medwireNews: A study of patients with mutations or terminal deletions in the insulin-like growth factor 1 receptor gene (IGF1R) shows that the majority are small for gestational age (SGA), short and microcephalic, with an elevated serum IGF-1 level.

Using this information, Marie-Jose Walenkamp (Vrije Universiteit Amsterdam, the Netherlands) and team created a novel clinical score, which they say “can assist the physician to select patients for genetic testing of IGF1R.”

Specifically, patients meeting three or more of the following criteria would be eligible for IGF1R analysis: a birthweight and/or birth length standard deviation score (SDS) below –1.0; a height SDS below –2.5 at presentation; a head circumference SDS below –2.0 at presentation; and a serum IGF-1 SDS above 0.0.

Walenkamp and co-authors report in The Journal of Clinical Endocrinology & Metabolism that the score achieved a sensitivity of 76% in their cohort of 25 patients with an isolated molecular defect in IGF1R. Specificity, tested in a separate cohort of 64 short children, was 87%, while sensitivity and specificity were 75% and 69%, respectively, in a cohort of 372 patients born SGA.

The researchers calculated that at a pre-test probability of 1% among children presenting with short stature (irrespective of birth size), one case with a pathogenic or likely pathogenic IGF1R mutation would be identified for every eight patients sent for analysis based on their clinical score.

Among the 25 patients with an isolated IGF1R molecular defect, 18 had pathogenic or likely pathogenic mutations and seven had a terminal 15q deletion.

At presentation, their mean head circumference SDS was significantly lower than at birth (–2.5 vs –1.6), while height SDS was nonsignificantly lower than birth length SDS (–3.0 vs –2.7). Mean birthweight SDS was –2.1.

Mean IGF-1 SDS at presentation was 1.2, and significantly increased during 3 years of growth hormone (GH) therapy, which the investigators say reflects “the state of IGF-I resistance.”

In total, 19 patients were treated with recombinant human GH, at a mean starting dose of 1.1 mg/m2 per day. After 3 years, height gain was 0.9 SDS among the 12 patients with a pathogenic IGF1R mutation who received the treatment and 1.3 SDS among the seven with a terminal 15q deletion, with no significant difference between the groups.

Both groups gained significantly less height, however, than did a cohort of 41 children born SGA and treated with a similar dose. The gain in this group was 1.8 SDS.

Delayed mental development was reported in five of 13 patients with an IGF1R pathogenic mutation, while two of 11 had some degree of delayed motor development. Conversely, all seven patients with a terminal 15q deletion showed delayed mental development and three had delayed motor development.

In addition, 15 patients had experienced feeding problems during the first years of life, typically vomiting and food refusal during infancy.

Walenkamp et al note that “[f]eeding problems have been described in a few cases before” but the large number of patients with such problems in the current study leads them to believe “that feeding problems are a relevant clinical feature associated with IGF1R defects.”

The authors say they consider it important to establish a partial IGF-I resistance diagnosis because it can offer “an explanation of clinical features, such as short stature and feeding problems, that would otherwise lead to extensive and prolonged further investigations.”

They add that such a diagnosis also “has important consequences for decisions on GH treatment: the expected efficacy is lower than for the average SGA-born short child, the potential risks may be different, and a higher serum IGF-I is expected on a regular GH dosage”, they conclude.

By Laura Cowen

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J Clin Endocrinol Metab 2019; doi:10.1210/jc.2018-02065