A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes.

BACKGROUND: Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage, often leading to immunodeficiency, growth retardation and increased risk of malignancy. CASE PRESENTATION: We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia. She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E. CONCLUSION: This is the second family with POLE1-deficency, with the affected individual demonstrating a more severe phenotype than previously described.

Family history and clefting as major criteria for CHARGE syndrome.

CHARGE syndrome is an autosomal dominant malformation syndrome associated with mutations in CHD7. The condition is typically sporadic with few familial cases reported. The diagnosis of CHARGE syndrome is based on a combination of major and minor criteria comprised of structural and functional abnormalities, most of which are part of the original CHARGE acronym, although additional anomalies have been added. To date, family history has not been considered in the diagnostic criteria. Here we report a family with a previously unreported missense mutation in exon 31 of CHD7, in which family history played a role in the diagnosis of CHARGE syndrome. Given the tremendous phenotypic variability and the dominant nature of CHARGE syndrome, we propose that family history be included as a major diagnostic criterion. A positive family history would include any individual with an apparently isolated unilateral major CHARGE anomaly or someone with a few of the minor features. Our cases support this proposal; had family history not been considered in this case, CHD7 testing might not have been pursued, leading to incomplete medical follow-up and erroneous genetic counseling. Additionally, with the increased incidence of orofacial clefting in this family, as well as in the literature, we suggest that cleft lip and/or palate be added to the major diagnostic criteria for CHARGE syndrome.