Achondrogenesis, Type Ib

A number sign (#) is used with this entry because of evidence that achondrogenesis type IB (ACG1B) is caused by homozygous or compound heterozygous mutation in the DTDST gene (606718) on chromosome 5q32.

Description

The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues.

Classification of Achondrogenesis

Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA (ACG1A; 200600), corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB, corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder.

Clinical Features

In a patient considered to have achondrogenesis type IB, Superti-Furga (1994) found that cartilage extracts showed a reduced content of proteoglycans and that unlike control cartilage they did not stain with toluidine blue and did not bind to DEAE. Impaired synthesis of sulfated proteoglycans was observed in fibroblast cultures from the patient. Radioactive labeling and immunoprecipitation studies indicated that core protein and side chains of proteoglycans were synthesized normally but were not sulfated. Analysis of sulfate metabolism in cultured fibroblasts in the patient's cells showed normal intracellular levels of free sulfate but markedly reduced levels of the 2 intermediate compounds in the sulfate activation pathway, adenosine-phosphosulfate and phosphoadenosine-phosphosulfate. Superti-Furga (1994) suggested that the results can be explained by deficient activity of one of the enzymes responsible for the biologic activation of sulfate, possibly similar to that observed in cartilage (but not in skin) of the recessive, nonlethal mouse mutant 'brachymorphic' and leading to defective sulfation of macromolecules (Orkin et al., 1976; Sugahara and Schwartz, 1979; Sugahara and Schwartz, 1982).

Superti-Furga et al. (1995) identified a sulfation defect in tissues and/or cells of 5 other type IB patients.

Diagnosis

Superti-Furga et al. (1996) observed that elucidation of the basic defect in ACG1B allows diagnosis by biochemical and molecular studies. They emphasized that accurate genetic counseling, particularly the distinction between ACG1B (which has a 25% recurrence risk) and the more frequent, autosomal dominant condition ACG2 (which usually involves the occurrence of new mutations and has a much lower recurrence risk), will be improved, and heterozygous carriers can be more readily detected. Couples at risk for having a child with ACG1B may decide to take advantage of molecular prenatal diagnosis by chorionic villus sampling, which can be done earlier than ultrasonographic diagnosis.

Molecular Genetics

In 6 patients with ACG1B, Superti-Furga et al. (1996) identified 7 different, putatively pathogenic, homozygous or compound heterozygous mutations in the DTDST gene (see, e.g., 606718.0005 and 606718.0006). The mutations were identified by genomic PCR, SSCP, and direct sequencing. One of the mutations (606718.0001) had previously been identified in patients with diastrophic dysplasia (222600). Thus, achondrogenesis type IB is a recessive disorder allelic to diastrophic dysplasia.