Segmental basal cell naevus syndrome caused by an activating mutation in smoothened.

Aberrant sonic hedgehog signalling, mostly due to PTCH1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma (BCC), as well as in basal cell naevus syndrome (BCNS). Mutations in smoothened (SMO) encoding a receptor for sonic hedgehog have been reported in sporadic BCCs but not in BCNS. We report a case with multiple BCCs, pits and comedones in a segmental distribution over the upper part of the body, along with other findings compatible with BCNS. Histopathologically, there were different types of BCC. A heterozygous mutation (c.1234C>T, p.L412F) in SMO was detected in three BCCs but not in peripheral blood lymphocytes or the uninvolved skin. These were compatible with the type 1 mosaic form of BCNS. The p.L412F mutation was found experimentally to result in increased SMO transactivating activity, and the patient responded to vismodegib therapy. Activating mutations in SMO may cause BCNS. The identification of a gain-of-function mutation in SMO causing a type 1 mosaic form of BCNS further expands our understanding of the pathogenesis of BCC, with implications for the treatment of these tumours, whether sporadic or inherited.

Non-syndromic autosomal recessive congenital ichthyosis in the Israeli population.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is the term given to a complex and heterogeneous group of cornification disorders associated with mutations in at least eight distinct genes. Mutation distribution and prevalence rates are instrumental for the design of diagnostic strategies in ARCI but have not yet been systematically explored in the Israeli population. Previous data suggest that the demographic features specific to Middle Eastern populations, such as a high frequency of consanguineous marriages, may have an effect on the molecular epidemiology of genodermatoses. METHODS: We systematically assessed all families with ARCI presenting at our clinics over a period of 9 years, using a combination of homozygosity mapping, direct sequencing and PCR-restriction fragment length polymorphism assays. RESULTS: In total, 20 families with ARCI were assessed, and causative mutations were identified in 7 genes: TGM1 (30% of patients), ALOX12B (20%), ABCA12 (5%), CYP4F22 (10%), ALOXE3 (10%), LIPN (5%) and NIPAL4 (5%) Two families (10%) had mutations mapped to an ARCI-associated locus on 12p11.2-q13, while no mutation was found for one additional kindred. In the subgroup of families of Arab Muslim origin, mutations were identified most frequently in ALOX12B and TGM1 (31%), whereas the other subgroups displayed a subtype distribution very similar to that previously reported in western populations. CONCLUSIONS: The present data point to the need for population-tailored mutation screening strategies in genetically heterogeneous genodermatoses, based on the relative prevalence of the disease subsets.

Novel mutations in DSG1 causing striate palmoplantar keratoderma.

BACKGROUND: Striate palmoplantar keratoderma (SPPK) has been shown to be caused by mutations in at least three genes: DSG1, DSP and KRT1. METHODS: Three families with nine affected members were assessed using a candidate gene-based screening approach. RESULTS: In all three families, new heterozygous mutations were found in DSG1. CONCLUSION: Direct sequencing of cDNA derived from affected skin in one patient failed to reveal a pathogenic mutation, suggesting that SPPK results from haploinsufficiency for DSG1.

Novel CDH3 mutations in hypotrichosis with juvenile macular dystrophy.

BACKGROUND: Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short hair, heralding progressive degeneration of the retinal pigment epithelium, which leads to blindness by the second decade of life. The disorder is caused by mutations in CDH3, a gene encoding P-cadherin, a major component of adherens junctions. Most HJMD cases reported to date have been shown to be caused by homozygous CDH3 mutations segregating in consanguineous families. AIM AND METHODS: To elucidate the genetic basis of HJMD in two nonconsanguineous families, we established the coding sequence of CDH3 in four patients and their healthy siblings. RESULTS: The four patients demonstrated markedly variable degrees of visual acuity impairment. Novel biallelic recessive mutations were identified in all affected individuals. One patient in the first family was found to carry two heterozygous mutations, IVS2 + 1G-->A and p.E504K; the other three patients in the second family were compound heterozygous for a missense mutation, p.H575R, and a nonsense mutation, p.R221X. CONCLUSION: This paper expands the spectrum of known mutations in CDH3 and points to the existence of clinical heterogeneity in this syndrome.

A homozygous missense mutation in PEPD encoding peptidase D causes prolidase deficiency associated with hyper-IgE syndrome.

BACKGROUND: Prolidase deficiency is a complex disease characterized by various skin manifestations accompanied by mental retardation, facial dysmorphism and susceptibility to pyogenic infections. METHODS: We assessed a patient presenting a peculiar phenotype combining manifestations of prolidase deficiency with features typical of hyper-IgE syndrome. Mutation analysis was performed using direct PCR amplification and PCR restriction fragment length polymorphism analysis. RESULTS: We identified a novel homozygous recessive mutation in the PEPD gene, which was found to segregate in the family of the patient with the disease and was not found in a panel of DNA samples representative of all major Druze families living in northern Israel. DISCUSSION: Our results suggest that prolidase deficiency associated with hyper-IgE syndrome, a rare disorder, can be caused by mutations in PEPD.

Molecular basis of hypotrichosis with juvenile macular dystrophy in two siblings.

BACKGROUND: Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short scalp hair from birth, followed within a few years by progressive macular degeneration leading to blindness. HJMD was shown to result from mutations in CDH3 encoding P-cadherin. OBJECTIVES: In the present study, we attempted to identify the molecular basis of abnormal hair growth in two siblings of Arab Muslim origin with hypotrichosis but no visual symptoms. METHODS: Mutation analysis was performed using direct sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Patients displayed sparse and short hair since birth. Significant macular degenerative pigmentary changes were noticed in the face of normal visual acuity. Despite the fact that a single CDH3 mutation had previously been described in several families of Israeli Arab Muslim origin, the two affected patients were found to be homozygous carriers of a novel nonsense mutation (Y615X) predicted to result in premature termination of P-cadherin translation. CONCLUSIONS: The present results indicate that all patients with congenital hypotrichosis should undergo thorough fundus examination, which, when revealing pigmentary macular changes, can be considered as indicative of an underlying CDH3 causative mutation.

Epidermolytic hyperkeratosis type PS-1 caused by aberrant splicing of KRT1.

Mutations in the keratin 1 (KRT1) gene underlie epidermolytic hyperkeratosis (EHK). This autosomal dominant disorder is characterized by phenotypic heterogeneity. In the present study, we assessed a 33-year-old individual presenting with severe palmoplantar keratoderma and histopathological findings suggestive of EHK. We analysed genomic DNA extracted from the patient's blood lymphocytes for pathogenic mutations in KRT1. A heterozygous 4-bp deletion was identified in intron 1 of the gene (591+3_+6delGAGT), suggesting the possibility that it may interfere with the normal splicing of intron 1. We detected a 66-bp deletion in KRT1 mRNA extracted from the patient's skin, predicted to result in the translation of a mutant KRT1 lacking 22 amino acids, including the conserved helix initiation motif. The identification of this unusual and novel mutation underscores the diagnostic importance of sequence analysis of keratin gene noncoding regions.

Compound heterozygosity for mutations in the hairless gene causes atrichia with papular lesions.

BACKGROUND: Congenital atrichias represent a complex and heterogeneous group of genodermatoses, which have been shown in several consanguineous families to result from homozygous mutations in the hairless gene (HR). OBJECTIVES: To identify the molecular basis of congenital atrichia in a non-consanguineous family. METHODS: Genetic analysis was carried out in a two-generation family with two children with congenital atrichia and one healthy child. RESULTS: We established a diagnosis of atrichia with papular lesions based on clinical and histopathological data. We identified a heterozygous 11-bp deletion (189-199del) in the two affected children and their mother. In addition, the two affected children and their father were shown to carry a non sense mutation (Q478X), which has previously been described in a Pakistani family. Haplotype analysis revealed that mutation Q478X occurred independently in the two families. CONCLUSIONS: We have identified the first case of compound heterozygosity for mutations in HR as well as the first instance of a recurrent mutation in this gene. These data further expand our understanding of the molecular pathomechanisms underlying congenital atrichias.