Gomathy Sethuraman

The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1

Abstract:  Lipoid proteinosis (OMIM 247100), also known as Urbach–Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoprotein extracellular matrix protein 1 (ECM1). ECM1 has since been shown to have several important biological functions. It has a role in the structural organization of the dermis (binding to perlecan, matrix metalloproteinase‐9 and fibulin) as well as being targeted as an autoantigen in the acquired disease lichen sclerosus. ECM1 also shows over‐expression in certain malignancies and is abnormally expressed in chronologically aged and photo‐aged skin. Thus far, 26 different inherited mutations in ECM1 have been reported in lipoid proteinosis. In this article, we provide an update on the molecular pathology of lipoid proteinosis, including the addition of 15 new mutations in ECM1 to the mutation database, and review the biological functions of the ECM1 protein in health and disease.

Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome

Olmsted syndrome (OS) is a rare genodermatosis that is often difficult to diagnose because of clinical overlap with other disorders and its uncertain mode of inheritance. The molecular basis of OS was investigated in an Indian boy using comparative exome sequencing and Sanger sequencing data. Sequencing identified a G‐to‐A transition at position c.573 in the TRPV3 gene, producing the missense mutation p.Gly573Ser in the proband. This mutation was not identified in the mother. This study supports the recent finding of TRPV3 as the gene implicated in OS and suggests that the mutation p.Gly573Ser may be a recurrent abnormality in this genodermatosis.

Mutation analysis of the cathepsin C gene in Indian families with Papillon-Lefèvre syndrome

BackgroundPLS is a rare autosomal recessive disorder characterized by early onset periodontopathia and palmar plantar keratosis. PLS is caused by mutations in the cathepsin C (CTSC) gene. Dipeptidyl-peptidase I encoded by the CTSC gene removes dipeptides from the amino-terminus of protein substrates and mainly plays an immune and inflammatory role. Several mutations have been reported in this gene in patients from several ethnic groups. We report here mutation analysis of the CTSC gene in three Indian families with PLS.MethodsPeripheral blood samples were obtained from individuals belonging to three Indian families with PLS for genomic DNA isolation. Exon-specific intronic primers were used to amplify DNA samples from individuals. PCR products were subsequently sequenced to detect mutations. PCR-SCCP and ASOH analyses were used to determine if mutations were present in normal control individuals.ResultsAll patients from three families had a classic PLS phenotype, which included palmoplantar keratosis and early-onset severe periodontitis. Sequence analysis of the CTSC gene showed three novel nonsense mutations (viz., p.Q49X, p.Q69X and p.Y304X) in homozygous state in affected individuals from these Indian families.ConclusionsThis study reported three novel nonsense mutations in three Indian families. These novel nonsense mutations are predicted to produce truncated dipeptidyl-peptidase I causing PLS phenotype in these families. A review of the literature along with three novel mutations reported here showed that the total number of mutations in the CTSC gene described to date is 41 with 17 mutations being located in exon 7.

Cutaneous Tuberculosis in Children

Abstract:  Cutaneous tuberculosis is a rare form of extrapulmonary tuberculosis that accounts for 1% to 2% of cases. Childhood skin tuberculosis represents 18% to 82% of all cutaneous tuberculosis cases. Scrofuloderma and lupus vulgaris are the two most common clinical forms in children. An increase in the number of tuberculids, especially lichen scrofulosorum, has been observed in the last several years. Cutaneous tuberculosis in children can be severe and have a protracted course. Multiplicity of lesions and multifocal disseminated involvement in scrofuloderma and lupus vulgaris is common. Scrofuloderma progressing to gummatous lesions (scrofulous gumma) is mostly described in children. Morbidities and deformities are more severe in children.

Evolution of clinical pattern of parthenium dermatitis: a study of 74 cases

Our aim was to study the evolution of clinical pattern of parthenium dermatitis. Patients with clinical picture consistent with parthenium dermatitis for 3 years or more along with positive patch test to parthenium were studied. Patients were questioned regarding the site(s) of dermatitis at the onset and change in localization in the following years. Patients were classified into airborne contact dermatitis, chronic actinic dermatitis (CAD) pattern or mixed pattern dermatitis. There were 74 patients (49 men and 25 women) with an age range of 22–70 years and the mean duration of 7.7 years. 60 (39 men and 21 women) patients had airborne contact dermatitis, 5 mixed pattern and 9 CAD pattern at the onset. Of the 60 patients with airborne contact dermatitis, 27 (19 men and 8 women) changed to CAD pattern and 11 (6 men and 5 women) to mixed pattern after an average period of 4.2 years. Of the 19 patients photopatch‐tested with parthenium, 3 showed photoallergic reaction and the other 3 showed photoaggravation. Our results suggest that the clinical pattern of parthenium dermatitis undergoes a significant change after the onset, i.e. progresses from airborne contact dermatitis to mixed pattern or CAD pattern.

Invasive dermatophytosis with lymph node involvement in an immunocompetent patient

A 23‐year‐old man presented with annular and arcuate, hyperpigmented, itchy, scaly plaques over the trunk and lower extremities for 5 years progressing to verrucous papules and nodules for the last 1.5 years. He also had nontender, inguinal and axillary lymphadenopathy. Skin and lymph node biopsies showed granulomatous inflammation and special stains demonstrated long septate hyphae. Tissue cultures grew Trichophyton verrucosum. The patient was treated with itraconazole 100 mg twice daily for 8 months, resulting in complete clearance of the lesions.

Ichthyosiform erythroderma with rickets: report of five cases.

We describe five children with ichthyosis and rickets. The association of ichthyosis and rickets is very rare. Four children had lamellar ichthyosis and one child had nonbullous ichthyosiform erythroderma/psoriasis with atopy. All had biochemical and radiological evidence of rickets. Three had clinically evident rickets, of whom two had very severe skeletal deformities. Such a severe skeletal involvement due to rickets in association with ichthyosis is exceptionally rare. We suggest that children with severe ichthyosis, in particular those with pigmented skin, need to be evaluated for rickets, especially in developing countries where there is a background prevalence of vitamin D deficiency.

Parthenium dermatitis treated with azathioprine weekly pulse doses

BACKGROUND Parthenium dermatitis is a serious problem in India. Corticosteroids are the mainstay of treatment but the prolonged use of corticosteroids can cause serious side effects. Azathioprine used in daily doses has been shown to be effective. AIM We have evaluated the effectiveness of azathioprine weekly pulse doses for the treatment of parthenium dermatitis. METHODS Twelve patients, ten males and two females, aged between 39 and 65 years (mean +/- SD = 53.5 +/- 8.7) having air-borne contact dermatitis to Parthenium hysterophorus for 3-19 years (mean = 6.33) were included in the study. The diagnosis in each patient was confirmed by patch-testing. The severity of the disease was determined by clinical severity score (CSS) on the basis of erythema, itching, type of lesions, and areas of body involved. RESULTS The pretreatment CSS in these patients varied from 29.7 to 55.5 (mean +/- SD: 40.40 +/- 7.95). After clinical and laboratory evaluation, the patients were treated with 300-mg azathioprine once-weekly doses for 6 months. Clinical and laboratory evaluations were repeated at weeks 1, 2, and then every 4 weeks until the end of therapy to evaluate the therapeutic response and side effects. The response was excellent (80-100% clearance of disease) in seven (58.33%) patients and good (60% clearance) in five (41.66%) patients. The post-treatment CSS decreased from the mean +/- SD of 40.4 +/- 7.95 to 10.9 +/- 8.43 (P = 0.002). There were no significant side effects of the therapy. CONCLUSIONS In this preliminary open study, azathioprine in weekly pulse doses has been found to be effective without any serious adverse effects in the treatment of parthenium dermatitis. The cost of therapy with this regimen is reduced by 60%.

Osteoma cutis in pseudohypoparathyroidism.

Osteoma cutis is the formation of normal bone in the skin. Primary osteoma cutis occurs de novo, whereas the secondary type develops in association with the underlying inflammatory, tumorous or traumatic conditions. Primary osteoma cutis is also associated with Albrights hereditary osteodystrophy (AHO), which can include hypocalcaemic‐type pseudohypoparathyroidism (also known as pseudohypoparathyroidism type Ia) or normocalcaemic‐type pseudohypoparathyroidism (also known as pseudopseudohypoparathyroidism). We describe a case of osteoma cutis in a 7‐year‐old boy who had cutaneous, biochemical and phenotypic features of pseudohypoparathyroidism type Ia and AHO.

An Indian child with Kindler syndrome resulting from a new homozygous nonsense mutation (C468X) in the KIND1 gene

Kindler syndrome is an inherited skin condition that presents with blistering followed by photosensitivity and a progressive poikiloderma. The disorder results from mutations in the KIND1 gene, encoding the protein kindlin‐1, a recently characterized 677‐amino acid protein involved in anchorage of the actin cytoskeleton to the extracellular matrix. We report the clinical features of an 11‐year‐old boy with Kindler syndrome from a consanguineous Indian family and the identification of a homozygous nonsense mutation (C468X) in exon 12 of the KIND1 gene in his genomic DNA. This mutation has not been described previously but is similar to the 17 previously published KIND1 mutations that are all predicted to lead to loss of kindlin‐1 protein expression and function. The clinical features in this boy highlight the relevance of kindlin‐1 in skin biology, specifically to epidermal adhesion and response to acute and chronic sun exposure. Delineation of this new pathogenic mutation in KIND1 is also useful for genetic counselling in this family and in assessing carrier status in unaffected family members.