ESPE Abstracts

Background: We present a patient with co-existence of two rare conditions 3β-Hydroxysteroid dehydrogenase type 2 deficiency (HSD3B2) the rarest form of Congenital Adrenal Hyperplasia (CAH) and Bartter’s Syndrome (hypokalaemic alkalosis secondary to hyperaldosteronism).

Case Report: A female infant (46XX) born at 34/40 weeks weighing 2.67 kg to non-consanguineous parents presented on day four of life with significant weight loss. Subsequent investigations revealed hyponatraema (Na:126 mmol/l), hypochloraemia (Cl:87 mmol/l), metabolic alkalosis, elevated levels of 17-hydroxyprogesterone >110 nmol/l (normal<1), ACTH: 553 ng/l (10–50) and renin: 2,206 mU/l (5.4–30). Urine steroid profile suggested HSD3B2 deficiency, confirmed by the identification of a homozygous HSD3B2 mutation c.745C>T, p. Arg249*. Genitalia were normal with no virilisation. She was started on hydrocortisone, fludrocortisone and sodium chloride. Renin levels decreased to <500 mU/l, however, hypochloraemic alkalosis persisted. Hypokalaemia (as low as 2.1 mmol/l) persisted even after withholding fludrocortisone and an underlying renal tubulopathy was suspected. Bartter’s type 3 was established by identification of a homozygous CLCKNB deletion. The co-existence of two rare recessive conditions due to homozygous mutations raised the possibility of uniparental isodisomy. A SNP microarray analysis confirmed 2 segments of homozygosity on chromosome 1 of maternal ancestry, encompassing both HSD3B2 and CLCKNB.

Conclusions: Uniparental isodisomy, the presence of two identical copies of a given genomic region inherited from one parent results from an error in meiosis. It predisposes to recessive diseases, as each heterozygous variant of that parent in the genomic region will be present in homozygous state in the child. Thus, identification of a homozygous rare mutation in an offspring of non-consanguineous parents should raise suspicion of this condition, especially if the phenotype is unusual, potentially encompassing more than one disorder. Despite identifying the genetic cause, hypokalaemic alkalosis, the biochemical fingerprint of hyperaldosteronism in a child with CAH (hypoaldosteronism) remains unexplained and challenges our current understanding of mineralocorticoid-mediated effects in the collecting duct.