ESPE Abstracts (2015) 84 P-2-528

Correlation of Clinical Phenotype and Genotype of Prader-Willi Syndrome and the Deletion of Paternal MKRN3 Allele in PWS Patients with Central Precocious Puberty

Ja Hyang Choa, Eungu Kanga, Jin-Ho Choia, Gu-Hwan Kimb, Eul-Ju Seob & Han-Wook Yooa,b


aDepartment of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea; bMedical Genetics Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea


Background: Prader-Willi syndrome (PWS) is caused by the deletion of the paternally-derived 15q11-13 region or the maternal uniparental disomy of chromosome 15 (mUPD(15)). Puberty is usually delayed and central precocious puberty (CPP) is very rare in PWS.

Objective and hypotheses: This study was undertaken to correlate clinical features focusing on pubertal progression with genotype with or without MKRN3 deletion to understand the mechanism of CPP in patients with PWS.

Method: A total of 114 patients were enrolled. Genetic study was done utilizing routine chromosome, fluorescent in situ hybridization, and methylation-specific PCR analyses. The presence of MKRN3 deletion was determined by multiple ligation-dependent probe amplification analysis in patients with microdeletion of 15q11-q13 region.

Results: Microdeletion of paternally-derived chromosome 15q11-q13 was observed in 81 patients (71.1%), while the other 33 (28.9%) had mUPD(15). MKRN3 was deleted in 29 of 81 patients (35.8%) with microdeletion, while 11 of them (13.6%) did not have deletion of MKRN3. Patients with microdeletion presented with hypopigmentation and feeding difficulty in the neonatal period more frequently than those with mUPD(15). HbA1c levels were significantly higher in microdeletion group. There were no significant differences in height-, weight-SDS, height velocity, and BMI between the two groups. Notably, 10 of 33 patients (30.3%) with mUPD(15) showed advanced bone age than those with microdeletion. Two females manifested CPP and one girl had early puberty in mUPD(15) group, while one male was diagnosed with CPP among MKRN3 deletion group.

Conclusion: Patients with microdeletion of chromosome 15q11-q13 region displayed feeding difficulty in infancy and severe hyperglycemia more frequently than those with mUPD(15). CPP in PWS is presumed to be caused by a deletion of active paternal MKRN3 allele. Further study should be needed to elucidate functional impact of MKRN3 and interaction with other adjacent genes deleted in PWS patients with CPP.

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