Mantovani Giovanna, De Menis Ernesto, Borretta Giorgio, Radetti Giorgio, Bondioni Sara, Spada Anna, Persani Luca, Beck-Peccoz Paolo
Institute of Endocrine Sciences, University of Milan, Padiglione Granelli, Ospedale Maggiore IRCCS, Via F. Sforza 35, 20122 Milan, Italy.
Eur J Endocrinol. 2006 May;154(5):685-9. doi: 10.1530/eje.1.02132.
Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC.
DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment.
We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients' peripheral blood leukocytes and the coding region, splice sites, and promoter (-240 bp) region of DAX1 were directly sequenced.
Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelve-month treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis.
These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.
编码孤儿核受体DAX1的基因突变会导致X连锁先天性肾上腺发育不全（AHC）。患病男孩通常在婴儿早期或儿童期出现原发性肾上腺功能衰竭。青春期时，由于促性腺激素缺乏性性腺功能减退导致的性发育障碍会显现出来。此外，来自Dax1基因敲除小鼠和少数AHC患者的证据表明，DAX1突变可能直接导致精子发生异常。本研究的目的是对5例AHC患者进行临床和基因特征分析。
DNA测序分析、内分泌检测、睾丸超声检查以及促性腺激素治疗后1年随访的精液分析。
我们报告了5例具有典型AHC表现的男性患者。从患者外周血白细胞中提取基因组DNA，并对DAX1的编码区、剪接位点和启动子（-240 bp）区域进行直接测序。
在这些患者的DAX1编码序列中检测到3个已知突变和2个新突变。对5例患者中的4例进行了精液分析，结果显示无精子症。促性腺激素治疗12个月未能恢复这些患者的生育能力。与Dax1基因缺陷小鼠睾丸网异常不同，所有患者的睾丸多普勒超声均正常。
这些病例进一步扩大了文献中报道的DAX1突变数量，以及我们对这种罕见疾病的临床认识。
