Abstract 6: Trichotomous presentation of a rare NROB 1 mutation in a single family

Background: X-linked adrenal hypoplasia congenital (AHC) is an uncommon etiology for congenital adrenal insufficiency due to mutations in NROB1 gene. Presentations are variable, though it usually presents as adrenal insufficiency in infancy or early childhood and hypogonadotrophichypogonadism later in life. Extremely uncommon presentations are as central precocious puberty or isolated hypoaldosteroism. Here, we present a very interesting case series with 4 members of a family, the mother and 3 siblings presenting with the same NROB1 mutation with different presentations. This is first case report of NROB1 mutation presenting with peripheral precocious puberty. Case Report: Index case, first child of parents born of a non-consanguineous marriage presented on Day 5 of life with hyperpigmentation, dehydration hypoglycemia, hypotension and hyperkalemia and elevated ACTH and low serum cortisol. He was provisionally diagnosed as congenital primary adrenal insufficiency and treated with hydrocortisone and fludrocortisone. 4.5 years later, his younger male sibling presented at 2.5 years of age with development of pubic hair and increased penile length. On evaluation he was found to have hyperpigmentation, low cortisol, slightly elevated potassium and elevated 17-OH progesterone and ACTH, a presentation typical of salt losing CAH. The 2 boys had another younger male sibling 2 years old who appeared unaffected and whose electrolytes and serum cortisol were normal. Given the dichotomous presentation of two siblings in the same family, they were advised to get genetic evaluation done but were lost to follow–up. Subsequently, after 2 years when they came back for review, the clinical presentation remained consistent with the first sibling having a phenotype of primary adrenal insufficiency while the second sibling had the phenotype of classical CAH. The third sibling on evaluation had normal electrolytes, with elevated ACTH and low cortisol with no signs or symptoms suggesting adrenal insufficiency or CAH phenotype. Results: On whole exome sequencing of the index case he was found to have a hemizygous mutation c.129C>A (p.Cys43Ter) in the NR0B1 gene. Sanger sequencing carried out in his 2 siblings detected the same hemizygous mutation while his mother was heterozygous for the same mutation. Discussion: Adrenal insufficiency and Hypogonadotropichypogonadism is classic presentation of X-linked AHC but rarely cases can present with precocious puberty. Presentation is usually with true precocious puberty (1) or at times with slightly elevated testosterone level in infancy (2), but this is a rare presentation where one sibling has appeared with the extremely rare presentation of peripheral precocious puberty, another sibling with early onset primary adrenal insufficiency and the third sibling with slowly progressive adrenal insufficiency, while the mother was unaffected as she is heterozygous for this mutation while the children are hemizygous. One possible explanation for this trichotomous presentation can be derived from the wide spectrum of NROB1 gene and mice models(3,4) DAX-1 is expressed in a population of progenitor stem cells, where it represses differentiation to allow expansion of the cell pool. In the absence of DAX-1, the progenitor cells can prematurely differentiate into steroidogenic cells before expansion of cell number. This model may partially account for the early hyperfunction of the gonad. Further research in this field may help elucidate the definite mechanism. Nevertheless, excessive activation of the HPGA in early period is likely to contribute to precocious puberty.