Читать книгу Nutrition and Growth - Группа авторов - Страница 25

Plachy L^1,2, Strakova V^1,2, Elblova L^1,2, Obermannova B^1,2, Kolouskova S^1,2, Snajderova M^1,2, Zemkova D^1,2, Dusatkova P^1,2, Sumnik Z^1,2, Lebl J^1,2, Pruhova S^1,2

¹Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; ²University Hospital Motol, Prague 5, Czech Republic

J Clin Endocrinol Metab 2019;104:4273–4281

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 growth hormone (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 insulin-like growth factor (IGF) 1R), 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.

Reprinted with permission from Oxford University Press.

Comments

In the present study, the authors aimed to identify the genetic etiology of severe familial short stature (FSS). They classified short child (height ≤2 SD) as having FSS if at least one of his/her parents is also short (height ≤2 SD). They defined severe FSS if both the child and the shorter parent had height below –2.5 SD. It is true that more and more cases with idiopathic short stature actually are identified as suffering from different genetic variants of genes responsible for key processes that occur within the growth plate during the linear growth process. Several familial cases were already described in the literature. The surprise finding of the present manuscript is the fact that 30/33 (90%) of the children with severe FSS enrolled to the study were found to have at least one variant with potential clinical significance genes known to affect growth. It is almost like we can delete the term idiopathic familial severe short stature from our textbook and lists of potential diagnosis in our clinical practice since most cases (90%) are not idiopathic anymore. I think it is too early to do that, and more studies in different centers and geographical areas are needed to confirm that very important and interesting finding.

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