X-linked adrenal hypoplasia congenita: clinical and follow-up findings of two kindreds, one with a novel NR0B1 mutation

Abstract

SUMMARYX-linked adrenal hypoplasia congenita typically manifests as primary adrenal insufficiency in the newborn age and hypogonadotropic hypogonadism in males, being caused by mutations in NR0B1 gene. We present the clinical and follow-up findings of two kindreds with NR0B1 mutations. The proband of kindred A had a diagnosis of primary adrenal insufficiency when he was a newborn. Family history was relevant for a maternal uncle death at the newborn age. Beyond 2 year-old steroid measurements rendered undetectable and delayed bone age was noticed. Molecular analysis of NR0B1 gene revealed a previously unreported mutation (c.1084A>T), leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were asymptomatic carriers. At 14 year-old he had 3 mL of testicular volume and biochemical surveys (LH < 0.1 UI/L, total testosterone < 10 ng/dL) concordant with hypogonadotrophic hypogonadism. Kindred B had two males diagnosed with adrenal insufficiency at the newborn age. By 3 year-old both siblings had undetectable androgen levels and delayed bone age. NR0B1 molecular analysis identified a nonsense mutation in both cases, c.243C>G; p.Tyr81*, in exon 1. Their mother and sister were asymptomatic carriers. At 14 year-old (Tanner stage 1) hypothalamic-pituitary-gonadal axis evaluation in both males (LH < 0.1UI/L, total testosterone < 10 ng/dL) confirmed hypogonadotropic hypogonadism. In conclusion, biochemical profiles, bone age and an X-linked inheritance led to suspicion of NR0B1 mutations. Two nonsense mutations were detected in both kindreds, one previously unreported (c.1084A>T; p.Lys362*). Mutation identification allowed the timely institution of testosterone in patients at puberty and an appropriate genetic counselling for relatives. Arch Endocrinol Metab. 2015;59(2):181-5

Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected

“…Note, though that skin hyperpigmentation is familiar in PAI, absence of obvious hyperpigmentation can not rule out adrenal insufficiency (12). CAH often present with ambiguous or male-appearing external genitalia in girls, while the externalia of patients with AHC or FGD1 often present normal in the neonatal period (6,13).…”

“…The prevalence is 1:140000∼1:1200000 (5). The clinical feature of AHC caused by glucocorticoid and mineralocorticoid deficiency is similar to CAH in neonates, but without high androgens levels, along with impaired pubertal development and hypogonadism (6,7). FGD is a rarer autosomal recessive condition of PAI with a prevalence of < 1:1000000 (8), as it has little more than 50 cases reported in the literature (9).…”

Case Report: A Novel Truncating Variant of NR0B1 Presented With X-Linked Late-Onset Adrenal Hypoplasia Congenita With Hypogonadotropic Hypogonadism

“…The nuclear receptor subfamily 0 group B member 1 ( NR0B1) gene encodes DAX1, an orphan nuclear receptor that plays a critical role in the development and differentiation of the adrenal gland and hypothalamus-pituitary-gonadal axis ( 1 ). It is predominantly expressed in the adrenal cortex, hypothalamus, pituitary gland, and gonads (testis and ovary).…”