Currently, there are no studies in the literature evaluating genital development or pubertal progression in ADA-SCID patients. No abnormalities of the gonads, uterus, and vagina were detected in the female subgroup, even if these data should be taken with caution since only a minor proportion of female subjects was studied. Therefore, we cannot exclude the association of urogenital abnormalities in female ADA-SCID. Conversely, we identified a high proportion of congenital and acquired undescended testes. In particular, the incidence of congenital undescended testes was higher in our cohort (22%) compared with healthy full-term neonates (0.5–4%, few authors report incidence up to 9%) [6,7,8]. Moreover, while in the general population 70–80% of undescended testes resolve spontaneously with only 23% requiring orchidopexy, the proportion of ADA-SCID patients eventually requiring orchidopexy was higher, with 64% of finally requiring surgery.
A higher incidence of congenital undescended testes is detected in premature neonates (up to 45%) [6, 7] but all patients with cryptorchidism in our sample were born at term (Table 2). Congenital cryptorchidism is a manifestation of numerous clinical syndromes; the ratio of non-syndromic to syndromic cryptorchidism is described to be greater than 6:1 . In our sample there is high percentage of consanguinity (54% of patients with congenital undescended testes have consanguineous parents, Tables 1 and 2). Given the high rate of consanguinity in our cohort we cannot rule out the possibility of an additional inherited defect accounting for this increased incidence. However, even in patients without consanguineous parents, the incidence remains high compared with the general population (5/51, 10%).
Considering the pathogenesis, cryptorchidism is due to aberrant embryological development. The embryology of testicular descent is complex involving numerous anatomical structures and hormones [6–7]. Androgens are known to play a role in this as HH and panhypopituitarism are associated with bilateral cryptorchidism . Also, the possibility that environmental chemicals interfere with normal reproductive tract development has been raised . We feel we can exclude the hypothesis of HH here as we did not detect a delay in puberty usually associated with HH. Thirty-five percent of our patients entered spontaneous pubertal development and progression with adequate hormone levels; the remaining patients are aged 14 years or less. One can hypothesize that ADA may play a role in testicular embryological development/descent, and/or it is possible that toxic purine metabolites could interfere with this process.
In our population, we also identified a high incidence of acquired undescended testis (16%), with 87% of cases requiring orchidopexy. In a healthy population, acquired undescended testes are reported to occur in 1–3% of cases . Acquired undescended testes have a different pathogenesis compared with congenital undescended testes , mainly related to adhesions or increased stiffness/shortness of anatomical barriers involved. It is possible that metabolic abnormalities related to ADA deficiency could alter the histologic structure of these tissues. The toxic effect of ADA metabolites has been reported on different tissues, and it is well described how purinergic signaling plays an important role in fibrosis damage of several organs (skin, heart, liver, and lung) during tissue repair. For example, the profibrotic role of ADA deficiency in the lung has been clearly shown in an animal model with adenosine deaminase-deficient mice developing adenosine-dependent pulmonary fibrosis due to accumulation of ADA metabolites [10, 11]. We can hypothesize that ADA deficiency could cause fibrosis in tissues that are crossed by testes, increasing the stiffness of the physiologic anatomical barriers.
In our patients receiving PEG-ADA ERT, BMT, or GT (with or without conditioning), FSH was not elevated. Thus, in our sample, neither ADA deficiency nor the treatments received negatively affected pubertal development or gonadic function. We did not perform specific tests to evaluate fertility in our cohort, mainly due to the young age of the patients. We can assume that our patients have functional endocrine regulation of puberty as they have normal pubertal development and normal testosterone or estradiol levels. The oldest patient is 30 years, but the mean age of the group is 19 years. However, we cannot know whether a dysfunction of endocrine gonadal component will have a later onset. No data are available in the literature regarding fertility in ADA-SCID. For patients undergoing BMT, there is a risk of infertility which of infertility is higher (> 80%) in patients treated with conditioning regimens containing TBI, high-dose cyclophosphamide, melphalan, and busulfan. The use of a reduced-intensity conditioning regimen is expected to decrease HSCT-related side effects. Recently, the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation has established recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who undergo life-saving allogeneic SCT . Emerging reports describe fertility and gonadal function in transplanted SCID [13,14,15], but actually, no specific studies on ADA-SCID have been performed. We recommend that these aspects deserve special attention considering the systemic manifestations of the condition (ADA-SCID) and the potential effects of its treatments on gonadal function.
In the literature, excess of adenosine in murine penile erectile tissues has been described associated with priapism : This study highlights how adenosine deaminase plays a biological role in different tissues and systems. Considering our sample’s age, we did not analyze the erectile dysfunction.
The major limit of this report is the number of patients evaluated: We recognize that this study is based on limited sample size, but it is expected considering that ADA-SCID is an ultra-rare disease (from 1:200,000 to 1:1,000,000 births).