A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

Abstract

SUMMARYWe report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient. Arq Bras Endocrinol Metab.2012;56(8):496-500 SUMÁRIO Relatamos um caso de hipoplasia adrenal congênita (HAC) e hipogonadismo hipogonadotrófico (HH) causado por uma nova mutação do gene DAX1. Paciente do sexo masculino com 19 meses de idade, hiperpigmentação e desenvolvimento inadequado foi encaminhado ao nosso serviço. Antecedente familiar de três irmãos falecidos por falência da adrenal, e um primo materno portador de insuficiência adrenal. Excluída a hipótese de adrenoleucodistrofia. A RM demonstrou hipófise e hipotálamo normais. Os níveis de hormônios plasmáticos mostraram alta concentração de ACTH (até 2.790 pg/mL) e baixos níveis de androstenediona, DHEA-S, 11-deoxicortisol e cortisol. Aos 14 anos de idade, o paciente ainda era pré-púbere, com peso de 43,6 kg (SDS: -0,87) e altura de 161 cm (SDS: -0,36), proporcionado. O teste do GnRH mostrou níveis basais e máximos de LH e FSH, respectiva mente, iguais a 0,6/2,1 e < 1,0/< 1,0 U/L. A análise molecular identificou uma nova mutação que consiste da deleção do códon 372 (AAC; asparagina) no éxon 1 do gene DAX1. Essa mutação não foi encontrada em 200 alelos de indivíduos normais. A análise no site PredictProtein indicou que essa alteração, localizada no domínio de ligação do DAX1, pode danificar a proteína. Nossa hipótese é que essa nova mutação (p.Asp372del) do gene DAX1 pode levar a uma alteração na função da proteína DAX1 e está provavelmente envolvida no desenvolvimento da HAC e HH nesse paciente. Arq Bras Endocrinol Metab. 2012;56(8):496-500

Genetic regulation of sex determination and maintenance in zebrafish (Danio rerio)

“…In mice, Nr0b1 is expressed in all tissues that constitute the hypothalamus-pituitary-gonad axis (HPG). In mammals NR0B1 is X-linked and duplication of NR0B1 in human males caused male-to-female sex reversal, while mutations in NR0B1 resulted in adrenal hypoplasia congenita syndrome with associated hypogonadotropic hypogonadism (Bardoni et al, 1994; Battistin et al, 2012). In zebrafish, nr0b1 is expressed in the brain and interrenal gland, the fish equivalent of the adrenal gland, during early development (Zhao et al, 2006).…”

Nueva Variante Patogénica en el Gen NR0B1 Asociada a Hipoplasia Adrenal Congénita

“…Al año 2006 se habían descrito cerca de 80 a 100 diferentes mutaciones en NR0B1, pero a la fecha, ya son más de 200 mutaciones identificadas 19 . La variante c.1275A > T; p.Arg425Ser en el gen NR0B1 no ha sido descrita previamente, pero su veredicto es de una variante posible patogénica de tipo 'missense' 13 .…”

“…Si bien en la mayoría de los casos no establecen una correlación genotipo-fenotipo, hay excepciones como las variantes en región amino-terminal tipo 'nonsense' o variantes región unión a ligando alrededor de 'core' hidrofóbico se asocian a inicio tardío de la enfermedad 5,19,21 . Adicionalmente la mayoría de los casos asociados a mutaciones tipo 'nonsense' o 'frameshift' establecen una proteína ausente o truncada con un fenotipo grave secundario.…”

Adrenal Hypoplasia Congenita: A Rare Cause of Primary Adrenal Insufficiency and Hypogonadotropic Hypogonadism

“…NR0B1 gene is located in the short arm of X chromosome and is expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. 4 Most mutations and large deletions lead to severe neonatal abnormalities, whereas some missense mutations or single deletions become apparent only in adulthood. 5 Clinical presentation is highly variable regarding the age of onset and the severity of adrenal failure, and even identical mutations may be associated with different phenotypes.…”