%208500
ICD+
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| ASPHYXIATING THORACIC DYSTROPHY 1; ATD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| JEUNE SYNDROME THORACIC-PELVIC-PHALANGEAL DYSTROPHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: ATD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 15q13 Genomic coordinates (GRCh37): 15:28,100,000 - 33,600,000 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Phenotypic Series | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Asphyxiating thoracic dysplasia (ATD), also known as Jeune syndrome, is a rare autosomal recessive chondrodysplasia characterized by a severely constricted thoracic cage, short-limbed short stature, and polydactyly. It often leads to death in infancy due to respiratory insufficiency. Affected individuals who survive early childhood usually develop chronic cystic renal and hepatic disease (Oberklaid et al., 1977). Other features include retinal degeneration (Bard et al., 1978) and pancreatic cysts (Hopper et al., 1979). Genetic Heterogeneity of Asphyxiating Thoracic Dysplasia Asphyxiating thoracic dysplasia is a genetically heterogeneous disorder. ATD1 has been mapped to chromosome 15q13. See also ATD2 (611263), caused by mutation in the IFT80 gene on chromosome 3q; ATD3 (613091), caused by mutation in the DYNC2H1 gene (603297) on chromosome 11q; ATD4 (613819), caused by mutation in the TTC21B gene (612014) on chromosome 2q24; and ATD5 (614376), caused by mutation in the WDR19 gene (608151) on chromosome 4p14. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Maroteaux and Savart (1964) described asphyxiating thoracic dystrophy, and noted that the skeletal changes in the rib cage, pelvis, and limbs were similar to those observed in Ellis-van Creveld syndrome (EVC; 225500). Pirnar and Neuhauser (1966) reported 3 affected brothers, and noted the presence of polydactyly without dysplasia of the fingernails. Those who survived early childhood tended to develop other disorders, including chronic nephritis (Wahlers, 1966) and intestinal malabsorption (Karjoo et al., 1973). Hanissian et al. (1967) reported 2 families, each with 2 affected brothers; 1 family was of African descent. These authors thought that the family reported by Shapira et al. (1965) had this condition. Langer (1968) pointed out that in those cases with polydactyly, differentiation from Ellis-van Creveld syndrome may not be possible on radiologic grounds alone. Polydactyly is an inconstant feature of ATD and, when present, usually also affects the feet. In contrast, polydactyly of the hands is a constant feature in EVC, but the feet are uncommonly affected. The main visceral abnormality in ATD is renal, whereas it is cardiac in EVC. Shokeir (1970) described 5 related affected persons of Norwegian extraction with asphyxiating thoracic dystrophy. Cystic renal changes (Potter type IV) were described. Cystic lesions may occur in the kidney, liver, and pancreas (Hopper et al., 1979; Landing et al., 1980). Finegold et al. (1971) reported a case with hypoplastic lungs and a marked reduction in the number of alveoli at autopsy. Oberklaid et al. (1977) reported 10 cases. Renal and hepatic changes were progressive, and renal failure was the cause of death in at least 2 patients. One remarkable case was that of a boy who was still alive at age 15 years and at the 25th percentile for height. He had a small chest, but short ribs were the only radiologic finding. A 32-year-old patient was reported by Friedman et al. (1975). Turkel et al. (1985) studied 7 neonatal cases at autopsy; 2 were sibs born of consanguineous parents. Dwarfing was not pronounced; the limbs were short in only one infant who also had polydactyly. Enchondral ossification was irregular in sections of femur, vertebra, and rib. Pulmonary hypoplasia was associated with the small thorax. Periportal fibrosis, bile duct proliferation, cirrhosis (in 1 case), and variable pancreatic fibrosis were also described. From clinicopathologic investigation of 8 patients, Yang et al. (1987) suggested the existence of 2 types of ATD: type 1 was characterized by the presence of radiologically irregular metaphyseal ends and histopathologically irregular cartilage-bone junction with patchy distribution of the physeal zone of hypertrophy; type 2 showed radiologically smooth metaphyseal ends and histopathologically diffusely retarded and disorganized physes with smooth cartilage-bone junctions. The authors were impressed with the similarities between type 1 ATD and short rib-polydactyly syndrome (SRPS) type III (263510). Whitley et al. (1987) described liver dysfunction associated with direct hyperbilirubinemia and hepatic fibrosis in the newborn period. Hudgins et al. (1990) described 2 sibs with this disorder who had progressive hepatic dysfunction associated with cirrhosis. Giorgi et al. (1990) described 2 sisters with a mild form of the syndrome. Labrune et al. (1999) reported 3 children with Jeune syndrome who had clinical and laboratory evidence of liver disease. The liver involvement was severe, and led to hepatic fibrosis and later to biliary cirrhosis with portal hypertension. In one patient, prolonged neonatal cholestasis was the initial manifestation, whereas in the other 2, hepatic lesions were recognized late when fibrosis or even cirrhosis had developed. Treatment with ursodeoxycholic acid appeared to control the progression of hepatic dysfunction, based on improvement in clinical and laboratory data. The authors suggested that hepatic function should be followed regularly in patients with Jeune syndrome, including measurements of serum biliary acid concentration. Kajantie et al. (2001) described 3 sibs with ATD whose neonatal symptoms ranged from mild respiratory distress to asphyxia and death. The authors reported difficulties in the prenatal diagnosis of the younger sibs prior to the third trimester. They proposed that even severely affected patients may have a favorable prognosis given new neonatal intensive care treatment options. Tuysuz et al. (2009) reported 13 patients with Jeune syndrome from 11 families and emphasized the clinical variability of the disorder, particularly regarding prognosis. The diagnosis was established in the prenatal period in 4 patients, infancy in 6 patients, and childhood in 3 patients. Two affected fetuses were terminated. The living patients all had small thorax deformity, classified as bell-shaped or long narrow, varying degrees of mesomelic shortness, and mild to severe brachydactyly. Tuysuz et al. (2009) classified them into 3 groups according to clinical features: 7 with severe pulmonary involvement; 1 with renal failure; and 2 with a milder form of the disorder. The degree of respiratory distress varied from negligible to fatal and improved with age. Short stature was sometimes present at birth, but also developed in the postnatal period. Patients with severe pulmonary involvement had a bell-shaped thorax and mild brachydactyly, the patient with renal involvement had a long narrow thorax and severe brachydactyly, whereas those with mild involvement presented with polydactyly and moderate to severe brachydactyly. Important radiologic findings included metaphyseal widening and trident appearance of the acetabular margin, which improved with age in 2 older patients. Other radiologic features included high handlebar clavicles, shortness of the metacarpals and second and distal phalanges, and hypoplastic ileum. In the follow-up period, 8 had respiratory distress, which was lethal in 6 before age 2 years, and 1 died of chronic renal failure at age 13. None had ocular involvement, ectodermal dysplasia, cardiac, or urogenital anomalies, thus distinguishing the disorder from short rib-polydactyly syndrome and Ellis-van Creveld syndrome. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal degeneration resembling Leber congenital amaurosis (104000) was described by Allen et al. (1979), Bard et al. (1978), and Phillips et al. (1980). Wilson et al. (1987) described the progressive electroretinographic abnormalities in an affected brother and sister. Singh et al. (1988) described 4 patients, including 2 sibs, with Jeune syndrome and mild congenital hydrocephalus. All 4 were males; 3 had postaxial polydactyly. Rinaldi et al. (1990) reported 2 sisters who had both Jeune syndrome and cystinuria (220100). The parents, living in Italy, were presumably unrelated. The possibility of linkage of the 2 genes was considered. Ho et al. (2000) reported a family with 2 brothers affected with mild Jeune syndrome, and a stillborn male infant, the product of a marriage between the paternal first cousin and a maternal aunt of the 2 boys, with lethal SRPS type III. The authors suggested that these conditions may be variants of a single disorder. They proposed that the intrafamilial variability may reflect the effects of modifying loci on gene expression. Lehman et al. (2010) reported 2 sibs, born of consanguineous Filipino parents, with a combination of ATD and Joubert syndrome (213300). Features included developmental delay, hypotonia, molar tooth sign on brain MRI, small thorax, short limbs and ribs, progressive renal failure, bile duct dilatation, oculomotor apraxia, and retinal dystrophy in 1. Lehman et al. (2010) described 2 additional unrelated patients with similar features of both Joubert syndrome and ATD, although without renal or hepatic involvement. The clinical observation of cooccurrence of ATD and Joubert syndrome in these patients suggested the involvement of a single causative ciliary gene required for both skeletal and neurologic development. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Shokeir et al. (1971) presented strong evidence for recessive inheritance of ATD in a Norwegian kindred, and raised the possibility that chest deformity may be a manifestation of the gene in the heterozygote. Tuysuz et al. (2009) reported 10 patients with Jeune syndrome, all of whom were born of consanguineous parents. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Barnes et al. (1971) reported successful thoracic reconstruction in a child whose sib had died of the disorder and whose mother was thought to have been affected (Barnes et al., 1969). (This family was later thought (Burn et al., 1986) to have a 'new' disorder called Barnes syndrome; see 187760.) Takada et al. (1994) reported surgical thoracic expansion according to the procedure of Todd et al. (1986) in a 15-month-old girl requiring mechanical ventilation for asphyxiating thoracic dystrophy. At the age of 4 years, she was free from respiratory distress, was of normal intelligence, and was able to lead an active life. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Morgan et al. (2003) performed a genomewide linkage search using autozygosity mapping in 4 consanguineous families with ATD: 3 from Pakistan and 1 from southern Italy. In these families, as well as in a fifth consanguineous family from France, they localized a novel ATD locus (ATD1) to 15q13 with a maximum cumulative 2-point lod score of 3.77 at theta = 0.00 for marker D15S1031. Investigation of a further 4 European kindreds with no known parental consanguinity showed evidence of marker homozygosity across a similar interval of 1.2 cM on chromosome 15. Families with both mild and severe forms of ATD mapped to 15q13, but mutation analysis of 2 positional candidate genes, gremlin (GREM1; 603054) and formin (FMN1; 136535), did not show pathogenic mutations. By homozygosity mapping of 2 sibs, born of consanguineous parents, with a phenotype overlapping ATD and Joubert syndrome (213300), Lehman et al. (2010) found a shared homozygous 530-kb region on chromosome 15q13 that overlapped by about 310 kb with the region reported by Morgan et al. (2003). Sequencing of the coding regions of the MTMR10, MTMR15 (613534), and TRPM1 (603576) gene in 1 sib revealed no mutations. Sequencing of several other candidate genes in another patient with this phenotype also revealed no pathogenic mutations. Exclusion Studies Because of long-term speculation that ATD and SRPS type III represent the severe end of the Ellis-van Creveld syndrome spectrum, Krakow et al. (2000) performed linkage analysis using markers from the EVC region on 4p in 7 families manifesting either ATD or SRPS type III. In 2 of the families, 1 segregating ATD and the other SRPS, linkage of the phenotype to the EVC region was excluded. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nagai et al. (1995) described a 5-year-old Japanese boy who had radiographic findings characteristic of Jeune syndrome or EVC syndrome in association with a de novo del(12)(p11.21p12.2). He also had mild mental retardation, short stature, hypoplastic hair and skin, oligodontia, small thoracic cage, hypoplastic pelvis, and cone-shaped epiphyses of the hands. Nagai et al. (1995) suggested that the locus for Jeune syndrome or EVC, or both, may be located on chromosome 12p. (EVC was subsequently mapped to 4p.) See also 112410. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cortina et al. (1979); Elejalde et al. (1985); Gruskin et al. (1974); Herdman and Langer (1968); Jeune et al. (1955); Kozlowski and Masel (1976); Phillips et al. (1974); Schinzel et al. (1986); Shah (1980); Tahernia and Stamps (1977); Yang et al. (1976) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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