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Roland Pfäffle

Although an impaired longitudinal growth is a part of many chromosomal aberrations and a variety of single gene mutations, rarely is it the only symptom of patients with genetic syndromes. Otherwise, in a healthy child, the influence of parental height on the adult height of their children is well established. Although this genetic influence can be easily demonstrated by statistics and is observed over generations, the hormonal and metabolic factors that control the quantitative marker ‘growth’ remain difficult to establish. Genetics has used different approaches to address this question. Linkage studies so far have yielded some new, but partially conflicting, data about the key factors that influence growth and finally adult height. In contrast, the examination of ‘candidate genes’ has been very fruitful in identifying those genes that are responsible for some well-defined hormonal deficiencies in patients with severe short stature.

As the systematic examination of such genes in short children with and without hormonal deficiencies has become feasible, it appears that the phenotypic appearance of some of these disorders is variable to an extent that makes it difficult to differentiate them from a ‘short normal child’. Both the ‘candidate gene’ and the ‘reverse genetics’ approaches using linkage analysis on a whole genome scale have produced results that have already furthered our understanding of the complex mechanisms that influence growth. Both the approaches have come closer to each other, but so far they have not produced the overlap of evidence that one had initially anticipated.

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Denise Rockstroh, Heike Pfäffle, Diana Le Duc, Franziska Rößler, Franziska Schlensog-Schuster, John T Heiker, Jürgen Kratzsch, Wieland Kiess, Johannes R Lemke, Rami Abou Jamra and Roland Pfäffle


The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation.


Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation.


The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

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Marie-Hélène Gannagé-Yared, Jürgen Klammt, Eliane Chouery, Sandra Corbani, Hala Mégarbané, Joelle Abou Ghoch, Nancy Choucair, Roland Pfäffle and André Mégarbané


Heterozygous mutations in the IGF1 receptor (IGF1R) gene lead to partial resistance to IGF1 and contribute to intrauterine growth retardation (IUGR) with postnatal growth failure. To date, homozygous mutations of this receptor have not been described.


A 13.5-year-old girl born from healthy first-cousin parents presented with severe IUGR and persistent short stature. Mild intellectual impairment, dysmorphic features, acanthosis nigricans, and cardiac malformations were also present.


Auxological and endocrinological profiles were measured. All coding regions of the IGF1R gene including intron boundaries were amplified and directly sequenced. Functional characterization was performed by immunoblotting using patient's fibroblasts.


IGF1 level was elevated at 950 ng/ml (+7 s.d.). Fasting glucose level was normal associated with high insulin levels at baseline and during an oral glucose tolerance test. Fasting triglyceride levels were elevated. Sequencing of the IGF1R gene led to the identification of a homozygous variation in exon 2: c.119G>T (p.Arg10Leu). As a consequence, IGF1-dependent receptor autophosphorylation and downstream signaling were reduced in patient's fibroblasts. Both parents were heterozygous for the mutation.


The homozygous mutation of the IGF1R is associated with severe IUGR, dysmorphic features, and insulin resistance, while both parents were asymptomatic heterozygous carriers of the same mutation.