ESPE Abstracts

Background: Subtle phenotypic differences have previously been described among children with varied genetic subtypes of Prader-Willi syndrome (PWS) – 15q11-q13 paternal microdeletion, maternal uniparental disomy (mUPD), and rare imprinting center defects. The MKRN3 gene, located on 15q11.2, is a master regulator of pubertal initiation and is a candidate gene for abnormal pubertal development in PWS.

Objective and hypotheses: We hypothesized that the abnormal pattern of pubertal development in PWS may be associated with altering MKRN3 expression in individual genetic subtypes.

Method: We investigated 37 individuals with PWS (18 females, 19 pubertal) currently aged 11.1 years (median; 5.4 – 18.8 years, 5th – 95th percentile). All these patients started growth hormone treatment early in life at 0.9 years (median; 0.3 – 4.0 years, 5th – 95th percentile). We used MS-MLPA and Sanger sequencing to investigate individual genetic subtypes and determine MKRN3 expression and sequence. Moreover, we evaluated age at pubarche (PH2) and at pubertal onset (B2 or testicular volume 4 ml; gonadarche), subsequent puberty progression and skeletal maturation.

Results: From the 37 probands, 23 had PWS caused by 15q11-q13 microdeletion and the remaining 14 had mUPD. Regardless of the genetic subtype, all children with PWS started with pubarche (adrenarche) early at -2.4 ± 1.3 SDS (mean ± SD) of appropriate age (P< 0.0001). In girls with PWS, the mean chronological age at pubarche was 7.4 years (-3.4 ± 1.1; SDS ± SD), and in boys 9.4 years (-2.1 ± 0.8). But those children had normal mean age at gonadarche (-0.2 ± 1.3 SDS). In girls with PWS, the mean chronological age at gonadarche was 10.3 years – similar to the healthy population (0.3 ± 1.0; SDS ± SD), and in boys 11.0 years (-0.7 ± 1.0). The bone age at gonadarche tended to be advanced by 0.5±1.1 years (P = 0.07), but there was not significant correlation between skeletal advancement and age of pubertal onset (r = 0.4, P= 0.12). The subsequent pubertal progression was slow and only exceptionally lead to spontaneous achievement of full pubertal maturation.

Conclusions: Children with PWS, regardless of the genetic subtype and the MKRN3 status, have precocious pubarche and normal age at gonadarche, however they show insufficient subsequent pubertal progression. The bone age is a poor predictor of pubertal onset.