Candidate gene analysis of tooth agenesis identifies novel mutations in six genes and suggests significant role for WNT and EDA signaling and allele combinations.

Failure to develop complete dentition, tooth agenesis, is a common developmental anomaly manifested most often as isolated but also as associated with many developmental syndromes. It typically affects third molars or one or few other permanent teeth but severe agenesis is also relatively prevalent. Here we report mutational analyses of seven candidate genes in a cohort of 127 probands with non-syndromic tooth agenesis. 82 lacked more than five permanent teeth excluding third molars, called as oligodontia. We identified 28 mutations, 17 of which were novel. Together with our previous reports, we have identified two mutations in MSX1, AXIN2 and EDARADD, five in PAX9, four in EDA and EDAR, and nine in WNT10A. They were observed in 58 probands (44%), with a mean number of missing teeth of 11.7 (range 4 to 34). Almost all of these probands had severe agenesis. Only few of the probands but several relatives with heterozygous genotypes of WNT10A or EDAR conformed to the common type of non-syndromic tooth agenesis, incisor-premolar hypodontia. Mutations in MSX1 and PAX9 affected predominantly posterior teeth, whereas both deciduous and permanent incisors were especially sensitive to mutations in EDA and EDAR. Many mutations in EDAR, EDARADD and WNT10A were present in several families. Biallelic or heterozygous genotypes of WNT10A were observed in 32 and hemizygous or heterozygous genotypes of EDA, EDAR or EDARADD in 22 probands. An EDARADD variant were in seven probands present together with variants in EDAR or WNT10A, suggesting combined phenotypic effects of alleles in distinct genes.

Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth.

Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.

Survival predictors in patients treated with a molecular adsorbent recirculating system.

AIM: To identify prognostic factors for survival in patients with liver failure treated with a molecular adsorbent recirculating system (MARS). METHODS: MARS is a liver-assisting device that has been used in the treatment of liver failure to enable native liver recovery, and as a bridge to liver transplantation (LTX). We analyzed the 1-year outcomes of 188 patients treated with MARS, from 2001 to 2007, in an intensive care unit specializing in liver disease. Demographic, clinical and laboratory parameters were recorded before and after each treatment. One-year survival and the number of LTXs were recorded. Logistic regression analysis was performed to determine factors predicting survival. RESULTS: The study included 113 patients with acute liver failure (ALF), 62 with acute-on-chronic liver failure (AOCLF), 11 with graft failure (GF), and six with miscellaneous liver failure. LTX was performed for 29% of patients with ALF, 18% with AOCLF and 55% with GF. The overall 1-year survival rate was 74% for ALF, 27% for AOCLF, and 73% for GF. The poorest survival rate, 6%, was noted in non-transplanted patients with alcohol-related AOCLF and cirrhosis, whereas, patients with enlarged and steatotic liver had 55% survival. The etiology of liver failure was the most important predictor of survival (P < 0.0001). Other prognostic factors were encephalopathy (P = 0.001) in paracetamol-related ALF, coagulation factors (P = 0.049) and encephalopathy (P = 0.064) in non-paracetamol-related toxic ALF, and alanine aminotransferase (P = 0.013) and factor V levels (P = 0.022) in ALF of unknown etiology. CONCLUSION: The etiology of liver disease was the most important prognostic factor. MARS treatment appears to be ineffective in AOCLF with end-stage cirrhosis without an LTX option.