Autosomal Dominant Skin Disorder Research Articles

Dermoscopy in Darier Disease: A Missing Link in an Unusual Hyperkeratotic Disorder

Darier disease is a rare autosomal dominant skin disorder resulting from mutation of the ATP2A2 gene on chromosome 12. Its progressive course makes its precise diagnosis crucial for a good prognosis. A 60-year-old female presented with multiple non-itchy papules over the face, trunk, and extremities since childhood and photosensitivity with similar lesions in the mother and two elder sisters. Examination revealed skin-coloured-to-hyperpigmented, firm and greasy papules with cobblestone appearance. Dirty yellowish-white wart-like lesions were noted over the toes. Histopathology revealed parakeratosis, papillomatosis, suprabasal acantholysis, and cleft with corps rounds in the granular layer. Dermoscopy revealed cobblestone appearance of the toes with tire-tread and cracked river-bed-like appearance and nails showing palmar hemorrhages and V-shaped nicking. The patient was diagnosed with Darier disease and treated accordingly. Uniquely, the cobblestone appearance was noted first over the dorsa of hands and feet. Dermoscopy may be used diagnose the disease while awaiting histopathological evidence.

Darier Disease with Acrokeratosis Verruciformis of Hopf and their Aggravation on Lithium Therapy for Bipolar Disorder

Abstract Darier disease (DD) and acrokeratosis verruciformis of Hopf are rare autosomal dominant skin disorders. Both are caused by a single gene mutation, i.e., ATP2A2 located on chromosome 12, which is expressed in the skin and brain. However, both the diseases are clinically and histopathologically distinct. DD is associated with many neuropsychiatric conditions such as depression, bipolar disorder (BPD), and seizures. Lithium is commonly used as a mood stabilizer in psychiatry and is reported to aggravate DD. We report a case of a 17-year-old female with DD and acrokeratosis verruciformis with associated with BPD Type 1 presenting with an aggravation of skin lesions after starting lithium therapy.

277 Human iPSC-derived-keratinocytes, a new useful model to identify and explore pathological phenotype of Epidermolysis Bullosa Simplex

Epidermolysis Bullosa Simplex (EBS), an autosomal dominant skin disorder, is characterized by skin fragility. Genetically, majority of cases are related to missense mutations in two keratin genes, KRT5 or KRT14, leading to cytolysis of basal keratinocytes and intraepidermal blistering. Progress towards identification of treatments have been hampered by incomplete understanding of the mechanisms underlying this disease, and availability of relevant and reliable in vitro models recapitulating the physiopathological mechanisms.

Hailey-Hailey Disease Treated with Individualised Homoeopathy—An Evidence-Based Case Report

AbstractHailey-Hailey disease (HHD) is a rare autosomal dominant skin disorder presented as blistering dermatosis with recurrent erythematous plaques, leading to erosions, fissures and vegetations seen in the skin folds. Prevalence of this disease occurs in 1 to 4 per 100,000 affected between third and fourth decade, mostly either under-reported or misdiagnosed. Under standard conventional treatment, recurrence and remissions are typical. Therefore, it affects the quality of life compared with other skin disorders. However, with the individualised homoeopathic medicine, Psorinum, this rare case was treated without topicals; no recurrence of the complaints and adverse effects were observed in 1 year of follow-up. Furthermore, changes in the dermatology life quality of life questionnaire score from 20 (at baseline) to zero have been noticed; the modified Naranjo criteria for homeopathy total score was +9 out of +13, providing evidence attributed by the intervention. This case report reinforces that individualised homoeopathic intervention is beneficial in rare skin disorders like HHD, and pooling such data will develop future research concepts in this area.

Impaired calcium signalling and neuropsychiatric disorders in Darier disease: An exploratory review.

Darier (Darier-White) disease (DD) is an autosomal dominant skin disorder caused by pathogenic mutations in the ATP2A2 gene which encodes a calcium ATPase in the sarco-endoplasmic reticulum (SERCA2). Defects in the SERCA2 protein lead to an impairment of cellular calcium homeostasis, which in turn, triggers cell death pathways. There is a high prevalence of neuropsychiatric disorders in patients affected by this condition, namely intellectual disability, bipolar disorder, schizophrenia, and suicidality. Though these associations have been well-documented over the years, little has been discussed or investigated regarding the pathophysiological mechanisms. The goal of this article is to review the literature related to the most commonly associated neuropsychiatric disorders found in patients with DD, highlight the pathophysiological mechanisms underlying each condition, and examine potential interventions that may be of interest for future development. A literature search was performed using PubMed to access and review relevant articles published in the last 40 years. Keywords searched included Darier disease neuropsychiatric, Darier disease pathophysiology, SERCA2 central nervous system, SERCA 2 skin, ATP2A2 central nervous system, ATP2A2 skin, sphingosine-1-phosphate signalling skin, sphingosine-1-phosphate signalling central nervous system, P2X7 receptor skin, and P2X7 receptor central nervous system. Our search resulted in 2692 articles, of which 61 articles were ultimately included in this review.

406 Modulation of calcium channel activity in Darier’s disease keratinocytes improves disease phenotypes

Darier’s disease (DD) is an autosomal dominant skin disorder characterized by acantholysis and dyskeratosis associated with mutations in ATP2A2 encoding for the sarco/endoplasmic reticulum Ca2+-ATPase pump type 2 (SERCA2), resulting in patients being functionally haploinsufficient for SERCA2. DD keratinocytes displayed a 1.5-fold increase in Ca2+ levels above that observed in control keratinocytes. This Ca2+ imbalance negatively influenced localization of protein constituents of the cell-cell adhesive junction, the desmosome, resulting in decreased desmosome function and loss of epidermal integrity.

Human-Induced Pluripotent Stem Cell‒Derived Keratinocytes, a Useful Model to Identify and Explore the Pathological Phenotype of Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex (EBS), an autosomal dominant skin disorder, is characterized by skin fragility. Genetically, the majority of cases are related to missense sequence variations in two keratin genes K5 or K14, leading to cytolysis of basal keratinocytes (KCs) and intraepidermal blistering. Progress toward the identification of treatments has been hampered by an incomplete understanding of the mechanisms underlying this disease and availability of relevant and reliable invitro models recapitulating the physiopathological mechanisms. Recent advances in stem cell field have fueled the prospect that these limitations could be overcome, thanks to the availability of disease-specific human induced pluripotent stem cells (hiPSCs). In this study, we generated hiPSC-derived KCs from patients carrying keratin gene K5-dominant sequence variations and compared them with nonaffected hiPSC-derived KCs as well as their primary counterparts. Our results showed that EBS hiPSC-derived KCs displayed proliferative defects, increased capacity to migrate, alteration of extracellular signal‒regulated kinase signaling pathway, and cytoplasmic keratin filament aggregates as observed in primary EBS KCs. Of interest, EBS hiPSC-derived KCs exhibited downregulation of hemidesmosomal proteins, revealing the different effects of keratin gene K5 sequence variations on keratin cytoskeletal organization. With a combination of culture miniaturization and treatment with the chaperone molecule 4-phenylbutyric acid, our results showed that hiPSC-derived KCs represent a suitable model for identifying novel therapies for EBS.

The c.323 G>C mutation in LORICRIN causes new-found late-onset autosomal dominant loricrin keratoderma in a Chinese Han Pedigree

BackgroundLoricrin keratoderma is a rare early-onset autosomal dominant skin disorder. At present, no clinical reports have been published on characteristics of progressive aggravation and late-onset. ObjectivesTo identified a new-found pedigree with c.323 G>C mutation leading to progressive aggravation and late-onset loricrin keratoderma. MethodsTargeted next-generation sequencing of 267 genes associated with all skin abnormalities, sanger sequencing, and bioinformatics tools were used to identify the mutation in this new-found pedigree. Palm skin biopsy was used to observe the clinicopathological features of patient. Further, we constructed pcDNA3.1/V5-His-wild-LORICRIN, pcDNA3.1/V5-His-c.323G>C-LORICRIN, and pcDNA3.1/V5-His-730insG-LORICRIN vectors, nucleofected into HaCaT strain to observe the subcellular localization of loricrin by using the laser scanning confocal microscopy. ResultsThe proband and his affected father carried a heterozygous c.323 G>C missense mutation (p.Gly108Ala) on LORICRIN. Bioinformatics analysis hinted that it had potential pathogenicity; the types of ligands, enzyme commission active sites, and the spatial structure of protein changed enormously. Laser scanning confocal microscopy showed that the signals from cells transfected with the pcDNA3.1/V5-His-730insG-LORICRIN vector were distributed mainly in the nucleus, whereas those from cells transfected with the pcDNA3.1/V5-His-c.323G>C-LORICRIN vector were mainly located in the cytoplasm. Wild type loricrin was distributed in the nucleus and cytoplasm homogeneously ConclusionThe heterozygous c.323G>C missense mutation on LORICRIN caused late-onset and progressive loricrin keratoderma in this large Chinese family. Our study revealed that a large number of loricrin gathered in the cytoplasm may disturb the normal proliferation and terminal differentiation of keratinocytes and lead to the late-onset loricrin keratoderma disease.

Identification of Two Novel Frameshift Mutations of the ADAR1 Gene in Two Chinese Families With Dyschromatosis Symmetrica Hereditaria.

Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant skin disease. The mutation of the ADAR1 gene is the pathogenesis of this disorder. This study aimed to identify the mutations of the ADAR1 gene in two Chinese families with DSH. Eight patients from two Chinese families were diagnosed with DSH clinically. Blood samples were collected from the patients and unaffected individuals. Sanger sequencing for all polymerase chain reaction products of the whole coding regions of the ADAR1 gene was performed to identify the mutations. Mutation Taster software was used to predict the impact of the variant on the resultant protein. The c.3358-3359insT (p.L1053fs-1092X) mutation in exon 12 was found in affected members of the pedigree1. In pedigree2, the c.3820-3821insG (p.G1207fs-1213X) mutation in exon 15 was found. These two mutations were not found in 100 unrelated healthy people. In this study, both mutations were damaged by the Mutation Taster software. We identified two novel frameshift mutations in the ADAR1 gene. Our study expands the database of ADAR1 gene mutations in DSH.

Progressive Osseous Heteroplasia is not an Autosomal Dominant Trait but Reflects Superimposed Mosaicism in Different GNAS Inactivation Disorders.

Progressive osseous heteroplasia (POH) is a rarely occurring genetic condition characterized by severe segmental ossification involving the skin and deep connective tissues including the muscles. So far, the disorder is generally described as an autosomal dominant trait. By contrast, the following arguments are in favor of the alternative concept that POH should rather be taken as a non-specific segmental manifestation of different GNAS inactivation disorders such as Albright hereditary osteodystrophy (AHO) with hormone resistance, AHO without hormone resistance, and osteomatosis cutis. Presently, POH has got its own OMIM number 166350 but this is obviously wrong because the disorder does not reflect heterozygosity for a GNAS mutation. Conversely, the disorder is most likely due to an early event of postzygotic loss of heterozygosity with loss of the corresponding wild-type allele. This alternative concept, as proposed in 2016, offers a plausible explanation for the following features of POH. Familial occurrence is usually absent. POH is usually observed in families with one of the three GNAS inactivation disorders as mentioned above. Mosaicism is suggested by the pronounced segmental manifestation of POH and by its lateralization. Some patients have, in addition to POH, bilaterally disseminated features of osteomatosis cutis or AHO, and other patients have family members with one of these nonsegmental disorders. Remarkably, POH tends to appear much earlier than the nonsegmental GNAS inactivation disorders. – Molecular support of the concept was documented in a superficial variant of POH called 'plate-like osteoma cutis'. In several other autosomal dominant skin disorders, molecular corroboration of the theory of superimposed mosaicism has been provided. – For all of these reasons, it is unlikely that POH can further be taken as a distinct autosomal dominant trait. Generation of more molecular data in multiple cases of POH occurring in GNAS inactivation disorders will be crucial to corroborate the proposed concept.

18781 A familial case of white sponge nevus and review of the literature

White sponge nevus (WSN) is an autosomal dominant skin disorder characterized by white corrugated and diffuse plaques mainly affecting the non-keratinised stratified squamous epithelium. Although WSN is usually seen in the oral mucosa, other sites, such as the nasal, esophageal, laryngeal, and anogenital mucosa, may also be involved. We describe a case a 11-year-old girl who presented with asymptomatic rough, diffuse, white patches in the bilateral buccal mucosa gingiva with extension to the esophagus that was evident on esophageal gastroduodenoscopy. A biopsy of esophageal tissue confirmed the presence of WSN. Her father had a similar biopsy-proven but more widespread appearance in the buccal mucosa and esophagus as well. WSN is caused by germline variants of the keratin genes KRT4 or KRT13, located, respectively, at chromosomes 12q13 and 17q21-q22. Extra-oral affected sites have been shown to arise only from KRT13 variants. It is important to recognize this benign entity and to differentiate it from other acquired causes of intra-oral white plaques such as leukoplakia, candidiasis and lichen planus. A thorough history and physical examination would help to exclude other genodermatoses like pachyonychia congenita, hereditary benign intraepithelial dyskeratosis, Darier disease, and dyskeratosis congenita.

A Novel Small Deletion in the ATP2A2 Gene in a Patient with Sporadic Darier's Disease and Concomitant Depression: A Case Report

Abstract Introduction: Darier's disease is a rare autosomal dominant skin disorder caused by mutations in ATP2A2. Recently, the high prevalence of neuropsychiatric symptoms is frequently reported in Darier's disease patients. We present a case of patient with concurrence of Darier's disease and depression and detected the mutations in ATP2A2. Case presentation: A 29-year-old man presented with a 15-year history of brown, harsh keratotic papules on his scalp, face, neck, trunk, axilla, ingunia and upper limbs. Meanwhile, he had persistent depression. He was diagnosed as Darier's disease according to clinical manifestations and result of histological examination. We sequenced all coding regions of ATP2A2. The mutation c.2993_2994del (p. Val998Alafs∗33) in exon 20 of ATP2A2 was detected. Discussion: Darier's disease has been associated with several extracutaneous manifestations, in particular neuropsychiatric morbidity. Likely gene disrupting mutations in ATP2A2 was reported to have a close relationship to Darier's disease cases with reported co-occurring neuropsychiatric features. Consistent with the previous reports, an likely gene disrupting mutations was detected in our patient with concurrence of DD and depression. Conclusion: The psychiatric disorders in patients with Darier's disease should be well appreciated .The underlying mechanism in correlation between the mutation in ATP2A2 and neuropsychiatric phenotypes in Darier's disease remain unclarified and warrants further investigation.

Oral White Sponge Nevus: An Exceptional Differential Diagnosis in Childhood

White sponge nevus is an autosomal dominant skin disorder characterized by white, irregular, diffuse plaques mainly affecting the oral mucosa. Histological findings of white sponge nevus are characteristic but not pathognomonic. We report a case of an oral white sponge nevus in a 6-year-old girl, which poses a problem in differential diagnosis with oral candidiasis. No treatment was performed because of the benign and asymptomatic nature of the lesions.

AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer.

Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles. PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations. It has been suggested that PPPK1 may be associated with an increased predisposition to systemic malignancies. To evaluate the presence of AAGAB mutations in Canadian families with PPPK1 and the possible increased predisposition to systemic malignancies. Eighteen unrelated Canadian families with PPPK1 were recruited for this study. Genomic DNA was extracted from saliva and PCR amplification was performed for all AAGAB exons and exon/intron junctions. PCR products were sequenced and analyzed for mutations. A family history of malignancy was obtained from the index case and, when possible, from other family members. We have identified 5 heterozygous AAGAB loss of function mutations in 11 families. The mutation c.370 C>T, p.Arg124* was the most prevalent and was identified in 6 families. A splice site mutation, c.451+3delAAGT, was identified in 2 families. The other mutations c.473delG, p.Gly158Glufs*0; c.550-551insAAT, p.Gly183*; and c.505-506 dupAA, p.Asn169Lysfs*6 were each identified in 1 family. Different cancers were reported in 11 families (Table 1 and Supplemental Figure S1). AAGAB mutations were found in 11 of 18 families with PPPK1. In some families there appears to be an association with cancer.

Seven novel mutations of ADAR in multi-ethnic pedigrees with dyschromatosis symmetrica hereditaria in China.

BackgroundDyschromatosis symmetrica hereditaria (DSH;OMIM: #127400) is a rare autosomal dominant skin disease of hyperpigmented and hypopigmented macules on the dorsal aspects of the feet and hands. The adenosine deaminase RNA‐Specific (ADAR;OMIM: *146920) gene was identified as causing DSH. Although more than 200 mutations are reported, no research has included the pedigrees of ethnic minorities in China. To investigate clinical features and genetic factors among multi‐ethnic families, seven multi‐ethnic pedigrees with DSH were collected for analysis of hereditary characteristics and ADAR mutations.MethodsAll 15 exons and exon–intron sequences of the ADAR gene were amplified and Sanger sequenced from 25 patients and 36 normal controls from seven multi‐ethnic DSH families with 100 healthy normal controls. Seven mutations were analyzed by Polyphen 2, SIFT and Provean. All mutations in ADAR with DSH were reviewed and genetic and clinical features were summarized for analysis. The ADEAMc domain may be a hot spot of ADAR mutations among patients with DSH.ResultsSeven novel mutations were identified in seven multi‐ethnic pedigrees: c.497delA(p.Arg105fs), c.3352C>T(p.Gln1058*) and c.3722delT(p.Ser1181fs) were found in three Uygur families with DSH; c.1330A>G(p.Val332Met) and c.2702A>T(p.His841Leu) were found in two Kazakh pedigrees and c.1176G>A(p.Lys326Glu) and c.2861G>A(p.Arg892His) in two Hui pedigrees. We summarized 203 different mutations of ADAR from people with DSH.ConclusionsSeven novel mutations were identified in seven multi‐ethnic families with DSH. Our study expands the genetic spectrum of ADAR mutations in DSH.

Altered levels of focal adhesion and extracellular matrix-receptor interacting proteins were identified in Hailey-Hailey disease by quantitative iTRAQ proteome analysis.

Benign chronic familial pemphigus or Hailey-Hailey disease (HHD, OMIM 169600) is a rare, autosomal dominant blistering skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. To date, the proteomic changes in skin lesions from HHD patients has not been reported yet. In this study, a sample of skin lesions from HHD patients was collected for isobaric tags for relative and absolute quantitation to analyze proteome changes compared with unaffected individuals. The 134 differentially expressed proteins were assigned to at least one Gene Ontology term, and 123 annotated proteins with significant matches were assigned to 187 known metabolic or signaling pathways listed in the Kyoto Encyclopedia of Genes and Genomes. Most of the altered proteins in skin lesions of HHD patients were enriched in pathways involved in the PI3K-Akt signaling, focal adhesion, extracellular matrix (ECM)-receptor interaction, and protein digestion and absorption, such as collagen family members, microfibril-associated glycoprotein 4 and plakophilin. The changes of proteins related to cell adhesion, ECM-receptor interaction, and protein folding and glycosylation suggested that strategy targeted to alter cell junction and extracellular microenvironment might provide a potential treatment for HHD.

Genotype-phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype.

Darier disease (DD) is an autosomal dominant skin disorder caused by mutations in ATP2A2 encoding the sarco/endoplasmic reticulum Ca2+ ATPase Isoform 2 (SERCA2). Evidence of a population-level association between DD and psychiatric disorders suggests that mutations in ATP2A2 may have pleiotropic effects on the brain as well as skin. Evidence of genotype-phenotype relationships between ATP2A2 mutations and neuropsychiatric phenotypes would further support this suggestion. We investigated genotype-phenotype correlations between lifetime neuropsychiatric features and ATP2A2 mutation type (dichotomized into likely gene disrupting [LGD] or protein altering) in 75 unrelated individuals with DD. We also looked for evidence of clustering of mutations within SERCA2 according to neuropsychiatric features. Combining our data with the existing literature, the rate of LGD mutations was found to be significantly higher among DD cases/families with bipolar disorder, schizophrenia, or affective psychosis (p = .011). We also found a significant relationship between mutations located in the S4-M4 region of the protein and the presence of a severe neuropsychiatric phenotype (p = .032). Our findings add support to the hypothesis that Darier-causing mutations in ATP2A2 confer susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness. This, together with evidence from research on common polymorphisms confirms ATP2A2 as a gene at which variation influences susceptibility to major psychiatric illness.

Archetypical Patterns of Skin Manifestations in Neurocutaneous Disorders

AbstractThe distribution of the cutaneous manifestations in neurocutaneous disorders is not casual; rather, it reflects predetermined patterns of skin arrangements, due to the action of the underlying genes, proteins, and/or metabolic pathways on the skin texture and appendages. These patterns of distribution are pathognomonic for each neurocutaneous disorder and can occur either in specific areas of the body (e.g., the forehead, the face, the trunk, the nails, one limb or one of more segments of the body) or following specific lines (e.g., lines of Blaschko) or taking peculiar shapes (e.g., leaf-like, ovoid, whorled, “S” or “V” shaped). These patterns of abnormal skin often mirror similar phenomena in extra-cutaneous organs/tissues, principally in the central nervous system but also in the eye, bone, heart/vessels, lung, kidney, and gut. A classification system, including several patterns of cutaneous arrangements (archetypical patterns) was proposed by the German dermatologist Rudolf Happle in 1993 and later expanded until 2014: this classification, originally meant to broadly explain (genetic and nongenetic) mosaic skin disorders and phenomena, was later expanded to explain the patterns of distribution of skin manifestations in some autosomal dominant skin disorders (genodermatoses). Currently, we recognize: (1) six archetypical patterns, including type 1 “along the lines of Blaschko” in (a) narrow or (b) large bands, type 2 “checkerboard” pattern, type 3 “phylloid” pattern, type 4 “patchy pattern without midline separation,” type 5 “lateralization” pattern, and type 6 “sash-like” pattern; (2) three less well-defined (so far unclassifiable) archetypical patterns, including (a) a diffuse hypopigmentation of the trunk versus smaller areas of normal skin on a unilateral aspect of the thorax and a segmental hyperpigmentation involving both arms and the trunk, (b) an “atypical” pattern along the Blaschko's lines, (c) the “mesotropic facial pattern,” and (iii) segmental manifestations of monogenic disorders, including (type 1) segmental areas of skin affected with the typical manifestations of a disease associated to otherwise unaffected skin and (type 2) segmental areas of skin affected with a very pronounced degree of the typical skin manifestations of a disease. In this article we review the existing literature on the early history of Blaschko's lines, the presentation of the (well-defined and unclassified) archetypical patterns and the segmental manifestations of monogenic disorders tailoring these concepts to neurocutaneous disorders.

Chronic pain in pachyonychia congenita: evidence for neuropathic origin.

Pachyonychia congenita (PC) is a rare autosomal dominant skin disease, with chronic pain being the most prominent complaint. Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy. Here, for the first time, we aim to evaluate systematically the sensory function of patients with PC vs. controls, in order to investigate the pathophysiology of PC. Patients (n = 62) and controls (n = 45) completed the McGill and Douleur Neuropathique-4 (DN4) questionnaires. Sensory testing included detection and pain thresholds, pathological sensations, conditioned pain modulation (CPM) and temporal summation of pain. A moderate-to-severe chronic pain in the feet, throbbing and stabbing in quality, was highly prevalent among patients with PC (86%) and was especially debilitating during weight bearing. In addition, the majority of patients had a DN4 score ≥ 4 (62%), static allodynia (55%) and tingling (53%) in the feet. Compared with controls, patients with PC exhibited thermal and mechanical hypoaesthesia and mechanical hyperalgesia in the feet. CPM was reduced among the patients, and was associated with more enhanced mechanical hyperalgesia in the feet. The specific gene and nature of the causative mutation did not affect any of these features. Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC. The clinical features and DN4 scores support this possibility and therefore neuropathic pain medications may be beneficial for patients with PC.

The concept of type 2 segmental mosaicism, expanding from dermatology to general medicine.

In autosomal dominant skin disorders, the well-known type 1 segmental mosaicism reflects heterozygosity for a postzygotic new mutation. By contrast, type 2 segmental mosaicism originates in a heterozygous embryo from an early postzygotic mutational event giving rise to loss of the corresponding wild-type allele, which results in a pronounced segmental involvement being superimposed on the ordinary, non-segmental phenotype. Today, this concept has been proven by molecular analysis in many cutaneous traits. The purpose of this review was to seek publications of cases suggesting an extracutaneous manifestation of type 2 segmental mosaicism. Case reports documenting a pronounced extracutaneous segmental involvement were collected from the literature available in PubMed and from personal communications to the author. Pertinent cases are compared to the description of cutaneous segmental mosaicism of type 1 or type 2 as reported in a given trait. In total, reports suggesting extracutaneous type 2 segmental mosaicism were found in 14 different autosomal dominant skin disorders. In this way, clinical evidence is accumulated that extracutaneous type 2 segmental mosaicism does likewise occur in many autosomal dominant skin disorders. So far, however, molecular proof of this particular form of mosaicism is lacking. The present review may stimulate readers to inform colleagues of other specialties on this new concept, in order to initiate further research in this particular field of knowledge that has important implications for diagnosis, treatment and genetic counselling.