Additional clinical features point to likely monogenic cause of short stature

medwireNews: The likelihood of finding an underlying genetic cause of short stature in children is markedly increased if they have additional factors such as dysmorphic facial features or skeletal dysplasia, say researchers.

The study by Xiumin Wang (Shanghai JiaoTong University School of Medicine, China) and co-authors included 438 boys and 376 girls who were a median age of 6.5 years when they were diagnosed with short stature, with an average height standard deviation score (SDS) of –3.04. Of these, 330 underwent genetic testing using whole-exome sequencing, and 484 using an inherited disease panel.

These approaches identified potential genetic causes of short stature in 361 (44.3%) children. Specifically, 279 had pathogenic or likely pathogenic genetic variants in 111 genes, 72 had copy number variations and 11 had chromosomal abnormalities.

“RASopathies caused by mutations in genes of the Ras-MAPK pathway comprised the most important etiology of short stature in our cohort”, the researchers write in The Journal of Clinical Endocrinology and Metabolism.

However, the team found that the chances of finding a monogenic cause varied according to the children’s additional clinical features.

For example, the presence of dysmorphic facial features was one of the most common characteristics, affecting 186 children, 70.4% of whom had potentially causative genetic variations. For 51.6% of these children, dysmorphic facial features were the only indicator of disease in addition to short stature.

“Our findings suggested that short stature combined with facial dysmorphism indicates a need for genetic testing”, comment Wang and team.

Skeletal dysplasia was also common, identified in 235 of the children, 64.7% of whom had genetic variations likely to cause short stature. Such variants were also identified in 66.7% of children with cryptorchidism, 53.3 % of those with congenital heart disease and 53.1% of those with differences in sexual development.

Among patients with severe short stature (height SDS below –3.0), 39.3% had potentially causative genetic variations, but this fell to just 11.1% of those who had no additional features besides short stature.

Likewise, relevant variants were found in 31.1% of children born small for gestational age who did not have catch-up growth and had syndromic causes but just 16.7% of those without a syndromic cause.

Genetic variations likely to cause short stature were more common in children with multiple pituitary hormone deficiency than in those with isolated growth hormone deficiency (36.4 vs 25.0%), and were less common again in those with growth hormone insensitivity (20.5%).

Finally, the team identified three patients who had potentially pathogenic mutations in genes not previously associated with short stature, namely GATA6RYR1 and PLCB4. They suggest these “could possibly be novel candidate genes responsible for short stature”.

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Endocrinol Metab 2021; doi:10.1210/clinem/dgab863
Martin Savage
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