ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2019; 104(8): 3157–3171.

The IGF receptor gene IGF1R is located at 15q26.3 locus and encodes for a tyrosine kinase receptor which mediates the IGF-I biological actions. The key role of IGF-IR in growth and development was proved in IGF1R null mice that had severely impaired prenatal growth and invariably died at birth from respiratory insufficiency [1]. Consistently, only two patients with homozygous mutations have been reported so far [2], suggesting that in humans only mild homozygous mutations of IGF1R are compatible with survival. The cases reported with a lack of IGF1R are either heterozygous carriers [3,4] or, in only three patients, compound heterozygous carriers [5].

IGF1R defects are associated with both intrauterine and postnatal growth failure, microcephaly, and IGF-I levels above the reference range, although IGF-I levels can be initially low for feeding problems. IGF1R defects are recognized in SGA subjects [3, 6]. Interestingly, terminal deletions of chromosomal region 15q, including the IGF1R locus, have been reported in patients with impairment of growth and development and abnormalities in the skeleton and heart. The diagnosis of IGF1R defects can be challenging due to the broad phenotypic variability. Conflicting data on the efficacy of GH therapy in children with IGF1R heterozygous mutations have been reported so far.

This retrospective study based on the clinical data of 32 patients with IGF1R defects, proposed a novel clinical score for the diagnosis of IGF1R mutations, inspired by the score used to diagnose Silver-Russell syndrome. This IGF1R score is based on birth size, height (Ht) and head circumference (HC). A score ≥3 (birth weight and /or length SDS < −1; Ht at presentation < −2.5 SDS; HC at presentation < −2 SDS; and IGF-I > 0 SDS) had a sensitivity of 76% in identifying patients harboring IGF1R defects. The score was then applied to a large cohort (n=372) of patients born SGA, with sensitivity and specificity of 75% and 69%, respectively.

The 19 children treated with GH were stratified into two groups: group 1 with IGF1R pathogenic mutations and group 2 with 15q deletions including IGF1R. Overall, responses to GH therapy were moderate. Patients from group 1 gained an average of 0.50, 0.65 and 0.91 SDS in height during the 1, 2 and 3 first years of therapy, respectively. For patients from group 2 this was 0.75, 1.10 and 1.30 SDS, respectively. In children born SGA, height gain was 0.90, 1.45 and 1.82 SDS, respectively. In the 6 patients for whom data on adult height were available, mean adult Ht SDS was −2.0 (range −3.5 to −0.6), compared to an initial height SDS of −3.4 SDS (range −5.5 to −1.2). The mean adult height gain was 1.0 SDS after a variable duration of treatment ranging from 1.25 to 9.58 years. These results suggest that in the first years of GH treatment, linear growth increases less than documented for patients with SGA, in spite of considerably higher serum IGF-I concentrations. However, the adult height gain may be similar.

This is the largest cohort of patients with IGF1R defects described so far. The merit of this study is to provide a comprehensive view of the clinical features, biochemistry, and response to long-term GH therapy according to the underlying genetic defect. Moreover, the proposed novel clinical score will be extremely helpful in assisting the physician to select patients for genetic testing.

References: 1. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 1993;75:59–72.

2. Gannage-Yared MH, Klammt J, Chouery E, Corbani S, Megarbane H, Abou Ghoch J, Choucair N, Pfaffle R, Megarbane A. Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations. Eur J Endocrinol 2013;168:K1–7.

3. Leal AC, Montenegro LR, Saito RF, Ribeiro TC, Coutinho DC, Mendonca BB, Arnhold IJ, Jorge AA. Analysis of the insulin-like growth factor 1 receptor gene in children born small for gestational age: in vitro characterization of a novel mutation (p.Arg511Trp). Clin Endocrinol 2013;78:558–563.

4. Harmel EM, Binder G, Barnikol-Oettler A, Caliebe J, Kiess W, Losekoot M, Ranke MB, Rappold GA, Schlicke M, Stobbe H, Wit JM, Pfaffle R, Klammt J. Alu-mediated recombination defect in IGF1R: haploinsufficiency in a patient with short stature. Horm Res Paediatr 2013;80:431–442.

5. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003;349:2211–2222.

6. Klammt J, Kiess W, Pfaffle R. IGF1R mutations as cause of SGA. Best Pract Res Clin Endocrinol Metab 2011;25:191–206.