A case of mosaicism in ectodermal dysplasia-skin fragility syndrome

Vázquez‐Osorio, Igor; Chmel, Nadja; Rodríguez‐Díaz, Eloy; Gonzalvo‐Rodríguez, P.; Happle, Rudolf; Bueno, Elena Villamañán; Has, Cristina; Torrelo, Antonio

doi:10.1111/bjd.15374

Cited by 13 publications

(11 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mosaicism in recessive disorders has been described as a cause of postzygotic homozygosity. 10 However, in this case the phenotype could eventually be explained by the combination of a germline mutation and an acquired postzygotic mutation in ABCA12, resulting in the diagnosis of a mosaic manifestation of autosomal recessive congenital ichthyosis. We propose the term 'recessive mosaicism' for this specific kind of manifestation.…”

Section: Discussionmentioning

confidence: 89%

Recessive mosaicism in ABCA12 causes blaschkoid congenital ichthyosiform erythroderma

et al. 2019

View full text Add to dashboard Cite

Summary We report the unique case of a 3‐year‐old girl who presented with linear erythematosquamous lesions following the lines of Blaschko, suggestive of genetic mosaicism in the skin. Single‐candidate gene analyses were performed on DNA from blood, excluding Conradi–Hünermann–Happle syndrome, erythrokeratodermia variabilis and a mosaic presentation of pityriasis rubra pilaris. With whole‐exome sequencing (WES) on DNA from the patient's blood, a heterozygous missense mutation in exon 25 of the ABCA12 gene was detected. By manually scrutinizing the WES data, another low‐percentage pathogenic frameshift mutation was found in the adjacent exon 26 of the same gene. This frameshift mutation was confirmed with Sanger sequencing in DNA isolated from a lesional skin biopsy. A subsequent cloning experiment was performed to prove that the patient is compound heterozygous for both mutations in the affected skin, explaining the blaschkoid ichthyosiform erythrodermic phenotype. The patient's phenotype was elucidated by the combination of a germline mutation and an acquired postzygotic mutation in ABCA12, resulting in the diagnosis of a mosaic manifestation of autosomal recessive congenital ichthyosis. Postzygotic compound allelic loss in autosomal recessive disorders is extremely rare and will not appear as the typical phenotype of the known germline mutation‐associated disease. This is the first report of a proven biallelic mosaic presentation of an autosomal recessive genodermatosis, and we propose the term ‘recessive mosaicism’ for this kind of manifestation. What's already know about this topic? Specific mutations in the ABCA12 lipid transporter are known to cause different phenotypes like harlequin ichthyosis, congenital ichthyosiform erythroderma and lamellar ichthyosis. In mosaicism, two or more cell populations that are genetically different arise postzygotically in the developing embryo. In the skin, mosaicism can present itself in different patterns of affected skin, often caused by a dominant genetic mutation. What does this study add? We report a unique patient with blaschkoid congenital ichthyosiform erythroderma due to biallelic mutations, one inherited germline missense mutation and the other a postzygotic frameshift mutation in the ABCA12 gene. This study describes the diagnostic approach and applied research that can be used if one encounters a similar diagnostic dilemma with manifestations suspected for genetic mosaicism. We propose the term ‘recessive mosaicism’ for this kind of mosaic presentation of an autosomal recessive genodermatosis.

show abstract

Section: Discussionmentioning

confidence: 89%

Recessive mosaicism in ABCA12 causes blaschkoid congenital ichthyosiform erythroderma

et al. 2019

View full text Add to dashboard Cite

show abstract

“…We identified 16 individual cases of EDSF syndrome caused by bi‐allelic PKP1 germline mutations and 1 case caused by postzygotic mosaicism; we also include two further cases that are reported in this article (Tables 1 and 2). [ 10,12‐25 ] Consanguinity was present in 68.8% of the cases (11/16; not reported in 2 cases). None of the heterozygous carrier parents reported any skin or ectodermal abnormalities.…”

Section: Resultsmentioning

confidence: 99%

“…There was 1 case that involved postzygotic mosaicism. [ 25 ] In 15/18 cases, mutations were homozygous. Of the cases that reported PKP1 protein expression, all had either reduced skin labelling or a complete absence of immunostaining.…”

Section: Resultsmentioning

confidence: 99%

“…[ 16 ] Another case of interest (Tables 1 and 2—footnote) involved both a frameshift deletion mutation and a postzygotic somatic mutation, yet only presented with mild unilateral superficial erosions in a mosaic pattern, PPK and nail dystrophy. [ 25 ] Immunofluorescence analysis in this case showed negative staining for anti‐PKP1 antibodies in a mosaic pattern, but reduced immunoreactivity in surrounding, unaffected skin compared to control skin. The molecular pathology involved a heterozygous germline mutation that appeared to be homozygous in affected skin, possibly due to a loss of heterozygosity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ectodermal dysplasia‐skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis

Doolan

Gomaa

Fawzy

et al. 2020

Experimental Dermatology

View full text Add to dashboard Cite

Background: Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997. Methods: To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019. Results: Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections. Conclusion: These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis. K E Y W O R D S desmosome, ectodermal dysplasia-skin fragility syndrome, Plakophilin 1 | 521 DOOLAN et AL.

show abstract

“…Thirdly, there are conditions in which the germline genotype is of a single recessive mutation, which does not confer a clinical phenotype or a recognizable syndrome itself, but where a second recessive mutation will lead to a mosaic disorder phenotype. A recent first published example of this at genetic level is ectodermal dysplasia skin fragility syndrome …”

Section: Definition Of Mosaic Abnormalities Of the Skin And Of Mosaimentioning

confidence: 99%

Mosaic abnormalities of the skin: review and guidelines from the European Reference Network for rare skin diseases

et al. 2019

Self Cite

View full text Add to dashboard Cite

Summary Background Cutaneous mosaicism is an area of dermatology in which there has been an explosion of knowledge within the current decade. This has led to fundamental changes in the understanding of the conditions in this field, and to an ongoing paradigm shift in the approach to management of mosaic skin disorders. Objectives To lay out the general principles of mosaicism as they are currently understood, summarize the known cutaneous mosaic abnormalities of the skin with associated phenotypic and genotypic information, review the latest trials on targeted therapies and propose guidelines for the general approach to a patient with suspected mosaicism. Methods This was a consensus expert review as part of the European Reference Network project (ERN‐Skin). Conclusions This study provides clinicians with a practical approach to the patient with suspected mosaicism, redefines mosaicism for the modern genetic era, and proposes a new classification system based on genetic mechanism. What's already known about this topic? Cutaneous mosaicism is a complex field of dermatology that encompasses most birthmarks, and many rare syndromes. Some cutaneous patterns are known to be seen in mosaicism. Very few treatment options are available for most mosaic abnormalities of the skin. Recent high‐sensitivity genetic techniques have led to an explosion of knowledge about genotype and phenotype in the literature. What does this study add? Expert consensus from the European Reference Network project. Review of knowledge of confirmed mosaic abnormalities of the skin, including cutaneous phenotype, extracutaneous associated features and genotype. Proposed new classification of mosaic abnormalities of the skin by genetic mechanism and therefore inheritance potential. Practical tips on correct sample collection and genetic investigation. Review of trials of targeted therapies. Guidelines for a practical clinical approach to the patient with suspected mosaicism.

show abstract

A case of mosaicism in ectodermal dysplasia-skin fragility syndrome

Cited by 13 publications

References 8 publications

Recessive mosaicism in ABCA12 causes blaschkoid congenital ichthyosiform erythroderma

Recessive mosaicism in ABCA12 causes blaschkoid congenital ichthyosiform erythroderma

Ectodermal dysplasia‐skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis

Mosaic abnormalities of the skin: review and guidelines from the European Reference Network for rare skin diseases

Contact Info

Product

Resources

About