Children with SRS (OMIM 180860) are mostly born SGA, have short stature and relative macrocephaly, a triangular shaped face with frontal bossing, clinodactyly, and asymmetry of face and/ or extremities. Severe feeding difficulties are often present, especially during infancy. Mean adult height is around – 4 SDS. SRS is primarily a clinical diagnosis, which can be established with the Netchine– Harbison clinical scoring system.
In around 60% of children with SRS, an underlying cause can be identified. Fifty percent are caused by a loss of methylation (LOM) of the telomeric domain in the 11p15.5 region, resulting in downregulation of paternal IGF2 expression. The 11p15.5 region has two imprinting control regions, which affect imprinted genes involved in the regulation of pre- and postnatal growth. Two rare genetic causes of SRS were found in the same 11p15 region: (1) an increased expression of CDKN1C (by a gain-of-function mutation or maternal duplication), which can be associated with the IMAGe syndrome (OMIM 614732); the latter is characterized by pre- and postnatal growth failure, metaphyseal dysplasia, congenital adrenal hypoplasia, genital anomalies and early- onset DM; and (2) an IGF2 loss- of-function mutation (OMIM 616489) resulting in a paternally transmitted SRS (Table 1). Disruptions in the HMGA2- PLAG1- IGF2 pathway can also cause an SRS phenotype, while copy number variants (CNVs) involving the 11p15.5 region can result in a specific SRS phenotype depending on CNV size, location, and parental origin.
Table1. Monogenic disorders in short children born SGA with normal head circumference
Between 5% and 10% of children with SRS have a maternal uniparental disomy of chromosome 7 (upd(7)mat), with potential causative genes including GRB10 (7p12.1) and MEST (7q32). In 35%, the genetic cause is yet unknown (i.e. clinical SRS). Patients with 11p15 LOM have a more ‘classic’ SRS phenotype with a higher prevaence of asymmetry than those with upd(7)mat, but the latter ones carry a higher risk of behavioural problems. More widespread use of methylation studies will probably uncover more epigenetic dis orders in short SGA children, as shown by a study in patients with suspected SRS or unexplained short stature/ IUGR, in whom 37% showed abnormal methylation in eleven imprinted loci.
Long- term GH treatment has proven to be safe and effective in improving adult height in SRS, with similar results as non- SRS subjects born SGA. As the rapid bone maturation during puberty may compromise adult height, it is recommended to add (2 years of) GnRH agonist treatment in GH- treated SRS patients with a poor adult height prognosis at the onset of puberty [34]. The metabolic health profile of GH- treated young adults with SRS was similar to that of GH- treated non- SRS subjects born SGA.
