Introduction: We present a patient with co-existence of 3β-Hydroxysteroid dehydrogenase type 2 deficiency (HSD3B2) the rarest form of Congenital Adrenal Hyperplasia (CAH) and Bartter Syndrome (hypokalaemic alkalosis secondary to hyperaldosteronism), a unique dual combination of opposing pathologies that has never been reported in the literature.
Case Report: A female infant (46XX) born at 34/40 weeks gestation, weighing 2.67 Kg (−1.54 SDS) to non-consanguineous parents presented on day four of life with significant weight loss. Subsequent investigations revealed hyponatraemia hypochloraemia, metabolic alkalosis, elevated 17hydroxyprogesterone (>110 nmol/l), ACTH (553 ng/l; normal:1050) and renin (2,206 mU/l; normal: 5.430). Urine steroid profile suggested HSD3B2 deficiency, which was confirmed by the identification of a homozygous HSD3B2 mutation [c.745C>T, p. Arg249*]. Genitalia was normal with no virilisation. She was started on hydrocortisone, fludrocortisone and sodium chloride. Plasma renin concentration remained >500 mU/l, and she had persistence of the hypochloraemic alkalosis. and developed a worsening hypokalaemia even after withholding fludrocortisone, hence an underlying renal tubulopathy was suspected. Exome sequencing revealed homozygous deletion in CLCNKB, establishing the diagnosis of Bartter syndrome type 3. The mother was found to be heterozygous for both the mutations in HSD3B2 and CLCNKB mutations and the father was negative for both. The co-existence of two rare recessive conditions due to homozygous mutations raised the possibility of uniparental isodisomy (UPD). SNP (Single Nucleotide Polymorphism) microarray analysis confirmed 2 segments of homozygosity on chromosome 1 of maternal ancestry, encompassing both HSD3B2 and CLCKNB. She is managed with high doses of oral sodium and potassium supplements,hydrocortisone,fludrocortisone and indomethacin. The clinical course is complicated by recurrent admissions secondary to severe electrolyte imbalance.
Conclusions: UPD, the presence of two identical copies of a given genomic region inherited from one parent, predisposes to recessive diseases, as each heterozygous variant of the parent will be present in the homozygous state, in the child. Thus, identification of a homozygous rare mutation in an offspring of non-consanguineous parents should raise suspicion of UPD. Despite identifying the genetic cause, hypokalaemic alkalosis, the biochemical fingerprint of hyperaldosteronism in a child with CAH remains unexplained and challenges our current understanding of mineralocorticoid-mediated effects in the collecting duct.
23 - 25 Nov 2016
British Society for Paediatric Endocrinology and Diabetes