Genetic IGF1R defects: new cases expand the spectrum of clinical features
1Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine, 06100, Ankara, Turkey. ngonc@hacettepe.edu.tr.
Insights
Insulin-like growth factor 1 receptor (IGF1R) defects were found in 14% of short children with normal growth hormone (GH) secretion. Phenotypic presentation and long-term complications vary, necessitating lifelong patient monitoring.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Short stature in children can stem from various genetic factors.
- Insulin-like Growth Factor 1 Receptor (IGF1R) plays a crucial role in growth and development.
- Identifying genetic causes of short stature is vital for appropriate management.
Purpose of the Study:
- To investigate the phenotypic spectrum of Insulin-like Growth Factor 1 Receptor (IGF1R) gene defects.
- To analyze short children with normal growth hormone (GH) secretion and identify IGF1R variations.
- To characterize the auxological and metabolic profiles associated with IGF1R defects.
Main Methods:
- Enrolled 50 children with short stature and normal GH levels.
- Utilized Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing for IGF1R defect detection.
- Conducted auxological and metabolic evaluations on patients and available first-degree relatives.
Main Results:
- Identified IGF1R defects in 14% (7/50) of the cohort, including deletions and heterozygous variants.
- Observed significant variability in height, birth weight, head circumference, and IGF-1 levels among affected children.
- Noted diverse clinical presentations, including intellectual disability in one case and metabolic/gonadal complications in adult carriers of IGF1R mutations.
Conclusions:
- IGF1R deletions or variants are present in a notable proportion of short children with normal GH.
- Phenotypic expression of IGF1R defects is highly variable, affecting growth parameters, cognition, and physical features.
- Adults with IGF1R mutations may develop metabolic and gonadal complications, underscoring the need for long-term follow-up.
Purpose:
We aimed to identify the phenotypic variability of IGF1R defects in a cohort of short children with normal GH secretion gathered through the last decade.
Patients And Methods:
Fifty children (25 girls) with short stature and a basal/stimulated growth hormone (GH) over 10 ng/ml having either a low birth weight or microcephaly were enrolled. MLPA and then Sanger sequence analysis were performed to detect IGF1R defects. The auxological and metabolic evaluation were carried out in index cases and their first degree family members whenever available.
Results:
A total of seven (14%) IGF1R defects were detected. Two IGF1R deletions and five heterozygous variants (one frameshift, four missense) were identified. Three (likely) pathogenic, one VUS and one likely benign were classified by using ACMG. All children with IGF1R defects had a height < - 2.5SDS, birth weight < - 1.4SDS, and head circumference < - 1.36SDS. IGF-1 ranged from - 2.44 to 2.13 SDS. One child with a 15q terminal deletion had a normal phenotype and intelligence, whereas low IQ is a finding in a case with missense variant. Two parents who carried IGF1R mutations had diabetes mellitus, hypertension and hyperlipidemia, one of whom also had hypergonadotropic hypogonadism.
Conclusion:
We found a deletion or variant in IGF1R in 14% of short children. Birth weight, head circumference, intelligence, dysmorphic features, IGF-1 levels and even height are not consistent among patients. Additionally, metabolic and gonadal complications may appear during adulthood, suggesting that patients should be followed into adulthood to monitor for these late complications.
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