Introduction

Short stature is one of the most common symptoms encountered by pediatric endocrinologists. Defects in a wide variety of genes can cause severe growth disorders. However, these defects are hard to detect. Targeted next-generation sequencing (NGS) is an advanced and inexpensive method for rapid genetic assessment of short stature.

We identified a novel heterozygous type-I insulin-like growth factor receptor (IGF-1R) gene mutation in a severely short Chinese boy using targeted NGS. Our findings provide essential information about IGF-1R mutations in the Chinese population.

Material and methods

Case presentation

The patient first presented at the age of 5 years and 11 months to our centre for short stature. He presented with a height of 97.3 cm (−4.74 standard deviation score (SDS)), weight of 13 kg (−3.7 SDS) and body mass index of 13.82 \(\hbox {kg/m}^{2}\, ({<}-2 \hbox {SD})\). He was born at 36 weeks of gestation with a birth weight of 2.15 kg (−2.85 SDS), birth height of 50 cm, and head circumference of 47 cm (−2.0 SDS). His mother’s height was 145 cm (−3.05 SDS). The other family members of the patient also displayed short stature (figure 1). The patient’s bone age was 2.5 years, and was delayed by 3 years. Laboratory tests including growth hormone (GH) stimulation test, serum IGF-1 levels, IGF-binding protein (IGFBP)-3, serum luteinizing hormone, follicle-stimulating hormone, oestradiol, and testosterone were normal. Magnetic resonance imaging revealed a relatively small pituitary gland.

Fig. 1
figure 1

The pedigree and sequencing results of IGF-1R mutation. (a) The family history of patients with IGF-1R mutations, proband gene mutation from his mother and grandfather. (b) Proband IGF-1R gene c.926C\({>}\)T (p. S309L); (c) normal control. An arrow represents the point of variation.

Full size image

NGS targeting 277 short stature-associated genes and 19 related copy number variation regions was performed according to the manufacturer’s protocol (MyGenostics, Baltimore, USA) (table 1). A novel heterozygous mutation of exon 3 (\(\hbox {c.926C}{>}\hbox {T}\), p.S309L) in the IGF1R gene was identified in the proband and his mother (figure 1a). However, the mutation was not detected in the coding region of the IGF-1R gene in his father and 100 unrelated healthy individuals (figure 1, b&c). This mutation has not been previously reported in the single-nucleotide polymorphism (SNP) database (http://www.ncbi.nlm.nih.gov/SNP/), and it was predicted to be deleterious by Align-GVGD software.

Treatment with rhGH (0.2 U/kg/d) (Simon et al. 2008) commenced at 5 years and 11 months of age. Changes in height, body weight, and bone age were evaluated every 3 months. IGF-1 and IGFBP3 levels were also regularly monitored. The rhGH was well tolerated. After one year, height SDS had increased by 0.763. The 8 cm per year growth rate was significantly higher compared to the rate before treatment (table 2).

Table 1 List of 277 short stature-related genes and 19 short stature-associated copy number variation regions.
Full size table

Signed parental informed consent was obtained for the publication of this case report.

Results and discussion

Components of the IGF system are ubiquitously expressed throughout foetal and postnatal life, and regulate the development of multiple tissues and organs (Klammt et al. 2011). The mitogenic and metabolic effects of IGF-1 are mediated through the IGF-1R cell-surface tyrosine kinase receptor.

Several IGF-1R mutations have been recently described as the cause of prenatal and postnatal growth retardation in humans because of IGF-1 insensitivity (Juanes et al. 2015). Our previous studies on 1327 samples revealed the association of an SNP of IGF-1R with genetic susceptibility to idiopathic short stature (Yang et al. 2013).

Defects in IGF-1R have been associated with intrauterine and postnatal growth retardation in over 20 families. However, the correlation between genotype and phenotype has remained unclear. The variability in specific clinical and biochemical features in individuals with different IGF-1R mutations may be related to the specific functions of the mutated IGF-1R regions or variations in genetic background.

Overall, these studies indicate that IGF-1R plays a pivotal role in development and that its mutations should be evaluated to identify the specific functional change and clinical symptoms. Nevertheless, the clinical diagnostic criteria of molecular screening for IGF-1R mutations are unclear and data from more clinical cases would be helpful to complement the characteristics of the phenotypic spectrum.

Table 2 Clinical and biochemical characteristics of the proband after rhGH treatment.
Full size table

The present report describes the case of a Chinese boy with small for gestational age, short stature, microcephaly, and delayed body age. We identified a \(\hbox {c.926C}{>}\hbox {T}\) (p. S309L) missense mutation in IGF1R using targeted NGS. The mutation was predicted to be deleterious using the Align-GVGD web portal (http://agvgd.iarc.fr/). The proband’s mother and grandfather harboured the same mutation; the SD of their height was −3.1 (short stature) −1.7 (mild short), respectively, indicating a critical family history in this case. Therefore, we believe that this mutation is the most likely cause of short stature observed in this pedigree. We looked into the effect of the mutation on the protein three-dimensional structure and interaction with IGF, but did not find any supporting evidence through computer docking studies. Further functional analysis is needed to confirm the possible effects of the mutation.

The majority of IGF-1R mutations are heterozygous and most are missense mutations (Essakow et al. 2016). These might cause IGF-1R deficiency and impair ligand binding and signal transduction, eventually resulting in growth retardation (Kawashima et al. 2014; Ocaranza et al. 2017). Most IGF-1R deficient patients of short stature are diagnosed as microcephaly after birth (Fujimoto et al. 2015; Juanes et al. 2015). The symptoms of the patients analysed in the present study are consistent with the reported clinical features of IGF-1R mutations.

Several patients with IGF-1R abnormalities have received GH treatment (Muller et al. 2012; Mahmoud et al. 2017), which has produced effective height gain in all cases without side effects. In the present study, rhGH treatment was effective. The patient responded well to the treatment. However, due to the limited number of cases and treatment period, no definite conclusion can be drawn, and further functional research is needed. These results provide important and novel insights into short stature disorders.