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The article reports on a paternally inherited IGF2 peptide hormone variant with evidence of pathogenicity in a multigenerational family. It notes that four members showed intrauterine and postnatal growth restriction, and a phenotype similar to Silver-Russell syndrome, a syndromic growth-retardation disorder. A table is presented on the clinical features of patients with growth restriction who had IGF1, IGF2, and IGF1R mutations, and with the Silver-Russell Syndrome with ICR1 hypomethylation.

Abstract: Deregulation of the Wnt signalling pathway is a key event in the development of a broad spectrum of human malignancies and mutations in β-catenin (CTNNB1), a central component of the Wnt pathway, have been detected in 10–15% of Wilms tumors (nephroblastoma). Furthermore, nuclear immunoreactivity for β-catenin has been described even in the absence of detectable β-catenin mutations. This suggests that other components of the Wnt pathway may be involved in the pathogenesis of a subgroup of Wilms tumors. Chibby (C22ORF2) is a recently identified antagonistic component of the Wnt pathway that inhibits the transcriptional activity of β-catenin. Our study addresses the question whether mutation or down-regulation of Chibby is involved in Wilms tumorigenesis. We analysed the expression of Chibby by real time RT-PCR in 142 Wilms tumors, but there was no significant expression difference in any group of tumors stratified according to clinical, histological and mutational criteria. Mutation analysis of a smaller cohort did not reveal any mutations of the coding sequence. We only detected a constitutive splice variant leading to the absence of exon 4 in all Wilms tumors as well as in normal tissues. In addition, we detected a frequent silent polymorphism in the Chibby exon 4 sequence (435T/C). These data strongly suggest that despite its attractive function as a modulator of β-catenin activity, Chibby is not involved in Wilms tumorigenesis. [Copyright &y& Elsevier]

Background: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by early-onset episodes of hemiplegia, dystonia, various paroxysmal symptoms, and developmental impairment. Almost all cases of AHC are sporadic but AHC concordance in monozygotic twins and dominant transmission in a family with a milder phenotype have been reported. Thus, we aimed to identify de-novo mutations associated with this disease.Methods: We recruited patients with clinically characterised AHC from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. We used whole-exome sequencing of three proband-parent trios to identify a disease-associated gene and then tested whether mutations in the gene were also present in the remaining patients and their healthy parents. We analysed genotypes and characterised their associations with the phenotypic spectrum of the disease.Findings: We studied 15 female and nine male patients with AHC who were aged 8-35 years. ATP1A3 emerged as the disease-associated gene in AHC. Whole-exome sequencing showed three heterozygous de-novo missense mutations. Sequencing of the 21 remaining affected individuals identified disease-associated mutations in ATP1A3 in all patients, including six de-novo missense mutations and one de-novo splice-site mutation. Because ATP1A3 is also the gene associated with rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) we compared the genotypes and phenotypes of patients with AHC in our cohort with those of patients with rapid-onset dystonia-parkinsonism reported in the scientific literature. We noted overlapping clinical features, such as abrupt onset of dystonic episodes often triggered by emotional stress, a rostrocaudal (face to arm to leg) gradient of involvement, and signs of brainstem dysfunction, as well as clearly differentiating clinical characteristics, such as episodic hemiplegia and quadriplegia.Interpretation: Mutation analysis of the ATP1A3 gene in patients who met clinical criteria for AHC allows for definite genetic diagnosis and sound genetic counselling. AHC and rapid-onset dystonia-parkinsonism are allelic diseases related to mutations in ATP1A3 and form a phenotypical continuum of a dystonic movement disorder.Funding: Eva Luise and Horst Köhler Foundation for Humans with Rare Diseases. [ABSTRACT FROM AUTHOR]