Identical Twins with Infantile Systemic Hyalinosis: Case study and review of literature.

INTRODUCTION: Infantile Systemic Hyalinosis (ISH) is a rare and fatal genetic disorder with mutations in Capillary morphogenesis gene-2 CMG2 / Human anthrax toxin receptor gene-2 ANTXR2 resulting in spindle cell proliferation, altered collagen metabolism with extensive deposition of amorphous eosinophilic PAS positive hyaline material in the connective tissues of various organs. The common presenting features would be progressive stiffness of multiple joints, skin lesions, multiple episodes of protracted infections, prolonged diarrhoea and failure to thrive. ISH is a rapidly progressive painful disorder of infancy with a very short life expectancy. CASE PRESENTATION: 3 months old identical twins born to a 5th degree consanguinous couple were brought with complaints of excessive cry, deformity of all four limbs, recurrent episodes of respiratory tract infections and diarrhoea since birth. Evaluation of both the probands revealed facial dysmorphism with perinasal nodules, gingival hypertrophy, fixed deformities of multiple joints bilaterally, umbilical hernia, fleshy perianal nodules and pigmented patches over knuckles and ankle. A clinical diagnosis of ISH was suspected and confirmed by detection of homozygous c.277_278insATTATTT (or p.L93Yfs*14) in exon 3 of the ANTXR2 gene. The probands were managed symptomatically and parents were counselled regarding prenatal diagnosis in future pregnancies. CONCLUSION: IHS is commonly misdiagnosed as Arthrogryposis Multiplex Congenita and is often mismanaged with manipulation of the stiff joints and invasive surgical procedures. Prenatal diagnosis by chorionic villus biopsy is possible once causative mutation in a family is identified. Invasive surgical interventions for histopathological analysis can be avoided as clinical features are most often classical and genetic analysis is confirmatory. Management is conservative and symptomatic. We report this case of identical twins with features of ISH in view of its rarity as timely clinical suspicion can avoid painful and invasive procedures for diagnosis and management.

Clinical profile and mutation analysis of xeroderma pigmentosum in Indian patients.

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by cutaneous and ocular photosensitivity and an increased risk of developing cutaneous neoplasms. Progressive neurological abnormalities develop in a quarter of XP patients. AIM: To study the clinical profile and perform a mutation analysis in Indian patients with xeroderma pigmentosum. METHODS: Ten families with 13 patients with XP were referred to our clinic over 2 years. The genes XPA, XPB and XPC were sequentially analyzed till a pathogenic mutation was identified. RESULTS: Homozygous mutations in the XPA gene were seen in patients with moderate to severe mental retardation (6/10 families) but not in those without neurological features. Two unrelated families with a common family name and belonging to the same community from Maharashtra were found to have an identical mutation in the XPA gene, namely c.335_338delTTATinsCATAAGAAA (p.F112SfsX2). Testing of the XPC gene in two families with four affected children led to the identification of the novel mutations c.1243C>T or p.R415X and c.1677C>A or p.Y559X. In two families, mutations could not be identified in XPA, XPB and XPC genes. LIMITATION: The sample size is small. CONCLUSION: Indian patients who have neurological abnormalities associated with XP should be screened for mutations in the XPA gene.

Chronic myeloid leukemia in case of Klinefelter syndrome.

Klinefelter syndrome (KS) is a sex chromosome disorder and has been reported to be associated with increased risk for malignancies. We report a 22-year-old male patient who was diagnosed to have chronic myeloid leukemia in chronic phase. Bone marrow cytogenetic examination revealed karyotype 47, XXY, t (9; 22)(q34, q11) suggestive of KS with presence of Philadelphia chromosome. The patient was treated with oral imatinib mesylate (400 mg/day). Complete hematological response was achieved after 2 months of therapy. The bcr-abl/abl transcript percentage measured from peripheral blood at baseline, 1 and 2 years after imatinib were 97%, 1.99%, 0.007%, respectively. He remains in complete hematological and major molecular remission after 2 years of continued imatinib therapy.

Identification of novel ROR2 gene mutations in Indian children with Robinow syndrome.

OBJECTIVE: Robinow syndrome (RS) is an extremely rare genetic disorder characterized by short-limbed dwarfism, defects in vertebral segmentation and abnormalities in the head, face and external genitalia. Mutations in the ROR2 gene cause autosomal recessive RS (RRS) whereas mutations in WNT5A are responsible for the autosomal dominant (AD) form of RS. In AD Robinow patients, oral manifestations are more prominent, while hemivertebrae and scoliosis rarely occur and facial abnormalities tend to be milder. METHODS: Three unrelated patients from different parts of India were studied. These patients were diagnosed as RRS due to presence of characteristic fetal facies, mesomelia, short stature, micropenis, hemivertebrae and rib abnormalities. One of the patients had fetal facies and micropenis but unusually mild skeletal features. This patient's mother had mild affection in the form of short stature and prominent eyes. Testosterone response to human chorionic gonadotropin was investigated in two patients and were normal. The exons and exon-intron boundaries of the ROR2 gene were sequenced for all probands. Bioinformatics analysis was done for putative variants using SIFT, PolyPhen2 and Mutation Taster. RESULTS: Patients 1, 2 and 3 were homozygous for c.G545A or p.C182Y in exon 5, c.227G>A or p.G76D in exon 3 and c.668G>A or p.C223Y in exon 6 respectively. Prenatal diagnosis could be performed in an ongoing pregnancy in one family and the fetus was confirmed to be unaffected. CONCLUSION: ROR2 mutations were documented for the first time in the Indian population. Knowledge of the molecular basis of the disorder served to provide accurate counseling and prenatal diagnosis to the families.

Serum 17 alpha hydroxyprogesterone in normal full term and preterm vs sick preterm and full term newborns in a tertiary hospital.

OBJECTIVES: To determine the variables affecting serum 17 hydroxyprogesterone (17OHP) in neonates born at a tertiary hospital in Mumbai, India. METHODS: Serum 17OHP was measured in peripheral venous blood between 3rd to 5th day of life by competitive radioimmunoassay and on follow up at 3 mo of age. Serum 17OHP was compared among four groups [full term healthy(FT), full term stressed(FS), preterm healthy(PT), preterm stressed(PS)] by non-parametric tests (Kruskal Wallis (KW) test and Mann- Whitney (MW) test). Pearson's test was used to correlate natural log of serum 17OHP (ln17OHP) with variables like gestational age, birth weight, stress factor, sex, antenatal administration of glucocorticoids to mothers, Apgar score at 5 min and mode of delivery. Linear regression analysis was done using significant variables in Pearson's test to determine best predictors of ln17OHP. RESULTS: The initial median (number of cases, inter-quartile range) serum 17OHP (ng/ml) for the four groups was as follows; FT 8.4 (33, 6-13); PT 20 (36, 11-29.5); FS 34 (29, 26-45) and PS 58 (24, 40.75-76.5) [total N = 122 newborns, p = 0.001]. Pearson's test showed that gestational age, birth weight, stress factor, Apgar score were negatively correlated with 17OHP whereas stress factor, mode of delivery, use of antenatal steroids in mothers were significantly positively correlated. However, stress factor emerged as the most important significant positive predictor (multiple R = 0.643, P = <0.0001). On follow up at 3 mo age, the median 17OHP (N = 73 newborns) had significantly decreased to normal level. CONCLUSION: Stress due to neonatal illnesses like meconium aspiration, sepsis, birth asphyxia, etc. significantly elevate serum 17OHP and may lead to false positives in newborn screening for congenital adrenal hyperplasia.