A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population.

CONTEXT: Pseudohypoaldosteronism (PHA) is a condition in which serum aldosterone level is normal or elevated but its action is deficient. OBJECTIVE: This study describes the molecular genetics of PHA 1b in the highly consanguineous population of 2 Arabian Gulf countries, Saudi Arabia and Oman. METHODS: This study enrolled 22 patients from 13 unrelated families (2 families with 5 patients from Oman and 11 families with 17 patients from Saudi Arabia). All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension. We isolated DNA from peripheral blood and PCR-sequenced all exons and exon-intron boundaries of SCNN1A and, if negative, SCNN1B and SCNN1G using the Dideoxy Chain termination method. RESULTS: We found a total of 8 mutations in 13 families as follows: 6 mutations in SCNN1A, 1 in SCNN1B, and 1 in SCNN1G. All of these mutations were novel except one. SCNN1A mutations were: c.1496A>G, p.Q499R (novel) in 1 patient; c.1453C>T, p.Q485X (novel) in 1 patient; c.1322_1322delA, p.N441Tfs*41 (novel) in 2 patients of 1 family; c.876 + 2 delGAGT (novel) in 3 patients of 1 family; c.203_204 delTC, p.I68Tfs*76 (a known mutation) in 8 patients of 5 families; and whole SCNN1A gene deletion (novel) in 2 patients of 2 families. In addition, a nonsense SCNN1B mutation c.1694C>A, p.S565X (novel) was found in 3 siblings from 1 Omani family, and an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in 2 siblings from another Omani family. CONCLUSION: We characterized a unique genotype of PHA 1b with several novel gene structure-disrupting mutations in SCNN1A, SCNN1B, and SCNN1G in a highly consanguineous population.

Use of ambulatory glucose monitoring and analysis of ambulatory glucose profile in clinical practice for diabetes management; a position statement of the Arab Society of Paediatric Endocrinology and diabetes.

BACKGROUND AND AIM: Diabetes mellitus imposes a significant burden around the world generally and in the Middle East and North Africa specifically. Glucose monitoring is a cornerstone of diabetes management. METHODS: Glycated haemoglobin has always been the main metric for assessing glycaemic control, but its use is linked with multiple pitfalls. As an alternative, continuous glucose monitoring is becoming a standard of care in many countries. Intermittent scanning glucose monitoring (isCGM) has acquired a worldwide popularity and has been proven to improve glycaemic control, hypoglycaemia detection and prevention, and quality of life. RESULTS: The most recent International Society of Paediatric and Adolescent Diabetes practice. guidelines recommended its use in young people with diabetes observing Ramadan to ensure safe fasting. At a meeting in Abu Dhabi in November 2019, the Arab Society for Paediatric. Endocrinology and Diabetes brought together a number of regional diabetes experts, patient. representatives and international expert advisors to review the evidence for isCGM and propose. guidelines for its use in the Middle East and North Africa region. CONCLUSION: In this paper, the authors strongly recommend the use of isCGM for patients in MENA and present general recommendations and compressive specific guidance for physicians and patients, which they believe will also have wider resonance.

Case Report: Investigation and molecular genetic diagnosis of familial hypomagnesaemia.

Genetic mutations causing familial hypomagnesaemia syndromes are well-recognised.  Affected patients can present with severe symptoms of hypomagnesaemia, such as seizures or cardiac arrhythmia.  We report an affected child, from a consanguineous family, who presented in the first weeks of life with seizures secondary to hypomagnesaemia, without other associated clinical features.  We performed whole exome sequencing in the affected child and segregation analysis within the family, which revealed a novel homozygous missense mutation in TRPM6, which was confirmed as a heterozygous allele in both parents and two younger siblings who had transient hypomagnesaemia. Using in silico modelling, we provide evidence that the missense variant p.(K1098E) in TRPM6 is pathogenic, as it disrupts stabilising TRP domain interactions. Management of familial hypomagnesaemia relies on prompt recognition, early magnesium replacement and lifelong monitoring.

Agammaglobulinaemia despite terminal B-cell differentiation in a patient with a novel LRBA mutation.

Mutations in lipopolysaccharide-responsive vesicle trafficking, beach and anchor-containing protein (LRBA) cause immune deficiency and inflammation. Here, we are reporting a novel homozygous mutation in LRBA allele in 7-year-old Omani boy, born to consanguineous parents. He presented with type 1 diabetes, autoimmune haematological cytopenia, recurrent chest infections and lymphocytic interstitial lung disease. The patient was treated with CTLA4-Ig (abatacept) with good outcome every 2 weeks for a period of 3 months. He developed complete IgG deficiency, but remarkably, histological examination revealed germinal centres and plasma cells in lymphoid and inflamed lung tissue. Further charatecterisation showed these cells to express IgM but not IgG. This ex vivo analysis suggests that LRBA mutation confers a defect in class switching despite plasma cell formation.

A Novel Mutation Causing 17-ß-Hydroxysteroid Dehydrogenase Type 3 Deficiency in an Omani Child: First Case Report and Review of Literature.

This is the first case report in Oman and the Gulf region of a 17-ß-hydroxysteroid dehydrogenase type 3 (17-ß-HSD3) deficiency with a novel mutation in the HSD17B3 gene that has not been previously described in the medical literature. An Omani child was diagnosed with 17-ß-HSD3 deficiency and was followed up for 11 years at the Pediatric Endocrinology Clinic, Royal Hospital, Oman. He presented at the age of six weeks with ambiguous genitalia, stretched penile and bilateral undescended testes. Ultrasound showed no evidence of any uterine or ovarian structures with oval shaped solid structures in both inguinal regions that were confirmed by histology to be testicular tissues with immature seminiferous tubules only. The diagnosis was made by demonstrating low serum testosterone and high androstenedione, estrone, and androstenedione:testosterone ratio. Karyotyping confirmed 46,XY and the infant was raised as male. Testosterone injections (25mg once monthly) were given at two and six months and then three months before his surgeries at five and seven years of age when he underwent multiple operations for orchidopexy and hypospadias correction. At the age of 10 years he developed bilateral gynecomastia (stage 4). Laboratory investigations showed raised follicle-stimulating hormone, luteinizing hormone, androstenedione, and estrone with low-normal testosterone and low androstendiol glucurunide. Testosterone injections (50mg once monthly for six months) were given that resulted in significant reduction in his gynecomastia. Molecular analysis revealed a previously unreported homozygous variant in exon eight of the HSD17B3 gene (NM_000197.1:c.576G>A.Trp192*). This variant creates a premature stop codon, which is very likely to result in a truncated protein or loss of protein production. This is the first report in the medical literature of this novel HSD17B3 gene mutation. A literature review was conducted to identify the previous studies related to this disorder.

A novel leprechaunism mutation, Cys807Arg, in an Arab infant: a rare cause of hypoglycaemia.

Leprechaunism is a rare autosomal recessive disorder which is usually fatal in early infancy or childhood. There is a paucity of genetic data on leprechaunism in the Arab population. A 4-month-old boy presented with jaundice, asymptomatic hypoglycaemia and growth retardation with features of leprechaunism. A novel Cys807Arg was identified, which could facilitate antenatal diagnosis for families in the Middle East.