Genetic testing aids diagnosis for short stature children from consanguineous parents

medwireNews: Genetic testing can lead to a diagnosis in around three quarters of children with short stature from consanguineous families, suggests a study of Turkish patients.

Testing was especially effective at identifying genetic alterations in children with severe growth hormone (GH) deficiency or insensitivity, microcephaly or syndromic short stature, say Sjoerd Joustra (Leiden University Medical Center, The Netherlands) and co-authors.

“Diagnosing these patients has important clinical consequences and provides more insights into the scope of the clinical features associated with monogenic causes of short stature”, they write in Hormone Research in Paediatrics.

The study included 42 children with short stature from 34 families attending one of six Turkish paediatric endocrinology centres. The children had consanguineous parents and at least one other factor indicating a potential genetic defect.

Overall, a genetic cause was identified for 81% of the children and 76% of the families assessed, the researchers report.

This included a diagnosis for all 18 children from 12 families who had clinical features indicating a specific genetic alteration to the GH–insulin-like growth factor (IGF)-1 axis and following assessment with a candidate gene approach.

Specifically, the cause of GH-deficiency type 1A and neonatal hypoglycaemia was confirmed as GH1 deletion in two children from one family, one of whom had microcephaly, while nine children from five different families were found to have four likely pathogenic variants of GHR, confirming suspected diagnoses of Laron syndrome.

A novel homozygous STAT5B truncating variant was identified in a girl with short stature, ichthyosis, midface hypoplasia, frontal bossing and hyperprolactinemia, as well as normo-gonadotropic primary amenorrhoea, who was diagnosed with growth hormone insensitivity syndrome with immune dysregulation 1. Four families were found to have likely pathogenic homozygous or compound heterozygous variants of IGFALS (insulin-like growth factor binding protein, acid labile subunit), confirming a diagnosis of acid-labile subunit deficiency.

A second cohort of 24 children from 22 families without clinical indications of a specific genetic defect was also assessed using gene panels, microarray analysis, and whole-exome sequencing.

Eleven of these patients (10 families) had severe short stature and microcephaly and a pathogenic or likely pathogenic genetic alteration was detected in 10 of these patients: five patients had PCNT variants indicating microcephalic osteodysplastic primordial dwarfism type 2; two children had SMARCAL1 alterations associated with Schimke immuno-osseous dysplasia; and there were individual cases of children with alterations to SRCAP (Floating-Harbor syndrome), WDR4 (primordial dwarfism) and GHSR (unknown significance but phenotype may include delayed puberty and normal or low GH).

A second subgroup of 10 patients (nine families) with syndromic short stature was also assessed and a diagnosis was made in six of these children from five families.

One child born extremely small for gestational age had two novel 17p13.3 microdeletions that affected the YWHAE gene and 34 other known protein-coding genes in regions that have previously been linked to three different contiguous gene deletion syndromes. The patient was classified as having YWHAE and/or CRK deletion syndrome, and her clinical features were similar to those of other children with this genotype, the researchers write.

In addition, one child had a TTC37 alteration associated with trichohepatoenteric syndrome 1 and two siblings had a novel variant of SCUBE3 that has subsequently been linked to a new genetic disorder – Short Stature, Facial Dysmorphism, and Skeletal Anomalies with or without Cardiac Anomalies 2.

Finally, one patient carried a new alteration to NSD2 that has been linked to Rauch-Steindl syndrome and another had an alteration to RABGAP1, a gene that has previously been linked to a neurodevelopmental syndrome in five children associated with intellectual disability, microcephaly, bilateral sensorineural hearing loss, seizures and dysmorphic features.

Testing was nonconclusive for the nonspecific GH deficiencies of the third subgroup of three unrelated patients. Nonetheless, one child and his mother shared a nonsense mutation in CAST that the researchers believe likely explains his skin symptoms of severe eczema, acral punctate keratosis, cheilitis, onychomycosis and peeling.

Joustra et al say that “[a]s expected for offspring of consanguineous couples, most patients were homozygous carriers of gene variants (21 families),” but they note that four families had children with short stature caused by a heterozygous alteration, one was affected by compound heterozygosity, and some children had additional mutations that explained other clinical symptoms.

The researchers conclude that “increasing the number of patients with short stature who undergo genetic testing will lead to a better insight into the broadness of the spectrum of clinical phenotypes associated with genetic syndromes,” as well as “lead to the uncovering of novel syndromes, such as the syndrome caused by bi-allelic SCUBE3 variants which we discovered in the two affected siblings”.

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

Horm Res Pediatr 2024; doi:10.1159/000539696
Martin Savage
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