Endocrine Abstracts

JOINT2256

Background: The 15q11.2-q13 duplication syndrome is a rare genetic condition caused by the duplication of a chromosomal segment that is particularly prone to genetic rearrangements and subject to imprinting. It presents with a highly variable phenotype, including neurodevelopmental disorders and distinct craniofacial anomalies. This region includes the MKRN3 gene, which is maternally imprinted and plays a critical role in regulating pubertal timing by inhibiting GnRH release. Paternally inherited loss of function mutation of MKRN3 can lead to altered neuroendocrine signaling, impacting the onset of puberty and in particular causing central precocious puberty. Duplications of this chromosomal region have not been previously associated with alterations in pubertal timing to date.

Case Presentation: We report the case of a 16-year-old male with severe short stature, delayed pubertal development (Tanner stage 2, bilateral testicular volume of 8 mL with pubertal development arrest for two years, LH 1.6 IU/l, FSH 2.3 IU/l, Testosterone 95 ng/dl), and intellectual disability.

Materials and Methods: The patient’s DNA was initially analyzed using Array – Comparative Genomic Hybridization (Array-CGH). To further characterize the identified duplication, MS-MLPA was performed to assess copy number variations and methylation status of the 15q11 region in genomic DNA extracted from peripheral whole blood samples (SALSA MLPA Probemix ME028-D1 Prader-Willi/Angelman, MRC Holland). Furthermore, to assess the impact of the 15q11-q13 microduplication on MKRN3 expression in the patient’s blood, quantitative real-time RT-PCR was conducted using the 2-ΔΔCT method.

Results: Genetic analysis identified a paternally inherited heterozygous interstitial duplication of the 15q11 region, spanning chromosomal positions 22,812,154 to 27,845,031, encompassing the NIPA1, MKRN3, and OCA2 genes. Molecular analysis revealed a 67% reduction in methylation, consistent with paternal inheritance of the duplication. Quantitative analysis of MKRN3 expression also showed an increase of over 2-fold compared to a healthy control.

Conclusion: The increased gene dosage of MKRN3, combined with reduced methylation, may enhance its inhibitory effect on the hypothalamic-pituitary-gonadal axis, delaying the pulsatile release of GnRH and contributing to the delayed sexual maturation observed in our patient. This observation, within the context of a structural genomic rearrangement, adds a novel contribution to the literature, expanding the spectrum of clinical manifestations associated with 15q11.2-q13 duplications.