Achondroplasia and nail-patella syndrome: the compound phenotype.

EDITOR—Achondroplasia (MIM 100800) is one of the most common chondrodysplasias with a prevalence rate of around 1 in 26 000 live births. Inheritance is autosomal dominant, but in around 85% the phenotype is the result of a new mutation. Common features include disproportionate short stature with short limbs, particularly rhizomelic shortening, true megalencephaly with hydrocephalus in a minority, midface hypoplasia, a trident hand configuration, and joint hyperextensibility. Motor development delay is common owing in part to generalised mild hypotonia and in part to megalencephaly. Otitis media (OM) is a common complication with around 95% of subjects having an episode of OM at some time and over 80% requiring the insertion of PE tubes on at least one occasion. Neurological compromise can result from either stenosis of the foramen magnum usually presenting in childhood or stenosis of the thoracolumbar spine in adults. Hydrocephalus, thought to result from stenosis of the jugular foramina, requires the insertion of ventriculoperitoneal shunts in approximately 10% of cases; however, benign ventriculomegaly is a common finding. Bowing of the legs with proximal and distal tibial varus is common but is often asymptomatic. Cognitive function is normal. In 1994 specific mutations in the FGFR3 gene were found to cause achondroplasia. 4 Nail-patella syndrome (MIM 161200) (NPS) is an autosomal dominant disorder characterised by dysplasia of the nails, hypoplastic or absent patellae, and dysplasia of the elbow, with nephropathy in around 30% of cases. Iliac horns are not always observed but are a pathognomonic radiographic sign when present. Cognitive function is again normal. Recently, loss of function mutations in the LMX1B gene were found in patients with nail-patella syndrome. 6 We report the case of a child, born to unaVected parents, with phenotypic features of both achondroplasia and NPS. De novo heterozygous mutations were identified in both the FGFR3 and LMX1B genes, confirming the presence of both conditions in the one person. The proband was born at 36 weeks’ gestation after an uncomplicated pregnancy. Birth weight was 2580 g and there were no neonatal problems. He was the third child of a non-consanguineous Asian couple. At the time of conception, the father was 33 years of age and the mother 27 years. There was no family history of either achondroplasia or NPS. Examination of the parents and sibs showed no clinical features of NPS. At birth he was noted to have macrocephaly, frontal bossing, rhizomelic limb shortening, a trident hand configuration, and generalised hypotonia. A clinical diagnosis of achondroplasia was made and this was confirmed radiographically (fig 1). The patient was also noted to have dysplastic nails and hypoplastic patellae with iliac horns (fig 1). The clinical and radiographic diagnosis of NPS was therefore also made. Developmental progress was normal with only the expected gross motor delay associated with achondroplasia. Cognitive function was normal. General health was good and renal function normal. An MRI scan of the brain showed minimal ventricular dilatation; however, head growth was consistently 1 SD above the mean on growth charts for children with achondroplasia. Height at the age of 6 was also 1 SD above the mean. A polysomnogram performed in response to snoring showed no evidence of obstructive or central sleep apnoea. Marked genu valgum with lateral instability developed initially unilaterally but subsequently aVected both knees. This became suYciently severe that gait was compromised with a fibular thrust. Bilateral fibular and tibial osteotomies were performed at 7 years with good results. Elbow movements were only mildly aVected with mild limitation of extension and supination. To determine whether the phenotype in the proband was the result of the coincidental occurrence of distinct genetic disorders or a previously undescribed condition, molecular studies were undertaken. DNA was extracted from whole blood samples from the proband and his parents and tested for the common achondroplasia mutation in FGFR3, G380R, using standard techniques. A number of diVerent LMX1B mutations have been reported in NPS patients, so sequencing of the entire coding region was initiated as previously described. Analysis of the homeodomain identified a single base change resulting in the replacement of an arginine at codon 198 by a stop codon. Restriction enzyme digestion indicated that both mutations had arisen de novo. There are a number of previous reports of children heterozygous for two dominant chondrodysplasias. In 1987, Sommer et al reported follow up of a patient first described by McKusick et al in 1973 with achondroplasia and hypochondroplasia. This child had unique clinical and radiographic features distinct from both achondroplasia and hypochondroplasia including more marked short stature than seen in achondroplasia with severe shortening of the long bones, both proximal and distal segments being involved, severe foramen magnum and spinal stenosis, flaring of the metaphyses, and large cartilaginous structures in the joints. Recently, two further cases of compound achondroplasia hypochondroplasia were reported. 10 Both of these children had more severe features than would be expected in either achondroplasia or hypochondroplasia alone. One child had seizures on day 2 of life and both had significant respiratory distress. The features of these cases can be explained in the context of what we now know about mutations in FGFR3. Both achondroplasia and hypochondroplasia are caused by mutations in FGFR3 which cause activation of the receptor and inhibit endochondral ossification. Compound heterozygosity for mutations in FGFR3 would therefore be expected to cause additive eVects on bone growth. The mental retardation is more diYcult to explain although children with the recently described SADDAN (severe achondroplasia, developmental delay, acanthosis nigricans) phenotype also caused by mutations in FGFR3 also have mental retardation and exhibit greater activation of FGFR3. 12 A number of CNS abnormalities, thought to be the result of neuronal migration defects, have been shown in thanatophoric dysplasia (MIM 187600) and in situ hybridisation experiments have shown that FGFR3 is expressed in the developing brain. Other cases have been reported where the two conditions are not allelic. Young et al described the male child of a father with spondyloepiphyseal dysplasia congenita (SEDc) (MIM 183900) and a mother with Electronic letter 1 of 3