Atelosteogenesis, Type Ii

A number sign (#) is used with this entry because of evidence that atelosteogenesis type II (AO2) and de la Chapelle dysplasia are caused by homozygous or compound heterozygous mutation in the SLC26A2 gene (606718), which encodes the diastrophic dysplasia sulfate transporter (DTDST), on chromosome 5q32.

For a discussion of genetic heterogeneity of atelosteogenesis, see AO1 (108720).

Clinical Features

Sillence et al. (1987) described 4 cases of neonatal death dwarfism resembling atelosteogenesis but with some distinctive radiographic and characteristic histopathologic features. They proposed the name atelosteogenesis II. Atelosteogenesis type II, also called neonatal osseous dysplasia I, is characterized by severely shortened limbs, small chest, scoliosis, clubfoot of the equinovarus type (talipes equinovarus), abducted thumbs and great toes, and cleft palate. Radiographic findings include cervical kyphosis, scoliosis, and lumbar hyperlordosis with horizontal sacrum, flattened vertebrae with coronal clefts, and round-shaped iliac bones with flat acetabulae. The distal humerus is typically bifid, and the distal femur rounded. The second and/or third metacarpals and first and second metatarsals are often larger than the other bones of the hand and foot. Patients die of respiratory insufficiency shortly after birth because of the collapse of the airways and pulmonary hypoplasia due to the small rib cage. On the basis of reports of parental consanguinity and recurrence among offspring of unaffected parents, AO II is presumed to be inherited as an autosomal recessive trait. AO II is similar to but more severe than the generally nonlethal autosomal recessive chondrodysplasia, diastrophic dysplasia (DTD; 222600) (Sillence et al., 1987; Hastbacka et al., 1996).

De la Chapelle Dysplasia

De la Chapelle et al. (1972) described a hitherto unrecognized skeletal dysplasia in a stillborn son and daughter of consanguineous parents. The limbs were strikingly short, with almost triangular fibula and ulna. The middle phalanges were curiously double. Both sibs had cleft palate and patent foramen ovale and ductus Botalli. The boy also had endocrine and hematologic abnormalities. A relationship of this skeletal dysplasia to mesomelic dwarfism of the hypoplastic ulna, fibula and mandible types (249700) could be suggested. Whitley et al. (1986) reported a third affected child (daughter) in the original family and a sporadic case in a male infant born to unrelated parents. Cleft palate was present in all. Respiratory insufficiency was the apparent cause of death in each patient. Cartilage from respiratory structures was abnormal and the abnormality accounts for the consistent triad of laryngeal stenosis, tracheobronchomalacia, and pulmonary hypoplasia. According to Whitley et al. (1986), the possible case of de la Chapelle dysplasia reported by Salonen (1982) has been reclassified as atelosteogenesis type I (108720).

Diagnosis

Prenatal Diagnosis

Nores et al. (1992) described a case labeled AO type II in which prenatal sonographic and neonatal radiographic findings were correlated to provide the basis of prenatal diagnosis of the entity. Autosomal recessive inheritance was supported by recurrence in a subsequent pregnancy. The following morphologic features could be recognized by prenatal ultrasonography: coronal clefts of the vertebral bodies, metaphyseal and epiphyseal abnormalities, spinal deviations such as cervical kyphosis and a horizontal sacrum, additional ossification centers in the pelvis, and preaxial deviation of the thumbs and toes.

Molecular Genetics

Because of similarities between atelosteogenesis type II and the much milder, generally nonlethal diastrophic dysplasia, Hastbacka et al. (1995, 1996) studied cultured skin fibroblasts of 3 patients with AO2 and found them to have defective sulfate transport and defective sulfation of proteoglycans as in diastrophic dysplasia. Furthermore, by direct sequencing they observed mutations in all 3 patients in the DTDST gene (see 606718.0002-606718.0004). One of the mutations had also been found in diastrophic dysplasia patients. Thus it is probably no accident that AO2 was described by de la Chapelle of Helsinki because diastrophic dysplasia is unusually frequent in Finland. Cases of AO2 may be caused by compound heterozygosity for a mutation that causes diastrophic dysplasia when homozygous and another mutation that causes a more severe defect.

Rossi et al. (1996) studied fibroblast cultures of 3 patients with mutations in the DTDST gene: one with diastrophic dysplasia (the least severe of the conditions caused by DTDST mutations), one with the more severe atelosteogenesis type II, and one with an intermediate phenotype designated AO2/DTD. Reduced incorporation of inorganic sulfate into macromolecules was found in all 3. Each of the 3 patients was found to be heterozygous for an arg279-to-trp mutation (606718.0002) in the third extracellular loop of the DTDST gene product. In 2 patients (DTD and OA2/DTD), no other structural mutation was found, but PCR amplification and SSCP analysis of fibroblast cDNA showed reduced mRNA levels of the wildtype DTDST allele. Rossi et al. (1996) stated that these 2 patients may be compound heterozygotes for the 'Finnish' mutation which had as yet not been characterized at the DNA level and which was known to cause reduced expression of DTDST. The third patient (with AO2) had the R279W mutation compounded with a novel mutation, the deletion of cytosine-418, predicting a frameshift with premature termination. This allele was underrepresented in the cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels. The presence of the DTDST R297W mutation in a total of 11 patients with AO2 or DTD emphasized the overlap between these conditions. This mutation had not been found in 8 analyzed patients with achondrogenesis type IB (ACG1B), the clinically most severe member of this family of chondrodysplasias, suggesting that the R279W mutation allows some residual activity of the sulfate transporter.

In affected members of the patients reported by de la Chapelle et al. (1972), Bonafe et al. (2008) identified a homozygous mutation in the SLC26A2 gene (606718.0013). The findings confirmed that de la Chapelle dysplasia is allelic to other SLC26A2 disorders.

Genotype/Phenotype Correlations

In a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II, Macias-Gomez et al. (2004) identified compound heterozygosity for the R279W (606718.0002) and R178X (606718.0005) mutations in the SLC26A2 gene. The patient had cystic swelling of the external ears, cervical kyphosis, rhizomelia, 'hitchhiker' thumbs, bilateral talipes equinovarus, and short toes, features highly suggestive of diastrophic dysplasia. However, she also displayed severe and progressive cervical kyphosis, V-shaped distal humerus, bowed radii, horizontal sacrum, and gap between the first and second toes, features typical of atelosteogenesis type II. Macias-Gomez et al. (2004) concluded that the combination of a mild and a severe mutation led to an intermediate clinical picture, representing an apparent genotype-phenotype correlation.

Nomenclature

Stern et al. (1990) suggested that what has been called atelosteogenesis type II (Sillence et al., 1987) was in fact de la Chapelle dysplasia. They suggested that the term atelosteogenesis type II be discarded, but proposed the term atelosteogenesis III for a distinct condition (AO3; 108721). Superti-Furga et al. (1996) stated that it was 'still unclear' whether de la Chapelle dysplasia was identical to atelosteogenesis type II.