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DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients
Giovanna Mantovani1, Ernesto De Menis, Giorgio Borretta
1Institute of Endocrine Sciences, University of Milan, Padiglione Granelli, Ospedale Maggiore IRCCS, Via F. Sforza 35, 20122 Milan, Italy. giovanna.mantovani@unimi.it
Objective:
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.
Design:
DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment.
Methods:
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.
Results:
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.
Conclusions:
These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.
Insights
Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC), leading to adrenal failure and impaired sexual development. This study found azoospermia in affected males, indicating DAX1 mutations directly impair spermatogenesis and fertility.
Area of Science:
- Endocrinology
- Genetics
- Reproductive Medicine
Background:
- X-linked adrenal hypoplasia congenita (AHC) is caused by mutations in the DAX1 gene.
- AHC typically presents with primary adrenal failure and hypogonadotropic hypogonadism.
- DAX1 mutations are suspected to directly impact spermatogenesis.
Purpose of the Study:
- To clinically and genetically characterize five patients with AHC.
- To investigate the direct effect of DAX1 mutations on male fertility.
- To expand the understanding of DAX1 mutation spectrum and clinical manifestations.
Main Methods:
- DNA sequencing of the DAX1 gene (coding, splice sites, promoter).
- Endocrine testing, testicular ultrasound, and semen analysis.
- One-year follow-up of gonadotropin treatment for fertility assessment.
Main Results:
- Three known and two novel DAX1 mutations were identified.
- Four patients exhibited azoospermia, with no fertility restoration after gonadotropin treatment.
- Testicular ultrasound results were normal, contrasting with Dax1-deficient mouse models.
Conclusions:
- This study expands the known spectrum of DAX1 mutations.
- DAX1 mutations are confirmed to directly cause male infertility through azoospermia.
- Clinical knowledge of AHC and its impact on spermatogenesis is enhanced.
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