Diastrophic dysplasia and atelosteogenesis type II as expression of compound heterozygosis: First report of a Mexican patient and genotype–phenotype correlation

Abstract

The osteochondrodysplasias represent a heterogeneous group of cartilage and bone diseases. Among these, achondrogenesis 1B, atelosteogenesis type II, diastrophic dysplasia, and autosomal recessive multiple epiphyseal dysplasia are caused by mutations in the solute carrier family 26 (sulfate transporter), member 2 gene (SLC26A2). This group of osteochondrodysplasias shows a continuous spectrum of clinical variability and shares many features in common. Usually, it is difficult to distinguish clinically among these patients. To date, several efforts have been made to correlate mutations in the SLC26A2 gene with phenotypic severity in the patients. We report on a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II. Molecular analysis of the SLC26A2 gene in this patient showed compound heterozygosity for the R178X and R279W mutations. In this patient, the combination of a mild and a severe mutation has apparently led to an intermediate or transitional clinical picture, showing an apparent genotype-phenotype correlation.

Dysplastic spondylolysis is caused by mutations in the diastrophic dysplasia sulfate transporter gene

“…Clinical features of these disorders with hypomorphic missense mutations are summarized in Table S6 for a comparison with our cases. It seems that a genotype-phenotype correlation could be found among these disorders (32,33). In the lethal form of chondrodysplasia, a deficient ossification in the lumbar vertebrae was observed in ACG1B (34).…”

Genotype–phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family

“…Cases of the milder R279W plus a frameshift mutation have had DTD or AO2 [Macías‐Gómez et al, 2004; Rossi et al, 1996b]. The difference between a 50% residual activity versus a <5% residual activity at one allele seems to sometimes have an impact clinically (DTD in Macías‐Gómez et al 2004, compared to AO2 in Patient 3 of this paper), but not always (AO2 in Rossi et al 1996b and in Patient 3 of this paper). Furthermore, the Finnish mutation combined with a transmembrane domain missense mutation can cause ACG‐1B [Unger et al, 2001].…”

“…Literature review yielded 26 cases that met our inclusion criteria for genotype–phenotype analysis [Hästbacka et al, 1994, 1996, 1999; Rossi et al, 1996a,b, 1997; Superti‐Furga et al, 1996a, 1999; Cai et al, 1998; Mégarbané et al, 1999; Unger et al, 2001; Ballhausen et al, 2003; Mäkitie et al, 2003; Macías‐Gómez et al, 2004; Maeda et al, 2006; Bonafé et al, 2008; Panzer et al, 2008], to which are added the 2 genotypes described here and one unpublished observation [R.M. Pauli].…”

“…The DTDST family of bone dysplasias appears to contain at least seven different conditions. Furthermore, in addition to the various distinct phenotypes, cases of intermediate phenotypes have been reported [Rossi et al, 1996a; Mégarbané et al, 1999, 2002; Macías‐Gómez et al, 2004; Maeda et al, 2006; Miyake et al, 2008; Panzer et al, 2008]. Nonetheless, clinically, the named conditions remain relevant since their natural histories are distinguishable, if overlapping.…”

“…Cases for which only a prenatal description was available were included [Cai et al, 1998; Unger et al, 2001; Maeda et al, 2006], but with the understanding that distinctions based on ultrasonographic assessment are less certain. Clinical descriptions of intermediate or questionable diagnoses were reviewed; in four cases, we suggest alternative diagnoses to those proffered by the authors based on the clinical and radiological findings [Mégarbané et al, 1999; Macías‐Gómez et al, 2004; Maeda et al, 2006; Miyake et al, 2008]. Siblings with the same mutation combination and the same phenotype were only represented once in the tables to avoid ascertainment bias [Mégarbané et al, 2002; Patients 1 and 2 in this publication].…”