2024 Volume 71 Issue 7 Pages 687-694
Short stature with IGF-1 receptor (IGF1R) gene alteration is known as small-for-gestational-age (SGA) short stature with elevated serum IGF1 levels. Its prevalence and clinical characteristics remain unclear. No adapted treatment is available for short stature related to IGF1R gene alteration in Japan, and genetic testing is not yet widely accessible. We investigated short stature with IGF1R gene alterations and analyzed the clinical data of 13 patients using the results of questionnaires issued to the Japanese Society for Pediatric Endocrinology. Four cases were caused by a deletion of chromosome 15q26.3, and eight were caused by heterozygous pathogenic variants in the IGF1R gene. Cases with deletions showed a more severe degree of growth impairment (–4.5 ± 0.43 SD) than those caused by pathological variants (–2.71 ± 0.15 SD) and were accompanied by neurodevelopmental delay. However, cases caused by pathological variants lacked distinctive features. Only three of the 12 cases demonstrated serum IGF1 values exceeding +2 SD, and the other three had values below 0 SD. Four patients did not meet the criteria for SGA at birth. Six patients received GH therapy for SGA short stature and showed improvement in growth rate without any side effects or elevated serum IGF1 levels during treatment. Elevated IGF1 levels (over +2 SD) after GH treatment should be considered a suspicious finding. Owing to the lack of distinctive features, there was a possibility of undiagnosed cases of this condition. Promoting genetic testing and clinical trials on GH administration for this condition is recommended.
SHORT STATURE is the most common condition in pediatric endocrinology. Familial short stature constitutes a significant proportion of short stature cases, with a subset attributed to single-gene familial short stature [1, 2]. However, currently, only a few treatable conditions are covered by insurance [1]. GH treatment for idiopathic short stature (ISS) has not been approved in Japan. Moreover, diagnosis and treatment for short stature might not be as actively performed as for other medical conditions because it has less impact on the quality of life (QoL). Nevertheless, regardless of treatment, a decrease in the QoL has been reported among patients with short stature and their parents [1, 3]. Therefore, short stature therapy is an important but challenging area in pediatric endocrinology.
The type 1 insulin-like growth factor receptor (IGF1R) is widely expressed in many cell types in fetal and postnatal tissues [4]. IGF1R is activated by secreted growth factor ligands such as IGF1 and IGF2, which elicit cellular responses resulting in fetal somatic growth [5, 6]. IGF1R plays a significant role in growth. Recently, many patients with short stature due to IGF1R gene variants have been reported after the first report of a patient with short stature due to IGF1R gene variants was found in 2003 [7-14]. Short stature with haploinsufficiency of the IGF1R gene on chromosome 15q 26,3 has also been reported [13]. Currently, IGF1R gene variants account for approximately 2% of short stature cases attributed to single-gene abnormalities in patients with small-for-gestational-age (SGA) conditions, making them relatively common among this disorder [15]. In Japan, the first report was published in 2005 [9], and although the number of reports has increased [16-18], the actual frequency remains uncertain, and specific clinical features beyond growth disorders remain unclear [19]. Previous reports have indicated the effectiveness of GH treatment for this condition [19]. However, despite being registered as a Specific Pediatric Chronic Disease, established by The Ministry of Health, Labour and Welfare in Japan, there is no insurance coverage for GH treatment related to short stature with IGF1R gene alteration, while GH treatment for SGA short stature has received insurance approval in Japan [20]. Although short stature with IGF1R gene alteration is characterized by high IGF1 levels in patients with SGA, some patients are not born with SGA, and cannot receive GH treatment. Additionally, some patients may present with normal IGF1 levels, making it difficult to differentiate them from common SGA short stature, potentially leading to undiagnosed cases.
Here, we investigated short stature with IGF1R gene alteration to elucidate the detailed clinical characteristics and effectiveness of GH treatment.
We conducted a primary survey by issuing web-based questionnaires to council members under the approval of the Japanese Society for Pediatric Endocrinology (JSPE) from September to October 2022. In the primary questionnaire, we asked about experiences in clinical practice and the number of patients who had short stature with IGF1R gene alteration (IGF1R gene variant or defect). We also provided a secondary questionnaire for doctors who reported diagnosing short stature with IGF1R gene alteration in the primary survey. Additionally, participants from two facilities (the University of Tokyo and Shinshu University) other than the council members that treated the disease also participated in the second survey after the study design was approved by the Shimane University School of Medicine Ethics Committee. In the secondary questionnaire, we asked about each patient’s age; sex; birth weight (BW); birth length (BL); head circumference (HC); peak serum GH level in the GH provocation test; serum IGF1 level; height (including adult height); bone age; glycated hemoglobin (HbA1c) before, during, and after the GH treatment; period of puberty onset; complications; and cytomolecular analysis. The standard deviations (SDS) for BW, BL, HC, and height were calculated based on Japanese data regarding standard height by sex and age [21, 22]. The IGF1 SDS was calculated using Japanese reference values for serum IGF1 concentrations in children based on sex and age [21].
The Ethical Review Board of Shimane University Faculty of Medicine approved this study (KS20220406-1), which was performed in accordance with the principles stablished in the Declaration of Helsinki.
Of the 171 council members of the JSPE, 87 responded to the primary survey (response rate, 51%). Among them, nine facilities reported a diagnosis of IGF1R abnormalities, totaling 11 cases. In the secondary survey, seven of the nine responding facilities, along with the two facilities that did not respond to the primary survey and had patients, were involved in diagnosing 13 cases with the condition. Using the aforementioned method, a secondary survey was conducted to evaluate the clinical characteristics and effectiveness of GH treatment.
Clinical features of short stature with chromosome 15q26.3 deletionsClassic short stature with IGF1R gene alterations is associated with microcephaly and elevated IGF1 levels in individuals with SGA. Walenkamp et al. suggested considering this condition when the following characteristics are observed: BW and/or BL <–1 SDS, height at presentation <–2.5 SDS, HC at presentation <–2 SDS, and IGF1 >0 SDS. A Walenkamp’s score criteria (WSC) score >3 had 87% specificity [15]. In cases caused by deletion of chromosome 15q26.3, the features of IGF1R abnormalities are more pronounced, with a stronger likelihood for growth impairment and other complications [15].
Table 1 presents four cases with deletion of chromosome 15q26.3, where the IGF1R gene is located. Cases 3 and 4 had trisomy of chromosomes other than chromosome 15. Case 3 had trisomy of the short arm of chromosome 10, which is reported to be associated with neurodevelopmental delay, short stature, and congenital heart disease (CHD) [23]. Case 4 had partial trisomy of the long arm of chromosome 7 (7q25-qter), which is reported to be associated with neurodevelopmental delay [24].
The clinical features of short stature with chromosome 15q26.3 deletion
| Cases | Cytogenetical analysis | Sex | Age (yr) | Birth Weight (SD) | Birth Length (SD) | HC (SD) | GA (weeks) | Height (SD)* | IGF-1 (SD)* | BA (CA) | Maximum GH peak in GH provocation test (μg/L) | Neuro-develop-mental Delay | Other Compli-cations | GH Treat-ment | WSC |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 15q26.3 deletion | M | 6.4 | –1.76 | –0.57 | –0.09 | 37 | –3.71 | 2.09 | N/A | N/A | + | PVC | – | 3 |
| 2 | 15q26-qter deletion | F | 2.3 | –2.6 | –3.24 | –1.98 | 38 | –5.09 | 0.62 | N/A | N/A | + | VSD; HLHS | – | 3 |
| 3 | 15q26.2-q26.3 deletion, 10p15.3-p12.31 duplication, 10q11.21 duplication | F | 6.9 | –3.2 | –2.81 | –2.73 | 36 | –5.78 | 1.23 | 1.5 (3.1) | 16.6 (GHRP2) | + | PDA; urolithiasis | + | 4 |
| 4 | 46,XY,der(15)t(7;15)(q35;q26.2) | M | 2.7 | –2.36 | –2.67 | –0.35 | 37 | –3.8 | 1.33 | N/A | N/A | + | VSD; inguinal hernia; congenital clubfoot | – | 3 |
| mean ± SE | –2.48 ± 0.25 | –2.32 ± 0.51 | –1.28 ± 0.55 | –4.5 ± 0.43 | 1.31 ± 0.26 |
* before GH treatment.
HC, Birth head circumference; GA, Gestational age; BA, Bone age; CA, Chronological age; PVC, premature ventricular contraction; VSD, ventricular septal defect; HLHS, hypoplastic left heart syndrome; PDA, patent ductus arteriosus; WSC, Walenkamp’s score criteria
Case 1 was not born with SGA, and Cases 1 and 4 did not exhibit microcephaly less than –2.0 SD. The serum IGF1 levels were elevated by more than 2 SD only in Case 1; however, it is generally known that IGF1 levels in SGA-related short stature tend to be at the lower limit of normal. The mean height before GH treatment was –4.5 ± 0.43 SD, indicating a severe short stature. In all cases with 15q26.3 deletion related IGF1R alteration, the IGF1 levels were above 0 SD (mean: 1.31 ± 0.26 SD), meeting WSC for all cases. The onset of puberty could not be assessed because all patients were young.
Additionally, occasional neurodevelopmental delays were present in all cases. Cases 2 to 4 exhibited concomitant CHD.
Clinical features of short stature with heterozygous single-nucleotide variants in the IGF1R geneTable 2 presents the characteristics of short stature with heterozygous pathological variants in the IGF1R gene. Cases 7 to 12 have already been reported, and functional analysis has demonstrated impaired function of the IGF1R [9, 16-19]. Case 5, with a splicing variant, and Case 6 and 13 with a frameshift variant, have not been previously reported. All the cases involved heterozygous variants. Whole exome sequencing was performed in cases 5, 6, and 13, and targeted resequencing using TruSight One sequencing panels was performed in cases 10 and 12. Those cases have been analyzed for genes associated with GH-IGF signals and growth plate, as well as other causative genes associated with short stature, and excluded for other pathogenic variants in other growth-related genes. Although cases 7 to 9 have not been analyzed with whole exome sequencing, a familial and functional analysis has clearly demonstrated the impaired function of IGF1R and those variants proven by ClinVar [19].
Clinical features of short stature with heterozygous single-nucleotide variants in the IGF1R gene
| Cases [reference] | Genotype of IGF1R | Sex | Age | Birth Weight (SD) | Birth Length (SD) | HC (SD) | GA (weeks) | Height (SD)* | IGF-1 (SD)* | BA (CA) | Maximum GH peak in GH provocation test (μg/L) | Neuro-develop-mental Delay | Other Compli-cation | GH Treat-ment | WSC |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 5 | c.953+2T>C | M | 6.3 | –2.75 | –0.49 | –2.42 | 40 | –2.78 | 3.21 | 4.4 (4.25) | 18.3 (Arginine) | + | – | – | 4 |
| 6 | p.lle160fs | M | 9.7 | –3.85 | –2.41 | –2.34 | 41 | –2.98 | 0.06 | N/A | 23.4 (Arginine) | – | – | + | 4 |
| 7 [16] | p.Asp1135Glu | F | 18 | –1.3 | –2.16 | N/A | 37 | –3 | 2.57 | 5.8 (6.3) | 35.2 (Arginine) | – | – | + | 3 |
| 8 [17] | p.Trp1149* | F | 12 | –3.01 | –2.83 | –2.63 | 40 | –3 | 0.36 | 2.8 (3.4) | 20.76 (Arginine) 28.32 (Clonidine) |
– | – | + | 4 |
| 9 [19] | p.Tyr888* | F | 10.3 | –1.27 | –0.86 | –0.12 | 40 | –2.2 | –0.08 | 7.9 (9.9) | 65.5 (GHRP2) | – | – | – | 1 |
| 10 [19] | p.Tyr888* | M | 8.3 | –2.87 | –2.97 | –1.66 | 40 | –3.38 | –0.45 | 2 (4.5) | 30.5 (GHRP2) | – | – | + | 2 |
| 11 [9] | p.Arg739Gln | F | 24.7 | –1.26 | –0.78 | N/A | 40 | –2.3 | 1.41 | 3.9 (6.0) | N/A | + | – | – | 2 |
| 12 [18] | p.Arg461Leu | F | 20 | –1.66 | –2.77 | N/A | 39 | –3.43 | –0.32 | 3.5 (4.3) | 37.4 (L-DOPA) | – | – | + | 2 |
| 13 | p.Ser487fs* | M | 7.1 | –2.22 | –2.1 | N/A | 39 | –1.34 | 2.32 | 6.0 (7.1) | – | – | – | 2 | |
| mean ± SE | –2.24 ± 0.35 | –1.93 ± 0.36 | –1.83 ± 0.34 | –2.71 ± 0.15 | 1.0 ± 0.49 |
* before GH treatment.
HC, Birth head circumference; GA, Gestational age; BA, Bone age; CA, Chronological age; WSC, Walenkamp’s score criteria
Compared to the cases of IGF1R gene deletions shown in Table 1, those with pathological variants had fewer complications and tended to have milder degrees of growth disorder. The mean height before GH treatment was –2.71 ± 0.15 SD, while that of cases with IGF1R gene deletions was –4.5 ± 0.43 SD. Case 13 was born as SGA, with high serum IGF1 levels, but the height was within the normal range at –1.34 SD. Neurodevelopmental delay was observed in only two cases: Case 5 and 11. Seven of nine patients showed delayed bone age. Additionally, among the cases, three out of nine cases with available data did not meet the criteria for SGA, and only three out of nine cases had IGF1 values higher than 2 SD above the mean. Three of the nine cases had IGF1 values less than 0 SD. Among the nine cases, four had unknown HCs, and only four fit the previously mentioned WSC. Based on these observations, we believe that short stature caused by heterozygous pathological variants in the IGF1R gene lacks distinctive characteristics. Since not all cases reached puberty, information regarding pubertal onset was not fully assessed. None of the cases met the criteria for precocious or delayed puberty, and puberty commenced normally. No patient was found to have impaired glucose tolerance or diabetes before GH treatment. Five of nine patients with heterozygous IGF1R gene variant were receiving GH treatment for SGA short stature.
GH treatment for short stature with IGF1R gene alterationGH treatment for short stature with IGF1R gene alteration aims to increase the levels of IGF1 through GH treatment. As most cases involve haploinsufficiency or heterozygous variants, GH treatment targets the remaining IGF1R to stimulate growth, and its effectiveness has been widely reported [8, 14, 15, 19, 25-28]. In Japan, GH treatment for short stature with IGF1R gene alteration is not covered by insurance but is available for SGA short stature. Therefore, six patients with SGA short stature received GH treatment for SGA short stature in this study. Among these, five cases were due to heterozygous pathological variants, while one case (case 3) involved a deletion in the 15q26.2-26.3 region and partial trisomy of chromosome 10. Cases 7, 8, 10, and 12 were reported in our previous study. None of the six patients experienced any side effects during GH treatment, and no glucose intolerance or diabetes was observed. Additionally, case 12 received a GnRH analog, but no diagnosis of precocious puberty was made after GH treatment. The data regarding the first 2 years of clinical trials for GH treatment of SGA short stature before GH treatment became eligible for insurance coverage (case 12) are presented. At that time, the height response to GH was considered weak, and clinical trials for GH treatment were temporarily ceased. However, insurance coverage for GH treatment in cases of SGA short stature was approved, leading to its resumption. The LH-RH analog was concurrently administered for 2 years, and the adult height reached 148.5 cm (–1.81 SD). The GH dosage was within the range approved for GH treatment for SGA short stature in Japan. All cases were initially started at 0.23 mg/kg/week, which was gradually increased. The dose in case 3 was increased to 0.4 mg/kg/week, and that in case 7 was increased to 0.45 mg/kg/week. As shown in Fig. 1A, an improvement of more than 1 SD in height was observed after GH treatment. In our cases of heterozygous IGF1R pathogenic variant treated with GH treatment for 3 years, an average height increase of +1.23 ± 0.12 SD was observed, while cases with 15q26.2 deletions showed a height increase of +1.9 SD. Additionally, as shown in Fig. 1B, five of the six cases showed IGF1 values over 2 SDS, indicating significantly elevated IGF1 levels. Case 7, previously reported in our study, involved a pathological variant with dominant-negative effects. The mother of Case 7 also carried the same variant, exhibiting a height of 137 cm (–4 SD) and type 2 diabetes. However, case 7 achieved a final height of 149.8 cm (–1.61 SD).
GH treatment for short stature with IGF-1 receptor (IGF1R) gene alteration
A: Change in height SDS of five patients during 5 years of GH treatment. Cases 7 and 12 completed the GH treatment, and their final heights are indicated. B: Change in the mean serum IGF1 SDS of five cases during 5 years of GH treatment. The data regarding the first 2 years of clinical trials for GH treatment of SGA short stature before GH treatment became eligible for insurance coverage (case 12) are presented. At that time, the height response to GH was considered weak, and clinical trials for GH treatment were temporarily ceased. However, insurance coverage for GH treatment in cases of SGA short stature was approved, leading to its renewal. The LH-RH analog was concurrently administered for 2 years, and the adult height reached 148.5 cm (–1.81 SD).
Here, we present research findings on short stature with IGF1R gene alteration in Japan. The cases caused by pathological variants lacked distinctive features. Additionally, some cases were not born with SGA, had an IGF1 value below 0 SD, and did not receive GH treatment. Six patients received GH therapy, all of whom showed improvements without side effects.
The short stature phenotype associated with the IGF1R gene remains poorly understood. Cases with chromosome 15q26.3 deletions often involve unbalanced chromosomal abnormalities and deletion of the NR2F2 gene, a causative gene for CHD, in 15q26.2 [29]. Consequently, many cases showed characteristic complications, such as neurodevelopmental delay [25, 29, 30]. In this study, all cases with chromosome 15q26.3 deletions exhibited characteristic complications, including CHD, caused by the deletion of the NR2F2 gene, and developmental delay, meeting the WSC. When CHD and developmental delay meet the WSC, the condition can be suspected, and diagnosis can be readily made through chromosomal microarray analysis and G-banding. In contrast, in cases caused by heterozygous pathological variants, as in our previous study, eight of 11 cases did not meet the WSC (including those without apparent findings, such as HC). In this study, five out of 13 cases did not meet the WSC. However, this cannot be definitively stated because there were cases with insufficient information, such as HC. Additionally, the WSC is a combination of BW, BL, HC, IGF1 levels, and the degree of current growth impairment, because a significant characteristic of short stature with IGF1R gene alteration is a tendency for decreased height during fetal and postnatal development, with elevated IGF1 values. However, previous reports have observed that, even with similar mutations, heterozygous cases with the same heterozygous pathogenic variant exhibit wide variations in height, IGF1 levels, and intrauterine growth delay [11, 12]. This variability might be due to the nature of IGF1R, which is a heterotetrameric (α2β2) transmembrane glycoprotein. The tyrosine kinase domain present in the β chain of IGF1R allows access to mutual phosphorylation after binding with IGF1, transmitting the IGF1 signal. Additionally, IGF1 itself can bind to the insulin receptor. Hybrid receptors, such as the IGF1R and insulin receptor hybrid, contribute to the regulation of IGF1 signaling from multiple domains [4]. These factors are thought to be associated with the variability in expression observed in heterozygous variants of IGF1R. Furthermore, it should be noted that growth is not solely determined by the IGF1 signal. The clinical variation of BW, BL, HC, and IGF1 levels, which is a component of the WSC score, is commonly observed in ISS and is not considered a specific finding [31]. Based on the aforementioned previous studies and our research, specific findings for short stature with IGF1R gene alteration are lacking, especially those caused by heterozygous pathological variants, and genetic testing can be considered the most effective method for diagnosis. However, genetic testing requires ethical considerations. Therefore, if the WSC is met, or if elevated IGF1 levels or excessive response to GH stimulation tests occurs, as seen in this study and our previous study [19], IGF1R gene alteration should be suspected.
Currently, the treatment options for short stature are limited. GH treatment for SGA short stature has been approved, but not for ISS in Japan. Walenkamp et al. reported that in cases of SGA short stature, a height increase of +1.8 SD is typically achieved with GH treatment. However, in cases of heterozygous IGF1R pathogenic variant treated with GH treatment for 3 years (at a dosage of 1.1 mg/m2/day), an average height increase of +0.9 SD was observed, while cases with 15q26.2 deletions showed a height increase of +1.3 SD [15]. In our cases of heterozygous IGF1R pathogenic variant treated with GH treatment for 3 years, an average height increase of +1.23 ± 0.12 SD was observed, while cases with 15q26.2 deletions showed a height increase of +1.9 SD. Moreover, Yokota et al. reported an average height increase of 0.63 ± 0.12 SD per yearly GH treatment for Japanese SGA short stature; our study showed an increase of 0.71 ± 0.08 SD [20]. These results indicate that GH treatment for SGA short stature with IGF1R pathogenic variant does not differ significantly from that reported for SGA short stature thus far. On the contrary, cases of ISS treated with GH for 1 year (at the same dosage of SGA short stature) showed an increase of 0.3–0.5 SD, which is a weaker effect than that for SGA short stature [3]. rhGH treatment for short stature with IGF1R gene alterations caused by IGF1R gene defect or pathogenic variant is effective without significant adverse effects, according to previous studies, including our cases [15, 19]. In previous studies and this study, not all cases were diagnosed with SGA short stature. In Japan, GH treatment cannot be administered even with a diagnosis of IGF1R gene alteration caused by IGF1R gene defect or pathogenic variant if the patient is not born with SGA. Although it has been registered as a Specific Pediatric Chronic Disease in Japan, there is no insurance coverage for GH treatment related to short stature with IGF1R gene alteration, making it difficult for patients with IGF1R gene alterations without SGA to receive GH treatment. Moreover, if physicians find high IGF1 levels after GH treatment for SGA short stature, they usually decrease the GH treatment dose due to concerns about side effects such as cancer [32]. However, high IGF1 levels after GH treatment are expected for cases of short stature with IGF1R alteration; they will not experience side effects and will not be affected by a decreased GH dose. To resolve the issues mentioned above, awareness of short stature with IGF1R gene alteration caused by IGF1R gene defect or pathogenic variant, and genetic testing, including array comparative genomic hybridization, is warranted in Japan, along with appropriate GH treatment.
Some limitations should be noted. Two cases (3 and 4) with chromosome 15q26.3 deletions have other unbalanced chromosomal abnormalities, which can influence the clinical manifestations. Accordingly, not all findings presented in Case 3 and 4 were associated with chromosome 15q26.3 deletions. Although a familial and functional analysis demonstrated the impaired function of IGF1R, cases 7 to 9 were not excluded through a comprehensive gene search for other pathogenic variants in other growth-related genes. This study surveyed members of the JSPE and is not representative of research on all short stature cases with IGF1R gene alteration in Japan. Furthermore, due to the nature of the survey, detailed records rely on self-reported questionnaire responses, which may affect precision and accuracy.
In summary, we conducted research on short stature with IGF1R gene alteration in Japan. Our study revealed a lack of distinctive features, especially in patients with short stature with heterozygous IGF1R pathogenic variants. GH treatment was effective without any side effects. Nevertheless, the promotion of genetic testing and clinical trials on GH treatment administration for this condition is required.
The authors would like to thank all council members of the JSPE for cooperating in primary survey, Drs Hotsubo T in Sapporo Children’s Endocrine Clinic; Hamajima T in the Department of Pediatric Endocrinology and Metabolism, Aichi Children’s Health and Medical Center; Tanaka H in the Department of Pediatrics, the University of Tokyo Hospital; Nakamura C and Shibazaki T in the Department of Pediatrics, Shinshu University School of Medicine; Yoshii K in the National Center for Child Health and Development; Fujisawa Y in the Department of Pediatrics, Hamamatsu University School of Medicine; Hasegawa Y in the Tokyo Metropolitan Children’s Medical Center; and Nagasaki K in the Department of Pediatrics, Niigata University Graduate School of Medicine and Dental Sciences for providing case information.
None of the authors have any potential conflicts of interest associated with this research.
