Growth hormone releasing hormone receptor codon 72 mutation in a cohort of Sri Lankan patients with growth hormone deficiency.

INTRODUCTION: Growth hormone releasing hormone receptor (GHRH-R) codon 72 mutation is recognised as a common genetic cause of growth hormone deficiency (GHD) in the Indian subcontinent resulting in a characteristic lean phenotype. Genetic studies have not been previously carried out in Sri Lankans with GHD. METHODS: Patients with GHD presenting to a tertiary care referral centre were studied for GHRH-R codon 72 mutation by PCR amplification and sequencing. The phenotype of the cohort was described as the BMI SDS (Body mass index standard deviation score) based on the anthropometric data at the time of diagnosis. RESULTS: Among 91 patients from 88 families studied, eight (6 boys) carried the codon 72 mutation. The presence of this mutation was low among the Sinhalese ethnicity (3 out of 68) than among Tamil and Moor ethnicities. BMI SDS of <-2 was seen in 71% of mutation positive and 45.8% of mutation negative patients. CONCLUSIONS: Prevalence of GHRH-R codon 72 mutation in this group of GH deficient patients was 8.8%. The lean phenotype observed in 71% of the mutation positive patients was not a significant association when compared to a similar phenotype in 45.8% of the mutation negative patients.

Auxological outcome of growth hormone therapy at cessation of treatment in a cohort of growth hormone deficient Sri Lankan patients.

INTRODUCTION: Recombinant human growth hormone (r-hGH) for growth hormone deficiency (GHD) has been available free in the state hospitals of Sri Lanka since 2009. OBJECTIVES: The aims were to compare height standard deviation scores (SDS) before and after treatment and compare heights at final assessment in relation to the target height (TH) and TH range. METHODS: Patients with confirmed GHD followed up at the University Unit of the Lady Ridgeway Hospital, Colombo were studied. Anthropometric data were prospectively recorded from presentation to cessation of therapy. The height SDS before and after treatment were calculated and the heights at final assessment were compared with the TH and TH range. RESULTS: Sixteen patients (15 boys) had completed treatment. The mean age at diagnosis was 145.38 (SD=34.28) months with a mean skeletal age of 97.5 (SD=42.85) months. Mean ages at commencement was 164.75 (SD=36.81) months and at cessation of therapy 212.06 (SD=30.12) months duration of therapy was 47.31 (SD=23.99) months.Majority had isolated GHD and 8 patients had pituitary hypoplasia on neuro-imaging. The height SDS improved significantly with treatment from -4.438 (1.18) to -3.37 (0.81), p<0.001. When finally assessed at ages ranging from 15 years 10 months to 26 years 9 months, one patient had reached the TH while six were in the TH range. CONCLUSIONS: Auxological response to therapy was significant although treatment was started late due to financial constraints.

Androgen insensitivity syndrome in a cohort of Sri Lankan children with 46, XY disorders of sex development (46, XY DSD).

INTRODUCTION: There are several conditions giving rise to 46, XY disorders of sex development (DSD) with different modes of inheritance. Therefore definitive diagnosis based on molecular genetic confirmation would be the ideal to counsel parents regarding the future implications of the condition affecting their baby. This is the first report from Sri Lanka documenting the presence of mutations in the androgen receptor (AR) gene in a cohort of children with 46, XY DSD. OBJECTIVES: To describe the socio-demographic and clinical features and document the presence of mutations in the androgen receptor (AR) gene in a cohort of children with 46, XY DSD. METHODS: 46, XY patients with ambiguous genitalia followed up in the University Unit at the Lady Ridgeway Hospital, Colombo, and clinically identified as having androgen insensitivity syndrome (AIS) or a testosterone biosynthetic defect were recruited for the study. Their socio-demographic details and clinical features were documented. Exons 1 to 8 of the AR gene were screened for mutations by DNA sequencing on a venous blood sample. SRY gene mutations were also assayed. RESULTS: Thirty-four patients were studied, 3 of whom were clinically diagnosed as having complete androgen insensitivity syndrome (CAIS). Sex of rearing was female and male in 4 and 30 respectively. AR gene mutations were detected in 6 patients (17.6%). None of the patients had SRY gene mutations. CONCLUSIONS: Majority (88%) of the patients were raised as males. Six patients (17.6%) including the 3 with CAIS, had genetically confirmed AIS with the detection of AR gene mutations.

Novel gross deletion at the LHX4 gene locus in a child with growth hormone deficiency.

OBJECTIVE: To identify and characterize a novel deletion at the LHX4 gene locus in a proband with growth hormone deficiency (GHD). METHODS: Long range polymerase chain reaction (PCR) amplification was used to confirm the suspected deletion and to identify the rough locations of the end points. Sanger sequencing was carried out to identify the exact end points of the deletion. RESULTS: Suspected deletion was confirmed via long range PCR amplification. Sanger sequencing identified the end points of the deletion within three nucleotide repeat sequences ("CTT"). The total length of the deleted segment was 12 127 base pairs and it includes complete exon 5 and exon 6 of the LHX4 gene. Therefore the homeodomain motif coded by exons 4 and 5, might be affected. CONCLUSION: We have identified a novel deletion that spans exon 5 and exon 6 of the LHX4 gene that could have occurred via microhomology mediated non-recurrent rearrangement. The deletion characterized does not appear to have been reported before. To our knowledge this novel deletion is the first identified LHX4 variant from Sri Lanka and it explains the phenotype of the proband characterized by growth hormone deficiency, hypoplastic anterior pituitary and subsequent deficiency of thyroid stimulating hormone and adrenocorticotropic hormone (ACTH).

Assessment of the psychological status of children with growth hormone deficiency and their parents.

INTRODUCTION: Children with growth hormone deficiency may have psychological ramifications due to their disease condition. Having a child with growth hormone deficiency may affect the parents' psychological health. OBJECTIVES: To assess the psychological health of children with GHD and their parents. METHODS: A descriptive cross sectional study was done over four years from July 2006 on children with growth hormone deficiency. The self-administered, culturally validated Personality Assessment Questionnaire (PAQ) was given to children above 8 years of age. By considering seven personality dimensions, the PAQ assesses whether a child is psychologically maladjusted. A score > or = 89 indicates such maladjustment. The parents were given the self-administered General Health Questionnaire-30 (GHQ-30). A score > or = 4 is indicative of mental health difficulties in the respondent. RESULTS: Fourty of 56 children with GHD were more than 8 years of age and there were 33 boys. According to the PAQ, 24 children (60%: 19 boys) appeared to be psychologically maladjusted. Of the 74 parents (47 mothers) who answered the GHQ-30, forty (54%) were deemed to have mental health difficulties, a majority of them were mothers. CONCLUSIONS: Psychological maladjustment was observed in a majority of children in the study and most of their mothers had mental health difficulties.

Assessment of distance from skin surface to muscle for evaluation of the risk of inadvertent intramuscular insulin injection at potential injection sites among patients attending a tertiary care children's hospital in Sri Lanka-an observational study.

BACKGROUND: Insulin therapy is essential for type 1 diabetes. While a reasonable glycemic control prevents complications, inadvertent intramuscular (IM) insulin injection results in hypoglycemia and fluctuations of blood glucose levels. OBJECTIVE: To assess the subcutaneous thickness (SCt) at the potential insulin injection sites, in order to determine the suitable needle length. METHODS: Diabetic and non-diabetic children (n=125; aged 2-14 years) attending a tertiary care hospital were examined, after excluding those who had skin abnormality at the injection site, were hospitalized for>3 days, or had any other chronic illnesses. Dermal thickness (Dt) and SCt at the potential insulin injection sites were measured with ultrasonography. RESULTS: The mean age of the patients was 8 years and 57% were boys; mean Dt was 2.1±0.4 mm, SCt was 7.45.6±3.7 mm, and maximum SCt was 29.8 mm in the anterior abdominal wall. SCt increased with age and by raising a skin fold (sf). There was no difference (P>0.05) in Dt between genders, and limbs showed thinner Dt values than the abdomen. SCt changed with the injection site: it was the lowest in the thigh and the highest in the abdomen. SCt was thicker in females, with or without sf (P<0.001). For all sites, IM risk was high for 15-mm needles: it was highest in the thighs (98%) and reduced to 86% with sf. IM risk was low for 5-mm needles: it was highest in the thigh (38%), and reduced to 12% with sf. Compared with girls (up to 42%), IM risk was higher for boys (up to 54%), even for 5-mm needles with a sf. CONCLUSION: Using a short needle is recommended for children, particularly for boys. Regardless of the needle length, the raised sf technique is associated with reduced IM risk.

Metabolic consequences of childhood obesity--a preliminary report.

INTRODUCTION: Childhood obesity is increasing in Sri Lanka. Obesity related morbidity is mainly associated with the metabolic syndrome (MetS) and non-alcoholic steatohepatitis (NASH). Recent studies have shown these serious health consequences in obese children. OBJECTIVES: The objectives of our study were to document the presence of MetS and NASH in obese Sri Lankan children, to correlate the fat mass (FM) with the waist circumference (WC) and the body mass index (BMI), and to compare the association of the WC, BMI and the WHR (waist-hip ratio) with the metabolic derangements. METHOD: Children attending the Obesity Clinic at Lady Ridgeway Hospital, Colombo, from November 2004 to September 2005 were studied. The relevant sociodemographic data, anthropometric measurements and examination findings were documented. After a 12-hour overnight fast, blood was taken for estimation of lipid profile, serum insulin, liver enzymes and blood glucose. The oral glucose tolerance test (OGTT) was done in children over 5 years of age. Fatty infiltration of the liver was assessed by identifying specific features on ultrasonography and the degree of infiltration was given a score. We modified the International Diabetes Federation (IDF) 2004 guidelines to define MetS. NASH was defined as fatty infiltration of the liver associated with a raised serum ALT. RESULTS: Seventy children (40 boys) were studied. The mean (SD) age was 9.7 (2.5) and 9.3 (3.0) years for boys and girls respectively. Mean BMI was 25.9 in both groups. All patients had a WC > 98th percentile. MetS was found in 13 of the 63 (21%) children on whom all criteria were assessed. Sixty children had ultrasonography and NASH was seen in 11 (18%). The correlation of the percentage FM was greater with the BMI (r = 0.80; p < 0.001) than with the WC (r = 0.56; p < 0.001), but the WC was more significantly associated with the metabolic derangements than either BMI or WHR. CONCLUSIONS: Serious metabolic abnormalities are found in obese Sri Lankan children and the WC is a reliable indicator of these derangements.

Seroprevalence of hepatitis A antibodies in relation to social factors--a preliminary study.

INTRODUCTION: Hepatitis A is a benign illness in children with the rare possibility of fatal complications. Although an endemic disease, very few studies have been done in children regarding the seroprevalence of hepatitis A antibodies in Sri Lanka. OBJECTIVES: (i) To document the seropositivity for hepatitis A in a group of children admitted to a paediatric ward. (ii) To determine the relationship of hepatitis A viral infection to social factors in these children. METHOD: A prospective, descriptive, cross-sectional study was carried out in a ward at the Lady Ridgeway Hospital for 7 months from September 2001. Children admitted on predetermined days, needing venepuncture for their presenting illness, were studied while those who were seriously ill were excluded. Written consent was obtained and a questionnaire with details of socio-economic conditions, personal hygiene practices of the mother, access to water and sanitation and health related behaviour was administered. Total antibodies to hepatitis A were detected by ELISA on a sample of blood taken from each patient. RESULTS: Two hundred and eighty eight samples of blood were analysed. None of the children were immunised against hepatitis A. There were 158 boys (54.9%). Thirty one (10.8%) of the 288 patients had antibodies against hepatitis A. The seroprevalence was 11.6% in children under 10 years of age. Majority (78%) were from families with a monthly income of less than Rs 10,000/-. Fifteen (48.4%) of the 31 seropositive children were from families earning less than Rs 5000/- per month. Belonging to social classes IV and V and having mothers with only primary education were factors significantly associated with seropositivity. No significant difference in the presence of antibodies was observed regarding the personal hygiene practices analysed and access to basic amenities. Health related behaviour practices analysed were significantly associated with the presence of hepatitis A antibodies. CONCLUSIONS: Seroprevalence of 10.8% was observed in a selected group of children. Factors such as poor socio-economic background and having mothers with only primary education were associated with hepatitis A virus (HAV) antibodies as were certain health related behaviour practices of children.

24-hour ambulatory blood pressure profile in patients with congenital adrenal hyperplasia--a preliminary report.

BACKGROUND: Blood pressure (BP) is maintained within normal limits by the interplay of various mechanisms including the action of cortisol and aldosterone. However, these hormones when exogenously administered are not under the regulatory feedback mechanisms that maintain BP homeostasis. Treatment of congenital adrenal hyperplasia (CAH) requires glucocorticoid replacement (with or without additional mineralocorticoid) at supra-physiological doses to normalize the pituitary adrenocortical axis. HYPOTHESIS: Long-term use of glucocorticoids at supra-physiological doses may result in high BP. OBJECTIVE: To document any changes in BP in patients with CAH following long-term conventional glucocorticoid replacement therapy. PATIENTS AND METHODS: 24-hour ambulatory BP (AmBP) monitoring was performed in 11 patients with CAH, all of whom were on glucocorticoid replacement at supra-physiological doses. In addition, a single random BP measurement was taken in each patient at enrolment. Mean systolic and diastolic pressure during awake and sleep periods, systolic and diastolic BP loads, and systolic and diastolic BP dips were calculated from the 24-hour AmBP profile of each patient, which was correlated with demographic and treatment details. AmBP readings were compared to Task Force references for casual BP and also to recently available AmBP specific reference values. RESULTS: None of the patients had significant BP loads at the 95th percentile (hypertensive BP range) using references for casual BP readings. However, in the subgroup of patients who had significant BP load at the 90' percentile (high normal BP range), higher mean systolic and diastolic pressures were noticed during the awake period. Seven patients did not have a systolic dip with or without a diastolic dip. There was no significant correlation between various BP parameters and demographic or treatment details in our sample. However, one patient had daytime systolic hypertension and six had nocturnal hypertension using AmBP specific reference values. CONCLUSIONS: In this preliminary study, longterm glucocorticoid replacement therapy at supra-physiological doses does not seem to be associated with hypertension in young people with CAH when using casual BP references. However, higher mean BP was noticed in the subgroup of patients with significant systolic or diastolic BP load at high normal BP range, and evidence of daytime and nocturnal hypertension was uncovered using AmBP specific reference values. Further large trials using appropriate BP references are necessary to clarify the significance of these findings.

Ovarian lesions in children and adolescents--an 11-year review.

OBJECTIVE: To describe the spectrum of pediatric ovarian pathology, identifying the clinical features and ultrasound characteristics that help in decisions about patient management, and to correlate these with ovarian pathology. PATIENTS AND METHODS: Retrospective analysis of 134 records of patients admitted with ovarian lesions to Royal Children's Hospital, Melbourne over an 11-year period (1989-99 inclusive). RESULTS: The age of presentation varied widely from 2 days to 19 years with 63.4% being over 12 years of age. Eighty-one patients (60.4%) had physiological or functional ovarian cysts, 52 of which required surgical intervention. Forty-four patients (32.8%) had neoplastic lesions and a palpable abdominal mass was felt in 53.7% of them. Mature cystic teratoma or dermoid cyst, seen in 27 patients, was the commonest neoplasm, and 77.8% of these children were under 12 years. Six children had malignant ovarian neoplasms, of which five were germ cell in origin. Five patients had epithelial or stromal neoplastic lesions. Endocrine manifestations were seen in seven patients and included early or precocious puberty and virilization. Plain trans-abdominal ultrasonography was useful in identifying ovarian lesions in 94 (81.7%) of the 115 patients in whom it was performed, but was not helpful in determining the nature of the lesion. Neoplastic ovarian lesions were commonly greater than 10 cm in diameter CONCLUSIONS: Physiological or functional ovarian cysts are the most common ovarian lesions seen in the pediatric age group and malignant neoplasms are rare. A palpable abdominal mass or ovarian lesion >10 cm was significantly associated with the lesion being neoplastic. Lesions <5 cm in post-pubertal girls were significantly more likely to be non-neoplastic. Ultrasonography is useful in localizing ovarian lesions but is not helpful in determining their pathological nature. Endocrine manifestations sometimes occur with either benign or malignant lesions of the ovary.

Clinical examination in paediatrics at final MBBS: views of children and their parents.

INTRODUCTION: The final examination in paediatrics for medical undergraduates in Sri Lanka consists of a written and a clinical component. Each candidate at the clinical component sees one long case and two short cases. OBJECTIVES: To assess the views of the bystanders regarding their sick children participating at a clinical examination, and to evaluate the children's perceptions of the clinical component. METHODS: An interviewer-administered questionnaire was discussed separately with the participating children and their bystanders at the final year examination in paediatrics of the Faculty of Medicine, Colombo, in 1999. RESULTS: 116 patients participated at the clinical examination in paediatrics. 107 (92%) of the bystanders were the children's mothers. Informed consent had not been obtained for use in the examination from 59 (51%) of the children's mothers. Seven (6%) were not satisfied with the way their children were handled by the candidates, and 25 (21.5%) showed concern about the number of candidates examining their child. Bystanders who participated at the long cases were inconvenience more than those in the short cases. 34 children above the age of 5 years were also interviewed. An explanation regarding the examination had not been given to 31 (92%) of them. Six children (17%) said they were examined for too long. A majority of the bystanders welcomed the payments received and all of them were satisfied with the medical students' conduct and politeness. All of them agreed that this form of clinical examination was a good method of evaluating a student's professional competence. CONCLUSIONS: Several aspects of the clinical component of the final examination in paediatrics for medical undergraduates need to be improved to minimise the inconvenience experienced by the children and their parents.

Phaeochromocytoma presenting with polyuria: an uncommon presentation of a rare tumour.

UNLABELLED: Children rarely present with phaeochromocytoma. Their presentation differs from that of adults. The classic triad of sweating, headache and palpitation may not always present in children with phaeochromocytoma. In this study, we present a 6-year-old girl who came to us with polyuria and polydipsia for evaluation of suspected diabetes insipidus. She gave a clear history of increased sweating in the recent past. On clinical examination, she was noted to have high blood pressure. Subsequent investigations revealed a phaeochromocytoma. Her polyuria and hypertension resolved immediately after the surgery. We did not have the facilities to arrange for genetic tests; however, the patient and the family members are under follow-up for other associated conditions. LEARNING POINTS: Polyuria and polydipsia are rare symptoms of phaeochromocytoma.Complete physical examination prevented unnecessary investigations for polyuria and led to a correct diagnosis.Classic features are not always necessary for diagnostic evaluation of rare diseases.

Psychological impact on parents of children with congenital adrenal hyperplasia: a study from Sri Lanka.

INTRODUCTION: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessively inherited disorders with significant morbidity. The long-term implications result in immense psychological stress to the parents. This study assessing the psychological impact on the parents is a first in Sri Lanka and one of the few worldwide. OBJECTIVE: Document the presence of depressive symptoms in parents of children with CAH. DESIGN: Study participants were 37 parents of children diagnosed with CAH who were attending an endocrinology clinic of the largest children's hospital in Sri Lanka. Centre for Epidemiological Studies-Depression scale (CES-D), a psychometrically sound scale for assessing depressive symptomatology, was used. RESULTS: The study classified 59% of the parents as being affected, and the psychological impact on them did not reduce with time. CONCLUSION: Parents of children with CAH demonstrated symptoms of depression that did not abate with the passage of time.