MON-144 - Mosaic Cat Eye Syndrome Presenting as Isolated Spermatogenic Failure: A Genomic Diagnosis Hidden in Plain Sight

Cat Eye Syndrome (CES) is a rare chromosomal disorder caused by partial trisomy or tetrasomy of chromosome 22q11, classically associated with ocular, anal, and preauricular anomalies. Increasing recognition of mosaic forms has revealed marked phenotypic heterogeneity, with some individuals exhibiting minimal or atypical features. Endocrine and reproductive manifestations remain poorly characterised, particularly in adults, and infertility as a presenting feature is rare. We describe a case of mosaic CES identified during evaluation for cryptospermia, highlighting diagnostic challenges and the value of advanced genomic testing in unexplained male infertility.

A 35-year-old man was referred to a fertility clinic with difficulty conceiving. Semen analysis demonstrated cryptospermia. Initial biochemistry showed markedly elevated gonadotropins(FSH 35.6 IU/L, LH 17.3 IU/L), mildly elevated prolactin, and low-normal testosterone(8.6 nmol/L). Testicular ultrasound was normal, and standard investigations like, cystic fibrosis transmembrane conductance regulator mutation screening and Y-chromosome microdeletion analysis, were negative. He was reviewed in endocrinology for hyperprolactinaemia and an abnormal karyotype. Repeat testing showed persistently elevated FSH(39.3 IU/L), normal testosterone, normal LH(7 IU/L), and normalised prolactin.

Initial karyotyping demonstrated low-level mosaicism (47,XY,+mar/46,XY),raising the possibility of mosaic Klinefelter syndrome. However, the clinical and biochemical phenotype was atypical, prompting single-nucleotide polymorphism microarray analysis. This identified tetrasomy of 22q11.1–q11.21 in ~30% of cells, consistent with mosaic CES due to a bisatellited supernumerary marker chromosome. Patient had normal pubertal development, preserved pituitary and thyroid function, and no dysmorphic features. The mosaic supernumerary marker chromosome was concluded as cause of cryptospermia by geneticist.

Learning:
-CES may present in adulthood with infertility, and with no external markers to prompt suspicion.
-Mosaic sSMCs involving 22q11 can selectively impair germ cell development, escaping detection on routine infertility panels
-Mosaicism levels in blood do not reflect gonadal involvement; thus normal testicular imaging cannot exclude chromosomal causes of azoospermia.
-Misdiagnosis as Klinefelter syndrome is possible when gonadotropins are raised and low-level mosaic aneuploidy is present.
-Identification of CES is essential for accurate prognostication, recurrence risk counselling, and reproductive planning, given the real risk of transmitting the marker chromosome with assisted reproductive techniques.
-Advanced genomic testing is critical in unexplained male infertility when standard investigations are unrevealing, particularly in the presence of atypical or mosaic karyotypes.

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