Non-Virilizing Congenital Adrenal Hyperplasia in a Female Patient - Report of a Novel HSD3B2 Mutation
Presentation Number: SAT-0769
Date of Presentation: June 21st, 2014
Ursina A. Probst-Scheidegger*1, Christa E Flueck2, Dagmar l'Allemand3 and Nuria Camats4
1Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland, 2Pediatric Endocrinology and Diabetology, Bern, Switzerland, 3Children's Hospital of Eastern Switzerland, St.Gallen, Switzerland, 4University Children's Hospital Bern, Bern, Switzerland
Background: 3β-Hydroxysteroiddehydrogenase (3b-HSD) is a key enzyme in steroidogenesis, responsible for the conversion of Δ5- to Δ4-Steroids. Deficiency in 3b-HSD results in congenital adrenal hyperplasia (CAH) including glucocorticoid deficiency and a various degree of mineralocorticoid and sex steroid deficiency. The molecular etiology of 3b-HSD deficiency lies in a defect in HSD3B2gene, coding for the isoform II of the enzyme, present in adrenals and gonads.
Clinical Case: A healthy full-term female baby, born to a non-consanguineous Swiss couple, was admitted on day of life (DOL) 8 due to increased 17-OH-progesterone (17OHP) in newborn screening. She was in no physical distress, feeding well, and gaining weight appropriately. External genitalia were female without virilisation nor palpable gonads.
Ultrasound revealed female internal genitalia with slightly stimulated uterus and normal ovaries with few follicles. Biochemical analysis revealed increased ACTH (549 ng/l) with low cortisol (92 nmol/l), increased 17OHP (124 nmol/l), normal DHEA and 11-desoxycortisol, and increased renin (116 pg/ml).
The patient was immediately started on hydrocortisone (HC). The following day, she developed salt loss (Na of 129 mmol/l, K of 6.1 mmol/l) and was therefore started on fludrocortisone (FC) and NaCl. On continuous HC and FC replacement psychomotor and physical development were normal.
At 7 months of age, the patient was further evaluated for steroidogenic function. Serum steroids were measured 36h after last dose of HC and FC. Results confirmed glucocorticoid and mineralocorticoid deficiency with large increase in ACTH and renin, low cortisol and aldosterone. There was no increase, whatsoever, in 17OHP, DHEA, androstendione, 11-desoxycortisol and testosterone.
Molecular analysis discovered that the patient was compound heterozygote for 2 mutations in HSD3B2: a previously described c.512G>A (W171X) mutation in the paternal allele, and a novel frameshift mutation c.503delC (A168Vfs*6) in the maternal allele. Both mutations cause two shorter and aberrant gene products.
In retrospect, we interpreted the neonatally increased 17OHP as a product of the placental acitivity of 3β-HSD Type I activity. The absent increase in DHEA at 7 months is probably due to the immature zona reticularis at this age.
Conclusion: Our patient is compound heterozygote for two mutations in HSD3B2 causing two shorter and aberrant peptides. This clinically causes a severe loss of 3β-HSD II activity, leading to a nearly complete deficiency in glucocorticoids, mineralocorticoids and sex steroids in our phenotypically non-virilized female CAH patient. One of the mutations is novel: c.503delC (A168Vfs*6).
Nothing to Disclose: UAP, CEF, DL, NC