A Novel SCNN1A Variation in a Patient with Autosomal-recessive Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism type 1 (PHA1) is an autosomal-recessive disorder characterized by defective regulation of body sodium (Na) levels. The abnormality results from mutations in the genes encoding subunits of the epithelial Na channel. Patients with PHA1 present in infancy as being in adrenal crisis. A 41-day-old female who presented with recurrent adrenal crisis did not adequately respond to hydrocortisone and required mineralocorticoid therapy. The patient's demographic data and clinical features were recorded. Blood samples were collected and tested for endocrine and metabolic characteristics and for use in genetic studies. Bidirectional Sanger sequencing of SCNN1A was conducted. The entire coding region of 12 exons and 20 bp of flanking intron were sequenced. Genetic analyses revealed a new mutation - c.729_730delAG (p.Val245Glyfs*65) - in SCNN1A exon four. Adrenal crisis during the neonatal period highlights the importance of early screening for PHA1. Genetic testing could help to anticipate the prognosis, severity, onset of the disease, and the mode of inheritance, especially given its extensive phenotype.

Screening for testicular adrenal rest tumors among children with congenital adrenal hyperplasia at King Fahad Medical City, Saudi Arabia.

OBJECTIVES: To assess the incidence of testicular adrenal rest tumors (TARTs) among male children with congenital adrenal hyperplasia (CAH) in tertiary care centers. METHODS: All male children aged 1-14 years diagnosed with CAH due to 21-hydroxylase deficiency (21 HOD), 11ß-hydroxylase deficiency, and 3ß-hydroxysteroid dehydrogenase deficiency, confirmed by biochemical and/or genetic testing, underwent scrotal ultrasound examination to identify TARTs. After receiving the diagnosed patients' data, patients' electronic medical records were accessed to collect demographic data and scrotal ultrasound results, along with growth parameters and specific biochemical test results within 2 months of the ultrasound. RESULTS: TARTs were observed in 5 (10.9%) of 46 male children with CAH. Four patients with positive findings had 21 HOD classical CAH with salt loss and one had 21 HOD simple virilizing classical CAH. All patients had poor compliance and stage 2 bilateral TARTs. Three TART-positive patients (60.0%) had high ACTH levels, 5 patients (100%) had elevated 17-OHP levels, and 5 patients (100%) had advanced bone age. The youngest patient with positive findings was 4 years old. CONCLUSIONS: The prevalence of TARTs increases with age and can be present in young males with classical CAH with 21 HOD. It is associated with elevated 17-hydroxyprogesterone (17-OHP) and advanced bone age SDS. TARTs are less likely to be associated with nonclassical CAH with 21 HOD or other less common CAHs due to 11ß-hydroxylase deficiencies and 3ß-hydroxysteroid dehydrogenase deficiencies in children. Our study recommends early and routine screening of TARTs in children with CAH.

Epilepsy in patients with insulin-dependent diabetes and relation to glutamic acid decarboxylase 65.

OBJECTIVE: To report if the association of epilepsy in pediatric patients (below the age of 15 years) with Insulin-dependent Diabetes (IDDM) at King Fahad Medical City (KFMC) is higher than the prevalence of epilepsy in the same age group (who have no IDDM) in our community. Consequently, we would determine if there is a relationship between the presence of epilepsy in diabetic children and the presence of positive antiGAD65 antibodies. METHODS: This cohort study included 305 pediatric patients below the age of 15 years with Insulin-dependent Diabetes Mellitus (IDDM). They were randomly recruited at the Pediatric Endocrinology Clinic in KFMC. The patients` caregivers were given a questionnaire between December 2015 till March 2019 to determine the seizure disorder history. There was also a retrospective review of 214 patients` files for anti-GAD 65 positivity. RESULTS: Our study found a significant relation between the presence of epilepsy in children with IDDM. Therefore, we could confirm the relationship between the existence of epilepsy in children with IDDM and having positive GAD65 antibodies. CONCLUSION: Our study supports the presence of consistent relation between having IDDM and having epilepsy in children and between the latter and the presence of positive GAD65 antibodies.

Association of HLA-DR-DQ alleles, haplotypes, and diplotypes with type 1 diabetes in Saudis.

AIMS: Type 1 diabetes (T1D) is an autoimmune disease that affects many children worldwide. Genetic factors and environmental triggers play crucial interacting roles in the aetiology. This study aimed to assess the contribution of HLA-DRB1-DQA1-DQB1 alleles, haplotypes, and genotypes to the risk of T1D among Saudis. METHODS: A total of 222 children with T1D and 342 controls were genotyped for HLA-DRB1, -DQA1, and -DQB1 using reverse sequence-specific oligonucleotide (rSSO) Lab Type high definition (HD) kits. Alleles, haplotypes, and diplotypes were compared between cases and controls using the SAS statistical package. RESULTS: DRB1*03:01-DQA1*05:01-DQB1*02:01 (32.4%; OR = 3.68; Pc < .0001), DRB1*04:05-DQA1*03:02-DQB1*03:02 (6.6%; OR = 6.76; Pc < .0001), DRB1*04:02-DQA1*03:01-DQB1*03:02 (6.0%; OR = 3.10; Pc = .0194), DRB1*04:01-DQA1*03:01-DQB1*03:02 (3.7%; OR = 4.22; Pc = .0335), and DRB1*04:05-DQA1*03:02-DQB1*02:02 (2.7%; OR = 6.31; Pc = .0326) haplotypes were significantly increased in cases compared to controls, whereas DRB1*07:01-DQA1*02:01-DQB1*02:02 (OR = 0.41; Pc = .0001), DRB1*13:01-DQA1*01:03-DQB1*06:03 (OR = 0.05; Pc < .0001), DRB1*15:01-DQA1*01:02-DQB1*06:02 (OR = 0.03; Pc < .0001), and DRB1*11:01-DQA1*05:05-DQB1*03:01 (OR = 0.07; Pc = .0291) were significantly decreased. Homozygous DRB1*03:01-DQA1*05:01-DQB1*02:01 genotypes and combinations of DRB1*03:01-DQA1*05:01-DQB1*02:01 with DRB1*04:05-DQA1*03:02-DQB1*03:02, DRB1*04:02-DQA1*03:01-DQB1*03:02, and DRB1*04:01-DQA1*03:01-DQB1*03:02 were significantly increased in cases than controls. Combinations of DRB1*03:01-DQA1*05:01-DQB1*02:01 with DRB1*07:01-DQA1*02:01-DQB1*02:02 and DRB1*13:02-DQA1*01:02-DQB1*06:04 showed low OR values but did not remain significantly decreased after Bonferroni correction. CONCLUSIONS: HLA-DRB1-DQA1-DQB1 alleles, haplotypes, and diplotypes in Saudis with T1D are not markedly different from those observed in Western and Middle-Eastern populations but are quite different than those of East Asians.

Isolated cortisol deficiency: a rare cause of neonatal cholestasis.

For decades, congenital panhypopituitarism has been recognized to cause infantile cholestasis. However, the identity of the hormone whose deficiency causes such derangement of the liver is not clear. Here, we report four cases of isolated severe cortisol deficiency presenting with neonatal cholestasis and hypoglycemia, of whom two had familial primary glucocorticoid deficiency and the other two had isolated adrenocorticotropin deficiency. The resolution of cholestasis by hydrocortisone replacement therapy suggests a causal relationship between cortisol deficiency and the development of neonatal cholestasis. In conclusion, the presentation of a young infant with cholestasis and hypoglycemia should alert pediatricians to the possibility of cortisol deficiency and prompt investigation of adrenal function should be undertaken.

3M syndrome: an easily recognizable yet underdiagnosed cause of proportionate short stature.

OBJECTIVE: To characterize, via clinical and molecul criteria, a cohort of patients with 3M syndrome and thereby increase awareness of this syndrome as a recognizable cause of proportionate short stature. STUDY DESIGN: We conducted a case series of patients referred to clinical genetics for proportionate short stature. CUL7, OBSL1, and CCDC8 genes were clinically phenotyped and sequenced. RESULTS: In 6 Saudi families with 3M syndrome, we identified three CUL7, one OBSL1, and one CCDC8 novel mutations, which we show result in a remarkably similar clinical phenotype. Despite their typical and easily discernible clinical phenotype, all these patients have been extensively investigated for alternative causes of their short stature and received erroneous diagnoses. CONCLUSION: Increased awareness about this syndrome among pediatricians and endocrinologists is needed to avoid a costly and unnecessary diagnostic odyssey.