Clinical but Not Histological Outcomes in Males With 45,X/46,XY Mosaicism Vary Depending on Reason for Diagnosis

Abstract

Context Larger studies on outcomes in males with 45,X/46,XY mosaicism are rare. Objective To compare health outcomes in males with 45,X/46,XY diagnosed as a result of either genital abnormalities at birth or nongenital reasons later in life. Design A retrospective, multicenter study. Setting Sixteen tertiary centers. Patients or Other Participants Sixty-three males older than 13 years with 45,X/46,XY mosaicism. Main Outcome Measures Health outcomes, such as genital phenotype, gonadal function, growth, comorbidities, fertility, and gonadal histology, including risk of neoplasia. Results Thirty-five patients were in the genital group and 28 in the nongenital. Eighty percent of all patients experienced spontaneous pubertal onset, significantly more in the nongenital group (P = 0.023). Patients were significantly shorter in the genital group with median adult heights of 156.7 cm and 164.5 cm, respectively (P = 0.016). Twenty-seven percent of patients received recombinant human GH. Forty-four patients had gonadal histology evaluated. Germ cells were detected in 42%. Neoplasia in situ was found in five patients. Twenty-five percent had focal spermatogenesis, and another 25.0% had arrested spermatogenesis. Fourteen out of 17 (82%) with semen analyses were azoospermic; three had motile sperm. Conclusion Patients diagnosed as a result of genital abnormalities have poorer health outcomes than those diagnosed as a result of nongenital reasons. Most patients, however, have relatively good endocrine gonadal function, but most are also short statured. Patients have a risk of gonadal neoplasia, and most are azoospermic, but almost one-half of patients has germ cells present histologically and up to one-quarter has focal spermatogenesis, providing hope for fertility treatment options.

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

“…Sperm were cryopreserved from this patient, but no information about the functionality of the sperm was reported [138]. A recent study in a relatively large (n = 63) cohort of males with 45,X/46,XY mosaicism showed that the majority (79%) entered puberty spontaneously, but 39% of all individuals in the cohort required testosterone supplementation at some stage during follow-up [139]. Whilst the gonadal phenotype and histology was highly variable, the majority of patients had dysgenetic testes.…”

“…In the majority of postpubertal patients no evidence of spermatogenesis was found, although 25% had focal areas with spermatogenesis. Seventeen patients had semen analyzed and live spermatozoa were present in 17.6% (3/17), albeit with low total number of sperm [139]. Spontaneous pregnancies have been reported in females with mosaicism [140].…”

The Role of International Databases in Understanding the Aetiology and Consequences of Differences/Disorders of Sex Development

“…Collecting long-term outcome data in PAIS has been difficult to date and the utility of the I-DSD Registry was clearly proven in this context. Another challenging area that the I-DSD Registry has tackled is the long-term outcome of the gonads in cases of androgen insensitivity [13] as well as those cases with 45X/XY gonadal dysgenesis [14]. All of these research projects answer questions on DSD, which would not be possible in these rare diseases with only small local datasets.…”

DIAGNOSIS OF ENDOCRINE DISEASE: Sex steroid action in adolescence: too much, too little; too early, too late

“…Some patients are found in childhood because of developmental issues, some are found in adolescence because of a delayed or absent puberty, but most patients are not aware of their condition before they visit the fertility clinic, and most of them never seek medical attention and are never diagnosed. Other patients will, however, experience under masculinization in adolescence (44,45). Girls with Turner (TS) syndrome are characterized by complete or partial (mosaic) lack of one X chromosomes, causing short stature, hypergonadotropic hypogonadism, absence of puberty and fertility problems in adulthood.…”