Clinical and Radiological Characterisation of Patients with Mucopolysaccharidosis in a Genetic Clinic

Abstract The mucopolysaccharidoses (MPS) are a relatively uncommon group of inherited metabolic disorders. MPSs should be suspected in a child with coarse facies, organomegaly, recurrent respiratory tract infections, developmental delay, and hernias. Early diagnosis and treatment can greatly improve the quality of life in these children. In this study we studied 46 MPS patients diagnosed on enzyme and/or DNA testing and we found that the MPS II was the most common type followed by MPS I and MPS IVA. While the mean age of onset of symptoms was 12 months, the mean age at diagnosis was 4.5 years, a significant delay. One of major presenting features was recurrent respiratory problems, more prevalent in MPS II cases. Many patients also had short stature and contractures. Increasing awareness among physicians is of paramount importance for the early diagnosis and optimal treatment and prevention by prenatal testing and counselling.

Severe liver dysfunction in an infant with cystic fibrosis masquerading as metabolic liver disease.

We present a rare presentation of cystic fibrosis with neonatal cholestasis. Histological features of mucoviscidosis were present in liver involving the biliary tract, intestinal mucosa, pancreas, and lung. Besides, there was a rare association with autosomal dominant type of polycystic renal disease.

Thyroid Dysfunction in Indian Children with Down Syndrome.

This record review of 82 children with Down Syndrome (DS) between April 2004 and March 2014 who had thyroid dysfunction, showed that majority (76, 92.6%) had subclinical hypothyroidism. Of the 60 patients who underwent radionuclide scan, 63.3% had a normal gland; the rest exhibited only impaired tracer uptake. Ultrasonograms done in 20 patients showed reduction of thyroid gland size in 3 (15%) patients only.

Proteus syndrome: Clinical profile of six patients and review of literature.

OBJECTIVE: Proteus syndrome (PS) is characterized by patchy or segmental overgrowth and hyperplasia of multiple tissues and organs, along with susceptibility to development of tumors. Very few cases are reported in literature from developing countries. Due to certain overlapping features with other overgrowth syndromes, diagnosis is usually delayed. Our aim was to describe clinical profile of this rare condition in six patients. MATERIALS AND METHODS: Retrospective case sheet review of patients followed in a Pediatric Genetic and Metabolic clinic at a tertiary care institute of North India with a diagnosis of hemihypertrophy/overgrowth syndrome. RESULTS: Six cases presented with asymmetric overgrowth and peculiar features suggestive of PS were included in this study. Age at presentation was 2 months to 10 years; two were males and four were females. Hemihypertrophy was noticed in only one case at birth, and focal overgrowths in rest of other patients were seen later during childhood. CONCLUSION: Due to certain overlapping features with other overgrowth syndromes, diagnosis of PS is usually delayed. Pediatricians are the first persons who come across such patients and they should be aware about this rare condition.

Rubinstein-taybi syndrome: Clinical profile of 11 patients and review of literature.

Background: Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder, characterized by postnatal growth deficiency, typical dysmorphic features, broad thumbs and toes, and mental retardation. Very few cases are reported in literature from developing countries. Diagnosis is often delayed due to non-familiarity with the characteristic features of this syndrome. Aims: To report 11 cases of RSTS and to review the current literature. Settings And Design: Retrospective study conducted in genetic and metabolic unit of a tertiary care teaching hospital in north India over a period of 3½ years. Materials And Methods: 11 patients with diagnosis of RSTS were identified, and their case sheets were reviewed. Results: Developmental delay was presenting complaint in 10 patients, and seizure in 1 case. 7 patients had microcephaly (head circumference below −3 SD), and a prominent beaked nose was seen in 9 patients. The intelligence quotient (IQ) varied from 22-62 in 7 patients who had mental retardation. The most notable features in hands were broadness, shortening, and flattening of the distal phalanx of thumbs or great toes. Additionally, we also noted webbing of neck, microphthalmia, and pachygyria (on MRI brain) in 1 patient each. Conclusions: The diagnosis of RSTS is primarily clinical and based on characteristic phenotype that is often combined with a variety of somatic anomalies. An early diagnosis facilitates appropriate genetic counseling and in planning the management.

Craniosynostosis genetics: The mystery unfolds.

Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis is common form of isolated craniosynostosis. The sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. Crouzon syndrome is one of the most common of the craniosynostosis syndromes. Apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis require multidisciplinary management. The following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis and genetic counseling.

Seckel syndrome with chromosomal 18 deletion.

Four case records of patients with Seckel Syndrome (SS) were retrieved. Typical of bird headed dwarfism was seen in all. Chromosome 18 deletion was seen in one child with SS. MRI abnormalities were detected in 3 patients. Cytogenetic studies and neuroimaging is likely to provide important diagnostic and prognostic information.

Pediatric disorders of sex development.

The management of disorders of sexual differentiation (DSD) involves a multidisciplinary approach. The main aim of analysis was to study the phenotype-karyotype correlation in North Indian children with DSD. The records of pediatric DSD were retrieved and characteristics noted. Of total of 58 children, 43 (74.1%) and 10 (17.2%) were raised as males and females respectively. The mean age at presentation was 31.3±9 months. The karyotype was 46XY in 45 (77.6%) and 46XX in 12 (20.7%). CAH was commonest cause of DSD (36.2%), followed by gonadal dysgenesis. Of the 15 patients of 46 XY CAH, there were 5 with 17-α hydroxylase deficiency, 2 with 3-β HSD deficiency and one case of lipoid adrenal hyperplasia. There was an excess of genetic males, possibly due to prevalent socio-cultural factors and gender bias favoring males. There is a need to improve the diagnostic facilities and incorporate a team approach in management of DSD.

Fulminant candida infection in an infant with acrodermatitis enteropathica.

Acrodermatitis Enteropathica (AE) is an important nutritional disorder of children affecting both innate and cell mediated immunity. It predisposes to secondary bacterial and candida superinfections. We describe an infant with typical features of AE who had candida infection with a fulminant course. Need of early recognition and prompt initiation of therapy for fungal infection in AE is emphasized.

Effect of wheat grass therapy on transfusion requirement in beta-thalassemia major.

OBJECTIVE: To assess the efficacy of wheat grass juice on transfusion requirement in patients with beta thalassemia major. METHODS: Fifty-three patients of thalassemia major with a median age of 16 years were given wheat grass juice tablets. RESULTS: The Mean pre and post wheat grass therapy, the pack cell requirement was 288.06 +/- 53.25 gm/Kg/year and 301.25 +/- 54.86 gm/Kg/year (p =0.054) respectively. No adverse effects were noted. CONCLUSION: We conclude that wheat grass therapy for one year is not effective in reducing the transfusion requirement in transfusion dependent thalassemia.

HFE mutation H63D predicts risk of iron over load in thalassemia intermedia irrespective of blood transfusions.

Iron overload is a well-documented complication in thalassemia intermedia. Moreover, it is seen that the number of blood transfusions received does not correlate with the degree of overload. Since, HFE gene is associated with iron overload; the present study was conducted in an attempt to evaluate its role in thalassemia intermedia. The subjects were consecutive thalassemia intermedia cases attending the Hematology outpatient clinic. Controls were healthy hospital staff with negative family history of hemolytic anemia or liver disease. The molecular analysis for HFE mutations H63D and C282Y were done with primers described earlier. ELISA was used to measure serum ferritin. Sixty-three patients of thalassemia intermedia including 48 beta-homozygous/heterozygous thalassemia intermedia and 15 HbE-beta-thalassemia were studied. Six (12.5%) of the former and two (13.3%) of the latter were heterozygous for H63D; one of which, a 51-year old male also had clinical features of hemochromatosis. In healthy controls, prevalence of H63D heterozygosity was 7.5% (6/80). An interesting feature observed was that though the age and transfusions taken were similar in both groups, the serum ferritin greater than 500 ng/dl were observed in all patients (100%) with HFE mutation whereas it was seen in 12/42 (28.6 %) of patients without the mutation (p = 0.002). Thus, it is concluded that thalassemia intermedia patients with co-existent HFE mutation have a higher likelihood of developing iron overload and may require early iron chelation.

Spectrum of anemia in pregnant Indian women and importance of antenatal screening.

Anemia is a common health problem but control of anemia in pregnant women is less well studied. The purpose was to study prevalence of anemia in young pregnant women, correlate with indices and study significance of identification of hemoglobinopathies. Of the 120 pregnant women, Hb was less than 8 g% in 58 (44.2%). Seventy-eight (65%) had iron deficiency, 22 (18.3%) had dimorphic anemia, and 14 (11.6%) had hemolytic anemia. Megaloblastic anemia was present in 6 (5%). Of hemolytic anemia, 50% were thalassemia trait. MCV< 76 fl was observed in 88 (73.3 %) cases. MCV<76 fl and MCH < 27 pg had 100 % sensitivity and 28.7 % specificity for screening of beta-thalassemia trait. NESTROFT had comparable sensitivity but lower specificity (14.9%). Sixty-three percent (60/78) of IDA had increased RDW whereas 78 % (11/14) of hemolytic anemia had RDW value in normal range (p value< 0.05). MCV/RBC of <14 was more specific parameter (96.8%) for beta-thalassemia trait. Four high-risk couples were identified. Thus, moderate to severe anemia was observed in most pregnant women. Hemoglobinopathies should be screened in antenatal clinics to identify the couples that would need a prenatal test. A lower MCV/RBC with RDWin the normal range may be useful in screening for thalassemia trait in pregnant women.

Common queries in thalassemia care.

Beta thalassemia is a common genetic disorder in Indians. Around 10,000 thala-ssemia major cases are born every year. The treatment of thalassemia major patients imposes a financial burden on the family. Much progress has been made in last 15 years in understanding of the pathogenesis of thalassemia and development of effective management(1). These include development of a promising new oral iron chelator, intensive preparative regimens for stem cell transplantation and better vectors for gene therapy. In the present article, we highlight the common questions asked by the family and the general practitioners on thalassemia care.

Therapy-related acute promyelocytic leukemia after treatment of carcinoma breast--a case report.

We report a 43-year-old female, with acute promyelocytic leukemia occurring after 9 months of treatment for carcinoma breast. The diagnosis of APL was made on morphology, cytogenetics and molecular studies. In contrast to other published report of therapy related APL (tAPL) the present case presented early after the primary malignancy and underwent a rapid, downhill course.

Imatinib mesylate: A designer drug.

Molecularly targeted therapy is a novel approach in cancer treatment. Imatinib, a specific tyrosine kinase inhibitor, since its inception in 1990s, has become the first-line drug in management of chronic myelogenous leukemia (CML) chronic phase. It has also shown promising results in treatment of gastro-intestinal stromal tumors, clonal eosinophilic disorders and Philadelphia chromosome positive acute lymphatic leukemia. The efficacy of imatinib has geared up further research into development of designer drugs with molecular targets. This review gives a comprehensive description of the development, biology, utility, dosing, and limitations of imatinib mesylate.

Role of MTHFR C677T polymorphism in ischemic stroke.

BACKGROUND: Homozygosity for MTHFR C677T polymorphism can lead to significantly high homocysteine levels and hyperhomocysteinemia is an important risk factor for thrombotic events. AIMS: The aim was to determine role of MTHFR C677T polymorphism in North Indians with ischemic stroke. SETTINGS AND DESIGN: In a prospective study, the subjects of stroke were recruited from the neurology clinic of the hospital. Controls were healthy individuals from the Hematology clinic without any history of stroke. MATERIALS AND METHODS: Plasma homocysteine levels were measured by enzyme immuno assay method after 3 months of acute episode. Serum folate and Vitamin B12 levels were estimated by competitive inhibition radioassay. MTHFR polymorphism was detected by PCR-RFLP using Hinf I enzyme. Statistical analysis: The analysis of significance of results was done using SPSS software package. A p-value. RESULTS: Thirty-two acute ischemic stroke patients (aged 1-44 years) were studied. Fourteen (43.8%) had recurrent stroke. Nine (28%) had multiple infarcts. Four of 32 patients (12.5%) had high homocysteine levels. Three out of these 4 hyper-homocysteinemia patients were homozygous ( TT ) for MTHFR polymorphism (2 with recurrent stroke). Two of three homozygous cases with TT genotype had low serum folate. Five of 32 stroke cases (18.8%) were heterozygous ( CT ) genotype. CONCLUSIONS: Primary hyper-homocysteinemia appears to be an important risk factor for ischemic stroke in North Indians, most due to MTHFR C677T homozygosity. Folate levels may modify the presentation of the MTHFR TT genotype.

Fowler-like syndrome with extreme oligohydramnios, growth restriction and without muscular hypoplasia.

We report the seventh family of Fowler like syndrome (proliferative vasculopathy and hydrocephaly-hydrencephaly syndrome) and first case from Indian subcontinent. A 35 weeks extremely growth retarded male baby showed enlarged ventricles, thinned out cerebral cortex, diffuse intra-cerebral as well as peri-ventricular calcification, cerebral and corneal vasculopathy, unilateral micro-ophthalmia along with corneal opacity and depressed pulsatile anterior fontanel. This case was different from others concerning association with extreme oligohydramnios (in contrast to polyhydramnios), extreme growth restriction (in contrast to normal growth) and absence of gross muscle hypoplasia. No causative factors like TORCH infection, chromosomal abnormality or positive family history was noted in this case.