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Growth retardation in Down syndrome in relation to insulin-like growth factors and growth hormone
G Annerén1, K H Gustavson, V R Sara
1Department of Clinical Genetics, University Hospital, Uppsala, Sweden.
Insights
Children with Down syndrome (DS) experience growth retardation due to low insulin-like growth factor 1 (IGF-1) levels. Human growth hormone (hGH) therapy effectively increased growth velocity and normalized IGF-1 in DS patients.
Area of Science:
- Endocrinology
- Genetics
- Pediatrics
Background:
- Growth retardation is a primary characteristic of Down syndrome (DS), particularly after 6 months of age when growth becomes regulated by growth hormone (GH).
- DS individuals exhibit normal serum GH levels, but altered insulin-like growth factor (IGF) patterns may contribute to impaired growth.
Purpose of the Study:
- To investigate serum IGF patterns and receptor levels in fetuses with trisomy 21 and individuals with DS throughout their lifespan.
- To evaluate the efficacy of human growth hormone (hGH) therapy in addressing growth deficits in children with DS.
Main Methods:
- Serum IGF-1 and IGF-2 levels were measured using radioimmunoassays (RIA-IGF-1, RIA-IGF-2).
- Serum IGF activity was assessed via radioreceptor assay (RRA-IGF), which detects IGF-1, IGF-2, and fetal IGF variants.
- Binding sites for IGFs and insulin in fetal brain and liver were analyzed.
- Five growth-retarded children with DS received hGH therapy for six months.
Main Results:
- Serum RIA-IGF-2 levels were normal in DS individuals, but RIA-IGF-1 levels remained low throughout life.
- Fetal trisomy 21 showed a deficit in RRA-IGF, while postnatal and lifelong levels were elevated.
- No differences in IGF or insulin binding sites were observed in fetal tissues.
- hGH therapy in five DS children doubled growth velocity and normalized serum IGF-1 levels.
Conclusions:
- A potential delayed maturation and incomplete switch from fetal IGF to GH-regulated IGF-1 production may underlie growth retardation in DS.
- The deficit in IGF-1-like peptides likely contributes to the characteristic growth retardation in Down syndrome.
- DS children demonstrate a positive response to hGH treatment, indicating its therapeutic potential for growth enhancement.
Abstract:
Growth retardation is a cardinal characteristic of Down syndrome (DS). It is most pronounced from the age of 6 months, when growth starts to become growth hormone (GH) regulated. DS children have normal serum levels of GH. GH regulates the production of insulin-like growth factors (IGFs), which act as growth hormones. Therefore, the serum IGF pattern and the levels of their receptors were studied in fetuses with trisomy 21 and in patients with DS throughout life. Serum levels of IGF were determined by radioimmunoassays for insulin-like growth factors 1 and 2 (RIA-IGF-1 and RIA-IGF-2) showing normal serum RIA-IGF-2 levels throughout life. However, serum RIA-IGF-1 did not rise during childhood and remained at a low level throughout life. Determination of serum IGF by a radioreceptor assay (RRA-IGF), which detects both IGF-1 and IGF-2 as well as enhanced activity in the fetal circulation, showed a deficit in serum RRA-IGF in fetuses with trisomy 21, but at birth and throughout life elevated serum RRA-IGF levels. In spite of this, no differences were observed in fetal brain or liver binding sites for IGF-1, IGF-2, or insulin. Since in the RRA-IGF method IGF-1, IGF-2, and a fetal form of IGF-1 cross-react, it is possible that there is a delayed maturation with incomplete switching from production of the fetal form of IGF to production of the GH-regulated IGF-1 in DS. The deficit in IGF-1-like peptides might account for the growth retardation in DS. In order to study the effect of human growth hormone (hGH) therapy in DS, 5 growth-retarded children with DS were treated with hGH for 6 months. During this period the growth velocity doubled and the serum IGF-1 levels were restored to normal. Thus, DS children respond to hGH treatment.