Mutations In Desmoglein Research Articles

216-51: Clinical and genetic profile of arrhythmogenic cardiomyopathy with left ventricular involvement

Background: The natural history of arrhythmogenic cardiomyopathy (AC) with left ventricular involvement appears to be different from the exclusive right ventricular disease. Our aim is to analyze the clinical and genotypic features in our series of subjects with left ventricular AC comparing to the patients with the exclusive right ventricular disease. Methods: We studied 30 patients with AC. Information of clinical variables, advanced cardiac imaging and genetic testing was collected. These variables were compared in both groups of patients with AC, who presented or not left ventricular involvement. Results: Biventricular involvement was predominant (60%). There were significant differences in the arrhythmic profile of the patients, as well as for the burden of sudden cardiac death in relatives, that appeared to have a higher incidence in families with biventricular dysplasia. Left involvement was associated with worse functional class and lower ejection fraction of both left (63.1% vs 37.2%, p > 0.01) and right ventricles, with a non-significant trend to show higher mortality from cardiovascular disease. Genetic testing was positive in 63% of the families, with a tendency toward a higher prevalence of mutations in desmoglein 2 in those who presented biventricular dysplasia. Conclusions: AC with left ventricular involvement was related to a worse functional class, a more dilated left ventricle, a lower right and left ventricle ejection fraction and a higher arrhythmic risk, mostly because of the burden of sudden cardiac death in families of patients with biventricular involvement. Genetic testing was helpful in detecting silent carriers or patients with AC in the electrical phase of the disease.

Striate palmoplantar keratoderma (Brunauer-Fohs-Siemens syndrome)

A 64-year-old man presented with focal hyperkeratotic plaques on the fingers, palms, and soles. Histopathologic and electron microscopic results were consistent with striate palmoplantar keratoderma. Treatment with topical keratolytics was unsuccessful. Striate palmoplantar keratoderma or Brunauer-Fohs-Siemens syndrome is an autosomal dominant condition that presents with linear hyperkeratosis on the palms and fingers and focal plaques on the plantar aspects of the feet. Histopathologic features include hyperkeratosis, hypergranulosis, and acanthosis with no epidermolysis. Electron microscopic examination shows diminished desmosomes, clumped keratin filaments, and enlarged keratohyalin granules. The syndrome has been linked to mutations in desmoglein 1, desmoplakin, and keratin 1. Treatment may include keratolytics, oral retinoids, and surgical debridement.

Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins

Localized autosomal recessive hypotrichosis (LAH) is rare disorder affecting the scalp, trunk and extremities and largely sparing the facial, pubic and axillary hair. Mutations in desmoglein 4 (DSG4) gene are responsible for LAH which maps to human chromosome 18q12. In this study a recurrent intragenic deletion mutation (Ex5_8del) was identified in DSG4 gene in two Pakistani families of Balochi and Sindhi origins. Manifestation of identical intragenic deletion mutation in eight Pakistani families, six reported earlier and two here, is exceptionally evocative of the dispersion of ancestral chromosome in different ethnic groups through common ancestors.

Mutations in the Desmoglein 4 Gene Underlie Localized Autosomal Recessive Hypotrichosis with Monilethrix Hairs and Congenital Scalp Erosions

Localized autosomal recessive hypotrichosis (LAH) is a recently defined disorder characterized by fragile, short, sparse hairs on the scalp, trunk, and extremities. Mutations in desmoglein 4 (DSG4), a novel member of the desmosomal cadherin family that is expressed in the hair follicle as well as the suprabasal epidermis, have been found to underlie LAH. Thus far, the allelic series includes a recurrent intragenic deletion identified in affected Pakastani kindreds and a missense mutation detected in an Iraqi family. We report three siblings of Iraqi and Iranian origin with LAH that presented with congenital scalp erosions and monilethrix-like hairs, features that have not been previously described in this disorder. Follicular hyperkeratotic papules and marked pruritus were also prominent clinical findings. Novel compound heterozygous DSG4 mutations, including a splice-site mutation and a missense mutation that disrupts a conserved calcium-binding site in the extracellular (EC)2-EC3 interface, were found to underlie the disease in this family. These observations broaden the phenotypic and genotypic spectrum of LAH, further illustrating the consequences of DSG4 dysfunction on epidermal and hair shaft integrity.

An Autosomal Recessive Form of Monilethrix Is Caused by Mutations in DSG4: Clinical Overlap with Localized Autosomal Recessive Hypotrichosis

Monilethrix is a structural defect of the hair shaft usually inherited in an autosomal dominant fashion and caused by mutations in the hHb1, hHb3, and hHb6 keratin genes. Autosomal recessive inheritance in this disease has been sporadically reported. We encountered 12 Jewish families from Iraq, Iran, and Morocco with microscopic findings of monilethrix, but with no evidence of vertical transmission. Since no mutations were found in these three hair keratin genes, we examined nine chromosomal regions containing gene clusters encoding skin and hair genes. On chromosome 18q, a common haplotype in the homozygous state was found among all seven Iraqi patients, but not in 20 controls (P<0.0001). Sequencing of the main candidate gene from this region revealed four different mutations in desmoglein 4 (DSG4). Mutations in DSG4 have been previously reported in localized autosomal recessive hypotrichosis, a disorder that shares the clinical features of monilethrix but lacks the characteristic microscopic appearance of the hair shaft. Our findings have important implications for genetic counseling to monilethrix patients and families, and suggest that DSG4-associated hair disorders may be more common than previously thought.