ESPEYB19 4. Growth and Growth Factors New Perspectives (2 abstracts)
4.10. Genetic characterization of short stature patients with overlapping features of growth hormone insensitivity syndromes
Andrews A , Maharaj A , Cottrell E , Chatterjee S , Shah P , Denvir L , Dumic K , Bossowski A , Mushtaq T , Vukovic R , Didi M , Shaw N , Metherell LA , Savage MO & Storr HL
J Clin Endocrinol Metab. 2021;106(11):e4716-e4733. PMID: 34136918
Brief Summary: In this study, 149 children referred for suspected GH insensitivity (GHI) and short stature underwent genetic characterization through different techniques, including whole exome sequencing, targeted gene sequencing and array comparative genomic hybridization (array-CGH). Genetic alterations were identified in 80/149 subjects (54%), of which 45 were affected by GH–IGF-I axis defects and 35 were diagnosed with known genetic syndromes associated with multi-organ involvement. These results highlight the importance of genetic analysis in children with undefined short stature for a targeted management of comorbidities and specific therapeutic approaches.
This study aimed at defining genetic features of 149 short subjects (58% males) with suspicion of growth hormone insensitivity (GHI). The use of an extensive genetic approach (whole exome sequencing, targeted short stature gene panel, candidate gene sequencing and array-CGH) allowed to identify a genetic diagnosis in 54% (80/149) of subjects. Most of the defects (56%) involved the growth hormone-insulin like growth factor-I (GH-IGF-I) axis (GHR, IGFALS, IGF1R) but other genetic anomalies (associated with 3M syndrome, Noonan syndrome, Silver-Russell syndrome or conditions not previously related to GHI) were also identified. Most of the subjects (86%) with a specific genetic diagnosis had IGF-1 deficiency and were shorter than subjects without a recognized genetic abnormality (height: -4.9 vs -3.4 SDS).
The classical and most severe form of GHI syndrome, first described in 1966 and known as Laron syndrome, is caused by monogenic defects in the GH receptor (GHR) gene resulting in severe post-natal growth failure as a consequence of IGF-I deficiency. Over the years, genetic defects involving different components of GH-IGF-I axis, such as STAT5B, IGF-I, IGF-II, IGFALS, PAPPA2 have been recognized, expanding the phenotypic spectrum of GHI states (1).
Although GHR variants are the most frequent causes of GHI, this study confirms that the genetic spectrum of GHI is much broader than previously recognized. It shows that genetic characterization of children with severe growth retardation of unknown origin may be crucial for identifying rare conditions which require careful follow-up and multi-specialist care and to orientate treatment choice (e.g. avoiding rhGH treatment in conditions with increased tumor predisposition such as Bloom syndrome).
Reference: 1. Wit JM, de Luca F. Atypical defects resulting in growth hormone insensitivity. Growth Horm IGF Res. 2016;28:57–61.
Volume 19
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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