The four major entities in the spectrum of DTDST gene mutations will be highlighted and contrasted below, arranged in order of the clinical and severity of the condition,
from the most severe (achondrogenesis type 1B) through the least severe (recessive multiple epiphyseal dysplasia).
Achondrogenesis type 1B (Ach 1b)
Achondrogenesis type 1B (Ach 1b) is one of three radiographic subtypes of achondrogenesis which are radiographically similar but genetically quite distinct. Ach 1b was previously diagnosed on clinical,
radiographic,
and histological criteria,
with a characteristic "ring about the chondrocytes" the key diagnostic feature (Fig.
1). It is now recognized to be due to a mutation in the gene encoding for DTDST. This is a relatively rare dysplasia,
seen in 1:50,000 live births. Affected fetuses are often stillborn,
however,
and Ach 1b is lethal in the neonatal period.7,8
Patients with Ach 1b are homozygous for null mutations in the gene encoding for DTDST,
resulting in extremely minimal sulfate transport function. Null mutations identified to date include:2,7,9
- L483P
- delta V340
- G678V
- R178X
- N425D
- delta a1751
Clinical features include:5,7,8
- Extreme micromelia
- Thoracic hypoplasia
- Hydrops,
with soft tissue edema
- Polyhydramnios in utero
- Micrognathia and midface hypoplasia
Radiographic features include (Figs.
2 and 3):5,7,8
- Extremely deficient vertebral ossification
- Hypoplastic,
curved iliac wings
- Flattened acetabula
- Barrel chest with short,
thin ribs
- Extreme micromelia,
with squared or trapezoidal appearance of long bones that demonstrate cupped,
spurred metaphyses
- Poorly ossified calvarium
The diffential diagnosis for Ach 1b includes:
- Achondrogenesis type 1a (Ach 1a; unknown etiology - Fig.
4)
- Achondrogenesis type 2 (Ach 2; a type II collagenopathy - Fig.
5)
- Hypophosphatasia
- Thanatophoric dysplasia and thanatophoric variants (FGFR3 mutations)
Atelosteogenesis type II (AO-II)
This is a rare dysplasia that is usually lethal in the neonatal period,
though there are some longer-term survivors. Patients are heterozygous for both a null mutation and a partial-function mutation,
with residual sulfation capacity that is 39-62% of normal.1,2,9,10
Partial function mutations identified to date include:2,7,9
- A715V
- C653S
- Q454P
- R279W - the most common outside Finland
- IVS+2T>C - the common Finnish mutation,
the second most common outside Finland
There is some phenotypic overlap with Ach 1b,
as expected. Clinical features include:1,2,5,10
- Pulmonary hypoplasia
- Laryngeal stenosis
- Severe micromelia
- Talipes equinovarus
- "Hitchhiker" thumb and "sandal" first toe
- Micrognathia
- Large joint dislocations
- Lumbosacral lordosis
- Scoliosis in okder survivors
Radiographic features of AO-II include (Figs.
6-8):1,2,5,10
- Severe micromelia of upper and lower limbs
- Marked tapering of distal humerus and distal ulna
- Metaphyseal broadening of proximal humerus,
proximal and distal femur,
proximal tibia
- Extreme brachmetacarpalia and brachyphalangia,
with enlarged 2nd and 3rd metacarpals
- "Hitchhiker" thumb
- Vertical,
hypoplastic ischia
- Talipes equinovarus
- Dislocation at elbows and knees
- Scoliosis in older survivors
- +/- polydactyly
The differential diagnosis for AO-II includes:
- Atelosteogenesis type I (AO-I)
- Atelosteogenesis type III (AO-III)
- Diastrophic dysplasia
- Otopalatodigital syndrome type 2 (OPD 2)
Diastrophic dysplasia (DTD)
This is the prototype for disorders in the DTDST spectrum. DTD is a rare dysplasia, seen in 1:500,000 live births,
1:30,000 in Finland. Most patients with DTD are compound heterozygotes,
demonstrating one null mutation and one partial-function mutation. Residual sulfation capacity is 39-62% of normal.1,2,5,9,11
Clinical features of DTD include:1,2,5,11
- Short-limbed dwarfism,
apparent at birth
- Narrow nasal bridge and micrognathia
- Hypertrophic auricular cartilage ("cauliflower" ear)
- Ulnar deviation of hands and talipes equinovarus
- Symphangilism,
brachymetacarpalia and brachphalangy
- Proximal translation of shortened first metacarpal ("hitchhiker" thumb - Fig.
9)
- Progressive scoliosis; often with myelopathy
- Dislocation of hips,
knees,
and elbows
- Joint contractures
- Respiratory compromise in infancy
- Short neck,
often with cervical kyphosis
- Usually have a normal life span
Radiographic features of DTD include (Figs.
10-19):1,2,5,11
- Moderate to severe limb shortening
- Delayed ossification of femoral heads and other epiphyses
- Deficient lateral femoral condyles
- Large joint dislocations (hips,
knees,
elbows)
- Joint contractures
- Proximal shortening of fibulae
- Irregularly short tubular bones,
broad and irregular metacarpal and metatarsal heads
- Symphangilism
- Delta-shaped phalanges
- Shortened first metacarpal with proximal and radial translation of first proximal phalanx ("hitchhiker" thumb)
- Small and irregular carpal and tarsal bones,
often supernumerary
- Paradoxical advanced ossification of carpal and tarsal bones
- Severe talipes equinovarus
- Progressive kyphoscoliosis
- Platyspondyly
- Cervical kyphosis,
often with atlantoaxial subluxation and cervical cord compression
The differential diagnosis for DTD is that of large joint dislocations,
cervical kyphosis,
and short-limbed dwarfism:
- Larsen syndrome (Fig.
20)
- Campomelic dysplasia (Fig.
21)
- Arthrogryposis
- Atelosteogenesis types I-III
- Pseudodiastriophic dysplasia
- Pseudoachondroplasia
- Loeys-Dietz syndrome
- Type II collagenopathies
Recessive multiple epiphyseal dysplasia (rMED)
Multiple epiphyseal dysplasia (MED) is a heterogeneous group of dysplasias,
with an overall incidence of approximately 1:10,000 live births. This group of disorders is caused by defects in collagen oligomeric matrix protein,
collagen IX,
matrilin-3 (all autosomal dominant),
and DTDST (autosomal recessive).2,5,9,12-14
Recessive multiple epiphyseal dysplasia (rMED) is caused by homozygosity of the most common partial-function mutations R279W and C653S,
less commonly by compound heterozygosity with the common Finnish mutation and another partial-function mutation.2,9,12-14
Clinical features of rMED are variable,
and are less severe than those seen in DTD. These features include:5,12-14
- Normal to moderately short stature
- Variable joint manifestations,
predominantly hip dysplasia and patellar dislocation
- Joint contractures may be present
- Talipes equinovarus in 28%
- Brachymetacarpalia and brachydactyly
- Scoliosis
- Often technically misdiagnosed as "mild diastrophic dysplasia"
Radiographic features of rMED are also less severe than those seen in DTD,
and include (Figs.
22-28):5,12-14
- Scoliosis
- Talipes equnivarus
- Variable brachymetacarpalia and brachydactyly
- Milder form of the "hitchhiker" thumb
- Dysplastic femoral heads,
often leading to avascular necrosis
- Short,
broad femoral heads
- Proximal shortening of fibulae
- Slightly small and irregular carpal and tarsal bones
- Dysplastic femoral trochelar grooves and hypoplastic femoral condyles
- Characteristic double-layered patellae,
often subluxed or dislocated
- Mild platyspondyly