Short Focused Review Received: February 25, 2014 Accepted after revision: March 12, 2014 Published online: July 8, 2014
Dermatology 2014;229:55–64 DOI: 10.1159/000362200
Monogenic Human Skin Disorders Johannes R. Lemke a, d Kristin Kernland-Lang b Konstanze Hörtnagel e Peter Itin c
a Division of Human Genetics, University Children’s Hospital Inselspital, and b Department of Dermatology and Pediatrics, University Hospital Inselspital, Bern, and c Department of Dermatology, University Hospital Basel, Basel, Switzerland; d Institute of Human Genetics, University Hospital of Leipzig, Leipzig, and e CeGaT GmbH, Tübingen, Germany
Key Words Human genodermatoses · Monogenic human skin disorders · Tabular database
Abstract Human genodermatoses represent a broad and partly confusing spectrum of countless rare diseases with confluent and overlapping phenotypes often impeding a precise diagnosis in an affected individual. High-throughput sequencing techniques have expedited the identification of novel genes and have dramatically simplified the establishment of genetic diagnoses in such heterogeneous disorders. The precise genetic diagnosis of a skin disorder is crucial for the appropriate counselling of patients and their relatives regarding the course of the disease, prognosis and recurrence risks. Understanding the underlying pathophysiology is a prerequisite to understanding the disease and developing specific, targeted or individualized therapeutic approaches. We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We hope this may represent a use-
© 2014 S. Karger AG, Basel 1018–8665/14/2292–0055$39.50/0 E-Mail [email protected] www.karger.com/drm
ful tool in guiding dermatologists towards genetic diagnoses, providing patients with individual knowledge on the respective disorder and applying novel research findings to clinical practice. © 2014 S. Karger AG, Basel
Introduction
The number of known genodermatoses has constantly risen in the past years. In 1991, Moss [1] described 90 regionally assigned cutaneous traits, and one and a half decades later this number increased to 580 [2]. Due to significant technical improvements over the past years and novel sequencing techniques, this number has further augmented. Similar to other monogenetic disorders, a certain genodermatosis can sometimes be caused by genetic defects in several genes (genetic heterogeneity), and on the other hand, different disorders sometimes share similar underlying genetic aberrations (allelic variants). However, more than 80% of genetic skin disorders seem to be Peter Itin Dermatologie, Universitätsspital Basel Petersgraben 4 CH–4031 Basel (Switzerland) E-Mail peter.itin @ usb.ch
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Gene
Gene MIM No.
Disease
Phenotype MIM No.
Inheritance
ABCA12
607800
ABHD5 ALDH3A2 ALOX12B ALOXE3 AP1S1 AQP5 ATP2A2
604780 609523 603741 607206 603531 600442 108740
ATP2C1 CDSN CERS3 CLDN1 COL14A1 CSTA CTSC CYP4F22 DKC1 DSG1 DSP EBP ELOVL4 ENPP1 ERCC2 ERCC3 FLG GJB2 GJB3 GJB4 GJB6 GTF2H5 JUP KRT1 KRT10 KRT16 KRT17 KRT2 KRT6A KRT6B KRT9 KRT9 LIPN LOR MBTPS2 MBTPS2 MPLKIP NHP2 NIPAL4 NOP10 NSDHL PKP1 PNPLA1 POMP
604384 602593 615276 603718 120324 184600 602365 611495 300126 125670 125647 300205 605512 173335 126340 133510 135940 121011 603324 605425 604418 608780 173325 139350 148080 148067 148069 600194 148041 148042 607606 607606 613924 152445 300294 300294 609188 606470 609383 606471 300275 601975 612121 613386
Ichthyosis, autosomal recessive 4B (harlequin) Ichthyosis, congenital, autosomal recessive 4A Chanarin-Dorfman syndrome Sjögren-Larsson syndrome Ichthyosis, congenital, autosomal recessive 2 Ichthyosis, congenital, autosomal recessive 3 MEDNIK syndrome Palmoplantar keratoderma, Bothnian type Acrokeratosis verruciformis Darier disease Hailey-Hailey disease Ichthyosis-hypotrichosis Autosomal recessive congenital ichthyosis ILVASC Keratoderma, palmoplantar, punctate type IB Exfoliative ichthyosis Papillon-Lefèvre syndrome Ichthyosis, congenital, autosomal recessive 5 Dyskeratosis congenita Striate palmoplantar keratoderma (PPKS1) Striate palmoplantar keratoderma (PPKS2) Chondrodysplasia punctata, X-linked dominant Ichthyosis, spastic quadriplegia and mental retardation Cole disease Trichothiodystrophy Trichothiodystrophy Ichthyosis vulgaris KID syndrome Erythrokeratodermia variabilis et progressiva Erythrokeratodermia variabilis with erythema gyratum repens Ectodermal dysplasia, Clouston type Trichothiodystrophy Naxos disease Ichthyosis, cyclic, with epidermolytic hyperkeratosis Ichthyosis, cyclic, with epidermolytic hyperkeratosis Pachyonychia congenita type I (Jadassohn-Lewandowsky syndrome) Pachyonychia congenita type II (Jackson-Lawler syndrome) Ichthyosis bullosa of Siemens Pachyonychia congenita type I (Jadassohn-Lewandowsky syndrome) Pachyonychia congenita type II (Jackson-Lawler syndrome) Epidermolytic palmoplantar keratoderma Epidermolytic palmoplantar keratoderma Ichthyosis, congenital, autosomal recessive 8 Vohwinkel syndrome (ichthyotic variant) IFAP syndrome with or without BRESHECK syndrome Keratosis follicularis spinulosa decalvans, X-linked Trichothiodystrophy, non-photosensitive 1 Dyskeratosis congenita, autosomal recessive 2 Ichthyosis, congenital, autosomal recessive 6 Dyskeratosis congenita, autosomal recessive 1 CHILD syndrome Ectodermal dysplasia/skin fragility syndrome Ichthyosis, congenital, autosomal recessive 10 Keratosis linearis with ichthyosis congenita and sclerosing keratoderma
242500 601277 275630 270200 242100 606545 609313 600231 101900 124200 169600 146520 615023 607626 614936 607936 245000 604777 305000 148700 612908 302960 614457
AR AR AR AR AR AR AR AD AD AD AD AD/AR AR AR AD AR AR AR XL AD AD XL AR AD AR AR AD AD AD AD AD AR AR AD AD AD AD AD AD AD AD AD AR AD XL XL AR AR AR AR XL AR AR AR
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601675 601675 146700 148210 133200 133200 129500 601675 601214 607602 607602 148067 167210 146800 167200 167210 144200 144200 613943 604117 308205 308800 234050 613987 612281 224230 308050 604536 615024 601952
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Table 1. Inherited ichthyoses/generalized Mendelian disorders of cornification
Table 1 (continued)
Gene
Gene MIM No.
Disease
Phenotype MIM No.
Inheritance
RHBDF2 SAT1 SERPINB7 SLC27A4 SLURP1 SMARCAD1 SNAP29 SPINK5 ST14 STS SUMF1 TAT TERC TERT TGM1 TGM5 TINF2 WRAP53
614404 313020 603357 604194 606119 612761 604202 605010 606797 300747 607939 613018 602322 187270 190195 603805 604319 612661
Tylosis with oesophageal cancer Keratosis follicularis spinulosa decalvans Palmoplantar keratosis, Nagashima type Ichthyosis prematurity syndrome Mal de Meleda Adermatoglyphia CEDNIK syndrome Netherton syndrome Ichthyosis with hypotrichosis Ichthyosis, X-linked Multiple sulphatase deficiency Richner-Hanhart syndrome, tyrosinaemia, type II Dyskeratosis congenita, autosomal dominant 1 Dyskeratosis congenita, autosomal recessive 4 Ichthyosis, congenital, autosomal recessive 1 Peeling skin syndrome, acral type Dyskeratosis congenita, autosomal dominant 3 Dyskeratosis congenita, autosomal recessive 3
148500 308800
AD XL AR AR AR AD AR AR AR XL AR AR AD AR AR AR AD AR
608649 248300 136000 609528 256500 610765 308100 272200 276600 127550 613989 242300 609796 613990 613988
AR = Autosomal recessive; AD = autosomal dominant; XL = X-linked; MEDNIK = mental retardation, enteropathy, deafness, neuropathy, ichthyosis and keratoderma; ILVASC = ichthyosis, leucocyte vacuoles, alopecia and sclerosing cholangitis; KID = keratitis, ichthyosis and deafness; IFAP = ichthyosis follicularis, alopecia and photophobia; BRESHECK = brain anomalies, retarda-
tion, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism and kidney dysplasia/hypoplasia; CHILD = congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CEDNIK = cerebral dysgenesis, neuropathy, ichthyosis and keratoderma.
caused by a single gene defect, and more than 80% of gene defects cause only one condition [3]. Still, the current genetic knowledge has only marginally found its way into clinical practice. This may partly be due to (1) the enormous amount of genetic data that may sometimes appear to be difficult to access, interpret and filter for relevant information, (2) inconsistencies in nomenclature of entities termed after phenotypic versus genotypic aspects, (3) a considerable challenge in establishing a clear clinical diagnosis due to often non-specific and overlapping phenotypes, and (4) the expected lack of direct therapeutic consequences after genetic testing in many cases. However, a precise genetic diagnosis can be of great help in counselling the patient and his family regarding prognosis and recurrence risks, and in some cases it may even guide therapy. Understanding the underlying genetic defect and its consecutive pathomechanisms is a first step in understanding the disease, enabling the development of individualized therapeutic approaches targeting the actual molecular defect. Beyond that, even the knowl-
edge of a currently incurable and maybe fatal diagnosis can help in preventing unnecessary and often stressful diagnostic procedures as well as futile therapeutic attempts. Thus, the knowledge of the patient’s genotype is becoming increasingly important with respect to therapeutic decisions and is superior to a purely clinical alignment of the phenotype.
We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We searched the literature using PubMed (http://www.ncbi.nlm. nih.gov/pubmed/) and OMIM (http://www.ncbi.nlm.nih.gov/ omim/) for information regarding genodermatoses. Only entities with a known monogenetic aetiology were included, entities with only linkage loci or complex or unknown genetic origin were disregarded. Furthermore, we excluded entities where skin manifestations are very rare, secondary (e.g. caused by haematological or immunological problems) or represent only a minor or insignificant symptom compared to other features of the disorder.
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Monogenic Human Skin Disorders
Methods
Table 2. Genetic epidermolyses and blistering disorders
Gene
Gene Disease MIM No.
Phenotype InheriMIM No. tance
COL17A1 COL7A1
113811 120120
226650 226600 132000
DSP EXPH5 FERMT1 ITGA3 ITGA6 ITGB4
125647 612878 607900 605025 147556 147557
KRT1 KRT10 KRT5
139350 148080 148040
KRT14
148066
LAMA3
600805
LAMB3
150310
LAMC2
150292
PLEC1
601282
POFUT1 607491 POGLUT1 515618
Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa dystrophica, autosomal recessive Epidermolysis bullosa dystrophica, Bart type Epidermolysis bullosa dystrophica, localisata variant Epidermolysis bullosa dystrophica, autosomal dominant Epidermolysis bullosa dystrophica, autosomal recessive Epidermolysis bullosa pruriginosa Epidermolysis bullosa, pretibial Toenail dystrophy, isolated Transient bullous epidermolysis of the newborn Epidermolysis bullosa, lethal acantholytic Epidermolysis bullosa, non-specific, autosomal recessive Kindler syndrome Interstitial lung disease, nephritic syndrome and epidermolysis bullosa, congenital Epidermolysis bullosa, junctional, with pyloric stenosis Epidermolysis bullosa of hands and feet Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa, junctional, with pyloric atresia Ichthyosis, cyclic, with epidermolytic hyperkeratosis Ichthyosis, cyclic, with epidermolytic hyperkeratosis Dowling-Degos disease 1 Epidermolysis bullosa simplex with migratory circinate erythema Epidermolysis bullosa simplex with mottled pigmentation Epidermolysis bullosa simplex, Dowling-Meara type Epidermolysis bullosa simplex, Koebner type Epidermolysis bullosa simplex, Weber-Cockayne type Dermatopathia pigmentosa reticularis Epidermolysis bullosa simplex, Dowling-Meara type Epidermolysis bullosa simplex, Koebner type Epidermolysis bullosa simplex, recessive 1 Epidermolysis bullosa simplex, Weber-Cockayne type Naegeli-Franceschetti-Jadassohn syndrome Epidermolysis bullosa, generalized atrophic benign Epidermolysis bullosa, junctional, Herlitz type Laryngo-onychocutaneous syndrome Epidermolysis bullosa, junctional, Herlitz type Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa, junctional, Herlitz type Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa simplex with pyloric atresia Epidermolysis bullosa simplex, Ogna type Muscular dystrophy with epidermolysis bullosa simplex Dowling-Degos disease 1 Dowling-Degos disease
131750 226600 604129 131850 607523 131705 609638 615028 173650 614748 226730 131800 226650 226730 607602 607602 179850 609352 131960 131760 131900 131800 125595 131760 131900 601001 131800 161000 226650 226700 245660 226700 226650 226700 226650 612138 131950 226670 615327
AR AR AD AR AD AR AD/AR AD AD AD/AR AR AR AR AR AR AR AR AR AD AD AD AD AD AD AD AD AD AD AD AR AD AD AR AR AR AR AR AR AR AR AD AR AD AD
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For abbreviations, see table 1.
Table 3. Nuclear excision repair disorders
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
DDB2 ERCC1 ERCC2
600811 126380 126340
278740
ERCC3
133510
ERCC4 ERCC5 ERCC6
133520 133530 609413
ERCC8
609412
GTF2H5 MPLKIP POLH RECQL4 WRN XPA XPC
608780 609188 603968 603780 604611 611153 613208
Xeroderma pigmentosum, group E, DDB-negative subtype Xeroderma pigmentosum Xeroderma pigmentosum, group D Trichothiodystrophy Xeroderma pigmentosum, group B Trichothiodystrophy Xeroderma pigmentosum, group F Xeroderma pigmentosum, group G Cockayne syndrome, type B UV-sensitive syndrome 1 Cockayne syndrome, type A UV-sensitive syndrome 2 Trichothiodystrophy Trichothiodystrophy Xeroderma pigmentosum, variant type Rothmund-Thompson syndrome Werner syndrome Xeroderma pigmentosum, group A Xeroderma pigmentosum, group C
278730 601675 610651 601675 278760 278780 133540 600630 216400 614621 601675 234050 278750 268400 277700 278700 278720
AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR
DDB = Damage-specific DNA-binding protein; AR = autosomal recessive.
Table 4. Genetic disorders with hypo-and hyperpigmentations
Gene MIM No.
Disease
ADAM10 ADAR AP3B1 BLM BLOC1S3 BLOC1S6 BRAF C10ORF11 DTNBP1 EDN3 EDNRB ENPP1 HPS1 HPS3 HPS4 HPS5 HPS6 KIT MAP2K1 MAP2K2 MC1R MITF
602192 146920 603401 604610 609762 604310 164757 614537 607145 131242 131244 173335 604982 606118 606682 607521 607522 164920 176872 601263 155555 156845
MLH1 MLPH MSH2 MSH6
120436 606526 609309 600678
Reticulate acropigmentation of Kitamura Dyschromatosis symmetrica hereditaria Hermansky-Pudlak syndrome 2 Bloom syndrome Hermansky-Pudlak syndrome 8 Hermansky-Pudlak syndrome 9 Cardiofaciocutaneous syndrome Albinism, oculocutaneous, type VII Hermansky-Pudlak syndrome 7 Waardenburg syndrome, type 4B Waardenburg syndrome, type 4A Cole disease Hermansky-Pudlak syndrome 1 Hermansky-Pudlak syndrome 3 Hermansky-Pudlak syndrome 4 Hermansky-Pudlak syndrome 5 Hermansky-Pudlak syndrome 6 Piebaldism Cardiofaciocutaneous syndrome Cardiofaciocutaneous syndrome Oculocutaneous albinism, type II, modifier of Tietz albinism-deafness syndrome Waardenburg syndrome, type 2A MMR deficiency syndrome (Turcot syndrome) Griscelli syndrome, type 3 MMR deficiency syndrome (Turcot syndrome) MMR deficiency syndrome (Turcot syndrome)
Monogenic Human Skin Disorders
Phenotype MIM No.
Dermatology 2014;229:55–64 DOI: 10.1159/000362200
127400 608233 210900 614077 614171 115150 615579 614076 613265 277580 203300 614072 614073 614074 614075 172800 115150 115150 203200 103500 193510 276300 609227 276300 276300
Inheritance AD AD AR AR AR AR AD AR AR AR AR AD AR AR AR AR AR AD AD AD AD AD AD AR AR AR AR
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Gene
Table 4 (continued)
Gene
Gene MIM No.
Disease
Phenotype MIM No.
Inheritance
MYO5A NF1 NF2 OCA2
160777 613113 607379 611409
PAX3
606597
PMS2 PRKAR1A PTPN11 RAB27A RECQL4 SLC45A2 SNAI2
600259 188830 176876 603868 603780 606202 602150
SOX10 SPRED1 STK11 TYR
602229 609291 602216 606933
TYRP1
115501
Griscelli syndrome, type 1 Neurofibromatosis, type 1 Neurofibromatosis, type 2 Albinism, oculocutaneous, type II Albinism, brown oculocutaneous Waardenburg syndrome, type 1 Waardenburg syndrome, type 3 MMR deficiency syndrome (Turcot syndrome) Carney complex type I Leopard syndrome Griscelli syndrome, type 2 Rothmund-Thompson syndrome Oculocutaneous albinism, type IV Waardenburg syndrome, type 2D Piebaldism Waardenburg syndrome, type 4C Legius syndrome Peutz-Jeghers syndrome Albinism, oculocutaneous, type IA Albinism, oculocutaneous, type IB Albinism, oculocutaneous, type III
214450 162200 101000 203200 203200 193500 148820 276300 160980 151100 607624 268400 606574 608890 172800 613266 611431 175200 203100 606952 203290
AR AD AD AR AR AD AD/AR AR AD AD AR AR AR AR AR AR AD AD AR AR AR
AD = Autosomal dominant; AR = autosomal recessive; MMR = mismatch repair.
Table 5. Disorders of ectodermal appendages including ectodermal dysplasia
Gene
Gene MIM No.
Disease
Phenotype InheriMIM No. tance
ABCC9 ALMS1 APCDD1 ARHGAP31 AXIN2 BANF1 BCS1L CDH3 CYP26C1 DDX59 DLX3 DOCK6 DSC3 DSG4 DSP EDA EDAR EDARADD EFNB1 ERCC2 ERCC3 FOXN1 GJB6
601439 606844 607479 610911 604025 603811 603647 114021 608428 615464 600525 614194 600271 607892 125647 300451 604095 606603 300035 126340 133510 600838 604418
Cantú syndrome Alström syndrome Hypotrichosis simplex Adams-Oliver syndrome Ectodermal dysplasia and neoplastic syndrome Nestor-Guillermo progeria syndrome Bjørnstad syndrome Hypotrichosis with juvenile macular dystrophy Focal facial dermal dysplasia 4 Orofaciodigital syndrome V Trichodento-osseous syndrome Adams-Oliver syndrome Hypotrichosis and recurrent skin vesicles Hypotrichosis Skin fragility-woolly hair syndrome X-linked hypohidrotic ectodermal dysplasia (ED1) Ectodermal dysplasia, hypohidrotic Ectodermal dysplasia, hypohidrotic Craniofrontonasal dysplasia Trichothiodystrophy Trichothiodystrophy T-cell immunodeficiency, congenital alopecia and nail dystrophy Ectodermal dysplasia 2, Clouston type
239850 203800 605389 100300 608615 614008 262000 601553 614974 174300 190320 614219 613102 607903 607655 305100 224900 614941 304110 601675 601675 601705 129500
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AD AR AD AD AD AR AR AR AR AR AD AR AR AR AR XL AD AD XL AR AR AR AR
Table 5 (continued)
Gene
Gene MIM No.
Disease
Phenotype InheriMIM No. tance
HOXC13 HR HVEC IFT122 IFT43 IKBKG JUP KCTD1 KRT17
142976 602302 600644 606045 614068 300248 173325 613420 148069
KRT74 KRT75 KRT81 KRT83 KRT85 KRT86 LIPH LMNA LMX1B LPAR6
608248 609025 602153 602765 602767 601928 607365 150330 602575 609239
MSX1 PKP1 POC1A PORCN PVRL1 RBM28 RBPJ RMRP SNRPE SOX18 TP63 TRPS1 TWIST2 WDR35
142983 601975 614783 300651 600644 612074 147183 157660 128260 601618 603273 604386 607556 613602
Ectodermal dysplasia 9, hair/nail type Atrichia with 2 ocular lesions, also called congenital alopecia universalis Cleft lip/palate-ectodermal dysplasia syndrome Cranio-ectodermal dysplasia 1 Sensenbrenner syndrome Anhidrotic ectodermal dysplasia with immune deficiency Naxos disease Scalp-ear-nipple syndrome Steatocystoma multiplex Pachyonychia congenita, Jackson-Lawler type Woolly hair Pseudofolliculitis barbae Monilethrix Monilethrix Ectodermal dysplasia 4, hair/nail type Monilethrix Woolly hair Hutchinson-Gilford progeria Nail-patella syndrome Woolly hair Hypotrichosis 8 Ectodermal dysplasia 3, Witkop type Ectodermal dysplasia/skin fragility syndrome Short stature, onychodysplasia, facial dysmorphism and hypotrichosis syndrome Focal dermal hypoplasia Margarita Island type of ectodermal dysplasia (ED4) Alopecia, neurological defects and endocrinopathy syndrome Adams-Oliver syndrome Cartilage hair hypoplasia Hypotrichosis Hypotrichosis-lymphoedema-telangiectasia syndrome Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Trichorhinophalangeal syndrome, type I Focal facial dermal dysplasia 3, Setleis type Cranio-ectodermal dysplasia 2
614931 209500 225060 218330 614099 300291 601214 181270 184500 167210 194300 612318 158000 158000 602032 158000 604379 176670 161200 278150 278150 189500 604536 614813 305600 225060 612079 614814 250250 615059 607823 106260 190350 227260 613610
AR AR AR AR AR XL AR AD AD AD AD AD AD AD AR AD AR AD AD AR AR AD AR AR XL AR AR AD AR AD AD AD AD AR AR
Results
We summarized the genes according to their phenotypic spectra in tables 1–9.
Discussion
Historically, the classification of genodermatoses was based on clinical experience and a broad phenotypic knowledge of the treating physician. The OMIM database Monogenic Human Skin Disorders
is an important tool listing and describing phenotypes of Mendelian disorders as well as their known underlying genetic causes [3]. However, with respect to genodermatoses, its structure is often of limited use for diagnostic clinical purposes. Modern molecular genetics with novel high-throughput sequencing techniques have not only expedited the identification of countless disease-causing genes, it has also led to a widening of the associated phenotypes in various entities [4, 5]. We learned that the phenotypic spectrum of an individual disorder might go far beyond what Dermatology 2014;229:55–64 DOI: 10.1159/000362200
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For abbreviations, see table 1.
Table 6. Vascular disorders
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
ACVRL1 C1NH C7ORF22 ENG FLT4 FOXC2 GDF2 GLMN GNAQ
601284 606860 607929 131195 136352 602402 605520 601749 600998
KRIT1 PDCD10 RASA1
604214 609118 139150
TEK
600221
Telangiectasia, hereditary haemorrhagic, type 2 Angio-oedema, hereditary, types I and II Cerebral cavernous malformations Telangiectasia, hereditary haemorrhagic, type 1 Hereditary lymphoedema type I Lymphoedema-distichiasis syndrome Telangiectasia, hereditary haemorrhagic, type 5 Glomuvenous malformations (glomangiomas) Sturge-Weber syndrome Capillary malformations, congenital, 1, somatic, mosaic Cerebral cavernous malformations Cerebral cavernous malformations Capillary malformation-arteriovenous malformation Parkes Weber syndrome Venous malformations, multiple cutaneous and mucosal
600376 106100 603284 187300 153100 153400 615506 138000 185300 163000 116860 603285 608354 608355 600195
AD AD AD AD AD AD AD AD mosaic mosaic AD AD AD AD AD
AD = Autosomal dominant. Table 7. Connective tissue defects
Gene
Gene MIM No.
Disease
Phenotype Inheritance MIM No.
ABCC6 ADAMTS2 ALDH18A1 ATP6V0A2 ATP7A B3GALT6 B4GALT7 COL1A1
603234 604539 138250 611716 300011 615291 604327 120150
COL1A2 COL3A1 COL5A1
120160 120180 120215
COL5A2 EFEMP2 ELN FBLN5 FBN1 FBN2 LTBP4 PLOD1 PYCR1 SMAD3 TGFB2 TGFBR1 TGFBR2 TNXB
120190 604633 130160 604580 134797 612570 604710 153454 179035 603109 190220 190181 190182 600985
ZMPSTE24
606480
Pseudoxanthoma elasticum Ehlers-Danlos syndrome, type VIIC Cutis laxa Cutis laxa Menkes disease Ehlers-Danlos syndrome, progeroid type 2 Ehlers-Danlos syndrome, progeroid type 1 Ehlers-Danlos syndrome, type I Ehlers-Danlos syndrome, type VIIA Ehlers-Danlos syndrome, type VIIB Ehlers-Danlos syndrome, type IV Ehlers-Danlos syndrome, type II Ehlers-Danlos syndrome, type I Ehlers-Danlos syndrome, type I Cutis laxa Cutis laxa Cutis laxa Marfan syndrome Contractural arachnodactyly, congenital Cutis laxa Ehlers-Danlos syndrome, type VI Cutis laxa Loeys-Dietz syndrome Loeys-Dietz syndrome Loeys-Dietz syndrome Loeys-Dietz syndrome Ehlers-Danlos syndrome, autosomal dominant, hypermobility type Ehlers-Danlos syndrome, autosomal recessive, due to tenascin-X deficiency Restrictive dermopathy, lethal
264800 225410 219150 219200 309400 615349 130070 130000 130060 130060 130050 130010 130000 130000 614437 123700 614434 154700 121050 613177 225400 614438 613795 608967 609192 608967 130020 606408 275210
AR AR AR AR XL AR AD AD AD AD AD AD AD AD AR AD AD/AR AD AD AR AR AR AD AD AD AD AD AR AR
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For abbreviations, see table 1.
Table 8. Dermal mosaics
Gene
Gene MIM No. Disease
Phenotype MIM No. Inheritance
AKT1 BRAF FGFR3 GNAQ
164730 164757 134934 600998
GNAS HRAS
139320 190020
176920 115150 162900 185300 163000 174800 162900 163200
IDH1 IDH2 KRAS MAP2K1 MAP2K2 NRAS PIK3CA PORCN PTEN PTPN11 SOX10 SPRED1 TSC1 TSC2
147700 147650 190070 176872 601263 164790 171834 300651 601728 176876 602229 609291 605284 191092
Proteus syndrome Cardiofaciocutaneous syndrome Naevus, epidermal, somatic Sturge-Weber syndrome Capillary malformations, congenital, 1, somatic, mosaic McCune-Albright syndrome Naevus, epidermal, somatic Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic Ollier disease/Maffucci syndrome Ollier disease/Maffucci syndrome Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic Cardiofaciocutaneous syndrome Cardiofaciocutaneous syndrome Naevus, epidermal, somatic Naevus, epidermal, somatic Focal dermal hypoplasia Linear PTEN naevus Leopard syndrome Giant melanocytic naevus Legius syndrome Tuberous sclerosis complex Tuberous sclerosis complex
163200 615279 615280 162900 162900 305600 158350 151100 611431 191100 613254
mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic
PTEN = Phosphatase and tensin homologue.
Table 9. Genodermatoses with tumour predisposition
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
AKT1 APC ATM AXIN2 BLM CYLD DDB2 DKC1 ERCC2 ERCC3 ERCC4 ERCC5 FERMT1 FH FLCN GTF2H5 MLH1 MPLKIP MSH2 MSH6 NF1 NF2 NHP2
164730 611731 607585 604025 604610 605018 600811 300126 126340 133510 133520 133530 607900 136850 607273 608780 120436 609188 609309 600678 613113 607379 606470
Cowden syndrome Gardner syndrome Ataxia-telangiectasia Ectodermal dysplasia and neoplastic syndrome Bloom syndrome Tricho-epithelioma, multiple familial Xeroderma pigmentosum, group E, DDB-negative subtype Dyskeratosis congenita Xeroderma pigmentosum, group D Xeroderma pigmentosum, group B Xeroderma pigmentosum, group F Xeroderma pigmentosum, group G Kindler syndrome Leiomyomatosis with or without renal cell cancer Birt-Hogg-Dubé syndrome Trichothiodystrophy MMR deficiency syndrome (Turcot syndrome) Trichothiodystrophy MMR deficiency syndrome (Turcot syndrome) MMR deficiency syndrome (Turcot syndrome) Neurofibromatosis, type 1 Neurofibromatosis, type 2 Dyskeratosis congenita, autosomal recessive 2
615109 175100 208900 608615 210900 601606 278740 305000 278730 610651 278760 278780 173650 150800 135150 601675 276300 234050 276300 276300 162200 101000 613987
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Monogenic Human Skin Disorders
AD AD AR AD AR AD AR XR AR AR AR AR AR AD AD AR AR AR AR AR AD AD AR
Table 9 (continued)
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
NOP10 NOTCH3 PDGFRB PIK3CA PMS2 POLH PRKAR1A PTCH1 PTCH2 PTEN RECQL4 RHBDF2 STK11 TERC TERT TINF2 TSC1 TSC2 WRAP53 WRN XPA XPC
606471 600276 173410 171834 600259 603968 188830 601309 603673 601728 603780 614404 602216 602322 187270 604319 605284 191092 612661 604611 611153 613208
Dyskeratosis congenita, autosomal recessive 1 Myofibromatosis, infantile, 2 Myofibromatosis, infantile, 1 Cowden syndrome MMR deficiency syndrome (Turcot syndrome) Xeroderma pigmentosum, variant type Carney complex type I Naevoid basal cell carcinoma syndrome (Gorlin syndrome) Familial basal cell carcinoma Cowden syndrome Rothmund-Thompson syndrome Tylosis with oesophageal cancer Peutz-Jeghers syndrome Dyskeratosis congenita, autosomal dominant 1 Dyskeratosis congenita, autosomal recessive 4 Dyskeratosis congenita, autosomal dominant 3 Tuberous sclerosis complex Tuberous sclerosis complex Dyskeratosis congenita, autosomal recessive 3 Werner syndrome Xeroderma pigmentosum, group A Xeroderma pigmentosum, group C
224230 615293 228550 615108 276300 278750 160980 109400 605462 158350 268400 148500 175200 127550 613989 613990 191100 613254 613988 277700 278700 278720
AR AD AD AD AR AR AD AD AD AD AR AD AD AD AR AD AD AD AR AR AR AR
AD = Autosomal dominant; AR = autosomal recessive; DDB = damage-specific DNA-binding protein; XR = X-chromosomal recessive; MMR = mismatch repair.
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genetics of human skin disorders or even serve as templates for the design of novel targeted next-generation sequencing tools.
References
1 Moss C: Dermatology and the human gene map. Br J Dermatol 1991;124:3–9. 2 Leech SN, Moss C: A current and online genodermatosis database. Br J Dermatol 2007;156: 1115–1148. 3 Feramisco JD, Sadreyev RI, Murray ML, Grishin NV, Tsao H: Phenotypic and genotypic analyses of genetic skin disease through the Online Mendelian Inheritance in Man (OMIM) database. J Invest Dermatol 2009; 129:2628–2636. 4 Rehm HL: Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet 2013; 14:295–300. 5 Scott CA, Plagnol V, Nitoiu D, Bland PJ, Blaydon DC, Chronnell CM, Poon DS, Bourn D, Gardos L, Csaszar A, et al: Targeted sequence capture and high-throughput sequencing in the molecular diagnosis of ichthyosis and other skin diseases. J Invest Dermatol 2013; 133: 573–576.
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is apparent to us and what is considered to meet current diagnostic criteria. On the other hand, oligosymptomatic or overlapping phenotypes may not fit into current classification schemes. In addition, the borders of ‘clinically affected’ and ‘subclinical carrier’ of a genetic disease may sometimes be blurred. Due to sometimes extensive heterogeneity of disorders as well as little specificity of phenotypic features, we believe that novel sequencing approaches such as targeted next-generation sequencing will help to simplify genotype-phenotype correlations and possibly revolutionize our understanding of phenotypes in human skin disorders towards a more gene-based classification. Previous work on genodermatosis databases has been an important step in this direction [1, 2]. We hope the provided overview represents a useful current and slightly modified update of this previous work comprehensively summarizing the existing knowledge on genotype-phenotype correlations of monogenic skin disorders. We hope our tables make the current genetic data more accessible to dermatologists and may arouse interest in the
Dermatology 2014;229:55–64 DOI: 10.1159/000362200
Monogenic Human Skin Disorders Johannes R. Lemke a, d Kristin Kernland-Lang b Konstanze Hörtnagel e Peter Itin c
a Division of Human Genetics, University Children’s Hospital Inselspital, and b Department of Dermatology and Pediatrics, University Hospital Inselspital, Bern, and c Department of Dermatology, University Hospital Basel, Basel, Switzerland; d Institute of Human Genetics, University Hospital of Leipzig, Leipzig, and e CeGaT GmbH, Tübingen, Germany
Key Words Human genodermatoses · Monogenic human skin disorders · Tabular database
Abstract Human genodermatoses represent a broad and partly confusing spectrum of countless rare diseases with confluent and overlapping phenotypes often impeding a precise diagnosis in an affected individual. High-throughput sequencing techniques have expedited the identification of novel genes and have dramatically simplified the establishment of genetic diagnoses in such heterogeneous disorders. The precise genetic diagnosis of a skin disorder is crucial for the appropriate counselling of patients and their relatives regarding the course of the disease, prognosis and recurrence risks. Understanding the underlying pathophysiology is a prerequisite to understanding the disease and developing specific, targeted or individualized therapeutic approaches. We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We hope this may represent a use-
© 2014 S. Karger AG, Basel 1018–8665/14/2292–0055$39.50/0 E-Mail [email protected] www.karger.com/drm
ful tool in guiding dermatologists towards genetic diagnoses, providing patients with individual knowledge on the respective disorder and applying novel research findings to clinical practice. © 2014 S. Karger AG, Basel
Introduction
The number of known genodermatoses has constantly risen in the past years. In 1991, Moss [1] described 90 regionally assigned cutaneous traits, and one and a half decades later this number increased to 580 [2]. Due to significant technical improvements over the past years and novel sequencing techniques, this number has further augmented. Similar to other monogenetic disorders, a certain genodermatosis can sometimes be caused by genetic defects in several genes (genetic heterogeneity), and on the other hand, different disorders sometimes share similar underlying genetic aberrations (allelic variants). However, more than 80% of genetic skin disorders seem to be Peter Itin Dermatologie, Universitätsspital Basel Petersgraben 4 CH–4031 Basel (Switzerland) E-Mail peter.itin @ usb.ch
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Gene
Gene MIM No.
Disease
Phenotype MIM No.
Inheritance
ABCA12
607800
ABHD5 ALDH3A2 ALOX12B ALOXE3 AP1S1 AQP5 ATP2A2
604780 609523 603741 607206 603531 600442 108740
ATP2C1 CDSN CERS3 CLDN1 COL14A1 CSTA CTSC CYP4F22 DKC1 DSG1 DSP EBP ELOVL4 ENPP1 ERCC2 ERCC3 FLG GJB2 GJB3 GJB4 GJB6 GTF2H5 JUP KRT1 KRT10 KRT16 KRT17 KRT2 KRT6A KRT6B KRT9 KRT9 LIPN LOR MBTPS2 MBTPS2 MPLKIP NHP2 NIPAL4 NOP10 NSDHL PKP1 PNPLA1 POMP
604384 602593 615276 603718 120324 184600 602365 611495 300126 125670 125647 300205 605512 173335 126340 133510 135940 121011 603324 605425 604418 608780 173325 139350 148080 148067 148069 600194 148041 148042 607606 607606 613924 152445 300294 300294 609188 606470 609383 606471 300275 601975 612121 613386
Ichthyosis, autosomal recessive 4B (harlequin) Ichthyosis, congenital, autosomal recessive 4A Chanarin-Dorfman syndrome Sjögren-Larsson syndrome Ichthyosis, congenital, autosomal recessive 2 Ichthyosis, congenital, autosomal recessive 3 MEDNIK syndrome Palmoplantar keratoderma, Bothnian type Acrokeratosis verruciformis Darier disease Hailey-Hailey disease Ichthyosis-hypotrichosis Autosomal recessive congenital ichthyosis ILVASC Keratoderma, palmoplantar, punctate type IB Exfoliative ichthyosis Papillon-Lefèvre syndrome Ichthyosis, congenital, autosomal recessive 5 Dyskeratosis congenita Striate palmoplantar keratoderma (PPKS1) Striate palmoplantar keratoderma (PPKS2) Chondrodysplasia punctata, X-linked dominant Ichthyosis, spastic quadriplegia and mental retardation Cole disease Trichothiodystrophy Trichothiodystrophy Ichthyosis vulgaris KID syndrome Erythrokeratodermia variabilis et progressiva Erythrokeratodermia variabilis with erythema gyratum repens Ectodermal dysplasia, Clouston type Trichothiodystrophy Naxos disease Ichthyosis, cyclic, with epidermolytic hyperkeratosis Ichthyosis, cyclic, with epidermolytic hyperkeratosis Pachyonychia congenita type I (Jadassohn-Lewandowsky syndrome) Pachyonychia congenita type II (Jackson-Lawler syndrome) Ichthyosis bullosa of Siemens Pachyonychia congenita type I (Jadassohn-Lewandowsky syndrome) Pachyonychia congenita type II (Jackson-Lawler syndrome) Epidermolytic palmoplantar keratoderma Epidermolytic palmoplantar keratoderma Ichthyosis, congenital, autosomal recessive 8 Vohwinkel syndrome (ichthyotic variant) IFAP syndrome with or without BRESHECK syndrome Keratosis follicularis spinulosa decalvans, X-linked Trichothiodystrophy, non-photosensitive 1 Dyskeratosis congenita, autosomal recessive 2 Ichthyosis, congenital, autosomal recessive 6 Dyskeratosis congenita, autosomal recessive 1 CHILD syndrome Ectodermal dysplasia/skin fragility syndrome Ichthyosis, congenital, autosomal recessive 10 Keratosis linearis with ichthyosis congenita and sclerosing keratoderma
242500 601277 275630 270200 242100 606545 609313 600231 101900 124200 169600 146520 615023 607626 614936 607936 245000 604777 305000 148700 612908 302960 614457
AR AR AR AR AR AR AR AD AD AD AD AD/AR AR AR AD AR AR AR XL AD AD XL AR AD AR AR AD AD AD AD AD AR AR AD AD AD AD AD AD AD AD AD AR AD XL XL AR AR AR AR XL AR AR AR
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601675 601675 146700 148210 133200 133200 129500 601675 601214 607602 607602 148067 167210 146800 167200 167210 144200 144200 613943 604117 308205 308800 234050 613987 612281 224230 308050 604536 615024 601952
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Table 1. Inherited ichthyoses/generalized Mendelian disorders of cornification
Table 1 (continued)
Gene
Gene MIM No.
Disease
Phenotype MIM No.
Inheritance
RHBDF2 SAT1 SERPINB7 SLC27A4 SLURP1 SMARCAD1 SNAP29 SPINK5 ST14 STS SUMF1 TAT TERC TERT TGM1 TGM5 TINF2 WRAP53
614404 313020 603357 604194 606119 612761 604202 605010 606797 300747 607939 613018 602322 187270 190195 603805 604319 612661
Tylosis with oesophageal cancer Keratosis follicularis spinulosa decalvans Palmoplantar keratosis, Nagashima type Ichthyosis prematurity syndrome Mal de Meleda Adermatoglyphia CEDNIK syndrome Netherton syndrome Ichthyosis with hypotrichosis Ichthyosis, X-linked Multiple sulphatase deficiency Richner-Hanhart syndrome, tyrosinaemia, type II Dyskeratosis congenita, autosomal dominant 1 Dyskeratosis congenita, autosomal recessive 4 Ichthyosis, congenital, autosomal recessive 1 Peeling skin syndrome, acral type Dyskeratosis congenita, autosomal dominant 3 Dyskeratosis congenita, autosomal recessive 3
148500 308800
AD XL AR AR AR AD AR AR AR XL AR AR AD AR AR AR AD AR
608649 248300 136000 609528 256500 610765 308100 272200 276600 127550 613989 242300 609796 613990 613988
AR = Autosomal recessive; AD = autosomal dominant; XL = X-linked; MEDNIK = mental retardation, enteropathy, deafness, neuropathy, ichthyosis and keratoderma; ILVASC = ichthyosis, leucocyte vacuoles, alopecia and sclerosing cholangitis; KID = keratitis, ichthyosis and deafness; IFAP = ichthyosis follicularis, alopecia and photophobia; BRESHECK = brain anomalies, retarda-
tion, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism and kidney dysplasia/hypoplasia; CHILD = congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CEDNIK = cerebral dysgenesis, neuropathy, ichthyosis and keratoderma.
caused by a single gene defect, and more than 80% of gene defects cause only one condition [3]. Still, the current genetic knowledge has only marginally found its way into clinical practice. This may partly be due to (1) the enormous amount of genetic data that may sometimes appear to be difficult to access, interpret and filter for relevant information, (2) inconsistencies in nomenclature of entities termed after phenotypic versus genotypic aspects, (3) a considerable challenge in establishing a clear clinical diagnosis due to often non-specific and overlapping phenotypes, and (4) the expected lack of direct therapeutic consequences after genetic testing in many cases. However, a precise genetic diagnosis can be of great help in counselling the patient and his family regarding prognosis and recurrence risks, and in some cases it may even guide therapy. Understanding the underlying genetic defect and its consecutive pathomechanisms is a first step in understanding the disease, enabling the development of individualized therapeutic approaches targeting the actual molecular defect. Beyond that, even the knowl-
edge of a currently incurable and maybe fatal diagnosis can help in preventing unnecessary and often stressful diagnostic procedures as well as futile therapeutic attempts. Thus, the knowledge of the patient’s genotype is becoming increasingly important with respect to therapeutic decisions and is superior to a purely clinical alignment of the phenotype.
We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We searched the literature using PubMed (http://www.ncbi.nlm. nih.gov/pubmed/) and OMIM (http://www.ncbi.nlm.nih.gov/ omim/) for information regarding genodermatoses. Only entities with a known monogenetic aetiology were included, entities with only linkage loci or complex or unknown genetic origin were disregarded. Furthermore, we excluded entities where skin manifestations are very rare, secondary (e.g. caused by haematological or immunological problems) or represent only a minor or insignificant symptom compared to other features of the disorder.
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Methods
Table 2. Genetic epidermolyses and blistering disorders
Gene
Gene Disease MIM No.
Phenotype InheriMIM No. tance
COL17A1 COL7A1
113811 120120
226650 226600 132000
DSP EXPH5 FERMT1 ITGA3 ITGA6 ITGB4
125647 612878 607900 605025 147556 147557
KRT1 KRT10 KRT5
139350 148080 148040
KRT14
148066
LAMA3
600805
LAMB3
150310
LAMC2
150292
PLEC1
601282
POFUT1 607491 POGLUT1 515618
Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa dystrophica, autosomal recessive Epidermolysis bullosa dystrophica, Bart type Epidermolysis bullosa dystrophica, localisata variant Epidermolysis bullosa dystrophica, autosomal dominant Epidermolysis bullosa dystrophica, autosomal recessive Epidermolysis bullosa pruriginosa Epidermolysis bullosa, pretibial Toenail dystrophy, isolated Transient bullous epidermolysis of the newborn Epidermolysis bullosa, lethal acantholytic Epidermolysis bullosa, non-specific, autosomal recessive Kindler syndrome Interstitial lung disease, nephritic syndrome and epidermolysis bullosa, congenital Epidermolysis bullosa, junctional, with pyloric stenosis Epidermolysis bullosa of hands and feet Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa, junctional, with pyloric atresia Ichthyosis, cyclic, with epidermolytic hyperkeratosis Ichthyosis, cyclic, with epidermolytic hyperkeratosis Dowling-Degos disease 1 Epidermolysis bullosa simplex with migratory circinate erythema Epidermolysis bullosa simplex with mottled pigmentation Epidermolysis bullosa simplex, Dowling-Meara type Epidermolysis bullosa simplex, Koebner type Epidermolysis bullosa simplex, Weber-Cockayne type Dermatopathia pigmentosa reticularis Epidermolysis bullosa simplex, Dowling-Meara type Epidermolysis bullosa simplex, Koebner type Epidermolysis bullosa simplex, recessive 1 Epidermolysis bullosa simplex, Weber-Cockayne type Naegeli-Franceschetti-Jadassohn syndrome Epidermolysis bullosa, generalized atrophic benign Epidermolysis bullosa, junctional, Herlitz type Laryngo-onychocutaneous syndrome Epidermolysis bullosa, junctional, Herlitz type Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa, junctional, Herlitz type Epidermolysis bullosa, junctional, non-Herlitz type Epidermolysis bullosa simplex with pyloric atresia Epidermolysis bullosa simplex, Ogna type Muscular dystrophy with epidermolysis bullosa simplex Dowling-Degos disease 1 Dowling-Degos disease
131750 226600 604129 131850 607523 131705 609638 615028 173650 614748 226730 131800 226650 226730 607602 607602 179850 609352 131960 131760 131900 131800 125595 131760 131900 601001 131800 161000 226650 226700 245660 226700 226650 226700 226650 612138 131950 226670 615327
AR AR AD AR AD AR AD/AR AD AD AD/AR AR AR AR AR AR AR AR AR AD AD AD AD AD AD AD AD AD AD AD AR AD AD AR AR AR AR AR AR AR AR AD AR AD AD
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For abbreviations, see table 1.
Table 3. Nuclear excision repair disorders
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
DDB2 ERCC1 ERCC2
600811 126380 126340
278740
ERCC3
133510
ERCC4 ERCC5 ERCC6
133520 133530 609413
ERCC8
609412
GTF2H5 MPLKIP POLH RECQL4 WRN XPA XPC
608780 609188 603968 603780 604611 611153 613208
Xeroderma pigmentosum, group E, DDB-negative subtype Xeroderma pigmentosum Xeroderma pigmentosum, group D Trichothiodystrophy Xeroderma pigmentosum, group B Trichothiodystrophy Xeroderma pigmentosum, group F Xeroderma pigmentosum, group G Cockayne syndrome, type B UV-sensitive syndrome 1 Cockayne syndrome, type A UV-sensitive syndrome 2 Trichothiodystrophy Trichothiodystrophy Xeroderma pigmentosum, variant type Rothmund-Thompson syndrome Werner syndrome Xeroderma pigmentosum, group A Xeroderma pigmentosum, group C
278730 601675 610651 601675 278760 278780 133540 600630 216400 614621 601675 234050 278750 268400 277700 278700 278720
AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR
DDB = Damage-specific DNA-binding protein; AR = autosomal recessive.
Table 4. Genetic disorders with hypo-and hyperpigmentations
Gene MIM No.
Disease
ADAM10 ADAR AP3B1 BLM BLOC1S3 BLOC1S6 BRAF C10ORF11 DTNBP1 EDN3 EDNRB ENPP1 HPS1 HPS3 HPS4 HPS5 HPS6 KIT MAP2K1 MAP2K2 MC1R MITF
602192 146920 603401 604610 609762 604310 164757 614537 607145 131242 131244 173335 604982 606118 606682 607521 607522 164920 176872 601263 155555 156845
MLH1 MLPH MSH2 MSH6
120436 606526 609309 600678
Reticulate acropigmentation of Kitamura Dyschromatosis symmetrica hereditaria Hermansky-Pudlak syndrome 2 Bloom syndrome Hermansky-Pudlak syndrome 8 Hermansky-Pudlak syndrome 9 Cardiofaciocutaneous syndrome Albinism, oculocutaneous, type VII Hermansky-Pudlak syndrome 7 Waardenburg syndrome, type 4B Waardenburg syndrome, type 4A Cole disease Hermansky-Pudlak syndrome 1 Hermansky-Pudlak syndrome 3 Hermansky-Pudlak syndrome 4 Hermansky-Pudlak syndrome 5 Hermansky-Pudlak syndrome 6 Piebaldism Cardiofaciocutaneous syndrome Cardiofaciocutaneous syndrome Oculocutaneous albinism, type II, modifier of Tietz albinism-deafness syndrome Waardenburg syndrome, type 2A MMR deficiency syndrome (Turcot syndrome) Griscelli syndrome, type 3 MMR deficiency syndrome (Turcot syndrome) MMR deficiency syndrome (Turcot syndrome)
Monogenic Human Skin Disorders
Phenotype MIM No.
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127400 608233 210900 614077 614171 115150 615579 614076 613265 277580 203300 614072 614073 614074 614075 172800 115150 115150 203200 103500 193510 276300 609227 276300 276300
Inheritance AD AD AR AR AR AR AD AR AR AR AR AD AR AR AR AR AR AD AD AD AD AD AD AR AR AR AR
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Gene
Table 4 (continued)
Gene
Gene MIM No.
Disease
Phenotype MIM No.
Inheritance
MYO5A NF1 NF2 OCA2
160777 613113 607379 611409
PAX3
606597
PMS2 PRKAR1A PTPN11 RAB27A RECQL4 SLC45A2 SNAI2
600259 188830 176876 603868 603780 606202 602150
SOX10 SPRED1 STK11 TYR
602229 609291 602216 606933
TYRP1
115501
Griscelli syndrome, type 1 Neurofibromatosis, type 1 Neurofibromatosis, type 2 Albinism, oculocutaneous, type II Albinism, brown oculocutaneous Waardenburg syndrome, type 1 Waardenburg syndrome, type 3 MMR deficiency syndrome (Turcot syndrome) Carney complex type I Leopard syndrome Griscelli syndrome, type 2 Rothmund-Thompson syndrome Oculocutaneous albinism, type IV Waardenburg syndrome, type 2D Piebaldism Waardenburg syndrome, type 4C Legius syndrome Peutz-Jeghers syndrome Albinism, oculocutaneous, type IA Albinism, oculocutaneous, type IB Albinism, oculocutaneous, type III
214450 162200 101000 203200 203200 193500 148820 276300 160980 151100 607624 268400 606574 608890 172800 613266 611431 175200 203100 606952 203290
AR AD AD AR AR AD AD/AR AR AD AD AR AR AR AR AR AR AD AD AR AR AR
AD = Autosomal dominant; AR = autosomal recessive; MMR = mismatch repair.
Table 5. Disorders of ectodermal appendages including ectodermal dysplasia
Gene
Gene MIM No.
Disease
Phenotype InheriMIM No. tance
ABCC9 ALMS1 APCDD1 ARHGAP31 AXIN2 BANF1 BCS1L CDH3 CYP26C1 DDX59 DLX3 DOCK6 DSC3 DSG4 DSP EDA EDAR EDARADD EFNB1 ERCC2 ERCC3 FOXN1 GJB6
601439 606844 607479 610911 604025 603811 603647 114021 608428 615464 600525 614194 600271 607892 125647 300451 604095 606603 300035 126340 133510 600838 604418
Cantú syndrome Alström syndrome Hypotrichosis simplex Adams-Oliver syndrome Ectodermal dysplasia and neoplastic syndrome Nestor-Guillermo progeria syndrome Bjørnstad syndrome Hypotrichosis with juvenile macular dystrophy Focal facial dermal dysplasia 4 Orofaciodigital syndrome V Trichodento-osseous syndrome Adams-Oliver syndrome Hypotrichosis and recurrent skin vesicles Hypotrichosis Skin fragility-woolly hair syndrome X-linked hypohidrotic ectodermal dysplasia (ED1) Ectodermal dysplasia, hypohidrotic Ectodermal dysplasia, hypohidrotic Craniofrontonasal dysplasia Trichothiodystrophy Trichothiodystrophy T-cell immunodeficiency, congenital alopecia and nail dystrophy Ectodermal dysplasia 2, Clouston type
239850 203800 605389 100300 608615 614008 262000 601553 614974 174300 190320 614219 613102 607903 607655 305100 224900 614941 304110 601675 601675 601705 129500
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AD AR AD AD AD AR AR AR AR AR AD AR AR AR AR XL AD AD XL AR AR AR AR
Table 5 (continued)
Gene
Gene MIM No.
Disease
Phenotype InheriMIM No. tance
HOXC13 HR HVEC IFT122 IFT43 IKBKG JUP KCTD1 KRT17
142976 602302 600644 606045 614068 300248 173325 613420 148069
KRT74 KRT75 KRT81 KRT83 KRT85 KRT86 LIPH LMNA LMX1B LPAR6
608248 609025 602153 602765 602767 601928 607365 150330 602575 609239
MSX1 PKP1 POC1A PORCN PVRL1 RBM28 RBPJ RMRP SNRPE SOX18 TP63 TRPS1 TWIST2 WDR35
142983 601975 614783 300651 600644 612074 147183 157660 128260 601618 603273 604386 607556 613602
Ectodermal dysplasia 9, hair/nail type Atrichia with 2 ocular lesions, also called congenital alopecia universalis Cleft lip/palate-ectodermal dysplasia syndrome Cranio-ectodermal dysplasia 1 Sensenbrenner syndrome Anhidrotic ectodermal dysplasia with immune deficiency Naxos disease Scalp-ear-nipple syndrome Steatocystoma multiplex Pachyonychia congenita, Jackson-Lawler type Woolly hair Pseudofolliculitis barbae Monilethrix Monilethrix Ectodermal dysplasia 4, hair/nail type Monilethrix Woolly hair Hutchinson-Gilford progeria Nail-patella syndrome Woolly hair Hypotrichosis 8 Ectodermal dysplasia 3, Witkop type Ectodermal dysplasia/skin fragility syndrome Short stature, onychodysplasia, facial dysmorphism and hypotrichosis syndrome Focal dermal hypoplasia Margarita Island type of ectodermal dysplasia (ED4) Alopecia, neurological defects and endocrinopathy syndrome Adams-Oliver syndrome Cartilage hair hypoplasia Hypotrichosis Hypotrichosis-lymphoedema-telangiectasia syndrome Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Trichorhinophalangeal syndrome, type I Focal facial dermal dysplasia 3, Setleis type Cranio-ectodermal dysplasia 2
614931 209500 225060 218330 614099 300291 601214 181270 184500 167210 194300 612318 158000 158000 602032 158000 604379 176670 161200 278150 278150 189500 604536 614813 305600 225060 612079 614814 250250 615059 607823 106260 190350 227260 613610
AR AR AR AR AR XL AR AD AD AD AD AD AD AD AR AD AR AD AD AR AR AD AR AR XL AR AR AD AR AD AD AD AD AR AR
Results
We summarized the genes according to their phenotypic spectra in tables 1–9.
Discussion
Historically, the classification of genodermatoses was based on clinical experience and a broad phenotypic knowledge of the treating physician. The OMIM database Monogenic Human Skin Disorders
is an important tool listing and describing phenotypes of Mendelian disorders as well as their known underlying genetic causes [3]. However, with respect to genodermatoses, its structure is often of limited use for diagnostic clinical purposes. Modern molecular genetics with novel high-throughput sequencing techniques have not only expedited the identification of countless disease-causing genes, it has also led to a widening of the associated phenotypes in various entities [4, 5]. We learned that the phenotypic spectrum of an individual disorder might go far beyond what Dermatology 2014;229:55–64 DOI: 10.1159/000362200
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For abbreviations, see table 1.
Table 6. Vascular disorders
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
ACVRL1 C1NH C7ORF22 ENG FLT4 FOXC2 GDF2 GLMN GNAQ
601284 606860 607929 131195 136352 602402 605520 601749 600998
KRIT1 PDCD10 RASA1
604214 609118 139150
TEK
600221
Telangiectasia, hereditary haemorrhagic, type 2 Angio-oedema, hereditary, types I and II Cerebral cavernous malformations Telangiectasia, hereditary haemorrhagic, type 1 Hereditary lymphoedema type I Lymphoedema-distichiasis syndrome Telangiectasia, hereditary haemorrhagic, type 5 Glomuvenous malformations (glomangiomas) Sturge-Weber syndrome Capillary malformations, congenital, 1, somatic, mosaic Cerebral cavernous malformations Cerebral cavernous malformations Capillary malformation-arteriovenous malformation Parkes Weber syndrome Venous malformations, multiple cutaneous and mucosal
600376 106100 603284 187300 153100 153400 615506 138000 185300 163000 116860 603285 608354 608355 600195
AD AD AD AD AD AD AD AD mosaic mosaic AD AD AD AD AD
AD = Autosomal dominant. Table 7. Connective tissue defects
Gene
Gene MIM No.
Disease
Phenotype Inheritance MIM No.
ABCC6 ADAMTS2 ALDH18A1 ATP6V0A2 ATP7A B3GALT6 B4GALT7 COL1A1
603234 604539 138250 611716 300011 615291 604327 120150
COL1A2 COL3A1 COL5A1
120160 120180 120215
COL5A2 EFEMP2 ELN FBLN5 FBN1 FBN2 LTBP4 PLOD1 PYCR1 SMAD3 TGFB2 TGFBR1 TGFBR2 TNXB
120190 604633 130160 604580 134797 612570 604710 153454 179035 603109 190220 190181 190182 600985
ZMPSTE24
606480
Pseudoxanthoma elasticum Ehlers-Danlos syndrome, type VIIC Cutis laxa Cutis laxa Menkes disease Ehlers-Danlos syndrome, progeroid type 2 Ehlers-Danlos syndrome, progeroid type 1 Ehlers-Danlos syndrome, type I Ehlers-Danlos syndrome, type VIIA Ehlers-Danlos syndrome, type VIIB Ehlers-Danlos syndrome, type IV Ehlers-Danlos syndrome, type II Ehlers-Danlos syndrome, type I Ehlers-Danlos syndrome, type I Cutis laxa Cutis laxa Cutis laxa Marfan syndrome Contractural arachnodactyly, congenital Cutis laxa Ehlers-Danlos syndrome, type VI Cutis laxa Loeys-Dietz syndrome Loeys-Dietz syndrome Loeys-Dietz syndrome Loeys-Dietz syndrome Ehlers-Danlos syndrome, autosomal dominant, hypermobility type Ehlers-Danlos syndrome, autosomal recessive, due to tenascin-X deficiency Restrictive dermopathy, lethal
264800 225410 219150 219200 309400 615349 130070 130000 130060 130060 130050 130010 130000 130000 614437 123700 614434 154700 121050 613177 225400 614438 613795 608967 609192 608967 130020 606408 275210
AR AR AR AR XL AR AD AD AD AD AD AD AD AD AR AD AD/AR AD AD AR AR AR AD AD AD AD AD AR AR
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For abbreviations, see table 1.
Table 8. Dermal mosaics
Gene
Gene MIM No. Disease
Phenotype MIM No. Inheritance
AKT1 BRAF FGFR3 GNAQ
164730 164757 134934 600998
GNAS HRAS
139320 190020
176920 115150 162900 185300 163000 174800 162900 163200
IDH1 IDH2 KRAS MAP2K1 MAP2K2 NRAS PIK3CA PORCN PTEN PTPN11 SOX10 SPRED1 TSC1 TSC2
147700 147650 190070 176872 601263 164790 171834 300651 601728 176876 602229 609291 605284 191092
Proteus syndrome Cardiofaciocutaneous syndrome Naevus, epidermal, somatic Sturge-Weber syndrome Capillary malformations, congenital, 1, somatic, mosaic McCune-Albright syndrome Naevus, epidermal, somatic Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic Ollier disease/Maffucci syndrome Ollier disease/Maffucci syndrome Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic Cardiofaciocutaneous syndrome Cardiofaciocutaneous syndrome Naevus, epidermal, somatic Naevus, epidermal, somatic Focal dermal hypoplasia Linear PTEN naevus Leopard syndrome Giant melanocytic naevus Legius syndrome Tuberous sclerosis complex Tuberous sclerosis complex
163200 615279 615280 162900 162900 305600 158350 151100 611431 191100 613254
mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic mosaic
PTEN = Phosphatase and tensin homologue.
Table 9. Genodermatoses with tumour predisposition
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
AKT1 APC ATM AXIN2 BLM CYLD DDB2 DKC1 ERCC2 ERCC3 ERCC4 ERCC5 FERMT1 FH FLCN GTF2H5 MLH1 MPLKIP MSH2 MSH6 NF1 NF2 NHP2
164730 611731 607585 604025 604610 605018 600811 300126 126340 133510 133520 133530 607900 136850 607273 608780 120436 609188 609309 600678 613113 607379 606470
Cowden syndrome Gardner syndrome Ataxia-telangiectasia Ectodermal dysplasia and neoplastic syndrome Bloom syndrome Tricho-epithelioma, multiple familial Xeroderma pigmentosum, group E, DDB-negative subtype Dyskeratosis congenita Xeroderma pigmentosum, group D Xeroderma pigmentosum, group B Xeroderma pigmentosum, group F Xeroderma pigmentosum, group G Kindler syndrome Leiomyomatosis with or without renal cell cancer Birt-Hogg-Dubé syndrome Trichothiodystrophy MMR deficiency syndrome (Turcot syndrome) Trichothiodystrophy MMR deficiency syndrome (Turcot syndrome) MMR deficiency syndrome (Turcot syndrome) Neurofibromatosis, type 1 Neurofibromatosis, type 2 Dyskeratosis congenita, autosomal recessive 2
615109 175100 208900 608615 210900 601606 278740 305000 278730 610651 278760 278780 173650 150800 135150 601675 276300 234050 276300 276300 162200 101000 613987
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Monogenic Human Skin Disorders
AD AD AR AD AR AD AR XR AR AR AR AR AR AD AD AR AR AR AR AR AD AD AR
Table 9 (continued)
Gene
Gene MIM No.
Disease
Phenotype MIM No. Inheritance
NOP10 NOTCH3 PDGFRB PIK3CA PMS2 POLH PRKAR1A PTCH1 PTCH2 PTEN RECQL4 RHBDF2 STK11 TERC TERT TINF2 TSC1 TSC2 WRAP53 WRN XPA XPC
606471 600276 173410 171834 600259 603968 188830 601309 603673 601728 603780 614404 602216 602322 187270 604319 605284 191092 612661 604611 611153 613208
Dyskeratosis congenita, autosomal recessive 1 Myofibromatosis, infantile, 2 Myofibromatosis, infantile, 1 Cowden syndrome MMR deficiency syndrome (Turcot syndrome) Xeroderma pigmentosum, variant type Carney complex type I Naevoid basal cell carcinoma syndrome (Gorlin syndrome) Familial basal cell carcinoma Cowden syndrome Rothmund-Thompson syndrome Tylosis with oesophageal cancer Peutz-Jeghers syndrome Dyskeratosis congenita, autosomal dominant 1 Dyskeratosis congenita, autosomal recessive 4 Dyskeratosis congenita, autosomal dominant 3 Tuberous sclerosis complex Tuberous sclerosis complex Dyskeratosis congenita, autosomal recessive 3 Werner syndrome Xeroderma pigmentosum, group A Xeroderma pigmentosum, group C
224230 615293 228550 615108 276300 278750 160980 109400 605462 158350 268400 148500 175200 127550 613989 613990 191100 613254 613988 277700 278700 278720
AR AD AD AD AR AR AD AD AD AD AR AD AD AD AR AD AD AD AR AR AR AR
AD = Autosomal dominant; AR = autosomal recessive; DDB = damage-specific DNA-binding protein; XR = X-chromosomal recessive; MMR = mismatch repair.
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genetics of human skin disorders or even serve as templates for the design of novel targeted next-generation sequencing tools.
References
1 Moss C: Dermatology and the human gene map. Br J Dermatol 1991;124:3–9. 2 Leech SN, Moss C: A current and online genodermatosis database. Br J Dermatol 2007;156: 1115–1148. 3 Feramisco JD, Sadreyev RI, Murray ML, Grishin NV, Tsao H: Phenotypic and genotypic analyses of genetic skin disease through the Online Mendelian Inheritance in Man (OMIM) database. J Invest Dermatol 2009; 129:2628–2636. 4 Rehm HL: Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet 2013; 14:295–300. 5 Scott CA, Plagnol V, Nitoiu D, Bland PJ, Blaydon DC, Chronnell CM, Poon DS, Bourn D, Gardos L, Csaszar A, et al: Targeted sequence capture and high-throughput sequencing in the molecular diagnosis of ichthyosis and other skin diseases. J Invest Dermatol 2013; 133: 573–576.
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is apparent to us and what is considered to meet current diagnostic criteria. On the other hand, oligosymptomatic or overlapping phenotypes may not fit into current classification schemes. In addition, the borders of ‘clinically affected’ and ‘subclinical carrier’ of a genetic disease may sometimes be blurred. Due to sometimes extensive heterogeneity of disorders as well as little specificity of phenotypic features, we believe that novel sequencing approaches such as targeted next-generation sequencing will help to simplify genotype-phenotype correlations and possibly revolutionize our understanding of phenotypes in human skin disorders towards a more gene-based classification. Previous work on genodermatosis databases has been an important step in this direction [1, 2]. We hope the provided overview represents a useful current and slightly modified update of this previous work comprehensively summarizing the existing knowledge on genotype-phenotype correlations of monogenic skin disorders. We hope our tables make the current genetic data more accessible to dermatologists and may arouse interest in the
