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.

Functional Analysis of a Novel Connexin30 Mutation in a Large Family with Hearing Loss, Pesplanus, Ichthyosis, Cutaneous Nodules, and Keratoderma.

Mutations in the gap-junction gene Cx30 (Connexin30, GJB6) are a known cause of hearing loss. Here, we report our findings on a large multigeneration family in which severe to profound sensorineural hearing impairment is associated with a variety of skin-related anomalies. Genome-wide analysis of the family showed that the locus maps to chromosome region 13ptel-q12.1 and that a novel mutation, p.N54K, in Cx30, cosegregates with the phenotype. Unlike wild-type Cx30, p.N54K Cx30 is predominantly localized in the cytoplasm and does not permit transfer of neurobiotin, suggesting improper cellular localization and abolishment of gap-junction activity.

Pediatric dermatology inpatient consultations: a retrospective study.

OBJECTIVE: To describe the profile of inpatient consultations seen in department of pediatric dermatology at a tertiary care children's hospital. METHODS: The authors performed a retrospective review of all pediatric dermatology inpatient consultation data from medical record section over a period of 42 mo from January 2010 through June 2013. All children 18 y and below were included in the study. RESULTS: A total of 486 inpatient consultation services were given by pediatric dermatology department. About 124 (25.5 %) of consultations were in the age group of infancy followed by 103 (21.1 %) consultations in the school going age children. Most frequent consultation request was from general pediatrics (49.4 %) followed by pediatric intensive care (37.9 %). The most common diagnostic categories included cutaneous infection (115, 23.7 %), emergency skin conditions (62, 12.8 %), genodermatosis (58, 11.9 %) and skin disorders secondary to systemic illness (55, 11.3 %). CONCLUSIONS: This study highlights the spectrum of conditions that clinicians must be aware that can be seen in general pediatric wards and intensive care unit. This study also highlights the role of pediatric dermatologist in giving care to hospitalized children.

Focal dermal hypoplasia: a rare case report.

Focal dermal hypoplasia (Goltz syndrome) is a rare genetic multisystem disorder primarily involving the skin, skeletal system, eyes, and face. We report the case of an eight-month-old female child who presented with multiple hypopigmented atrophic macules along the lines of blaschko, skeletal anomalies, umbilical hernia, developmental delay, hypoplastic nails, syndactyly, and lobster claw deformity characteristic of Goltz syndrome.

Vesiculobullous Disorders in Children.

OBJECTIVE: To study the frequency and clinical pattern of vesiculobullous disorders in children. METHODS: A retrospective chart review of all children diagnosed with vesiculobullous disorders over a period of 36 mo from January 2011 through December 2013 was performed. All children 18 y and below were included in the study. RESULTS: A total of 213 children presenting with vesiculobullous lesions were examined during the study period. Vesiculobullous disorders constituted 3.6 % of the total 5889 dermatoses seen during this period. The most common vesiculobullous disorder in children was infections (129, 60.6 %), followed by genodermatoses (35, 16.4 %), inflammatory disorders (33, 15.5 %), drug reaction (7, 3.3 %) and trauma (5, 2.3 %). Autoimmune and metabolic disorders constituted 1.4 % (three children) and 0.5 % (one child) respectively. CONCLUSIONS: This study highlights the varied spectrum of vesiculobullous disorders seen in the pediatric population. Cutaneous infections and inherited disorders were the most common disorders observed in the present study.

Marie-unna hereditary hypotrichosis.

Marie-Unna type of hereditary hypotrichosis is a rare autosomal dominant disorder that has a distinctive type of hair loss pattern that varies with child's age. It is characterized by sparse or absent hair at birth with regrowth of coarse, wiry twisted hair from childhood, followed by progressive loss on approaching puberty. We report a 12-year-old male child with characteristic clinical features suggestive of hereditary hypotrichosis of Marie-Unna type.

Sjögren-Larsson syndrome: A study of clinical symptoms in six children.

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by triad of congenital ichthyosis, spastic paresis, and mental retardation. It is an inborn error of lipid metabolism caused by deficiency of the enzyme fatty aldehyde dehydrogenase. We report our observations of six children with SLS.

Congenital atrichia associated with situs inversus and mesocardia.

Congenital alopecia includes a broad differential diagnosis and presents a diagnostic and therapeutic challenge for the physician. Congenital atrichia is a rare form of irreversible alopecia that is usually inherited as an autosomal recessive pattern. We report a 2-year-old male child presenting with total alopecia of scalp, eyebrows, eyelashes, and body hair since birth. The child had cardiac malposition with situs inversus of the viscera. Computed tomography of the chest and abdomen revealed median position of the heart with transposition of abdominal viscera. To our knowledge, this is the first case of congenital atrichia associated with situs inversus and mesocardia.

Effectiveness of pulsed dye laser in the treatment of recalcitrant warts in children.

BACKGROUND: To determine the efficacy and safety of the 585-nm pulsed dye laser (PDL) in the treatment of recalcitrant warts in children. METHODS AND MATERIAL: Retrospective survey of the medical records of children with recalcitrant warts who were treated with PDL between March 1995 through January 1999 at the Children's Memorial Hospital outpatient subspecialty center, Chicago, Illinois. RESULTS: Sixty-one children with recalcitrant warts were treated with PDL; 75% of them had total clearance of warts after an average of 3.1 treatment sessions. Overall success rates were 100% for both perineal and perianal and face-only warts, 93% for hands, 69% for plantar warts, 67% when both face and extremities were involved, and 60% when multiple extremities were involved. Pain and other side effects were minimal. Mild scarring occurred in 2% of patients; 75% of patients remained free of warts after a follow-up period of 24 months or longer. CONCLUSION: PDL therapy is an effective, safe alternative therapy for treatment of recalcitrant warts in children, with few side effects and a low long-term recurrence rate.

Molecular diagnostics in genodermatoses - simplified.

The field of genetics in dermatology has progressed at an astonishing rate. Most of the known single gene disorders have at least been mapped to a particular chromosomal region and the causative genes have been identified and studied in many of them. However, most research work in genetics relating to genodermatoses has been confined to the western population. Very few reports, if any, have been published from Indian studies. A first step may be to develop a registry to link most of these cases providing a full description of the clinical phenotype. We would next need to attempt genetic analysis of these conditions thereby detecting any novel mutations in known and unknown genes different from the western population. This would help in designing indigenous assays appropriate to the Indian population. The review describes various techniques used in a molecular biology/ genetics laboratory with special focus on polymerase chain reaction (PCR), gene sequencing, genotyping and DNA micro arrays. Gene identification strategies have also been described with appropriate examples in dermatology.

Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.

Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227 (3'-untranslated region)-rs6887695 (60 kb, 5') and the IL23R haplotype rs7530511 (L310P)-rs11209026 (Q381R). We examined these four single-nucleotide polymorphisms (SNPs) for association with psoriasis in two groups of North American and German Caucasians: (1) 1,810 cases and 2,522 controls; and (2) 509 pedigrees. Both IL12B markers showed highly significant association with psoriasis in the case-control (rs3212227, odds ratio (OR)=1.62, P=1.7 x 10(-15); rs6887695, OR=1.49, P=2.7 x 10(-15)) and in the family-based analysis (rs3212227, P=2.2 x 10(-3); rs6887695, P=1.7 x 10(-3)). The IL23R SNPs also showed significant association in the cases and controls (rs7530511, OR=1.22, P=3.9 x 10(-3); rs11209026, OR=1.40, P=3.8 x 10(-4)). For both genes, common risk haplotypes were identified whose statistical significance approached (IL23R) or exceeded (IL12B) genome-wide criteria. We found no statistical evidence for interactions of these haplotypes with HLA-Cw6. Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.

Prevalence of antigliadin antibodies in patients with psoriasis is not elevated compared with controls.

BACKGROUND: Antigliadin antibodies (AGAs) are markers of celiac sprue but may have autoimmune implications in the absence of gastrointestinal disease. There is anecdotal evidence to suggest that gluten sensitivity may play a role in psoriasis, and patients with psoriasis in Europe have been reported to improve on a gluten-free diet. OBJECTIVE: To assess whether patients with psoriasis in the US have an increased prevalence of elevated AGAs. METHOD: A US sample of patients with psoriasis (n=100), patients with psoriasis and psoriatic arthritis (n=100), and age-matched control individuals without any personal or family history of autoimmune disorders (n=100) were tested for IgG and IgA AGAs. RESULTS: No difference in the prevalence of abnormal AGAs among patients with psoriasis (14%), combined psoriasis and psoriatic arthritis (18%), and control individuals (19%) was observed. No significant correlations between AGA positivity and psoriasis severity, joint involvement, or age of onset of psoriasis or arthritis were observed. CONCLUSION: We found no support for the results of prior studies showing that elevated AGAs occur with increased frequency in patients with psoriasis. Furthermore, the relatively high prevalence of abnormal AGAs in our control population suggests these antibodies may not be associated with autoimmune disease.

Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.

Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.