Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families

Abstract

belongs to the short rib polydactyly group and is characterized by a long and narrow thorax, short long bones and trident acetabular roof. Polydactyly, retinal degeneration, cystic renal and liver diseases have been occasionally reported. Today, mutations in IFT80 (MIM 611177), DYNC2H1 (MIM 603297), TCC21B (MIM 612014) and WDR19 (MIM 608151) genes have been reported in ATD. Through a national grant (PHRC, AOM 06031), we have collected 55 ATD cases including 29 fetuses issued from 42 families who benefit the combined approach of deep phenotyping and molecular screening of IFT80 and DYNC2H1. The series included 26 alive cases ranging in age from 6 months to 36 years. Respiratory treatment was needed in 46%, including positive pression respiration, and invasive or non-invasive ventilation. Cystic renal and liver diseases occur in 16% of cases; whereas retinal degeneration was present in 40 % cases aged more than 2 years (6/15). The molecular screening allowed us to detect DYNC2H1 mutations in 63% and IFT80 mutations in 6%. In 6 cases, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 31% cases. These preliminary results emphasize that DYNC2H1 is the major gene responsible for ATD. The presence of only one mutation (27% of mutated cases) may suggest a digenic diallelic inheritance. Ongoing studies will hopefully lead to the identification of other disease genes.

Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

“…Sensenbrenner patients with mutations were more likely to have sagittal craniosynostosis, joint laxity, dental anomalies, retinal abnormalities, and congenital heart defects. As expected, considerable overlap with ATD-JS was noted, but the distinctive Sensenbrenner facial appearance (dolichocephaly, high hairline, forehead bossing), sagittal craniosynostosis, ectodermal anomalies (teeth, hair, nails), and syndactyly appear to differentiate the two syndromes [Keppler-Noreuil et al, 2011;Baujat et al, 2013]. Severe forms of Sensenbrenner syndrome and ATD-JS have been diagnosed as short rib-polydactyly syndromes (SRPs).…”

“…We noted any type of eye problem more commonly in the patients with a mutation (21% vs. 12%), which compares to ATD-JS, and Joubert syndrome. Baujat et al [2013] observed a 50% frequency of eye problems in their patients with ATD-JS ($65% of whom had mutations in either DYNC2H1 or IFT80) who had systematic eye evaluations in their patients.…”

“…Liver involvement was seen in approximately half of the Sensenbrenner patients, regardless of mutation status, similar to that in ATD-JS. Liver disease in ATD-JS, including most commonly hepatic fibrosis, is reported in 28% of patients compared to 40-50% of patients with Sensenbrenner syndrome, regardless of mutation status [Keppler-Noreuil et al, 2011;Baujat et al, 2013]. In comparison, liver involvement is a universal finding in patients with MKS and COACH syndrome (a subset of JSRD) with cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis [Gunay-Aygun, 2009].…”

“…Fourteen patients had echogenic kidneys detected on ultrasound study, of which three were noted to be enlarged. The frequency of renal complications in ATD-JS is reported as 17-30% with fewer than half with renal involvement developing renal failure compared to those with Sensenbrenner syndrome, regardless of mutation status ($70%) [Keppler-Noreuil et al, 2011;Baujat et al, 2013].…”

Cilia Ift protein and motor -related bone diseases and mouse models

“…JATD is a rare autosomal recessive skeletal dysplasia with short limbs, narrow thorax, trident acetabular roof, and occasional polydactyly (107). Studies have suggested that mutations of Ift80, DYNC2H1, TTC21B (encoding Ift139) and WDR19 (encoding Ift144) are associated with JATD (33, 35, 40, 108–110). Respiratory failure is the usual cause of death in JATD in early infancy (110).…”