Dax-1 (NROB1) Mutation with Adrenal Hypoplasia Congenita & Hypogonadotropic Hypogonadism

Presentation Number: SAT-0760
Date of Presentation: June 21st, 2014

Inderpreet K Dardi and Serge Jabbour*
Thomas Jefferson University, Philadelphia, PA

Abstract

DAX-1 (NROB1) Mutation with Adrenal Hypoplasia Congenita & Hypogonadotropic Hypogonadism

Inderpreet K Dardi, MD & Serge A Jabbour, MD; Division of Endocrinology, Department of Medicine; Jefferson Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania

Background: X-linked Adrenal Hypoplasia Congenita is a rare disorder in which the adrenal cortex doesn’t develop normally and manifests as primary adrenal failure in early infancy. It is caused by mutations or deletions in DAX-1 (NROB1) dosage sensitive sex reversal, adrenal hypoplasia gene located on short arm of Chromosome X that is Xp21.Tissues of DAX-1 expression are adrenals, gonads, hypothalamus and pituitary gland and is responsible for controlling development and function of these tissues. More than 100 DAX-1 mutations have been described occurring throughout the coding region. Heterozygous females with this DAX-1 mutation are asymptomatic.

 Clinical Case: Mr.KM presented at age 3 weeks when he was noticed to have poor feeding. His sodium was 115mmol/L (135-146 mmol/L) and his potassium was 8.9 mmol/L(3.5-5.3 mmol/L). Subsequent testing revealed an ACTH of 606 pg/ml (9-46 pg/ml), renin activity of 8.56 ng/ml/h (0.25-5.82 ng/ml/h) and undetectable serum cortisol and aldosterone levels. In addition, his 11-deoxycorticosterone and 17-OH-progesterone levels were undetectable. Ultrasound of the abdomen showed no evidence of adrenal tissue. He was started on replacement hydrocortisone and fludrocortisone.

At age 14, he was noted to have delayed puberty. Testing showed FSH of 0.99 mIU/ml (1.5-12.4mIU/ml), LH 0.15 mIU/ml (1.7-8.6 mIU/ml) and testosterone of 22ng/dl (348-1197 ng/dl) with normal prolactin and pituitary MRI, all consistent with hypogonadotropic hypogonadism. DAX-1 mutation was hypothesized and genetic testing was done showing a maternally inherited large deletion of Xp21.2 diagnostic of X-linked Adrenal Hypoplasia Congenita. The patient received androgen replacement with normal attainment of secondary sex characteristics.

Review of his family history indicated the death of his mother’s half-brother with adrenal crisis at age 13 days and death of his maternal grandmother’s brother in early infancy of uncertain etiology. Mr.KM has only one female sibling who tested negative for DAX-1 mutation.

Conclusion: DAX-1 mutation can cause congenital adrenal hypoplasia and usually manifest very early with primary adrenal insufficiency. Most individuals develop hypogonadotropic hypogonadism usually recognized at the time of puberty. Abnormal spermatogenesis with sertoli cell defects is also noted in some patients. Secretion of other pituitary hormones is not impaired.

 

Nothing to Disclose: IKD, SJ