Campomelic Dysplasia

A number sign (#) is used with this entry because campomelic dysplasia, as well as acampomelic campomelic dysplasia, with or without sex reversal is caused by heterozygous mutation in the SOX9 gene (608160) on chromosome 17q24.

See 602196 for a disorder related to CMPD associated with translocation upstream of the SOX9 gene.

Description

Campomelic dysplasia (CMPD) is an autosomal dominant skeletal dysplasia characterized by congenital shortness and bowing of long tubular bones, especially in the lower extremities, as well as by hypoplastic scapulae, narrow iliac wings, and nonmineralized thoracic pedicles. CMPD is often lethal in the first year of life, due to respiratory insufficiency related to small chest size and tracheobronchial hypoplasia (summary by Matsushita et al., 2013).

SOX9 mutations causing campomelic dysplasia have also been associated with 46,XY sex reversal, with marked variability in the degree of gonadal dysgenesis among patients carrying the same mutation (Cameron and Sinclair, 1997).

Clinical Features

Caffey (1947) reported a congenital syndrome with prenatal bowing and thickening of tubular bones with multiple cutaneous dimples in the arms and legs. Angle (1954) reported congenital bowing and angulation of the long bones. Weller (1959) noted that congenital bowing of the legs occurs in osteogenesis imperfecta congenita (OIC; 166210) and in hypophosphatasia with congenital dimples (241500). Cutaneous dimpling can occur with any prenatal bowing (see 264050).

The designation campomelic (or camptomelic) dwarfism, proposed by Maroteaux et al. (1971), comes from the bowing of the legs, especially the tibias. The scapulas are very small and the pelvis and spine show changes. Eleven pairs of ribs are usually present. The inferior part of the scapula is hypoplastic. Cleft palate, micrognathia, flat face, and hypertelorism are also features. Most patients die in the neonatal period of respiratory distress. Disarray of the hair ('unruly' hair) is present in some patients. Severe anomalies of the lower cervical spine may lead to an appearance of pterygium colli. Pterygium syndrome was a referral diagnosis in at least 1 case.

Stuve and Wiedemann (1971) observed 2 sisters with 'congenital bowing of the long bones.' Lee et al. (1972) described 3 cases emphasizing the tracheobronchial hypoplasia as a significant factor in the neonatal respiratory deaths. Parental consanguinity was noted by Cremin et al. (1973) in only 1 of 11 reported cases.

Hovmoller et al. (1977) pointed out the association of sex reversal. In 9 previously reported cases the karyotype had been studied and in one of these cases a girl was found to have a 46,XY karyotype. Abnormal external genitalia were described in other cases. Hovmoller et al. (1977) described in detail 2 unrelated girls with XY karyotypes who died at ages 4 days and 11 months. Hoefnagel et al. (1978) described 2 female newborns with camptomelic dysplasia and XY gonadal dysgenesis. Hall and Spranger (1980) commented on the fact that some affected males have female external genitalia and vagina, uterus, and fallopian tubes. Dagna Bricarelli et al. (1981) described a family in which the brother of a typical case had features suggesting an abnormality but whose limbs showed very little bowing. Indeed, all the long bones of the arms and legs were slim and straight.

Houston et al. (1983) reported 17 cases of the campomelic syndrome and a follow-up of one of the original patients (by then 17 years old) of Maroteaux et al. (1971). Their review was based on 97 patients, including their own. They emphasized the diagnostic value of the very small, bladeless scapulas and hypoplastic pedicles of thoracic vertebrae. The hips were usually dislocated and talipes equinovarus deformities were present. The chondrocranium was small and the neurocranium disproportionately large. Respiratory distress was caused by small thoracic cage, narrow airways from defective tracheobronchial cartilages, and sometimes micrognathia, cleft palate, retroglossia and hypoplastic lungs. Absence of the olfactory bulbs and tracts, and heart and renal malformations have been noted. Most patients died in early infancy. Their 17-year-old surviving patient had an estimated IQ of 45 and hearing loss. Houston et al. (1983) reported affected sibs. Other reports of affected sibs referenced by them include those of Shafai and Schwartz (1976), Mellows et al. (1980), Dagna Bricarelli et al. (1981), and Fryns et al. (1981). Moedjono et al. (1980) described concordantly affected monozygotic female twins. Two XY females reported by Dagna Bricarelli et al. (1981) were H-Y negative.

Lynch et al. (1993) reported a mother and daughter with clinical and radiologic findings consistent with the diagnosis of campomelic dysplasia. They noted that the disorder had been thought to be autosomal recessive because of recurrence in sib pairs and also the presence of consanguinity in some families. Milder tibial bowing and significant shortening of the phalanges in both the hands and the feet were suggested as distinguishing features from the classic form of the disease. Lynch et al. (1993) pointed to the report by Thurmon et al. (1973) of campomelic dysplasia in half sibs, the mother of whom had mild tibial bowing. They suggested that this could be an example of autosomal dominant inheritance with reduced penetrance or maternal gonadal mosaicism.

Mansour et al. (1995) collected information on 36 patients with campomelic dysplasia from genetic centers, radiologists, and pathologists in the United Kingdom. The chromosomal sex ratio was approximately 1:1. There was a predominance of phenotypic females owing to sex reversal. Sex reversal or ambiguous genitalia was found in three-quarters of the chromosomal males. Three patients were still alive, 2 with chromosomal rearrangements involving 17q. Most of the patients died in the neonatal period. The 36 index cases had 41 sibs of whom only 2 were affected. Formal segregation analysis gave a segregation ratio of 0.05; 95% CI = approximately 0.00 to 0.11. This was considered to exclude autosomal recessive inheritance and to suggest that this disorder is a sporadic, autosomal dominant. Patients with a chromosomal rearrangement involving 17q23.3-q25.1 showed a milder phenotype. As in the case of other neonatal lethal autosomal dominant disorders that have been thought to be autosomal recessive (e.g., osteogenesis imperfecta congenita), parents of infants with campomelic dysplasia had probably often been dissuaded from having further children. Mansour et al. (1995) provided diagnostic criteria.

Mansour et al. (2002) described 5 patients with campomelic dysplasia who had survived to ages ranging from 7 to 20 years. All 5 had characteristic facial features, including flat face, hypertelorism, long philtrum, depressed nasal bridge, micrognathia, and relative macrocephaly. Complications included conductive hearing loss, developmental delay, kyphoscoliosis, and other orthopedic problems. The authors commented that surviving campomelic dysplasia is a recognizable entity.

Velagaleti et al. (2005) summarized the clinical features of campomelic dysplasia, noting the characteristic presence of skeletal anomalies such as bowed femurs and tibiae, hypoplastic scapulae, 11 pairs of ribs, pelvic malformations, Pierre Robin sequence, and clubbed feet. In two-thirds of affected individuals with a 46,XY karyotype, male-to-female sex reversal had been described.

Watiker et al. (2005) reported 2 patients originally diagnosed as having Cumming syndrome (211890) who were subsequently found to have mutations in the SOX9 gene, prompting reassessment of the cases and reclassification as campomelic dysplasia. Features consistent with Cumming syndrome included campomelia of prenatal onset, cystic hygroma, and a small chest; 1 patient also had a cleft palate and multicystic kidneys, and the other had a complex congenital heart defect. The patients also had short, irregular chondrocyte columns, whereas chondroosseous morphology appears normal in campomelic dysplasia except at the diaphyseal bend. Watiker et al. (2005) concluded that the presence of a narrow, tall pelvis, hypoplastic scapulae, and sex reversal are key findings in campomelic dysplasia that allow it to be differentiated from Cumming syndrome.

Acampomelic Dysplasia

Although campomelia is one of the most common clinical features of this disorder and the feature that gives it its name, cases without campomelia (acampomelic CMPD) have been reported (Macpherson et al., 1989; Friedrich et al., 1992). In angiographic studies in 4 patients with the campomelic syndrome, Rodriguez (1993) found striking abnormalities, particularly absence or marked deficiency of the anterior tibial artery. One of the 4, a phenotypic female with a 46,XY karyotype, lacked lower limb bowing and the talipes equinovarus typical of campomelic syndrome. This infant was thought to constitute a further example of campomelic syndrome without campomelia. In this case the other features of the syndrome were present: ovarian dysgenesis, craniofacial changes, and defective tracheal bronchial cartilage resulting in respiratory distress and death. The patient had a normal arterial pattern in the legs. Rodriguez (1993) thus concluded that there was a developmental association between vascular defects and lower limb anomalies in this disorder. The aberrant arterial pattern may affect muscle development. The shortness of the posterior femoral and calf muscles in turn fix the knee and the ankle joints, and bone bowing may be related to the abnormal mechanical forces applied to the developing long bones of the lower limb.

Glass and Rosenbaum (1997) presented 2 sisters with acampomelic CMPD between whom there were some clinical and radiographic differences and also variations from classic campomelic dysplasia. They described shallow orbits, a radiographic finding that had not previously been described in this dysplasia. Ozkilic et al. (2002) noted 9 reported cases of acampomelic dysplasia and added another case.

Cytogenetics

Cooke et al. (1985) described a typical case of campomelic dysplasia with sex reversal in a single family with a balanced t(5;8)(q33.1;q21.4) in 4 generations. The child had inherited the translocation from the father. The infant had female external genitalia and XY sex chromosome constitution. Primary follicles, each with a central ovum, were demonstrated in the dysgenetic gonads. The uterus and both fallopian tubes were morphologically normal.

Maraia et al. (1991) observed a de novo paracentric inversion of 17q in an infant with campomelic dysplasia, and they postulated involvement of the COL1A1 gene (120150) or the HOX2 gene (142960).

Young et al. (1992) described a typical case of campomelic dysplasia in a phenotypically female fetus with a de novo reciprocal translocation, 46,XY,t(2;17)(q35;q23-24). In light of the report also by Maraia et al. (1991) of a rearrangement involving the long arm of chromosome 17 in association with campomelic dysplasia, they considered it likely that a gene for this disorder lies on 17q. Tommerup et al. (1993) indicated that there are 5 known cases of campomelic dysplasia with a break in 17q25, either de novo or cosegregating. They proposed that 17q24.3-q25.1 is the site of an autosomal sex-reversal gene, which they called SRA1, that is mutated in CMPD.

Ninomiya et al. (1996) investigated a patient in whom acampomelic CMPD and sex reversal were associated with a de novo t(12;17) translocation. The breakpoint on 17q was located in the same region as that observed in translocation patients reported by others. Patients with acampomelic campomelic dysplasia have no long bone curvature. Affected children have a characteristically flat facial profile and present with respiratory distress. They all have markedly hypoplastic scapulas.

Savarirayan and Bankier (1998) described a child with a severe form of acampomelic dysplasia who had a de novo reciprocal translocation, 46,XX,t(5;17)(q15;q25.1). The child died at 11 days of age due to respiratory complications. Savarirayan and Bankier (1998) noted the similarity between their case and that reported by Maraia et al. (1991). The authors also noted that, contrary to previous reports, this child with acampomelic dysplasia associated with chromosome rearrangements was severely affected.

Pfeifer et al. (1999) presented 3 novel cases of CMPD associated with translocations and summarized features of the 11 translocation cases reported to that time, bringing the total to 14 cases. They noted the tendency of translocation patients to have a longer life expectancy than patients with mutations in the SOX9 coding region. They also noted that, whereas only 1 of 22 reported patients with SOX9 mutations had acampomelia, 7 of 14 translocation patients showed acampomelia or only mild bowing of the limbs.

Leipoldt et al. (2007) reported a patient with characteristic symptoms of CMPD and a 46,XY,t(1;17)(q42.1;q24.3) karyotype in whom they mapped the 17q breakpoint 375 kb upstream from SOX9 using standard and high-resolution fiber FISH. Another patient with a 46,X,t(Y;17)(q11.2;q24.3) karyotype had the acampomelic form of CMPD and complete XY sex reversal; using FISH and somatic cell hybrid analysis, the authors mapped the 17q breakpoint 789 kb from SOX9. Combining their data with previously published CMPD translocation breakpoints, Leipoldt et al. (2007) defined 2 clusters upstream of the SOX9 gene: a proximal cluster of breakpoints between 50 and 375 kb upstream and a distal cluster of breakpoints between 789 and 932 kb upstream.

Molecular Genetics

In 6 of 9 patients with campomelic dysplasia, Foster et al. (1994) identified mutations in single alleles of the SOX9 gene (e.g., 608160.0001). Both parents of 2 of the patients did not have the mutation. The de novo appearance of a mutation in a sex-reversed campomelic patient established that alterations in SOX9 caused both abnormalities. The findings in this case suggested to Foster et al. (1994) that campomelic dysplasia is an autosomal dominant disorder. They did not detect mutations in both SOX9 alleles of any patient. Dominance appeared to be due to haploinsufficiency rather than gain of function.

Wagner et al. (1994) likewise identified inactivating mutations in 1 SOX9 allele in nontranslocation CMPD-SOX9 cases, pointing to haploinsufficiency for SOX9 as the cause of both campomelic dysplasia and autosomal XY sex reversal (see 608160.0005).

Kwok et al. (1995) analyzed the SOX9 gene in 9 patients with campomelic dysplasia, 2 of whom had chromosome 17 rearrangements, and identified heterozygosity for 2 missense mutations, 3 frameshift mutations, and a splice site mutation, respectively, in 6 of the patients with no cytologically detectable chromosomal aberrations. An identical frameshift mutation (608160.0013) was found in 2 unrelated 46,XY patients, 1 exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). Kwok et al. (1995) attributed the difference in sexual phenotype of these two 46,XY individuals to incomplete penetrance of the disease that might result from differences in genetic background.

Cameron and Sinclair (1997) stated that 14 heterozygous mutations in SOX9 and 10 translocations involving 17q have been described in 28 patients with campomelic dysplasia. There had been no reported cases of patients having both a balanced 17q translocation and a mutation in SOX9. Ten of the 14 SOX9 mutations were associated with 46,XY sex reversal.

Olney et al. (1999) described a patient with campomelic dysplasia and complete deletion of 1 SOX9 gene. This was thought to represent the strongest evidence to date for dosage-dependent action of the SOX9 protein in normal chondrogenesis.

Smyk et al. (2007) reported 2 sisters with campomelic dysplasia who died within the first days of life. Genetic analysis identified a 4.7-Mb deletion involving the entire SOX9 gene. The father, who had subtle radiographic features of the disorder, was found to be mosaic for the deletion, which was detected in 64% of lymphocytes and 46% of skin fibroblasts. Due to lack of material from the sisters, the deletion was first detected using array comparative genomic hybridization and later confirmed in the father by FISH analysis.

Lecointre et al. (2009) studied a 6-year-old 46,XY girl with acampomelic campomelic dysplasia and complete sex reversal in whom high-density oligoarray CGH revealed a 960-kb deletion on chromosome 17q24, upstream of the SOX9 gene (608160.0015). The deletion was also present in her mildly affected mother, who was born with cleft palate and had mild microretrognathia, sandal gap, short great toes, and defective ischiopubic ossification; the unaffected father's DNA was normal. FISH analysis confirmed the presence of the deletion in the mother and daughter and its absence in the father; analysis of interphase nuclei in 3 different tissues from the mother demonstrated the presence of the deletion in 97 to 98.5% of nuclei, which suggested that the mother did not have somatic mosaicism. MLPA results were consistent with the interphase FISH analysis, again strongly suggesting that the mother was not a mosaic for the deletion.

In a 10-year-old Japanese boy with mild campomelic dysplasia who also exhibited clinical and radiologic features of small patella syndrome (147891), Matsushita et al. (2013) directly sequenced the SOX9 and TBX4 (601719) genes and identified a heterozygous missense mutation in both: H169Q in SOX9 (608160.0021) and P282T in TBX4. The TBX4 variant, inherited from his unaffected father, was at a nonconserved residue and was predicted to be neutral or benign by in silico analyses. In contrast, the SOX9 mutation, which was located at a highly conserved residue, was inherited from his mildly affected mother who had normal stature, facial features, and scapulae, but showed small patellae, brachydactyly with fifth-finger clinodactyly, mild recurvatum of the knees, and sandal gaps. Matsushita et al. (2013) noted that published reports of long-term survivors with CMPD have shown skeletal and facial features overlapping with those seen in small patella syndrome, including patellar aplasia or hypoplasia, defective ischiopubic junction ossification, hypoplastic lesser trochanters, sandal gaps, micrognathia/retrognathia, and cleft palate. However, scapular hypoplasia and/or spinal deformities, both of which were present in the Japanese proband, appeared to be key findings in CMPD that differentiate it from small patella syndrome.

Genotype/Phenotype Correlations

Meyer et al. (1997) succeeded in identifying the causative mutation in 11 of 12 patients with campomelic dysplasia: 10 novel mutations and 1 previously reported mutation (Y440X; 608160.0005). When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in 2 patients who survived for 4 and more than 9 years, respectively, exhibited some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This was apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations were found in patients with and without XY sex reversal, indicating that sex reversal in this disorder is subject to incomplete penetrance. Meyer et al. (1997) also studied 18 female patients with XY gonadal dysgenesis, or Swyer syndrome (233420, 400044) and found no altered SOX9 banding pattern by SSCP in any, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations. Meyer et al. (1997) stated that before their publication a total of 13 SOX9 mutations had been published as causes of CMD.

In a female infant with campomelic dysplasia and XY sex reversal who died of respiratory failure at 3 months of age, Pop et al. (2005) identified homozygosity for the Y440X mutation in the SOX9 gene, which arose by a mitotic gene conversion event between a de novo mutant maternal allele and a wildtype paternal allele. Transient cotransfection experiments in mouse Neuro2a cells demonstrated that the Y440X mutant retained some transactivation capacity on authentic SOX9-responsive promoters/enhancers, ranging from 5 to 22% of wildtype activity. Pop et al. (2005) suggested that this is a hypomorphic rather than a complete loss-of-function allele, which may account for the milder phenotype and longer survival seen in some patients with this mutation.

Animal Model

Bi et al. (2001) generated heterozygous Sox9 mutant mice that reproduced most of the skeletal abnormalities of campomelic dysplasia. The heterozygous Sox9 mice died perinatally with cleft palate, as well as hypoplasia and bending of many skeletal structures derived from cartilage precursors. In embryonic day (E) 14.5 embryos, bending of radius, ulna, and tibia cartilages was already prominent. In E12.5 embryos, all skeletal elements visualized by Alcian blue staining were smaller. In addition, the overall levels of type II collagen RNA at E10.5 and E12.5 were lower than in wildtype embryos. Bi et al. (2001) proposed that the skeletal abnormalities observed at later embryonic stages were caused by delayed or defective precartilaginous condensations. Furthermore, in E18.5 embryos and in newborns, premature mineralization occurred in many bones, including vertebrae and some craniofacial bones. Because Sox9 is not expressed in the mineralized portion of the growth plate, this premature mineralization is very likely the consequence of allele insufficiency existing in cells of the growth plate that express Sox9. Because the hypertrophic zone of the heterozygous Sox9 mutants was larger than that of wildtype mice, Bi et al. (2001) proposed that Sox9 also has a role in regulating the transition to hypertrophic chondrocytes in the growth plate. Despite the severe hypoplasia of cartilages, the overall organization and cellular composition of the growth plate were otherwise normal. The results suggested that 2 critical steps of the chondrocyte differentiation pathway are sensitive to Sox9 dosage: an early step presumably at the stage of mesenchymal condensation of cartilage primordia, and a later step preceding the transition of chondrocytes into hypertrophic chondrocytes.

History

Studying DNA from 5 cases, Ebensperger et al. (1991) could find no evidence of mutation in the SRY, ZFY (490000), ZFX (314980), or MEA1 (143170) genes. In addition to Southern analysis, gene expression of ZFY, ZFX, and MEA1 was found to be normal.