ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2019 Feb. doi: 10.1210/jc.2018-02288. [Epub ahead of print]

Short stature is the most common reason for referral to pediatric endocrinologists. Familial short stature (FSS) is used to describe a child with a stature below the normal but within the parental target range and with at least one short parent.

In the last years, there has been a widespread use of genetic analysis to identify the etiology of short stature and a high number of loci, accounting for approximately 30% of adult height variation, have been identified [1]. Milder forms of FSS are likely related to a polygenic inheritance whereas severe forms more often depend on a single gene anomaly. Monogenic causes involve either growth plate-related genes such as SHOX, ACAN, FGFR3, NPR2, COL11A1, COL9A2, COL2A2 or GH/IGF-I axis genes [2]. The current workup for short stature usually identifies the etiology in 1-40% of subjects [3] and most FSS cases remain without a definite diagnosis.

In this study, 33 children with severe familial short stature (FSS), treated with GH for SGA or GHD indications, underwent whole-exome sequencing (WES). This identified the underlying genetic cause in half of the patients (17/33 subjects, 52%), with a high prevalence of growth plate single-gene variants, especially in SGA subjects.

By applying next generation sequencing to FSS subjects, this study shows for the first time that monogenic conditions are a frequent cause of FSS and suggests that growth plate-related gene variants, usually involved in bone/cartilage dysplasias [4], should be investigated in subjects with severe FSS born SGA, even without disproportionate short stature. Furthermore, this study has also the merit to clearly demonstrate the pitfalls associated with the workup of short stature often leading to the erroneous diagnosis of GHD. Indeed, only 1/23 children with clinically diagnosed GHD was shown to carry a genetic variant affecting GH secretion whereas 7 GHD patients were shown to carry growth plate-related, IGF-related or Noonan syndrome-related gene variants [5]. The major limitation of the study is the lack of functional studies. Nevertheless, this study paves the way for a novel approach to the child with FSS based on the molecular characterization, thus favoring a tailored monitoring and management.

References: 1. Murray PG, Clayton PE, Chernausek SD. A genetic approach to evaluation of short stature of undetermined cause. Lancet Diabetes Endocrinol 2018;6:564–574.

2. Hattori A, Katoh-Fukui Y, Nakamura A, Matsubara K, Kamimaki T, Tanaka H, Dateki S, Adachi M, Muroya K, Yoshida S, Ida S, Mitani M, Nagasaki K, Ogata T, Suzuki E, Hata K, Nakabayashi K, Matsubara Y, Narumi S, Tanaka T, Fukami M. Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature. Endocr J 2017;64:947–954.

3. Dauber A, Rosenfeld RG, Hirschhorn JN. Genetic evaluation of short stature. J Clin Endocrinol Metab 2014;99:3080–3092.

4. Zhang H, Yang R, Wang Y, Ye J, Han L, Qiu W, Gu X. A pilot study of gene testing of genetic bone dysplasia using targeted next-generation sequencing. J Hum Genet 2015;60:769–776.

5. Baron J, Savendahl L, De Luca F, Dauber A, Phillip M, Wit JM, Nilsson O. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol 2015;11:735–746.