High prevalence of growth plate gene variants in children with familial short stature treated with GH
L Plachy, V Strakova, L Elblova… - The Journal of …, 2019 - academic.oup.com
L Plachy, V Strakova, L Elblova, B Obermannova, S Kolouskova, M Snajderova, D Zemkova…
The Journal of Clinical Endocrinology & Metabolism, 2019•academic.oup.comContext Familial short stature (FSS) is a term describing a growth disorder that is vertically
transmitted. Milder forms may result from the combined effect of multiple genes; more severe
short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not
been thoroughly elucidated to date. Objectives To identify the genetic etiology of severe FSS
in children treated with GH because of the diagnosis of small for gestational age or GH
deficiency (SGA/GHD). Design, Settings, and Patients Of 736 children treated with GH …
transmitted. Milder forms may result from the combined effect of multiple genes; more severe
short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not
been thoroughly elucidated to date. Objectives To identify the genetic etiology of severe FSS
in children treated with GH because of the diagnosis of small for gestational age or GH
deficiency (SGA/GHD). Design, Settings, and Patients Of 736 children treated with GH …
Context
Familial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date.
Objectives
To identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD).
Design, Settings, and Patients
Of 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height −2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines.
Results
In 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1).
Conclusions
Single-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.
Oxford University Press