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
J Endocrinol Invest
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
123
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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# 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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–
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
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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
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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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