GTP-Cyclohydrolase I deficiency presenting as malignant hyperphenylalaninemia, recurrent hyperthermia and progressive neurological dysfunction in a South Asian child - a case report.

BACKGROUND: Tetrahydrobiopterin (BH4) deficiencies are disorders affecting phenylalanine homeostasis, and catecholamine and serotonin biosynthesis. GTP-Cyclohydrolase I deficiency (OMIM 600225) is an extremely rare variant of inborn error of BH4 synthesis which exists in recessive and dominant forms. The recessive form presents with complex neurological and autonomic dysfunction whilst the dominant form presents as Dopa-responsive dystonia. CASE PRESENTATION: We describe a South Asian child who initially presented with neurological dysfunction and recurrent vomiting and later developed recurrent hyperthermia for several months. The child did not have screening for hyperphenylalaninemia at birth and was found to have marked hyperphenylalaninemia after clinical presentation at 5 months. Further evaluation revealed BH4 deficiency. GTP-Cyclohydrolase I deficiency (GTPCH) was identified based on normal dihydro pteridine reductase activity and markedly reduced neopterin in dried blood spot test. After institution of treatment and control of high phenylalanine levels, clinical deterioration decelerated yet with noticeable residual neurological dysfunction. CONCLUSION: To authors' knowledge, this is first report of GTPCH deficiency in a South Asian child. The case highlights practical issues regarding diagnosis of GTPCH deficiency, especially in countries without broader universal newborn screening programs for early detection of inherited metabolic disorders. Testing for GTPCH deficiency should be considered for patients with unexplained neurological and autonomic symptoms following initial metabolic screen.

Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features.

BACKGROUND: Gillespie syndrome is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia, non-progressive cerebellar ataxia and intellectual disability. Homozygous and heterozygous pathogenic variants of the ITPR1 gene encoding an inositol 1, 4, 5- triphosphate- responsive calcium channel have been identified in 13 patients recently. There have been 22 cases reported in the literature by 2016, mostly from the western hemisphere with none reported from Sri Lanka. CASE PRESENTATION: A 10-year-old girl born to healthy non-consanguineous parents with delayed development is described. She started walking unaided by 9 years with a significantly unsteady gait and her speech was similarly delayed. Physical examination revealed multiple cerebellar signs. Slit lamp examination of eyes revealed bilateral partial aniridia. Magnetic resonance imaging of brain at the age of 10 years revealed cerebellar (mainly vermian) hypoplasia. Genetic testing confirmed the clinical suspicion and demonstrated a heterozygous pathogenic variant c.7786_7788delAAG p.(Lys2596del) in the ITPR1 gene. CONCLUSION: The report of this child with molecular confirmation of Gillespie syndrome highlights the need for careful evaluation of ophthalmological and neurological features in patients that enables correct clinical diagnosis. The availability of genetic testing enables more accurate counseling of the parents and patients regarding recurrence risks to other family members.

The first Sri Lankan family with Dent disease-1 due to a pathogenic variant in the CLCN5 gene: a case report.

BACKGROUND: Dent disease-1 is a rare X-linked recessive renal tubular disorder caused by pathogenic variants in the chloride voltage-gated channel 5 (CLCN5) gene. It is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This is the first report of a CLCN5 pathogenic variant in a Dent disease-1 family of Sri Lankan origin, and it highlights the value of genetic evaluation in children with refractory proteinuria. CASE PRESENTATION: A 2-year-old boy with non-nephrotic range proteinuria was referred for evaluation. His maternally related 24-year-old uncle had been investigated for similar features at the age of 14 years and his renal histology had shown few sclerosed glomeruli. He remained asymptomatic apart from proteinuria. Biochemical investigation of the child showed ß-2 microglobulinuria and hypercalciuria. After providing pre-test counseling and obtaining written informed consent, the child, his mother and maternal uncle underwent genetic testing for confirmation of the clinically suspected diagnosis of Dent disease-1. Both the child and his maternal uncle were found to be hemizygous for a nonsense pathogenic variant in exon 9 of the CLCN5 gene [NM_000084.4; c.1399C>T; rs797044811] which results in a stop codon at residue 467, leading to a truncated non-functional protein [NP_000075.1; p.R467X]. His mother was confirmed to be an unaffected heterozygous carrier for the same variant. Following confirmation of the diagnosis our patient was started on thiazide diuretics and potassium citrate. CONCLUSIONS: Even though the typical phenotype of Dent disease-1 often enables a clinical diagnosis to be made, less severe sub-clinical cases may go undiagnosed. The underlying diagnosis may be missed especially in children who are treated for non-minimal change nephrotic syndrome with steroids. This case highlights the need for tubular proteinuria to be considered in the differential diagnosis of children with refractory proteinuria and for appropriate genetic evaluation to be done to confirm the precise underlying diagnosis in such cases.

Patterns of acute poisoning with pesticides in the paediatric age group.

BACKGROUND: Pesticides are identified as one of the dangerous poisons globally in children and are associated with increased short- and long-term morbidity. Pesticide poisoning is the most common method of self-poisoning among adults in rural Sri Lanka, and the clinical management is associated with significant healthcare costs to the country. There is however little data published on acute pesticide poisoning among children in rural Sri Lanka. The current study aimed to comprehensively evaluate clinical profiles, harmful first aid measures, emergency clinical management, complications and outcomes related to acute pesticide poisoning among children in the rural community of Sri Lanka. METHODS: This multicenter study was conducted in the North Central Province of Sri Lanka involving all children with acute pesticide poisoning and who were between 9 months and 12 years of age. Data were collected over 7 years (2007-2014), and children from 36 hospitals were recruited. Data collection was carried out by pretested, multi-structured, interviewer-administered questionnaires to identify clinical profiles of children, harmful first aid measures, emergency clinical management, reasons for delayed management, complications and outcomes of pesticide poisoning events. RESULTS: Among 1621 children with acute poisoning, 9.5% (155) comprised children with acute pesticide poisoning. Male children outnumbered female children, and the majority of children were less than 5 years. Most common pesticides implicated in poisoning of children were organophosphates and carbamates. Gastrointestinal and neurological symptoms were predominant clinical features. Limited transport and lack of concern regarding urgency among caregivers were leading reasons for delayed management. Most common location for poisoning was cultivation lands. Harmful first aid measures were practiced in 32.4%. 7.1% had intentional pesticide poisoning. The case fatality rate of all pesticide poisonings in the study was 1.9%. 58.1% of patients were transferred between regional hospitals and teaching hospital. Cardiac and respiratory arrests, aspiration pneumonia and convulsions were among the reported complications. CONCLUSIONS: Acute pesticide poisoning in paediatric age group (<12 years) is a relatively uncommon yet significant cause of child health-related morbidity and mortality in rural Sri Lanka. Patterns of poisoning represent the pattern of pesticide use by the rural community. The practice of harmful first aid measures by caregivers and delay in attending the emergency department may negatively impact patient outcomes.