medwireNews: Genetic testing has identified a likely cause for nonfamilial tall stature (nFTS) in 11% of children examined, show study findings published in the European Journal of Pediatrics.
Noting that two thirds of the six children in the study with a genetic cause for their nFTS had gonosomal aneuploidy, the team of Czech researchers recommends that paediatricians should refer children with nFTS for karyotyping “even in the absence of obvious syndromic features”.
Petra Dusatkova (Charles University and University Hospital Motol, Prague) and co-workers studied 31 girls and 24 boys, aged a median 13.0 years, with a height greater than +2 standard deviations (SD) compared with their peers but less than +2 SDs of their parents’ height; the median height in the children was +2.8 SD and the median midparental height was +0.7 SD.
Although the majority (78%) of the children had dysmorphic signs, 60% of these cases were mild and identified only on close anthropometric examination, the researchers say. More prominent dysmorphic features included pectus excavatum, pectus carinatum, dolichocephaly, macrocephaly, Ghent’s criteria, positive thumb and wrist sign, severe scoliosis, lumbar hyperlordosis and joint hypermobility,
While three children had precocious puberty, the researchers say that their TS persisted after long-term treatment and another cause for their height could not be excluded. None of the children in the study had significant learning difficulties.
Using karyotyping, SHOX gene dosage analysis or next-generation sequencing of 786 genes associated with growth, a genetic cause of TS was detected in six (11%) of the children, four of whom had syndromic features and two had mild dysmorphia.
Four children were diagnosed via karyotyping with two cases of 47,XXY, one case of 47,XXX and one case of 48,XXXX. In addition, one child had a complex rearrangement including SHOX duplication and one child was diagnosed with a pathogenic variant of TGFBR2 causing Loeys–Dietz syndrome.
Five children had cardiovascular conditions – foramen ovale apertum, essential hypertension, haemodynamically insignificant defect of the atrial septum, hypertrophy of the atrial septum and tricuspid insufficiency – while two children had low-grade gliomas, and one child Burkitt lymphoma. However, none of these children were found to have a pathogenic or likely pathogenic genetic alteration associated with TS.
A further 20% of the children in the study had genetic variants of unknown significance (VUS) detected in 11 different genes by NGS or exome sequencing.
The researchers point out that seven (12.7%) of the nFTS cohort overall, and 24.1% of the 29 nFTS children with connective tissue disorder-like dysmorphic features, had VUS in seven different genes that are associated with connective tissue disorders.
“[W]e believe that some of the respective alterations may represent variants with phenotypic relevance suggesting the carriers warrant close monitoring, family segregation analysis, and possibly future variant reclassification as more evidence accumulates”, Dusatkova et al advise.
For example, a patient with a VUS in COL21A had multiple marfanoid features and a Ghent score of 7, “suggesting a clinically significant connective tissue disorder”, they write.
The team compared the patients with nFTS with an earlier FTS cohort of 19 girls and 15 boys aged a median of 13.6 years. A genetic cause of TS was identified in 32.4% of these patients, including gonosomal aneuploidy in 5.9%, a complex rearrangement including SHOX duplication in 2.9%, and a monogenic likely pathogenic or pathogenic variant in 23.5%. Of note, 8.8% of children with FTS had a genetic syndrome associated with a high risk of cancer and 11.8% had a VUS in genes associated with a connective tissue disorder.
“Apart from obvious clinical differences between patients with nFTS and FTS, such as parental height, children with nFTS had a smaller median height and disproportionately lower body (with shorter lower limbs) than did those with FTS, indicating that children with FTS were referred to specialists more often with more severe clinical characteristics than were children with nFTS”, the authors observe.
“These data suggest that the current guidelines for the comprehensive examination of nFTS, which recommend genetic testing based on dysmorphic features or growth above TH, are adequate.”
However, they suggest that “these guidelines are not efficient in the case of FTS, as these children usually grow in accordance with their TH, and their dysmorphic signs can be underestimated because of the presence of similar signs in their parents.”
Dusatkova and co-authors therefore conclude: “More attention should be given to children with FTS, especially when mild dysmorphic features or disproportional growth are present, as monogenic causes are more common in these families than previously assumed. Therefore, referral to a pediatric endocrinologist, clinical anthropologist, and clinical geneticist is advisable.”
And they add: “In both groups, pediatricians should not rely solely on apparent normal psychosocial development or “benign” family history to rule out underlying pathology. This stepwise approach may help to identify hidden conditions with long-term health consequences and improve individualized care in children with TS.”
By Lynda Williams
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