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Asphyxiating Thoracic Dysplasia

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Ilkka Kaitila – 1st expert on this subject based on the ideXlab platform

  • familial Asphyxiating Thoracic Dysplasia clinical variability and impact of improved neonatal intensive care
    The Journal of Pediatrics, 2001
    Co-Authors: Eero Kajantie, Sture Andersson, Ilkka Kaitila

    Abstract:

    We describe 3 siblings with Asphyxiating Thoracic Dysplasia whose neonatal symptoms range from mild respiratory distress to asphyxia and death. The youngest sibling received aggressive modern respiratory intensive care, survived, and at 2 years showed no respiratory symptoms. Improved neonatal intensive care has implications for clinical decision making and genetic counseling.

  • Familial Asphyxiating Thoracic Dysplasia: Clinical variability and impact of improved neonatal intensive care
    The Journal of Pediatrics, 2001
    Co-Authors: Eero Kajantie, Sture Andersson, Ilkka Kaitila

    Abstract:

    Abstract We describe 3 siblings with Asphyxiating Thoracic Dysplasia whose neonatal symptoms range from mild respiratory distress to asphyxia and death. The youngest sibling received aggressive modern respiratory intensive care, survived, and at 2 years showed no respiratory symptoms. Improved neonatal intensive care has implications for clinical decision making and genetic counseling. (J Pediatr 2001;139:130-3)

Celine Huber – 2nd expert on this subject based on the ideXlab platform

  • wdr34 mutations that cause short rib polydactyly syndrome type iii severe Asphyxiating Thoracic Dysplasia reveal a role for the nf κb pathway in cilia
    American Journal of Human Genetics, 2013
    Co-Authors: Celine Huber, Genevieve Baujat, Sulin Wu, Sabine Sigaudy, Anna Sarukhanov, Valerie Serre, Kimhanh Le Quan Sang, David L Rimoin, Daniel H Cohn

    Abstract:

    Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondroDysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies.

  • WDR34 Mutations that Cause Short-Rib Polydactyly Syndrome Type III/Severe Asphyxiating Thoracic Dysplasia Reveal a Role for the NF-κB Pathway in Cilia
    American Journal of Human Genetics, 2013
    Co-Authors: Celine Huber, Genevieve Baujat, Sulin Wu, Sabine Sigaudy, Anna Sarukhanov, Valerie Serre, David L Rimoin, Kim-hanh Le Quan Sang, Daniel H Cohn

    Abstract:

    Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondroDysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies.

  • Asphyxiating Thoracic Dysplasia clinical and molecular review of 39 families
    Journal of Medical Genetics, 2013
    Co-Authors: Genevieve Baujat, Celine Huber, Roseline Caumes, Joyce El Hokayem, Claire Do Ngoc Thanh, Albert David, Annelise Delezoide, Anne Dieuxcoeslier, B Estournet, Christine Francannet

    Abstract:

    Background Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80 , DYNC2H1 , TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis. Methods We investigated 53 ATD cases (23 living cases and 30 fetuses) from 39 families. They benefited from a combined approach of deep phenotyping and IFT80 and DYNC2H1 molecular screening. Results Among the 23 postnatal cases, pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. Renal and liver diseases occurred respectively in 17% and 22% of cases, whereas retinal alteration was present in 50% of cases aged more than 5 years. We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). However, in six families, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 14 families (36%). Conclusions We conclude that DYNC2H1 is a major gene responsible for ATD, while IFT80 is rarely involved. The presence of only one mutation in six families and the exclusion of the two genes in 14 families support the involvement of other causal cilia genes. The long-term follow up emphasizes that the pulmonary prognosis is probably less pejorative and retinal involvement more frequent than previously thought.

Genevieve Baujat – 3rd expert on this subject based on the ideXlab platform

  • wdr34 mutations that cause short rib polydactyly syndrome type iii severe Asphyxiating Thoracic Dysplasia reveal a role for the nf κb pathway in cilia
    American Journal of Human Genetics, 2013
    Co-Authors: Celine Huber, Genevieve Baujat, Sulin Wu, Sabine Sigaudy, Anna Sarukhanov, Valerie Serre, Kimhanh Le Quan Sang, David L Rimoin, Daniel H Cohn

    Abstract:

    Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondroDysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies.

  • WDR34 Mutations that Cause Short-Rib Polydactyly Syndrome Type III/Severe Asphyxiating Thoracic Dysplasia Reveal a Role for the NF-κB Pathway in Cilia
    American Journal of Human Genetics, 2013
    Co-Authors: Celine Huber, Genevieve Baujat, Sulin Wu, Sabine Sigaudy, Anna Sarukhanov, Valerie Serre, David L Rimoin, Kim-hanh Le Quan Sang, Daniel H Cohn

    Abstract:

    Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondroDysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies.

  • Asphyxiating Thoracic Dysplasia clinical and molecular review of 39 families
    Journal of Medical Genetics, 2013
    Co-Authors: Genevieve Baujat, Celine Huber, Roseline Caumes, Joyce El Hokayem, Claire Do Ngoc Thanh, Albert David, Annelise Delezoide, Anne Dieuxcoeslier, B Estournet, Christine Francannet

    Abstract:

    Background Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80 , DYNC2H1 , TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis. Methods We investigated 53 ATD cases (23 living cases and 30 fetuses) from 39 families. They benefited from a combined approach of deep phenotyping and IFT80 and DYNC2H1 molecular screening. Results Among the 23 postnatal cases, pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. Renal and liver diseases occurred respectively in 17% and 22% of cases, whereas retinal alteration was present in 50% of cases aged more than 5 years. We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). However, in six families, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 14 families (36%). Conclusions We conclude that DYNC2H1 is a major gene responsible for ATD, while IFT80 is rarely involved. The presence of only one mutation in six families and the exclusion of the two genes in 14 families support the involvement of other causal cilia genes. The long-term follow up emphasizes that the pulmonary prognosis is probably less pejorative and retinal involvement more frequent than previously thought.