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AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome.

ABSTRACT: We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Trp663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonsense mutation is predicted to destroy the inhibitory action of AXIN2 on WNT signaling. Previous authors have described an unrelated family with autosomal dominant oligodontia and a variable colorectal phenotype segregating with a nonsense mutation of AXIN2, as well as a frameshift AXIN2 mutation in an unrelated individual with oligodontia. Our report provides additional evidence supporting an autosomal dominant AXIN2-associated ectodermal dysplasia and neoplastic syndrome.

SUBMITTER: Marvin ML

PROVIDER: S-EPMC3094478 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome.

Marvin Monica L ML Mazzoni Serina M SM Herron Casey M CM Edwards Sean S Gruber Stephen B SB Petty Elizabeth M EM

American journal of medical genetics. Part A 20110317 4

We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Trp663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonse ...[more]

PMID: 21416598

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Project description:BACKGROUND:Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in I?B? that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor ? light chain enhancer of activated B cells (NF-?B) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in I?B? have impaired noncanonical NF-?B activity and defective lymphorganogenesis. OBJECTIVE:We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS:A disease severity scoring system was devised. Stability of I?B? mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-?B signaling in skin-derived fibroblasts. RESULTS:Disease severity was greater in patients with I?B? point mutations than in those with truncation mutations. I?B? point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-?B-dependent IL-6 secretion and upregulation of the NF-?B subunit 2/p100 and RELB proto-oncogene, NF-?B subunit (RelB) components of the noncanonical NF-?B pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-?B-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus ?-lymphotoxin ? receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS:I?B? point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-?B activity in patients with AD EDA-ID.

Project description:INTRODUCTION:An analysis was made of three different syndromes associated with p63 gene mutations, known as ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC), ankyloblepharon-ectodermal dysplasia clefting syndrome (AEC or Hay-Wells) and Rapp-Hodgkin syndrome (RHS). The postoperative complications associated with their cleft reconstructions were also evaluated. MATERIALS AND METHODS:Extensive demographic information, in particular of the clinical appearances, associated malformations, and the types and complications of the reconstructive surgical procedures, were recorded of these syndromic cases occurring in a database of 3621 facial cleft deformity patients. The data was analyzed using the Microsoft Excel program. RESULTS:A total of 10 (0.28%) cases of p63 associated syndromes were recorded: EEC (6), RHS (3), and AEC (1). The following clinical cleft appearances were noted - EEC = 6: CLA 1 -right side unilateral (female); CLAP 4 - right side (1) + left side (1) unilateral (male + female); bilateral (2) (males); hPsP 1 (female) (divided in 3 Black, 2 White, 1 Indian); RHS = 3: CLAP 2 (White males); hPsP 1 (White female); AEC = 1: CLAP bilateral (White male). Other features of the syndromes were: skin, hand, foot, tooth, hair and nail involvement, and light sensitivity. Postoperative complications included: (i) stenosis of nasal opening, especially after reconstruction of the bilateral cleft lip and the columella lengthening (2 cases), (ii) premaxilla-prolabium fusion (2 cases), (iii) repeated occurrence of oro-nasal fistula in the hard palate (4 cases), and (iv) dysgnathial development of midfacial structures (3 cases). DISCUSSION:Three different p63 associated syndromes (EEC, AEC, and RHS) were diagnosed (0.27% of the total facial cleft deformities database). The majority of the cases presented with a bilateral CLAP in males only. A number of females and males had unilateral CLA. The hPsP-cleft was recorded in females only. The associated ectodermal component most probably had a profoundly negative influence on postoperatively wound healing, which was observed in particular at the nasal openings, the premaxilla sulcus and in the hard palate mucosa. The reconstruction of p63 associated syndromes is a greater challenge than the usual cleft reconstruction to the surgeon.

Dataset Information

AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome.

Publications

AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome.

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