Co-Occurrence of a Pathogenic HSD3B2 Variant and a Duplication on 10q22.3-q23.2 Detected in Newborn Twins with Salt-Wasting Congenital Adrenal Hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzyme deficiencies required for cortisol biosynthesis in the adrenal cortex. The majority of CAH are due to the deficiency of the 21-hydroxylase enzyme, while 3β-hydroxysteroid dehydrogenase type 2 deficiency accounts for less than five percent of all CAH cases. We report two Moroccan twins from a spontaneous triplet pregnancy. The 46,XY newborn exhibited a disorder of sexual differentiation (DSD) with hypo virilization, while the 46,XX newborn had normal female external genitalia. In the first week of life, they showed hyponatremia and primary adrenal insufficiency with a slight 17OHP elevation and increased DHEAS and renin levels. The aCGH-SNP analysis disclosed a 8.36 Mb long contiguous stretch of homozygosity (LCSH) on chromosome 1p13.2-p11.2 including the candidate HSD3B2 gene, a LCSH of 7.3 Mb on 14q31.1-q32.11, and a 7 Mb duplication on 10q22.3-q23.2. Clinical exome sequencing revealed the biallelic c.969T > G (p.Asn323Lys) HSD3B2, likely pathogenic, variant in both of the affected twins. This case emphasizes the importance of a prompt molecular diagnosis performed through the combination of aCGH and clinical exome, both for establishment of correct therapy and for follow-up, as the newborns also carry a genomic rearrangement with possible clinical implications.

Keywords: HSD3B2; LCSH; aCGH-SNP; congenital adrenal hyperplasia.

Figure 1

External genitalia of II-3 newborn at birth. Perineal hypospadias (black arrow) with small penis, hyper pigmented and fused scrotal folds containing palpable oval formations.

Figure 2

Array-CGH-SNP results. (A) The LCSH on chromosome 1p13.2-p11.2 is indicated by a black dashed rectangle. This region of 8.36 Mb containing 58 OMIM genes among which HSD3B2. (B) Duplication of 7 Mb,10q22.3-q23.2 (81,641,918_88,717,407)x3 which contains 17 OMIM genes.

Figure 3

Pedigree, sequencing results and schematic presentation of HSD3B2. (A) Pedigree of the family, the black arrow indicates the proband investigated through CES and array CGH. (B) Representative image of reads alignment showing the missense variant in the HSD3B2 gene (NM_000198.3:c.969T > G; p.Asn323Lys). (C) The variant c.969T > G was confirmed by Sanger sequencing. Segregation analysis revealed that the parents were heterozygous for the same variant. (D) Schematic diagram of the functional domains of HSD3B2, including cofactor binding domain (CBD), membrane-spanning domain (MSD), putative substrate-binding domain (PSBD) and substrate-binding domains (SBD). The red box shows the likely pathogenic variant detected in this study and located in the C-terminus.