Growth plate gene mutations may underlie many severe familial short stature cases

medwireNews: A probable underlying genetic cause may be found for the majority of children with severe familial short stature (FSS), with mutations in growth plate genes accounting for most of these, research shows.

From among all children receiving growth hormone at their centre, Stepanka Pruhova (Charles University in Prague, Czech Republic) and co-researchers identified 33 instances of FSS, where both the child and their shortest parent had a maximum height standard deviation score (SDS) of –2.5 or below.

Of the children, 64% were born small for gestational age and 70% were classified as having growth hormone deficiency (GHD), with a median maximum GH level after stimulation of 6.7 μg/L.

The 25 children with no previously identified genetic cause of their short stature underwent whole-exome sequencing, revealing genetic variants with potential clinical significance in 89% and variants that were pathogenic or likely pathogenic in 43%.

Pruhova and team say their study is the first of the genetics underpinning FSS using next-generation sequencing in a largely nonconsanguineous population.

They found that 17 (52%) of all 33 children had probable causative genetic variants, nine of whom had variants affecting the growth plate.

Specifically, the researchers found mutations in ACANCOL2A1 and COL11A1, which encode structural proteins of the cartilaginous extracellular matrix, each in two children; in the gene that encodes filamin B, which facilitates communication between the cell membrane and cytoskeletal network; and in the genes encoding fibroblast growth factor receptor 1 and insulin-like growth factor receptor 1.

Despite this high prevalence of variants affecting growth plate genes, the majority of the children had no outward signs of bone dysplasia, says the team, adding that “short children in our cohort had been frequently misdiagnosed as having GHD.”

Most (89%) of the children genetically identified as having growth plate disorders had been born small for gestational age, they note.

“Recognizing the etiology of short stature and clarifying the gene-specific reaction to GH treatment poses one of the important current challenges of pediatric endocrinology”, the researchers write in The Journal of Clinical Endocrinology & Metabolism.

Two families had genetic variants affecting genes that encoded proteins associated with insulin-like growth factor, and the other six had isolated, miscellaneous variants associated with, for example, GH secretion, neurofibromatosis type 1 and Noonan syndrome.

However, the team stresses: “Interpretation of the genetic findings in our study was not always simple. Some genetic variants did not explain all the features of the complex phenotype.”

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

J Clin Endocrinol Metab 2019; doi:10.1210/jc.2018-02288
Martin Savage
Programme Director

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