ESPE Abstracts

Background: Children with biallelic GHRHR gene pathogenic variants share a phenotype of growth failure starting in infancy and resulting in a proportionate short stature and bone age delay due to a complete isolated growth hormone (GH) deficiency. The genotype ranges from rare promotor mutations to the more frequent splicing mutations, some genotypes being specific to certain geographic areas. Diagnosis is mainly made around the age of 7 years and more often in children from consanguineous parents, given the autosomal recessive character of the condition. Our aim is to report the phenotypic and genetic characterization of the children with biallelic pathogenic GHRHR gene variants diagnosed in Belgium.

Patients and methods: Children with documented pathogenic biallelic GHRHR gene variants were retrieved from BELGROW, a national database of all rhGH treated patients. Their clinical and biological data were extracted. Height SDS was calculated using the Flemish growth study references.

Results: 8 cases (3 males) were retrieved. Four children were from Syrian origin, 2 of which are cousins. Median age at start of growth hormone treatment was 2.4 years (1.1 – 8.6 years). Median height SDS at start of treatment was -4.7 SDS (range -2.6 to -7.7). Serum IGF1 was below the lower limit in 7/8 patient, while peak GH level was below 3.4 µg/L in all patients. Birth weight and length were within normal limits. No frontal bossing or midfacial hypoplasia were seen. None had a breech delivery or neonatal hypoglycemia, although 2 patients had had neonatal icterus. Five patients were homozygous for a pathogenic variant. The 4 Syrian children from consanguineous families, had the same c.367G>T p.(Glu123*) variant in homozygous state. Three of the non-Syrian patients (2 siblings) harbored the c.674_677delinsGCTGTTGGCAGAAG p.(Val225Gly*fs165), either in homozygous (n= 1) or in compound heterozygous state. Brain MRI revealed an anterior pituitary hypoplasia in 6/8 patients. Height velocity during the first year of GH treatment was above 8 cm/year in all patients (above 11 cm in those treated before the age of 3 years).

Conclusion: Anterior pituitary hypoplasia was the most consistent finding in our series of children with GHRHR gene mutations. A dramatic growth response was observed in those who started GH therapy prior to 3 years of age. The c.674_677delinsGCTGTTGGCAGAAG p.(Val225Gly*fs165) mutation might be more prevalent in Belgian patients and the c.367G>T p.(Glu123*) mutation in the Syrian patients.