Pereira Bernardo Dias, Pereira Iris, Portugal Jorge Ralha, Gonçalves João, Raimundo Luísa
Hospital Garcia de Orta - E.P.E, Almada-Setúbal, Portugal.
Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
Arch Endocrinol Metab. 2015 Apr;59(2):181-5. doi: 10.1590/2359-3997000000032. Epub 2015 Apr 1.
X-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.
X连锁先天性肾上腺发育不全通常表现为新生儿期原发性肾上腺功能不全以及男性低促性腺激素性性腺功能减退，由NR0B1基因突变引起。我们报告了两个携带NR0B1基因突变家系的临床及随访结果。家系A的先证者在新生儿期被诊断为原发性肾上腺功能不全。家族史显示其母亲的一位兄弟在新生儿期死亡。2岁以后类固醇检测结果无法测出，并发现骨龄延迟。对NR0B1基因的分子分析揭示了一个此前未报道的突变（c.1084A>T），导致外显子1中出现提前终止密码子p.Lys362*。他的母亲和妹妹是无症状携带者。14岁时，他的睾丸体积为3 mL，生化检查结果（促黄体生成素<0.1 UI/L，总睾酮<10 ng/dL）与低促性腺激素性性腺功能减退相符。家系B有两名男性在新生儿期被诊断为肾上腺功能不全。3岁时，这两名同胞的雄激素水平均无法测出且骨龄延迟。NR0B1分子分析在两例中均鉴定出一个无义突变，即外显子1中的c.243C>G；p.Tyr81*。他们的母亲和妹妹是无症状携带者。14岁时（坦纳1期），对这两名男性的下丘脑-垂体-性腺轴评估（促黄体生成素<0.1UI/L，总睾酮<10 ng/dL）证实为低促性腺激素性性腺功能减退。总之，生化指标、骨龄以及X连锁遗传导致怀疑存在NR0B1基因突变。在两个家系中均检测到两个无义突变，其中一个此前未报道（c.1084A>T；p.Lys362*）。突变鉴定使得能够在患者青春期及时给予睾酮治疗，并为亲属提供适当的遗传咨询。
