The "chondrodysplasia family" concept as advocated by Spranger in 1988 states that distinct phenotypes with different degrees of severity may be caused by different mutations within a single gene. This concept has been validated through the study of genes encoding for type 2 collagen,
fibroblast growth factor 3 (FGFR3),
filamin B,
and others. This phenotypic variability often exhibits some overlap,
resulting in a continuum of clinical severity. This is particularly true for the DTDST gene.1
The gene encoding for the diastrophic dysplasia sulfate transporter (DTDST),
termed SLC26A2,
is located on chromosome 5,
in the region 5q32-q33.1. This gene has a total of 2834 base pairs. To date,
over 30 different point mutations within this gene have been described. However,
not all mutations result in clinically detectable disease. Five recurrent mutations result in approximately 66% of clinical cases,
with a particularly high indicence of one specific partial function mutation seen in the Finnish population (1:500).2
The diastrophic dysplasia sulfate transporter (DTDST) protein is a sulfate-chloride exchanger at the cell membrane level,
composed of 739 amino acids,
and is approximately 80kDa in size. Inactivation or reduced activity of this sulfate transporter results in absence or undersulfation,
respectively,
of chondroitin sulfate proteoglycans in chondrocytes and fibroblasts. Mutations resulting in stop codons or transmembrane domain substitutions result in severe phenotype,
due to markedly decreased or absent sulfation. Mutations producing other structural or regulatory defects usually cause a less severe phenotype,
due to residual sulfation capacity.2-4
The clinical spectrum in DTDST mutations ranges from lethal to relatively mild. Alll demonstrate autosomal recessive inheritance,
heterozygotes are asymptomatic. To date,
conditions known to be due to DTDST mutations include:
- Achondrogenesis type 1B (Ach 1b)
- de la Chapelle dysplasia (unique Finnish mutation)
- Atelosteogenesis type 2 (AO-II)
- Diastrophic dysplasia (DTD)
- Recessive multiple epiphyseal dysplasia (rMED)
Patients with Ach 1b are homozygous or compound heterozygous for null mutations. Patients with AO-II usually have one null mutation and one partial-function mutation. Patients with de la Chapelle dysplasia and rMED are homozygous for partial-function mutations,
or may demonstrate compound heterozygosity for two separate partial-function mutations. Patients with DTD are usually compound heterozygotes for partial-function mutations. Phenotypically,
Ach 1b is the most severe,
and rMED is the least severe.2
Historically,
diagnosis has been based on clinical and radiographic findings. Recent advances in genetic analysis can provide definitive diagnosis in affected individuals. Ach 1b,
AO-II,
and DTD have been diagnosed on antenatal ultrasound,
and all can now potentially be diagnosed via fetal DNA obtained through chorionic villus sampling.