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Editor—Hypochondroplasia is a mild, autosomal dominant skeletal dysplasia. The relative dearth of specific clinical manifestations and the absence of pathognomonic radiographic features often make the diagnosis of hypochondroplasia difficult.1-4 Short limbed dwarfism is rarely recognised before the age of 2 years and is usually mild with heights up to the low normal range. Muscular body build, macrocephaly with mild frontal bossing, and lumbar hyperlordosis are frequently reported. The radiographic features are variable and can be almost normal in mildly affected subjects.4 They most typically include no change or decrease in the interpedicular distance from the first to the fifth lumbar vertebral bodies, anteroposterior shortening of the lumbar pedicles, short iliac bones with flat acetabular roof, small sacrosciatic notches, short tubular bones, short and broad femoral necks, and relative elongation of the distal or proximal portion of the fibula.2 4 Proof that achondroplasia and hypochondroplasia are allelic disorders came with the discovery that both conditions map to the distal short arm of chromosome 4.5 6 Subsequently, mutation analysis of the FGFR3 gene, located in the 4p16.3 region, showed a recurrent mutation (N540K) in several unrelated hypochondroplasia patients.7 8 Recently, two novel mutations in the same region of the FGFR3gene causing hypochondroplasia have been identified: N540T in a Dutch family and I538V in a Swedish kindred.9 10 In some sporadic patients and families with clinical or radiographic features of hypochondroplasia, a causal involvement of theFGFR3 gene has been ruled out, suggesting locus heterogeneity.11-14
We report here a novel N540S mutation in theFGFR3 gene and provide evidence that this mutation causes hypochondroplasia in a Belgian family. The proband is an 8 year old girl referred to the paediatric endocrinologist because of short stature. She was born after an uncomplicated pregnancy to young and non-consanguineous Belgian parents. Birth weight was 3350 g (50th centile) and length 49 cm (25th-50th centile). Psychomotor development was normal. She presented at the age of 8 years 9 months with mild disproportionate short stature. Anthropometric measurements showed a height of 120.1 cm (3rd centile=123 cm), weight 23.8 kg (3rd centile), head circumference 52.5 cm (50th-75th centile), span 120 cm, lower segment 58 cm (upper to lower segment ratio 1.07), hand length 13.2 cm (3rd centile), and foot length 18 cm (3rd centile=18.7 cm). In addition, a prominent forehead, low nasal bridge, anteroposteriorly flattened thorax, and lumbar hyperlordosis were found on physical examination (fig 1). Radiographic study of the skeleton showed mild shortening of the tubular bones, minimal increase in lumbar interpedicular distance, anteroposterior shortening of the lumbar pedicles and vertebral bodies, and accentuated lumbar lordosis with horizontally tilted sacrum (fig 2). The 37 year old father is also short with a height of 167.9 cm (3rd-25th centile), head circumference 60.3 cm (98th centile=58 cm), span 175 cm, and lower segment 82 cm (upper to lower segment ratio 1.05). His clinical phenotype is characterised by macrocephaly with a prominent forehead, low nasal bridge, muscular build, and broad thorax. Radiographs of the skeleton showed mild shortening of the tubular bones, increase in lumbar interpedicular distance, anteroposterior shortening of the lumbar pedicles and vertebral bodies, long proximal portion of the fibula, and remarkably short femoral necks (fig 3).
Because the clinical and radiographic features in both father and daughter suggested the diagnosis of hypochondroplasia, sequence analysis of the tyrosine kinase I domain of theFGFR3 gene was performed. Genomic DNA was extracted from peripheral blood leucocytes by the Qiagen-Blood miniprep kit (Qiagen Inc, Chatworth, CA). Oligonucleotide primers and PCR conditions for amplification of exon 11 and part of exon 12 were used as previously described.8 The amplified DNA fragments were cloned using the TA cloning kit (Invitrogen) and sequenced. This analysis showed heterozygosity for an A to G transition in both patients, resulting in substitution of serine for asparagine at position 540 (N540S) of the FGFR3 protein (fig 4). This nucleotide sequence change creates a cleavage site for the restriction endonuclease MwoI. Restriction analysis of amplified genomic DNA fragments confirmed that both patients were heterozygous for the mutation and that neither unaffected family members nor any of a panel of 100 unrelated, healthy controls carried the nucleotide change (data not shown).
Both subjects are mildly but variably affected. The radiographic changes in the daughter are subtle whereas the father, with a height in the low normal range, shows convincing radiological features of hypochondroplasia. It is highly likely that this mutation is responsible for hypochondroplasia based on the following strong arguments. First, the mutation is not present in the unaffected family members or in 100 unrelated, healthy controls. Second, the mutation resides in a highly conserved region when comparing all four humanFGFRs.15 Third, the nucleotide change implies the replacement of the same amino acid as in the common N540K mutation, which has been clearly established to cause hypochondroplasia. Fourth, substitution of the same asparagine by threonine, a neutral and polar amino acid similar to serine, has been reported in hypochondroplasia.9
The identification of yet another novel mutation, resulting in the substitution of asparagine in position 540 of the FGFR3 protein and with hypochondroplasia as the phenotype, emphasises the important role of this specific site of the tyrosine kinase I domain in the pathogenesis of the disorder. Therefore, in patients with clinical/radiographic features of hypochondroplasia in whom restriction analysis or mutation detection methods do not show the presence of the common N540K mutation, sequence analysis of the tyrosine kinase I domain of the FGFR3 gene should be performed to exclude other nucleotide changes in that region.
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