medwireNews: Researchers have identified a novel mutation in the insulin-like growth factor (IGF)2 gene that they believe to be responsible for impaired pre- and postnatal growth in one of their patients.
This finding “argues for the inclusion of IGF2 in gene panels designed for routine diagnostics of intrauterine growth failure without postnatal catch-up growth”, write Denise Rockstroh (University of Leipzig, Germany) and study co-authors in the European Journal of Endocrinology.
The team says that only five pathogenic IGF2 mutations have so far been identified.
This latest mutation was a deletion in exon 3 of the IGF2 coding sequence: a heterozygous 195delC deletion at the coding DNA level, resulting in a protein level amino acid sequence of Ile66Serfs*93. In other words, there was a frameshift mutation, causing an early stop codon at position 93.
The resultant IGF2 protein was largely incapable of activating the IGF1 receptor.
The researchers identified this mutation in a male patient born to non-consanguineous Caucasian parents at 39 weeks’ gestation. Having had marked prenatal growth retardation, diagnosed at 28 weeks’ gestation, his birth length standard deviation score (SDS) was just –5.22. He also had a cleft palate.
His impaired growth continued after birth; when he was referred to the paediatric endocrine department at the age of 3.4 years, his height SDS was –5.41, his growth velocity was 5.1 cm/year (–2.98 SDS) and his bone age was delayed by around 1.7 years.
His head circumference SDS was also reduced but at –2.36 was large relative to his height, and he had frontal bossing. He also had a long philtrum, high forehead, retrognathia and clinodactyly, in addition to a patent ductus arteriosus, which closed spontaneously, and a penoscrotal transposition.
Overall, the patient’s clinical presentation was consistent with Silver–Russell Syndrome, but the team could not detect maternal uniparental disomy for chromosome 7 or hypomethylation of the imprinting control region 1 or 2. Neither were there alterations in any other growth-associated genes, including IGF1, IGF1R, IGFALS, IGFBP3, PLAG1 and HMGA2.
The patient had normal serum levels of IGF1 (110.9 µg/L), but “markedly decreased” levels of IGF2 (210 ng/mL) and IGF binding protein 3 (IGFBP3; 1.69 mg/L).
The researchers note that the low serum IGF2 levels occurred despite evidence that the mutated IGF2 gene produced a protein product, albeit inactive. They suggest that the “disturbed posttranslational processing” disrupted the IGF2 protein’s ability to form complexes with IGFBP3, resulting in a reduced half-life in the serum.
By Eleanor McDermid
Eur J Endocrinol 2018; doi:10.1530/EJE-18-0601
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