ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Sci Rep 2017; 16;7:15693

SRS is a rare congenital disorder, characterized by intrauterine growth restriction, postnatal growth impairment and a wide range of signs and symptoms such as dysmorphic features, severe feeding difficulties, body asymmetry, and neurodevelopmental delay. The molecular etiology is heterogeneous. Loss of methylation on chromosome 11p15 (11p15LOM) is detected in 20-60% and maternal uniparental disomy of chromosome 7 (mUPD7) in approximately 5-10%. Other chromosome abnormalities may occur in single cases. Nevertheless, in 40% of SRS cases the molecular etiology is unknown. SRS is currently a clinical diagnosis based upon the Netchine-Harbison scoring system (NH-CSS) [31].

The current study, using a genome-wide DNA methylation analysis, shows the presence of an epigenetic feature shared by most SRS subjects, independently of the molecular etiology. The HOXA4 gene region was hypomethylated in 55% of SRS subjects. HOXA4 hypomethylation was present also in the majority of subjects with severe intrauterine growth restriction and was also correlated with short stature in healthy subjects (controls). Hypomethylation of the HOXA4 promoter region has been associated with increased expression of HOXA4 in blood [32], indicating that this region influences gene expression. HOXA4 belongs to the Homeobox (HOX) gene family, encoding transcription factors that regulate various functions, including cell differentiation and embryonic development. Several HOX genes have been related to human disorders including skeletal abnormalities suggesting that abnormal HOXA4 methylation may be involved in the skeletal malformations observed in many SRS patients. In addition, the methylation of HOXA3, a gene mapping near HOXA4, has been related to birth weight, suggesting a role of this region on human growth. Limitations of the study include the poor characterization of the SRS subjects, involving a mixture of adult and pediatric patients and a vague diagnosis of “severe growth restriction”. Furthermore, methylation varies with time and the age at analysis may affect results. Nevertheless, this study opens new avenues for epigenetic investigations in the field of human growth.