Endocrine Abstracts

Background: The etiology of non-obstructive azoospermia (NOA) remains unknown in about 40% of cases and genetic factors are likely to be involved in a large proportion of them. Gene mutations involved in stem cell proliferation and DNA repair may cause isolated NOA or be responsible for syndromic diseases, such as Fanconi Anemia (FA). Although the most frequent presenting symptom in FA is bone marrow failure in childhood, in about 10% of cases the diagnosis is delayed until adulthood and in these late-onset cases the presenting syndrome is frequently a malignant tumor.

Methods: An idiopathic NOA patient (index case) with consanguineous parents was subjected to Whole-Exome Sequencing (WES) with the purpose to identify the etiology of NOA. In the second part of the study, two-steps Sanger sequencing of the FANCA gene in the brother of the index case and in 27 selected NOA patients was performed. DEB-induced chromosome breakage test was carried out to confirm the FA diagnosis.

Results: Through WES we identified a rare pathogenic homozygous FANCA variant (c.2639G>A) in the index case, affected by NOA due to Sertoli Cell only syndrome (SCOS). The patient’s brother (also affected by NOA) has been found to be a homozygous carrier of the same mutation. The two brothers did not manifest overt anemia, though chromosomal breakage test revealed a reverse somatic mosaicism in the index case and a typical FA picture in the brother. Following this incidental finding of FA, we selected 27 NOA patients with similar testicular phenotype and borderline/mild hematological alterations. Sanger sequencing of the FANCA gene in this selected group of patients allowed the identification of one additional SCOS patient showing compound heterozygous variants (c.3788_3790delTCT and c.3913C>T). Following our investigation, the three subjects with FANCA mutations are now receiving specific medical attention including strict follow-up by oncohematologists.

Conclusions: Our study reports an unexpectedly high frequency of occult FA in a specific subgroup of NOA patients with mild or borderline hematological alterations (7.1%). The screening for FANCA mutations in such patients may allow the identification of undiagnosed FA before the appearance of other severe clinical manifestations of the disease. Our finding highlights the importance to introduce the systematic evaluation of hematological parameters into the routine andrological workup in NOA patients. Moreover, corroborates previous epidemiological observations reporting a higher risk of morbidity (including cancer) and a lower life expectancy in infertile men in respect to fertile, normozoospermic men.