Clinical and allelic heterogeneity in dystrophic epidermolysis bullosa- lessons from an Indian cohort.

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is due to variation in the COL7A1 gene. The clinical phenotype and severity depends on the type of variation and domain of the affected protein. OBJECTIVES: To characterize the spectrum of COL7A1 variations in a cohort of DEB patients from India, to correlate these findings with clinical phenotypes and to establish a genotype-phenotype correlation. METHODS: This was a retrospective, observational study involving patients with DEB diagnosed on the basis of clinical manifestations, Immuno-fluorescence antigen mapping (IFM) and genetic analysis. A genotype-phenotype correlation was attempted and observations were further explained using IFM on skin biopsies and molecular dynamic simulations. Descriptive statistics were performed using SPSS version 20.0 with P values of <0.05 considered significant. RESULTS: We report 68 unrelated Indian DEB patients classified as RDEB-Intermediate (RDEB-I), RDEB-Severe (RDEB-S) or DDEB based on the EB diagnostic matrix, immunofluorescence antigen mapping and genetic data. Of 68 DEB patients, 59 (86.76%) were inherited in a recessive pattern (RDEB) and 9 (13.24%) in a dominant pattern (DDEB). Limbal stem cell deficiency was seen in four cases of RDEB-S very early in the course of the disease. A total of 88 variants were detected of which 66 were novel. There were no hotspots and recurrent variations were seen in a very small group of patients. We found a high frequency of compound heterozygotes (CH) in RDEB patients born out of non-consanguineous marriage. RDEB patients older than two years who had oral mucosal involvement, and/or deformities, were more likely to have esophageal involvement. Genotype phenotype correlation showed a higher frequency of extracutaneous manifestations and deformities in patients with Premature Termination Codons (PTCs) than in patients with other variations. Molecular simulation studies in patients with missense mutations showed severe phenotype when they were localized in interrupted regions of GLY-X-Y repeats. CONCLUSION: This large study of DEB patients in South Asia adds to the continually expanding genetic database of this condition. This study has direct implications on management as this group of patients can be screened early and managed appropriately.

Clinical heterogeneity in epidermolysis bullosa simplex with plectin (PLEC) mutations-A study of six unrelated families from India.

Epidermolysis bullosa simplex (EBS) with plectin mutations is a very rare subtype of EB usually associated with pyloric atresia (PA) or muscular dystrophy (MD). We report six unrelated children between ages 4 and 14 years from India with varied clinical manifestations. Only one had PA, and none has developed MD to date. All except the one with PA presented with early onset blistering along with laryngeal involvement in the form of hoarseness of voice and nail involvement. Patient with PA presented with aplasia cutis and died in the first week. Two patients had predominantly respiratory and gastrointestinal involvement with varying severity while two had features of myasthenic syndrome but no limb-girdle involvement and one patient phenocopied laryngo-onycho-cutaneous (LOC) syndrome. Using whole-exome sequencing, we identified novel mutations in PLEC. Histopathological analysis (Immunofluorescence antigen mapping) showed absence of staining to plectin antibodies. Our observations propose to append a phenotype of EBS, hoarseness of voice and nail dystrophy or LOC-like phenotype with plectin mutations. Long-term follow up is necessary to monitor for the development of muscular dystrophy.

Perineal warty plaques: A case of verrucous porokeratosis.

Nonvenereal genital dermatoses form an important category of disorders, and verrucous porokeratosis is a rare and less recognized entity among the same. We present the case of a young adult male with warty growths over scrotum and buttocks for a year. Characteristic cornoid lamellae with typical differentiating features were seen in the histopathology, establishing the diagnosis. This case emphasizes the rare nonvenereal cause for a condition clinically mimicking condyloma acuminata.

Relevant diagnostic implications of the therapeutic challenge with antitubercular therapy in an unusual case of sarcoidosis mimicking lupus vulgaris.

Cutaneous manifestations in sarcoidosis are seen in 25-35% of patients with systemic disease and may be the sole manifestation in few patients. It is known that isolated cutaneous sarcoidosis is a great mimicker and can be easily misdiagnosed as other granulomatous conditions especially lupus vulgaris in regions with high burden of tuberculosis (TB). Here we present a case with cutaneous sarcoidosis who was initially misdiagnosed and treated as bifocal lupus vulgaris with antitubercular therapy (ATT) for 6 months. This nonresponsiveness to therapy prompted us to investigate the patient further for other differentials, failing which a diagnosis of cutaneous sarcoidosis was made and the patient was treated with oral steroids and methotrexate with complete clearance of lesions after 14 weeks of therapy. Our case reemphasizes the value of therapeutic trial of ATT in diagnosis of cutaneous TB and highlights the remarkable clinical mimic of sarcoidosis with lupus vulgaris.

Silvery hair with dyschromatosis: Griscelli syndrome type 3 or familial gigantic melanocytosis.

We herein illustrate a case of an adult male presenting with silvery hair and generalized guttate hypopigmented macules on a background of diffuse cutaneous hyperpigmentation, since birth. Histopathology showed enlarged melanocytes with abundant melanin. Based on these clinicopathological features, differential diagnoses considered were Griscelli syndrome 3 (GS3) and familial giagantic melanocytosis. GS3 belongs to a group of inherited autosomal recessive (AR) disorders of partial albinism, known as silvery hair syndromes, while familial gigantic melanocytosis (FGM) is a putative disorder of dyschromia with silvery hairs. A pertinent literature search revealed hyperpigmentation or dyschromatosis as a rare manifestation of silvery hair syndromes, especially in dark-skin populations. A comparative analysis of previously reported cases depicted close morphological similarities between GS3 and FGM. We discuss the uncertainty pertaining to cases described in literature as FGM, to be truly representative of a distinctive entity, or merely a morphological variation of GS3.