Small testicular volume and elevated FSH in an adolescent with a maternally inherited 12p13.32 deletion encompassing CCND2

Background Proximal loss-of-function variants in Cyclin D2 (CCND2) cause a recognized syndrome of microcephaly, short stature, and developmental delay. Animal models establish an additional role for CCND2 in follicle-stimulating hormone (FSH)-driven gonadal cell proliferation. Human gonadal dysfunction associated with CCND2 haploinsufficiency has not previously been reported. Methods We performed detailed clinical, auxological, and endocrine phenotyping of an affected mother-son pair, followed by chromosomal microarray analysis and whole-exome sequencing to characterize the underlying genetic variant. Results A 15-year-old male and his mother were found to carry a heterozygous 1.74 Mb deletion at 12p13.32 encompassing CCND2. The proband presented with microcephaly (−4.8 standard deviation scores [SDS]), symmetric short stature (−2.8 SDS), and developmental delay. Physical examination revealed bilateral small testes (under 4 mL). Ultrasonography demonstrated testicular volumes of 3.1 mL (right) and 6.3 mL (left); after conversion to the reference formula, these corresponded to SDS of −3.0 and −1.9, respectively. Serial gonadal axis evaluation before aromatase inhibitor treatment showed a progressive rise in FSH (from 7.8 to 13.0 IU/L), with normal luteinizing hormone (LH) and testosterone levels. Together with progression of pubic hair development to Tanner stage P4–P5, this pattern suggests Sertoli cell dysfunction with preserved Leydig cell function. The mother, who carries the same deletion, had seven spontaneous pregnancies without fertility intervention. Conclusion These findings represent, to our knowledge, the first report of small testicular volume with elevated FSH in an individual with a deletion encompassing CCND2, suggesting that the phenotypic spectrum of CCND2-related disorder may extend to Sertoli cell dysfunction. Gonadal axis evaluation may warrant consideration in the clinical assessment of individuals with CCND2 loss-of-function variants or deletions encompassing CCND2.