Early‐Onset Heart Failure,Alopecia, and Cutaneous Abnormalities Associated with a Novel Compound Heterozygous Mutation in Desmoplakin

Mutations in the desmosomal protein desmoplakin have been associated with various conditions affecting the skin and heart. The prototype is Carvajal syndrome, characterized by cardiomyopathy, woolly hair, palmoplantar keratoderma (PPK), and skin fragility. We report the case of a 3‐year‐old boy presenting with severe left‐sided heart failure with a preceding history of cutaneous abnormalities including congenital alopecia, PPK, nail dystrophy, and follicular hyperkeratosis on the extensor surfaces. Genetic testing revealed a novel combination of two heterozygous mutations in the DSP gene encoding desmoplakin: R1400X and R2284X. Both are predicted to be deleterious to protein function. This case adds to our understanding of the spectrum of clinical presentations of syndromes associated with desmoplakin mutations and highlights the need for cardiac examination in patients with characteristic cutaneous findings.     

Carvajal综合征一例伴桥粒斑蛋白基因新突变

【摘要】 目的 对1例临床表现为羊毛状发,膝盖、掌跖角化性皮损,暂无心脏症状的患儿进行基因突变检测。方法 收集患儿及其父母的临床资料。提取患儿、其父母及100例无关健康对照者外周血DNA,采用二代皮肤靶向测序包检测患儿的基因突变,应用Sanger测序法进行验证。结果 患儿女,3岁,出生头发卷曲,8月龄出现掌跖角化并渐累及膝盖,其父母表型正常。测序发现,患儿桥粒斑蛋白（DSP）基因第23号外显子存在移码突变c.5152dupT（p.L1718Ffs*15）,DSP基因第24号外显子检测到无义突变c.C6478T（p.R2160X）。其母亲DSP基因第23号外显子亦存在c.5152dupT移码突变,但第24号外显子未检测到相关突变。其父亲及100例健康对照中均未检测到相关突变。诊断：Carvajal综合征。结论 该例Carvajal综合征患儿存在DSP基因复合杂合突变c.5152dupT（p.L1718Ffs*15）和c.C6478T（p.R2160X）,可能与其发病有关。     

Diagnostic Value of the Skin Lesions in Immune Dysregulation,Polyendocrinopathy, Enteropathy,X‐Linked Syndrome

We report a child with immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome due to a de novo c.1190G>A (p.R397Q) mutation in exon 11 of the forkhead domain of the FOXP3 gene. He had chronic dermatitis with an eczematous and ichthyosiform appearance and had an allogeneic bone marrow transplantation. IPEX syndrome is a rare, often fatal recessive disease caused by mutations in the FOXP3 gene on the X chromosome (Xp11.23‐q13.3).     

Lethal acantholytic epidermolysis bullosa due to a novel homozygous deletion in DSP: expanding the phenotype and implications for desmoplakin function in skin and heart

Desmoplakin is the major linker in desmosomes in epithelia and myocardium, anchoring intermediate filaments by the C‐terminus to plakoglobin and plakophilin in the desmosomal plaque. Mutations in the gene DSP encoding desmoplakin have been associated with various phenotypes affecting skin and/or heart. One of these phenotypes, lethal acantholytic epidermolysis bullosa (LAEB), is characterized by extensive postnatal shedding of epidermis leading to early demise and is caused by recessive mutations in the gene DSP resulting in truncation of the desmoplakin C‐terminus. Here we describe two infants born to the same consanguinous parents who suffered extensive epidermal dislodgment and died shortly after birth. In addition, universal alopecia, anonychia, malformed ears and cardiomyopathy were observed. As the clinical diagnosis was LAEB, DSP mutation analysis was performed. A homozygous deletion (c.2874del5) abrogating the donor splice site of exon 20 was found. The deletion is predicted to cause read‐through in intron 20 with subsequent recognition of a premature termination codon, resulting in desmoplakin lacking its rod domain and C‐terminus (p.Lys959MetfsX5). Electron microscopic analysis of skin biopsies showed absence of the desmosomal inner dense plaque and lack of tonofilament insertion. This is the second report of LAEB. These findings suggest DSP mutations as the aetiology of LAEB and cardiomyopathy as part of the phenotype. Furthermore, they indicate that in addition to the desmoplakin C‐terminus, the rod domain is dispensable for intrauterine development but is essential for the inner dense plaque of desmosomes.     

Successful use of topical minoxidil in the treatment of hypotrichosis associated with desmoplakin mutations

Syndromes associated with desmosomal protein mutations such as desmoplakin can result in hair abnormalities including congenital alopecia and hypotrichosis. Herein, we present an 8‐year‐old boy, with a combination of two heterozygous mutations in the DSP gene encoding desmoplakin associated with congenital alopecia and long‐standing hypotrichosis, who was treated with off‐label use of topical minoxidil 5% foam once daily with dramatic growth after 2 months of therapy and sustained results at 1 year. Topical minoxidil may be effective in management of congenital alopecia and hypotrichosis associated with desmoplakin mutations.     

Amelioration of junctional epidermolysis bullosa due to exon skipping

Mutations in the COL17A1 gene lead to the genetic blistering disorder junctional epidermolysis bullosa generalized intermediate type (JEB‐gen‐intermed). Antisense oligonucleotide‐mediated exon skipping is a strategy that aims to skip the mutation‐containing exon and thereby produce a smaller but functional protein. COL17A1 is an interesting candidate, as 53 of the 55 exons (96%) can be skipped without disturbing the reading frame. Information on the functionality of the shortened protein product is important in order to obtain support for this therapeutic strategy. Here we report a patient with JEB‐gen‐intermed with amelioration of the phenotype due to exon 49 skipping by two distinct mechanisms – premature termination codon‐induced exon skipping and revertant mosaicism – both of which induced skipping of the same exon. The patient was compound heterozygous for two inherited COL17A1 mutations, a frameshift mutation in exon 18 (c.1490_1491delinsT, p.Ala497Valfs*23) and a nonsense mutation in exon 49 (c.3487G>T, p.Glu1163Ter). Upon clinical examination, skin patches were found that were resistant to blister formation. In these patches, naturally corrected cells were present that harboured an additional splice‐site mutation, c.3419–1G>T, resulting in skipping of the mutation‐containing exon 49. This natural gene therapy phenomenon shows that type XVII collagen with residues 1140–1169 deleted is largely functional. In addition, in affected skin cells a low level of exon 49 skipping was observed. Our results support the notion that skipping of a mutated in‐frame exon in COL17A1 ameliorates the phenotype.     

Two novel mutations of the NCSTN gene in Chinese familial acne inverse

Background Acne inversa (AI; MIM 142690), or hidradenitis suppurativa (HS), is a type of autosomal‐dominant genodermatosis caused by mutations in γ‐secretase. The complex of γ‐secretase is a transmembrane protease that catalyses the cleavage of a set of membrane proteins and is comprised of four subunits encoded by four genes, including PSEN1, PSENEN, NCSTN and APH1. However, mutations associated with AI vary significantly, and it is important to define the specific mutation with a particular AI patient. Objective To determine specific mutations in the γ‐secretase gene associated with two Chinese AI families. Methods Two families of three generations with apparent AI symptoms were examined through proband analysis. Genomic DNAs of the family members and a cohort of 100 healthy individuals were isolated and subjected to polymerase chain reaction (PCR) and direct DNA sequencing. Results Two heterozygous missense mutations, c.647A>C (p.Q216P) in the exon 6, and c.223G>A (p.V75I) in the exon 3 of the NCSTN gene, were identified in the two families respectively. No mutations were found in 100 healthy individuals. Conclusions We have identified two novel mutations within the NCSTN gene associated with AI.     

Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia

Junctional epidermolysis bullosa with pyloric atresia (PA‐JEB) is a rare congenital bullous disease with gastrointestinal disturbance that has been associated with mutations in ITGA6 or ITGB4 encoding the α6 or β4 subunit of integrin, respectively. Only six ITGA6 mutations in PA‐JEB have been reported while many ITGB4 mutations have been identified, and all the ITGA6 mutations were homozygous. Here, we report a case of lethal type PA‐JEB, in which immunofluorescence showed the lack of both α6 and β4 integrins resulting from compound heterozygous splice site mutation in ITGA6, c.387G>T and c.2506‐1G>C. Maternal c.387G>T induced the skipping of the entire exon 3 and both exons 3 and 4, resulting in premature termination codon and in‐frame deletion, respectively. Paternal c.2506‐1G>C caused the skipping of the exon 20 and resulted in in‐frame deletion. As a reason why the present case showed lethal phenotype despite the in‐frame deletion mutation, rapid degradation of neo‐synthesized α6 protein and/or impaired transport of integrin were suggested from previous reports, and the lack of localization of integrin α6β4 to the epidermal basement membrane resulted in skin fragility. Our case expands the variety of integrin α6 mutations in PA‐JEB.     

Legius syndrome: A case report

Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss‐of‐function SPRED1 mutation. In Japan, a family with Legius syndrome was first described in 2015 by Sakai et al. We described a first solitary case of Legius syndrome identified by next‐generation sequencing in Japan. A 37‐year‐old woman presented with multiple café‐au‐lait macules and freckles but has no other features of neurofibromatosis type 1 (NF‐1). Sequencing results showed the presence of a mutation in exon 2 of SPRED1 c.70C>T, resulting in the protein at position 24 (p.Arg24X). When a dermatological clinician sees an adult patient showing only pigmented lesions and no other specifically diagnostic features of NF‐1, it is important to suspect the possibility of Legius syndrome.     

Severe dermatitis,multiple allergies and metabolic wasting (SAM) syndrome caused by de novo mutation in the DSP gene misdiagnosed as generalized pustular psoriasis and treatment of acitretin with gabapentin

Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 (DSG1) and desmoplakin (DSP) genes. Only two cases of SAM‐DSP have been reported. We report on a 2‐year‐old girl presenting with pustular lakes within areas of erythema and large accumulations of intraepidermal neutrophils, which initially led to our misdiagnosis of generalized pustular psoriasis. No mutation was found in either the IL36RN or CARD14 genes by Sanger sequencing. The distinctive manifestations of erythroderma with severe itching, hypotrichosis, enamel defects, onychodystrophy, palmoplantar keratoderma and the crucial result of de novo missense mutation in exon 14 of the DSP gene (c.1828T>C, p.S610P) discovered by next‐generation sequencing finally confirmed the diagnosis of SAM syndrome. The eruptions significantly improved after a 4‐week treatment with oral acitretin and topical pimecrolimus. Oral gabapentin was prescribed simultaneously for 4 months, relieving her skin pruritus and suggesting that early treatment with pimecrolimus, acitretin and gabapentin for SAM‐DSP syndrome is effective. It may even inhibit multiple allergies induced by skin barrier injury. In this work we also review the clinical features, differential diagnoses and pathological manifestations of SAM‐DSP syndrome.     

Loss of desmoglein 1 associated with palmoplantar keratoderma,dermatitis and multiple allergies

Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss‐of‐function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.     

Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis

Porokeratosis comprises heterogeneous keratinization disorders that are characterized by one or more atrophic patches surrounded by a ridge‐like cornoid lamella. In this study, we evaluated seven families affected by porokeratosis and five sporadic patients of the disease in a Chinese population. We performed Sanger sequencing of exons and flanking intron–exon boundaries of mevalonate pathway genes (MVD, MVK, PMVK and FDPS) and of SLC17A9. In five familial and three sporadic patients, we detected six variations, including four novel mutations (MVD c.1A>G; p.Met1?, c.916G>A; p.Ala306Thr, c.1013+1G>A, and PMVK c.65A>G; p.Lys22Arg) and two recurrent mutations (MVD c.746T>C; p.Phe249Ser, and MVK c.1028T>C; p.Leu343Pro). We then applied I‐TASSER and iGEMDOCK to assess these variants for probable functional impacts. The findings of this study extend the mutation spectrum of porokeratosis and provide further evidence for the genetic basis of this disease.     

Novel homozygous mutation,c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate‐ectodermal dysplasia syndrome in an Asian patient

Cleft lip/palate‐ectodermal dysplasia syndrome is a rare, autosomal recessive disorder caused by homozygous loss‐of‐function mutations of the poliovirus receptor‐like 1 (PVRL1) gene encoding nectin‐1. Nectin‐1 is a cell–cell adhesion molecule that is important for the initial step in the formation of adherens junctions and tight junctions; it is expressed in keratinocytes, neurons, and the developing face and palate. Clinical manifestations comprise a unique facial appearance with cleft lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers and/or toes, and in some cases, mental retardation. We present the first report, to our knowledge, of an Asian individual with cleft lip/palate‐ectodermal dysplasia syndrome with a novel PVRL1 mutation. A 7‐year‐old Japanese boy, the first child of a consanguineous marriage, showed hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair and hypodontia, the unique facial appearance with cleft lip/palate, cutaneous syndactyly of the fingers and mild mental retardation. Scanning electron microscopic examination of the hair demonstrated pili torti and pili trianguli et canaliculi. Mutation analysis of exon 2 of PVRL1 revealed a novel homozygous nonsense mutation, c.400C>T (p.Arg134*). His parents were heterozygous for the mutant alleles. All four PVRL1 mutations identified in cleft lip/palate‐ectodermal dysplasia syndrome to date, including this study, resulted in truncated proteins that lack the transmembrane domain and intracellular domain of nectin‐1, which is necessary to initiate the cell–cell adhesion process.     

Harlequin ichthyosis: a novel compound mutation of ABCA12 with prenatal diagnosis

Harlequin ichthyosis (HI) is the most severe form of recessive congenital ichthyosis, and is frequently lethal. We describe a family with prenatal diagnosis of HI in two siblings. We applied genomic capture and massively parallel sequencing to detect all mutations in 20 genes, including ABCA12, with inherited mutations that predispose to congenital ichthyosis. Sequence analysis of the ABCA12 gene identified two mutations, c.5232 G>A (p.Trp1744*) in exon 34 and c.6443 C>A (p.Pro2148Gln) in exon 44, each in a heterozygous state. Sanger sequencing confirmed that each parent was a heterozygous carrier for one of the variants. The spectrum of mutations identified in this study and previous studies reveals a novel compound mutation of ABCA12.     

Novel compound heterozygous mutation in LAMC2 genes (c.79G>A and 382insT) in Herlitz junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is a heritable blistering skin disease characterized by separation within the lamina lucida. It is caused by mutations in the LAMA3, LAMB3 and LAMC2 genes encoding the α3‐, β3‐ and γ2‐chains, respectively, of laminin‐332. JEB Herlitz type (JEB‐H) is a lethal blistering disease with severe cutaneous and extracutaneous involvements caused by null mutations in the gene encoding laminin‐332. Here, we report a proband with JEB‐H who is a compound heterozygote for two novel mutations in LAMC2; a missense mutation (c.79G>A) and an insertion mutation (382insT) leading to a premature termination codon.