Clinical and Functional Characterization of a Patient Carrying a Compound Heterozygous Pericentrin Mutation and a Heterozygous IGF1 Receptor Mutation

Abstract

Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): A potential role of pericentrin in hematopoiesis

“…In this review, leukocytosis and/or thrombocytosis was not mentioned as a finding . Our search of the literature showed that no study provided the leukocyte or platelet counts in patients with MOPD II , except for the above mentioned two case reports and Case 6 in the present study, which had been previously published in relation to moyamoya and recurrent strokes .…”

Alu-Mediated Recombination Defect in IGF1R: Haploinsufficiency in a Patient with Short Stature

“…Digenic or oligogenic inheritance patterns in the context of growth deficits have been recently suggested in a patient with IGF-1 deficiency due to a combined STAT5B and IGFALS mutation, although definite final evidence for the pathogenicity of either variant is lacking [40,41]. In contrast, the phenotype of a girl with a combined pericentrin ( PCNT ) and IGF1R mutation was shown to be merely attributable to the compound pericentrin mutations [42], emphasizing the need for thorough genetic and molecular evaluation.…”

Intrauterine Twin Discordancy and Partial Postnatal Catch-up Growth in a Girl with a Pathogenic <i>IGF1R</i> Mutation

“…The samples were sent to the Laboratory for Diagnostic Genome Analysis, Department of Clinical Genetics at the Leiden University Medical Center (LUMC) for routine genetic testing of IGF1R . Targeted Sanger sequencing of the complete coding region exon 1-21 including intron/exon boundaries (NM_000875.3) was performed as previously reported (10,16). Multiplex ligation-dependent probe amplification (MLPA) assay (MRC Holland kit P217-B2) containing probes for IGF1R exon 1-21 was performed for the detection of deletions or duplications (16).…”