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Editor—Diastrophic dysplasia was originally ascribed to sulphate transporter gene (DTDST) mutations. TheDTDST gene is now also known to account for a variety of bone dysplasias including diastrophic dysplasia, atelosteogenesis type II (AO2), and achondrogenesis Ib.1-3 Abnormally sulphated cartilage proteoglycans with deficient cartilage sulphate content has been reported in these conditions,4 suggesting that a variable residualDTDST activity probably accounts for the broad spectrum of clinical phenotypes at this locus.5
While a predominant founder mutation in the splice donor site of a previously undescribed 5′ untranslated exon accounts for the disease in Finland, more than 30 mutations have been reported so far world wide6 and compound heterozygosity for variably deleterious mutations probably explains the broad spectrum of clinical phenotypes at the DTDST locus.2 7 8 The R279W mutation is the most common mutation in non-Finnish patients and, apart from its original report in an AO2 patient, compound heterozygosity for this mutation has been consistently associated with a non-lethal phenotype.
Recently, Superti-Furga et al 9 reported homozygosity for the R279W mutation in an adult affected with multiple epiphyseal dysplasia, normal stature, club foot, and double layered patella. Here, we add further support to this view and report on the association of apparently isolated club foot with the homozygous R279W DTDSTmutation in two unrelated sibships of western French ancestry (Brittany).
In family 1, dizygotic twins, a boy and a girl, aged 14 years, were referred for moderate hand stiffness. They were born after a normal pregnancy (birth weight 2650 g and length 48 cm for the boy and birth weight 2700 g and length 47 cm for the girl). At birth, the girl had a metatarsus varus of the left foot which rapidly recovered after physiotherapy. She developed normally and at 14 years of age she had normal stature (height 158 cm), no facial dysmorphism or abnormal external ears, and did not complain of hip, knee, or ankle pain after physical exercise. At birth, her brother had bilateral club foot which required surgery with persistence of retraction on the left side. His stature was normal (height 160 cm at 14 years). There was no ear swelling, hitch hiker thumb deformity, or limitation of full extension of the elbow and his face and palate were normal. At birth,x rays showed a normal spine and lower limbs, but a bone age advanced by one year was observed when the boy was 2 year old. At 14 years, x rays showed enlarged metaphyses of the phalanges and shortened metacarpals (fig1A). When the radiographs were re-examined, mild epiphyseal dysplasia of the upper femoral neck (fig 1B) was noted but no knee abnormality or double layered patella were observed. The parents originated from the same region of Brittany but no consanguinity was known.
In family 2, the first child, a boy (birth weight 4650 g and length 52 cm) had bilateral club foot diagnosed during pregnancy by ultrasound examination. Associated with this, mild micromelia with a small chin and mouth was noted at birth. Neither ear swelling nor hand abnormalities were detected, but pronosupination of the elbows was limited. He grew slowly (height 90 cm at 3 years, 25th centile) andx rays of the long bones were considered to be normal (fig 1C). Retrospectively, however, a mild flaring of the metaphyses of the long bones with delayed ossification of the epiphyses of the hip were noted at 3 years of age. Vertebral bodies were normal. During the second pregnancy, short femora were detected antenatally. The baby, a girl (birth weight 3250 g, length 46 cm at 37 weeks of pregnancy), had micromelia with brachymesophalangy of the fifth finger and a narrow thorax. The thumbs and feet were normal but a subluxation of the left hip was detected on echography at 2 months and treated by abduction splinting. Radiographs of the upper limb showed two ossified carpal bones and a dislocated elbow at 4 months. Her stature at 9 months was 67 cm (25th centile). There was no functional deficit or pain in the two children. Their parents originated from two villages 10 kilometres apart, but no consanguinity was known.
Because a mild form of diastrophic dysplasia was considered, leucocyte DNA from the probands were screened for mutations in the coding region of the DTDST gene. Direct PCR sequencing was performed in both directions using Big Dye terminators ( Perkin- Elmer) on an Applied Biosystem 373A apparatus using the two following primers (forward: DTD5: TGC TCT GAT GAT ATG TCT CCA TGC and reverse: DTD8: TAT TCG ATC TAC AGC CAC ACT).6 Interestingly, the four probands were homozygous for the mutation R279W in the fifth extracellular loop of the sulphate transporter protein.
Club foot is a common malformation, either isolated or associated with various neurological syndromes or chondrodysplasias, including diastrophic dysplasia, spondyloepimetaphyseal dysplasia with joint laxity, Kniest disease, and multiple epiphyseal dysplasia (MED). Isolated club foot (or metatarsus varus with no other clinical abnormality or short stature) is currently regarded as a malformation with a multifactorial mode of inheritance with a recurrence risk of approximately 10%.10 11 In family 1, club foot was originally regarded as isolated, especially as the two affected children did not complain of functional deficit. They only complained of stiffness of the fingers and the diagnosis of MED was eventually considered after x ray discovery of small upper femoral epiphyses. At that time, the association of club foot (metatarsus varus), MED, and stiffness of the hand with short metacarpals and enlarged metaphyseal phalanges prompted us to consider and eventually confirm the diagnosis of a diastrophic dysplasia variant,12 despite the absence of the double layered patella. The diagnosis of MED has been difficult to reach in family 2 as well, because the two children were too young. However, the delayed ossification of the femoral epiphyses of the hips might have suggested this diagnosis to us earlier.
The association of MED with the homozygousDTDST R279W mutation has been previously noted and ascribed to the normal stability of the mutantDTDST mRNA.8 Recently, Superti-Furga et al 9 reported that autosomal recessive multiple epiphyseal dysplasia could result from homozygous DTDST R279W mutations. The patients reported here add to the view that the clinical spectrum ofDTDST mutations is much broader than originally believed and includes apparently isolated club foot. However, the molecular mechanisms underlying the intrafamilial or interfamilial clinical variability of the homozygous R279W mutation remain unexplained.5
Based on these observations, we suggest giving consideration toDTDST mutation analysis in apparently isolated club foot, especially in cases of familial recurrence. Skeletal x rays and molecular investigations should help to confirm this diagnosis and determine the actual incidence of DTDST mutations in apparently isolated club foot.