medwireNews: Researchers have found a large variety of genetic diagnoses in children with short stature investigated for suspected growth hormone insensitivity (GHI).

The findings highlight “the substantial diagnostic challenges” facing clinicians assessing children with short stature, say Helen Storr (Barts and the London School of Medicine and Dentistry, London, UK) and study co-authors.

The team reports data from 149 children (58% male, average age 6.9 years) with presumed GHI, having an average height standard deviation score (SDS) of –4.2 but an average peak stimulated GH level of 41.9 µg/L.

Genetic testing resulted in a firm diagnosis for 80 of these children, while 69 remained undiagnosed; these undiagnosed patients had a significantly higher height SDS than those with a specific genetic diagnosis, at –3.4 versus –4.9, and were less likely to have consanguineous parents, at 13% versus 53%.

A majority (56%) of the patients to receive a specific diagnosis had defects in the GH–insulin-like growth factor (IGF)-1 axis – mostly in the GHR gene, but four had IGFALS mutations and one a mutation in IGFIR. Almost two-thirds (64%) of this group had consanguineous parents, compared with 34% of the cohort overall.

The remaining 44% of the children with a specific diagnosis had defects in genes outside of the GH–IGF-1 axis, the researchers report in The Journal of Clinical Endocrinology & Metabolism.

The diagnoses in these 35 children included 3M syndrome in 10 (29%), Noonan syndrome in four and Silver-Russell syndrome in two, while 10 children had copy number variations.

There were also single diagnoses of disorders not previously linked to GHI: Barth syndrome; glycogen storage disease type IXb; multiminicore disease; macrocephaly, alopecia, cutis laxa and scoliosis syndrome; Bloom syndrome; achondroplasia; autoimmune lymphoproliferative syndrome; microcephalic osteodysplastic primordial dwarfism type II and lysinuric protein intolerance.

“Although the underlying disease mechanisms are diverse, we suggest these overlapping disorders be considered part of an extended GHI spectrum”, write the researchers.

Children with defects in genes outside of the GH–IGF-1 axis were more likely than the other children to be born small for gestational age, but less likely to have consanguineous parents and they had a higher height SDS, on average.

However, there were no differences between the two groups for age at presentation, sex, peak GH level or IGF-1 SDS.

“The clinical diagnosis of known genetic syndromes traditionally relies on identifying ‘classical’ features”, write Storr and team.

“We demonstrate that the predominant consistent feature of many of these conditions is short stature. The associated dysmorphic features can be subtle, overlap with other disorders and are frequently non-specific.”

The researchers emphasise that a definitive genetic diagnosis will prompt screening for the “significant co-morbidities” associated with many of the disorders identified in this study.

And they add: “A diagnosis also informs prognosis, clinical management and countenances genetic counselling.”

By Eleanor McDermid

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J Clin Endocrinol Metab 2021; doi:10.1210/clinem/dgab437

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