genitalia or normal female external genitalia. Skeletal (campomelic) dysplasia characterized by distinctive faces, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and club feet. Many affected infants die in the neonatal period

Female external and internal genitalia. Completely undeveloped (‘‘streak’’) gonads. Lack of pubertal development

Female external and internal genitalia. More severe phenotypes include primary adrenal failure; milder phenotypes have isolated partial gonadal dysgenesis

Female external and internal genitalia. Completely undeveloped (‘‘streak’’) gonads. Lack of pubertal development

Gradual and progressive neuromuscular disorder in which degeneration of lower motor neurons results in proximal muscle weakness, muscle atrophy, and fasciculations. Affected individuals often show gynecomastia, small testes, and reduced fertility as a result of mild androgen insensitivity

Wide range of phenotypes of external genitalia from predominantly male (hypospadias, cryptorchidism, micropenis), to ambiguous, to predominantly female (clitoromegaly and labial fusion, vaginal opening)

Female external genitalia. Absent or rudimentary wolffian duct derivatives. Cryptorchidism. Short blind-ending vagina. Scant or absent pubic and/or axillary hair

Incomplete male pseudohermaphroditism with pseudovaginal perineoscrotal hypospadias, clitoral-like phallus, markedly bifid scrotum, cryptorchidism. The uterus and fallopian tubes are absent

Phenotype

Hypergonadotropic hypogonadism secondary to testicular failure

Hypergonadotropic hypogonadism secondary to testicular failure

Hypergonadotropic hypogonadism secondary to testicular failure

Hypergonadotropic hypogonadism secondary to testicular failure

Slightly high T 9 LH product

Normal/high T with normal/high LH levels

High T with high LH levels

Baseline and post-hCG-stimulation elevated T-to-DHT ratio

Typical metabolic biomarkers

0.3/100,000

Unknown

Unknown

Unknown

1–9/ 100,000

1–2/ 100,000

Unknown

Unknown

Unknown

Unknown

1/30,000

Unknown

Unknown

Unknown

Unknown

2–5/ 100,000

Prevalence

Incidence

Birth

Adolescence/young adulthood

Adolescence/young adulthood

Adolescence/young adulthood

Adolescence/adulthood

Birth

Birth/puberty

Birth/puberty

Age range of expression

[224]

[223]

[222]

[221]

[220]

[219]

[218]

[217]

References

J Endocrinol Invest

123

OMIM phenotype number

# 136680

# 194080

# 607080

# 273300





# 424500

Disorder

3d) Frasier syndrome

4) Denys–Drash syndrome

5) 46, XY Gonadal dysgenesis, partial, with minifascicular neuropathy

6) Testicular germ cell tumor; TGCT

7) Testicular Leydig cell tumor

8) Testicular sertoli cell tumor

9) Gonadoblastoma: GBY

Table 9 continued

123 –







(605423)

DHH

(607102)

WT1

(607102)

WT1

OMIM gene/locus number

It affects dysgenetic gonads (DSD patients with Y chromosome)

Slowing growing testicular mass

Painless testicular enlargement. When arising in children it may present with precocious puberty (androgen secretion). In boys and adults it may be associated with gynecomastia and decreased libido (estrogen secretion)

Classified as seminoma and nonseminoma, it has no specific phenotype. Often men with TGCT notice a hard, painless lump on the testicle or a change in the size of their testicle

Ambiguous genitalia with partial gonadal dysgenesis and motor and sensory neuropathy

Diffuse mesangial sclerosis with nephrotic syndrome and renal faı`lure, pseudohermaphroditism, nephroblastoma (Wilms tumor)

Glomerular nephropathy with normal female external genitalia. High risk of gonadoblastoma

Phenotype

None

None

T or estradiol may be high

High beta-hCG, AFP, LDH levels

Hypergonadotropic hypogonadism secondary to testicular failure

Hypergonadotropic hypogonadism secondary to testicular failure

Hypergonadotropic hypogonadism secondary to testicular failure

Typical metabolic biomarkers

Unknown

Unknown

Unknown

2–9/ 100,000

\1/ 1,000,000

30–60 % of DSD patients

0.4–1.5 % of testicular tumors

1–3 % of testicular tumors

1–2/1,000

Unknown

Unknown

Unknown

\1/ 1,000,000 \1/ 1,000,000

Prevalence

Incidence

[229]

[230]

\30 years

[228]

[227]

[226]

[225]

[225]

References

45 years (mean age)

5–10 years, 30–60 years

15–40 years

Birth/infancy

Birth/infancy

Childhood

Age range of expression

J Endocrinol Invest

OMIM phenotype number

# 131100

# 171400

# 162300

# 610755

Disorder

1) Multiple endocrine neoplasia Type 1; MEN1

2) Multiple endocrine neoplasia Type 2A; MEN2A

3) Multiple endocrine neoplasia Type 2B; MEN2B

4) Multiple endocrine neoplasia Type 4; MEN4 CDKN1B (600778)

RET (164761)

RET (164761)

MEN1 (613733)

OMIM gene/locus number Parathyroid adenoma/hyperplasia, entero-pancreatic tumor (gastrinoma, insulinoma, nonfunctioning neuroendocrine tumor, glucagonoma, VIP-oma, somatostatinoma), Foregut carcinoid, thymic carcinoid, bronchial carcinoid, gastric enterochromaffin-like nonfunctioning tumors, anterior pituitary tumor (PRL, GH ? PRL, GH, non-functioning, ACTH, TSH), adrenal cortex nonfunctioning tumors, pheochromocytoma, lipomas, facial angiofibromas, collagenomas Medullary thyroid carcinoma, pheochromocytoma, parathyroid adenomas Associated characteristic features: cutaneous lichen amyloidosis, Hischprung’s disease rarely prominent corneal nerves Aggressive medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and thickened corneal nerves Associated characteristic physical features: full lips, thickened eyelids, high-arched palate, marfanoid habitus Intermediate features between MEN1 and MEN2 with the presence of neoplasms in at least 2 endocrine glands

Phenotype

Table 10 Rare diseases with possible endocrine multiple

Unknown

0.2–2/100,000

Incidence

High serum Ca, calcitonin, CEA, PTH, gastrin, insulin, VIP, PP, somatostatin, CgA, PRL, GH, IGF-1, ACTH, UFC, serum and urinary catecholamines levels. High or low glycemia, low serum P levels

Unknown

High serum basal and stimulated \1/500,000 calcitonin levels, high catecholamines, and catecholamine metabolites levels

High serum basal levels and stimulated calcitonin, elevated catecholamines and catecholamine metabolites, high serum Ca and PTH levels

High levels of one or more of the following markers: PRL, IGF1, gastrin, fasting glucose, insulin, PP, glucagon, VIP, CgA, Ca, PTH

Typical metabolic biomarkers

4/100,000

\1/100,000

1/30,000

1–3.3/ 100,000

Prevalence

50–55 years

Childhood (earlier onset in first years of life)

3–25 years

5–81 years

Age range of expression

[99]

[43]

[42]

[95]

References

J Endocrinol Invest

123

123

# 162200

# 160980

NF1 (613113)

# 300200

7) Adrenal hypoplasia, congenital; AHC 8) Neurofibromatosis type 1; NF1

9) Carney complex type 1; CNC1

DAX1 (300473)

# 193300

6) Von Hippel– Lindau; VHL

PRKAR1A (188830)

VHL (608537)

Type 1: TSC1 (605284) Type 2: TSC2 (191092)

# 191100 # 613254

5) Tuberous sclerosis; TSC

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 10 continued

Adrenal pheochromocytoma, Lysch nodules, caffe-au lat spots, cutaneous neurofibromas, neural crest-derived tumors, GIST Pigmented micronodular adrenal dysplasia, Cushing disease, acromegaly, thyroid follicular hyperplasia, associated with cardiac, cutaneous, and neural myxomatous tumors, pigmented lesions of the skin and mucosae

Mutated hamartin and tuberin

Skin abnormalities (patches of light-colored skin, facial angiofibromas), seizures, behavioral problems such as hyperactivity and aggression, intellectual disability or learning problems, developmental disorders, brain tumors, kidney tumors. Additionally, tumors can develop in the heart, lungs and retina Adrenal pheochromocytoma, retinal angioma, hemangioblastoma of the central nervous system, endolymphatic sac tumor, pancreatic endocrine tumor, clear cell renal cancer Congenital adrenal hypoplasia, hypogonadotropic hypogonadism

Variable, 20–30 % hypercortisolism with low ACTH levels, less frequently high levels of PRL, GH or IGF1, or high levels of T, high serum FT4, FT3 levels, low TSH level

High ACTH level, low serum cortisol, and gonadotropins levels High metanephrine, normetanephrine, 3 metossithyramine levels

High metanephrine, normetanephrine, 3 metossithyramine levels

Typical metabolic biomarkers

Phenotype

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma) Unknown

1/12,500

0.8/100,000 (for all types of pheocromocytoma/ paraganglioma)

1/10,000

Incidence

On 2010, 500 patients were known

Unknown

Unknown

Unknown

8.8/10,000

Prevalence

Variable

4–84 years

During childhood

4–60 years

Childhood but manifestations are often mild in childhood and overt in adulthood

Age range of expression

[233]

[168]

[232]

[100]

[231]

References

J Endocrinol Invest

OMIM phenotype number

# 240300

% 269200



Disorder

10) Autoimmune polyendocrine syndrome, type 1, with or without reversible metaphyseal dysplasia; APS1

11) Autoimmune polyendocrine syndrome, type 2; APS2

12) Autoimmune polyendocrine syndrome, type 3; APS3

Table 10 continued



Polygenic associated with HLADR3 and HLA-DR4 and nonHLA genes MICA (600169) PTPN22 (600716) CTLA4 (123890)

AIRE (607358)

OMIM gene/locus number

Autoimmune thyroid diseases associated to other autoimmune diseases (excluding Addison’s disease and/or hypoparathyroidism)

Association between autoimmune Addison’s disease and either autoimmune thyroid disease or type 1 diabetes, or both Further endocrine (hypogonadism, hypoparathyroidism), and nonendocrine component diseases (autoimmune gastritis, pernicious anemia, vitiligo, autoimmune hepatitis, and myasthenia gravis) may be present

Candidiasis (before 5 years) Hypoparathyroidism (before 10 years) Addison’s disease (before 15 years) ? 2–3 of the following: insulindependent diabetes, primary hypogonadism, pernicious anemia, alopecia, vitiligo, Hashimoto’s thyroiditis, gastritis, idiopathic hypopituitarism

Phenotype

Multiple auto-antibodies: 21OH Abs, ACA Abs, Islet cells Abs, GAD Abs, (optional IA2), MPC Abs, TPO Abs, H?–K? ATPase of the parietal cells Abs, intrinsic factor Abs High serum TSH, FSH, LH, glucose levels Low FT4, T, estradiol, fasting morning cortisol levels Assessment of serum Na, K, Ca, blood cell count and ACTH stimulation test (when adrenal antibodies are present) may be useful Fasting morning cortisol levels Anemia Multiple auto-antibodies: Islet cells Abs, GAD Abs, (optional IA2 Abs), TPO Abs, TSH receptor Abs, Cytochrome P450 enzymes Abs (especially 21-Hydroxylase), H?–K? ATPase of the parietal cells Abs, intrinsic factor Abs, tTGA Abs, (optional gliadin Abs) High serum TSH, FSH, LH, glucose levels Low FT4, T, estradiol, fasting morning cortisol levels Assessment of serum Na, K, Ca, blood cell count and ACTH stimulation test (when adrenal antibodies are present) may be useful Multiple auto-antibodies

Typical metabolic biomarkers

Unknown

Unknown

1/100,000 (juvenile) and 1/20,000 (adult)

Incidence

Unknown

1/20,000

From 1/14,000 in Sardinia to 1/129,000 Poland

Prevalence

Variable

Adulthood (20–60 years, mostly in the third or fourth decade)

5–15 years

Age range of expression

[236]

[235]

[234]

References

J Endocrinol Invest

123

123



13) Autoimmune polyendocrine syndrome, type 4; APS4 –

OMIM gene/locus number

OMIM phenotype number







Disorder

1) Vasoactive intestinal polypeptidesecreting tumor

2) Pancreatic polypeptidesecreting tumor

3) Sporadic somatostatinoma







OMIM gene/locus number

Table 11 Rare neuroendocrine tumors

OMIM phenotype number

Disorder

Table 10 continued

With no specific symptoms or found by chance that demonstrate immunohistochemical staining for somatostatin-like-immunoreactivity

Diabetes mellitus, gallbladder disease, diarrhea, weight loss, and steatorrhea (SSoma syndrome), but are cases

Non-specific abdominal pain

Large volume, watery diarrhea, dehydration, and hypokalemia. The excess vasoactive intestinal polypeptide (VIP) secretion also can result in hyperglycemia (20–50 %), hypercalcaemia (25–50 %), hypochlorhydria (20–50 %), and flushing (15–30 %). Rare in patients with MEN 1

Phenotype

C2 autoimmune diseases, which do not fall in types 1, 2 or 3. The major component of the disease is Addison disease Minor autoimmune diseases: Addison disease, premature gonadal failure, vitiligo, alopecia, celiac disease, chronic atrophic gastritis and Wherlof’s syndrome

Phenotype

High serum SS levels and/or high serum CgA levels

High serum PP levels and/or high serum CgA levels

High serum VIP levels (usually [500 pg/ml) (usually \190 pg/ml) ± high serum CgA levels

Typical metabolic biomarkers

Unknown

Unknown

Unknown

Unknown

Unknown

Prevalence

Unknown

Incidence

0.05–0.2/100,000

Incidence

Multiple auto-antibodies: 21OH Abs, ACA Abs, StCA Abs, 17a-OH Abs, SCC Abs, MPC Abs, tTGA Abs, PCA Abs High serum, FSH, LH, T, estradiol, fasting morning cortisol levels Assessment of serum Na, K, blood cell count and ACTH stimulation test (when adrenal antibodies are present) may be useful

Typical metabolic biomarkers

6–62 years

Age range of expression

Median onset 54 years (range 24–84)

Unknown

Median onset 40 years (range 11–75 years)

Age range of expression

Unknown

Prevalence

[240]

[239]

[238]

References

[237]

References

J Endocrinol Invest

OMIM phenotype number











Disorder

4) Familial somatostatinoma

5) Sporadic glucagonoma

6) Familial glucagonoma

7) Sporadic nonfunctional pancreatic neuroendocrine tumors

8) Familial nonfunctional pancreatic neuroendocrine tumors

Table 11 continued

(605284)

TSC2

(613254)

TSC1

(613113)

NF1

(608537)

Gastrointestinal hemorrhage, biliary or gastric outlet obstruction, abdominal mass, and pain can be present at the time of diagnosis; worse prognosis compared with functioning tumors

Rarely associate with Von Recklinghausen disease NF-1) and tuberous sclerosis

Disease (usually asymptomatic)

VHL

High penetrance 80–90 % at 60 years of age

(613733)

VHL

High serum CgA levels

MEN1

MEN1

High serum glucagone levels, with diagnostic levels generally [500 pg/ml (\120), anemia

High serum glucagon levels with diagnostic levels generally [500 pg/ml (\120), anemia

High serum SS levels and/or serum CgA levels

Typical metabolic biomarkers

High serum CgA levels

See above

Weight loss, necrolytic migratory erythema, diabetes, or glucose intolerance, mucosal abnormalities (glossitis, stomatitis), venous thromboembolism, neuropsychiatric disturbances (most often depression and/or psychosis), diarrhea, and rarely, dilated cardiomyopathy

Diabetes mellitus, gallbladder disease, diarrhea, weight loss, and steatorrhea (SSoma syndrome), but are cases with no specific symptoms or found by chance that demonstrate immunohistochemical staining for somatostatin-like-immunoreactivity; syndrome phenotype

Multiple endocrine neoplasia type 1 Von Hippel–Lindau syndrome neurofibromatosis type 1

Phenotype

Incidentally discovered in most cases, usually advanced disease ([60 % liver metastases). Symptoms can be caused by tumor growth: abdominal pain (40–60 %), weight loss (25–50 %), and jaundice (30–40 %)



(613733)

MEN1



(613113)

NF1

(608537)

VHL

(613733)

MEN1

OMIM gene/locus number

Unknown

0.1–0.4/100,000 (all types of pancreatic NET)

2–4/100,000 (associated with MEN 1 5 % of cases)

2–4/100,000

Unknown

Incidence

10–17 % of VHL patients

20–90 % of MEN 1 patients (most common gastroenteropancreatic tumor associated with MEN1)

Unknown

Unknown

Unknown

Unknown

Prevalence

Variable

Median age: 57 years (range 23–93)

Unknown

Middle-aged with a median age at the time of diagnosis of 53–55 years (range 43–71)

Unknown

Age range of expression

[244]

[243]

[242]

[241]

[240]

References

J Endocrinol Invest

123

123

MEN1



10) Familial gastrinoma









11a) Gastric neuroendo -crine tumor type 1

11b) Gastric neuroendocrine tumor type 2

11c) Gastric neuroendocrine tumor type 3

11d) Gastric neuroendocrine tumor type 4

(191170)

TP53

Loss of heterozygosity of the MENI (613733) gene locus on 11q13 has been described in 25–50 %

(613733)

MEN1

Loss of heterozygosity of the MENI (613733) gene locus on 11q13 has been described in 17–73 %

11) Gastric neuroendocrine tumor (GNET)

(613733)





9) Sporadic gastrinoma

OMIM gene/locus number

OMIM phenotype number

Disorder

Table 11 continued

Poorly differentiated tumor, highly aggressive. They may arise from ACTH or serotonin cells or are of mixed endocrine–exocrine etiology

Carcinoid syndrome is a rare presentation

Sporadic with high malignant potential

Hypertrophic fundic gastropathy, Zollinger–Ellison syndrome

Chronic atrophic gastritis, achlorhydria and G cell hyperplasia

MEN1 phenotype in all cases

Tumor mass signs and symptoms and/ or Zollinger–Ellison syndrome characterized by gastric acid hypersecretion resulting in severe peptic disease and gastroesophageal reflux disease

Tumor mass signs and symptoms and/ or Zollinger–Ellison syndrome, characterized by gastric acid hypersecretion resulting in severe peptic disease and gastroesophageal reflux disease

Phenotype

Normal gastrinemia and/or high serum CgA levels

They typically produce 5-HT and/or high serum CgA levels

Normal gastrinemia

High serum gastrin levels, high serum CgA levels, decreased gastric pH

High serum gastrin levels, and CgA levels, increased gastric pH

High serum gastrin and CgA levels

High serum gastrin and CgA levels

Typical metabolic biomarkers

0.2/100,000 (including Gastric neuroendocrine tumor type 1, 3, 4)

0.2/100,000 (including Gastric neuroendocrine tumor type 1, 3, 4)

Unknown

0.2/100,000 (including GNET type 1, 3, 4)

Unknown

0.4–0.8/100,000 (14–20 % of GNET)

Unknown

2–2.5/100,000 (70–80 % of GNET)

Gastrinoma in 30 % of MEN1 patients

All gastric neuroendocrine tumors: mean 60–64 years (range 21–96)

All gastric neuroendocrine tumors: mean 60–64 years (range 21–96)

Mean 50 years

Mean 63 years (range 21–96)

From 20 years to adulthood

Peak of incidence 50–80 years

Unknown

Both sporadic and familial gastrinoma: 0.05–0.2/ 100,000 (sporadic type is about 80 % of cases) Both sporadic and familial gastrinoma: 5–20/100,000 (familiar type is about 20 % of cases)

Age range of expression

Prevalence

Incidence

[246]

[246]

[247]

[246]

[245]

[245]

References

J Endocrinol Invest

OMIM phenotype number

# 613733







Disorder

12) Bronchial and thymic carcinoids

13) Sporadic insulinoma

14) Familial insulinoma

15) Duodenal neuroendocrine tumor

Table 11 continued

Several cancer-related pathways implicated, including PI3K/Akt/ mTOR signaling, the TGF-b pathway, through alterations in: SMAD, SRC (190090)

(recurrent somatic mutations and deletions)

(600778)

CDKN1B

(in familiar forms)

(613733)

Duodenal or biliary obstruction

Abdominal pain, often crampy, and paroxysmal are the most common symptoms. Abdominal pain and/or intermittent bowel obstruction may be due to the mechanical effect of the intraluminal tumor, or due to mesenteric lymph node involvement which can produce a secondary desmoplastic response. Desmoplasia can lead to bowel tethering and kinking as well as mesenteric ischemia

Multiple pancreatic lesions

MEN1

See above

(613733)

Patients are often overweight. The most dramatic symptoms of hypoglycemia, such as neuropsychiatric manifestations, oscillating moderate personality changes, confusion, and coma can lead to difficulties in diagnosis

Syndrome of hypoglycemia (100 %), usually during fasting, rarely in post-prandial phase, neuroglycopenic symptoms (80–100 %), and symptoms of adrenergic stimulation (80–100 %). It usually manifests with hunger, fatigue, nausea, vomiting, paresthesia, peripheral neuropathy, and blurred vision

In case of centrally located carcinoids recurrent infections, chest pain, cough, dyspnea, and pneumonia may occur. Peripherally located ones are generally incidental findings

Typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma; small cell neuroendocrine carcinoma

Phenotype

MEN1



(in familiar forms)

(613733)

MEN1

OMIM gene/locus number

High serum CgA levels

Fasting hypoglycemia, inappropriately high serum, insulin and C-peptide or proinsulin levels

Fasting hypoglycemia, inappropriately high serum, insulin and C-peptide or proinsulin levels

High serum CgA levels, and/ or 5-HIAA and NSE (in poorly differentiated subtypes)

Typical metabolic biomarkers

0.19/100,000

0.1/100,000

0.4/100,000

5.2/100,000

Incidence

Unknown

Insulinoma in 15–20 % of MEN1 patients

Unknown

Bronchial or thymic carcinoids in 7 % of MEN1 patients

Prevalence

Unknown

Mean 25 year (range 5–69)

Mean 45 year (range 8–82)

50–56 years

Age range of expression

[249]

[95]

[248]

[244]

References

J Endocrinol Invest

123

OMIM phenotype number









Disorder

16) Colonic neuroendocrine tumor

17) Rectal neuroendocrine tumor

18) Ileal neuroendocrine tumor

19) Jejunal neuroendocrine tumor

Table 11 continued

123

Usually grouped with either duodenal or ileal NETs



(600778)

CDKN1B





OMIM gene/locus number

Poorly characterized and heterogeneous ‘‘Duodenal-like’’ tumors of the upper jejunum usually share the same general behavior than their duodenal counterparts Jejunal entero chromaffin tumors share the same presentation and general clinical behavior than their ileal counterparts, including a strong tendency to local invasion, regional lymph node involvement, and metastatic dissemination

Atypical carcinoid syndrome: flushing, headache, lacrimation, hypotension, cutaneous edema, bronchoconstriction

Typical carcinoid syndrome: diarrhea, flushing, carcinoid heart disease and/or

Tumor mass signs and symptoms and/ or:

Bowel obstruction or systemic symptoms only with advanced disease

Symptoms if present are usually rectal bleeding, constipation or pain, and tenesmus. Carcinoid syndrome is very rare

Half of all are diagnosed upon routine lower endoscopy

There is an association between inflammatory bowel diseases and colon neuroendocrine tumors NETs

Less than 5 % have carcinoid syndrome

Most tumors arise in the caecum, followed by the ileocecal region and ascending colon. Patients present with pain, bleeding, altered bowel habits, weight loss, and anorexia. With advanced disease they may present with symptoms of bowel obstruction, anemia or a palpable liver

Phenotype

‘‘Duodenal-like’’ tumors of the upper jejunum usually synthesize gastrin

High serum CgA, serotonin, urinary 5-HIAA levels

Rarely high serum CgA levels

Rarely high serum CgA levels

Typical metabolic biomarkers

Unknown

0.29–1.08/ 100,000

0.1–1.0/100,000

0.17–0.40/ 100,000

Incidence

Unknown

Unknown

Unknown

Unknown

Prevalence

Unknown

Peak of incidence 59–65 years

56 years

Mean

Mean 65 years

Age range of expression

[252]

[251]

[250]

[250]

References

J Endocrinol Invest

[253] The mean age of diagnosis for Merkel cell carcinoma is 76.2 years for women and 73.6 for men. Only 4.0 % patients is 49 years or younger. Peak incidence: 70–80 years Unknown

The most common clinical features of Merkel cell carcinoma have been summarized by the acronym AEIOU: (1) A for asymptomatic/ lack of tenderness; (2) E for expanding rapidly (3 months); (3) I for immunosuppression; (4) O for older than age 50; and (5) U for UVexposed sites (location). Up to 89 % of patients with Merkel cell carcinoma met 3 or more of the AEIOU criteria

MCPyV is integrated at various locations in the MCC tumor genome in a clonal pattern, which strongly implies that infection of the cells occurred before their clonal expansion

1.45/100,000 Infection with Merkel cell polyomavirus (MCPyV) was found in most tumors (8 on 10 cases)

Highly aggressive, asymptomatic, non-tender tumor, usually on face and neck, expanding rapidly, ultraviolet-exposed/fair-skinned location, most frequent in chronic immunosuppression Deletion of the short arm of chromosome 1 (1p36) 40 % of Merkel cell carcinoma

– 20) Merkel cell carcinoma



Incidence Typical metabolic biomarkers OMIM phenotype number Disorder

Table 11 continued

OMIM gene/locus number

Phenotype

Prevalence

Age range of expression

References

J Endocrinol Invest

48 rare mineral and bone diseases, (Table 4) 41 rare diseases of the PTH/PTHr1 and PTHrp receptors, (Table 5) 69 rare metabolic diseases of glucose, lipids and mucopolysaccharides, (Table 6) 6 rare water metabolism diseases, (Table 7) 49 rare adrenal glands and paraganglia diseases, (Table 8) 20 rare ovarian diseases, (Table 9) 28 rare testicular diseases, (Table 10) 14 rare diseases with possible multiple endocrine involvement, and (Table 11) 23 rare neuroendocrine tumors. This report provides a complete taxonomy for the classification of REMDs of the adult. Although it is limited in terms of information included, it provides a comprehensive overview of rare disorders of the various endocrine systems and a primary diagnostic tool. This document is the starting point from which future studies can be pursued, such as the creation of registries of rare endocrine diseases, to collect data on cohorts of patients, and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease. This will help to plan and perform intervention studies in larger groups of patients to prove the efficacy, effectiveness and safety of a certain treatment, thus achieving the priority of testing and delivering new drugs for rare diseases by 2020. Acknowledgments This work was made possible through an unrestricted grant from F.I.R.M.O. Fondazione Raffaella Becagli. Conflict of interest disclose.

All authors have no conflict of interest to

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Rare diseases in clinical endocrinology: a taxonomic classification system.

Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endoc...
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