A Novel Dax-1 (NR0B1) Mutation in a Kindred with Variable Manifestations of X-Linked Adrenal Hypoplasia Congenita

Presentation Number: MON 367
Date of Presentation: April 3rd, 2017

Michelle Cerutti da Cruz Vargas*1, Cecília Pacheco Elias2, Sara Rezende Carvalho1, Nelson Rassi1, Ilda S. Kunii3, Magnus R. Dias da Silva3 and Flavia Amanda Costa Barbosa3
1Hospital Geral Dr Alberto Rassi, Goiânia, Brazil, 2University of Brasilia, 3Universidade Federal de São Paulo - UNIFESP, São Paulo, Brazil


Background: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder caused by variants or deletions throughout NR0B1 gene (DAX-1: dosage-sensitive sex reversal). DAX-1 is an “orphan” nuclear receptor located on short arm of the X-chromosome (Xp21), which plays a significant role in the development of adrenal, hypothalamus, pituitary, and gonads predominantly in pre-natal life.1 Though, the exact role of DAX -1 remains obscure. Affected individuals usually present with primary adrenal insufficiency (PAI) in early infancy or childhood associated with hypogonadotropic hypogonadism (HH). However, a clinical spectrum of AHC also includes unusual forms such as late-onset PAI, milder forms of HH and precocious puberty.2

Case report: 41yo man present with clinical of typical PAI. Cortisol levels were 2,2 μg/ml (5.5 - 30 μg/ml) and ACTH were 1,151 pg/ml (<46 pg/ml). His anti-21-hydroxylase antibody was negative. He has referred normal pubertal development, but since 25yo he noted frequent eretile disfunction and low libido, but never came to medical attention. Testosterone levels were 72.2 ng/dl (206-1,200 ng/dl), LH of 3.4 mUI/ml (1.5-9.3 mUI/ml) and FSH levels of 25.2 mUI/ml (1,4 - 18,1 mUI/ml), reduced testicular volume (right testicle: 2,6ml, left testicle: 3ml) and no eunochoidal phenotype. Abdominal CT revealed an important volume reduction of the adrenal glands. Treatment with glico and mineralocorticoids and testosterone were started. Interestingly, index family history was relevant for two cases of PAI diagnosed few months before him (brother at 33yo and maternal uncle at 60yo), but with no apparent reproductive phenotype. Due to X-linked inheritance pattern of PAI and absence of neurological phenotype, DAX-1 alteration was suspected. Direct sequencing of NR0B1revealed a novel missense mutation: p.Tyr378Cys that has segregated in all three PAI family members, but not to the healthy family sibling (index case´s brother). This variant is predicted to be damaging in three different protein prediction programs (MutationTaster, Polyphen, and Provean). Interestingly, the novel p.Tyr378Cys mutation is located close to other causing-disease mutations (p.Ile439Ser, p.Tyr380Asp) in Ligand Binding Domain (LDB) of DAX-1 that also present with mild clinical AHC phenotypes.3

Conclusion: We report a new mutation in LDB of DAX-1 that segregates in the family with several intriguing AHC manifestations. These clinical findings include 1) late onset of AHC in all three family members, 2) high FSH levels in index case indicating acquired significant Sertoli cell damage, and 3) variable reproductive phenotypes among family members, suggesting that other factors might be involved.


Nothing to Disclose: MCDCV, CPE, SRC, NR, ISK, MRD, FACB