medwireNews: Collagenopathies could account for around one in 10 cases of familial short stature even when there are no obvious signs of dysplasia, say researchers.
Stepanka Pruhova (Charles University in Prague and University Hospital Motol, Czech Republic) and colleagues identified genetic variants of collagen genes with potential clinical significance in 18.4% of the 87 children in their study, and pathogenic or likely pathogenic variants in 11.5%.
Each child plus their shortest parent had a life-minimum height standard deviation score (SDS) of –2 or less, and no known cause of familial short stature.
Collagenopathies have until now only been associated with syndromic short stature, say the researchers in The Journal of Clinical Endocrinology & Metabolism.
“Our study has extended the known phenotypical spectrum of collagenopathies by proving that short stature with no apparent signs of bone dysplasia is frequently caused by mutations in the genes encoding collagen molecules”, they write.
However, the team notes that “a detailed examination performed by an experienced clinical anthropologist revealed subtle signs of bone dysplasia in some affected children.”
Specifically, two of the 10 children with pathogenic variants had “mildly shorter limbs”, with seated height to height ratios of 1.2 and 1.9. Also, four children had mild signs of dysplasia such as scoliosis, increased lumbar lordosis, genua valga and limited elbow extension.
Of note, some signs of dysplasia developed in later childhood, and were more pronounced in parents with short stature, suggesting that these signs might progress with older age.
The children with pathogenic variants had a median height SDS of –3.1 prior to growth hormone (GH) treatment. Eighty percent were born small for gestational age, which was the indication for GH therapy; the other two had mild GH deficiency.
GH treatment was started at a median of 6 years and a median dose of 34 μg/kg per day, and was associated with an increase in height SDS to a median of –2.6 after 1 year and –2.2 after 3 years.
Four children reached their final adult height, with three at this point having improved on their pretreatment height SDS. However, the researchers say that two of these had final height SDSs that were “almost identical” to that “of their untreated parents with the same causative collagen gene variant”.
The fourth child had a height SDS that was lower than their pretreatment value and below that of the affected parent, although Pruhova and team note that the growth of this patient was affected by late-developing scoliosis.
The researchers say that “[t]here is no general definition of successful GH therapy”, but observe that the initial treatment response in their patients was similar to that reported for children with SHOX deficiency, which is an indication for GH treatment.
“On the other hand, the data from the very limited number of children who had reached their final height may indicate that GH treatment in some children with growth plate collagenopathies may not meet the expectations”, writes the team.
They suggest that these children may require higher GH doses, similar to those used in children with conditions such as Turner or Noonan syndrome, or SHOX deficiency.
By Eleanor McDermid
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J Clin Endocrinol Metab 2021; doi:10.1210/clinem/dgab084