ACAMPOMELIC CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL, INCLUDED
CAMPTOMELIC DYSPLASIA, INCLUDED
CMPD1/SRA1 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL, INCLUDED
ACAMPOMELIC CAMPOMELIC DYSPLASIA, INCLUDED
CMPD
CMD1
CMPD1
Campomelic dysplasia is a disorder of the newborn characterized by congenital bowing and angulation of long bones, together with other skeletal and extraskeletal defects. Up to two-thirds of affected XY individuals have a gradation of genital defects or ... Campomelic dysplasia is a disorder of the newborn characterized by congenital bowing and angulation of long bones, together with other skeletal and extraskeletal defects. Up to two-thirds of affected XY individuals have a gradation of genital defects or may develop as phenotypic females (Wagner et al., 1994).
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 ... 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.
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 ... 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.
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 ... 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.
The diagnosis of campomelic dysplasia (CD; derived from the Greek for “bent limb”) can usually be clearly established based on clinical and radiographic findings. Although no single clinical feature is obligatory, the radiographic features are consistent and are the most reliable diagnostic clues....
DiagnosisClinical DiagnosisThe diagnosis of campomelic dysplasia (CD; derived from the Greek for “bent limb”) can usually be clearly established based on clinical and radiographic findings. Although no single clinical feature is obligatory, the radiographic features are consistent and are the most reliable diagnostic clues.Clinical featuresRelatively large headPierre Robin sequence with cleft palateFlat faceLaryngotracheomalaciaRespiratory distressEleven pairs of ribsAmbiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotypeDislocatable hipsShort bowed limbs (lower limbs more frequently than upper limbs)Pretibial skin dimples (bowing of the lower leg is often associated with a skin dimple over the apex of curve)Club feetNote: Bowing of the limbs, the feature that gave the disorder its name, is not an obligatory finding. When the limbs are not bowed, the term “acampomelic campomelic dysplasia” is used.Radiographic findings (Figure 1, Figure 2, Figure 3)FigureFigure 1. Cervical spine changes (i.e., abnormal AP curvature and anterior dislocation of C2 on C3) (arrow) in a boy age 11 months with classic campomelic dysplasia FigureFigure 2. Mutation-proven “acampomelic” campomelic dysplasia A. Tracheostomy tube is in place and the scapulae are markedly hypoplastic (arrows). B. Vertically oriented narrow iliac wings C. Straight femora and (more...)FigureFigure 3. Classic radiographic features of campomelic dysplasia in a 24-week fetus. Note cervical spine abnormalities, hypoplastic thoracic vertebral pedicles, scapular hypoplasia, narrow iliac wings, bowing of the femora and the tibiae, and club feet. (more...)Cervical spine anomalies (variable, often kyphosis) (Figure 1)Scapular hypoplasia (Figure 2A, Figure 3)Hypoplastic thoracic vertebral pedicles (Figure 3)11 pairs of ribsScoliosis or kyphoscoliosisVertically oriented narrow iliac wings (Figure 2B)Bowed femora and/or tibiae (occasionally upper limb) (Figure 3)TestingCytogenetic testing. In approximately 5% of individuals with CD, routine karyotype analysis may identify one of the following:A de novo reciprocal translocation with one breakpoint in chromosome region 17q24.3-q25.1 where SOX9 is locatedA de novo interstitial deletion of 17qNote: In rare cases, the translocation may be familial; thus, parental karyotypes should be analyzed when an abnormality is found in the proband.Molecular Genetic TestingGene. SOX9 is the only gene in which mutations are known to cause CD [Meyer et al 1997, Pfeifer et al 1999, Leipoldt et al 2007].Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Campomelic DysplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySOX9Sequence analysisCoding regions and splice mutations~90%Clinical Deletion/duplication analysis 2Partial- or whole-gene deletions 3, 4~2% 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), array CGH and chromosomal microarray (CMA) that includes this gene/chromosome segment.3. Depending on the method employed by the laboratory, the extent of the deletion can be more or less precisely defined. 4. SOX9 duplication causes XX sex reversal only.5. Partial- and whole-gene SOX9 deletions in individuals with CD and a normal karyotype [Olney et al 1999, Pop et al 2004, Smyk et al 2007]Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at EuroGentest [Scherer et al 2012 (full text)].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandClinical and radiologic features can strongly suggest the diagnosis of CD.Single gene testing. One strategy for molecular diagnosis of a proband suspected of having CD is molecular genetic testing of SOX9. It is appropriate to initiate karyotype and sequence analysis at the time of clinical and radiographic diagnosis, followed by deletion analysis if the first two analyses are negative.Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having CD is use of a multi-gene panel.Prenatal diagnosis. Prenatal diagnosis for pregnancies at risk as a result of a mildly affected parent or potential somatic or germline mosaicism requires prior identification of the disease-causing mutation in a previously affected child or the mildly affected parent.Preimplantation genetic diagnosis (PGD) for pregnancies at risk as a result of a mildly affected parent or potential somatic or germline mosaicism requires prior identification of the disease-causing mutation in a previously affected child or the mildly affected parent.Genetically Related (Allelic) DisordersIsolated Robin sequence. Although it is likely to be rare, chromosomal translocations in the vicinity of SOX9 may cause isolated Pierre Robin sequence without other obvious findings of CD [Jakobsen et al 2007, Benko et al 2009, Gordon et al 2009].
Campomelic dysplasia (CD) is sometimes identified on prenatal ultrasound examination but may escape detection until after birth if the limbs are not bowed....
Natural HistoryCampomelic dysplasia (CD) is sometimes identified on prenatal ultrasound examination but may escape detection until after birth if the limbs are not bowed.Many newborns with CD die shortly after birth secondary to respiratory insufficiency. In comparison with other lethal skeletal dysplasias, the cause of death in CD is not related to thoracic cage hypoplasia but rather airway instability (tracheobronchomalacia) or cervical spine instability. Nonetheless, a number of infants with CD have survived the neonatal period [Mansour et al 2002].The facies in CD resembles the type 2 collagen disorders, such as Stickler syndrome, with marked micrognathia. In the newborn period, the midface is hypoplastic and the eyes are prominent. Relatively large head size (in comparison to total body length) is common. The limbs are short with body length often below the third percentile. Bowing of the limbs is often present but not obligate.Approximately 75% of individuals with CD who have a 46,XY karyotype have either ambiguous external genitalia or normal female external genitalia. The internal genitalia are variable, often with a mixture of müllerian and wolffian duct structures.Given the relatively small number of survivors described in the literature, it is difficult to make generalizations about the natural history. The following have been observed:Intellectual abilities are normal.Height is variably affected. Some newborns have significant short stature whereas others are within the normal range.When present, scoliosis is usually progressive, contributes to the short stature, and may result in neurologic signs and symptoms.Vertebral hypoplasia or malformation, particularly of the cervical spine, may lead to neurologic signs of cord compression unless surgically stabilized.Hearing impairment/loss in some can be significant enough to require hearing aids.A variety of congenital heart defects have been reported in a minority of cases.Histologic pancreatic abnormalities have been described in three newborns who died at term from CD; however, pancreatic dysfunction has not been seen in survivors with CD [Piper et al 2002].Ischio-pubic-patella syndrome (IPP). The phenotypic description of IPP is limited to findings in the pelvis and legs including hypoplastic patellae, hypoplastic lesser trochanters, and defective ischiopubic ossification. In several persons with this diagnosis, mutations of SOX9 or cytogenetic alterations in the vicinity of SOX9 have been reported [Mansour et al 2002]. It is now recognized that individuals with IPP have a mild form of campomelic dysplasia with survival to adulthood.
In the prenatal period, the most common error is to confuse osteogenesis imperfecta (OI) types 2 or 3 with campomelic dysplasia (CD). As OI is more common than CD, it is a more frequent cause of bowed limbs on antenatal ultrasound examination....
Differential DiagnosisIn the prenatal period, the most common error is to confuse osteogenesis imperfecta (OI) types 2 or 3 with campomelic dysplasia (CD). As OI is more common than CD, it is a more frequent cause of bowed limbs on antenatal ultrasound examination.Other genetic disorders of the skeleton with prenatal limb bowing to consider include hypophosphatasia, cartilage hair hypoplasia, and even thanatophoric dysplasia.After birth, the differential diagnosis is mainly spondyloepiphyseal dysplasia congenita (SEDC; COL2A1 mutations) because of the facial features, cleft palate, and short limbs. The milder type 2 collagenopathy, Stickler syndrome, may also be considered in the differential as the facial features are very similar. Radiographs distinguish between these conditions.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with campomelic dysplasia (CD), the following investigations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with campomelic dysplasia (CD), the following investigations are recommended:Karyotype analysis to identify abnormalities involving the SOX9 locus on 17q24.3-q25.1 and especially in phenotypic females to identify those with a 46,XY karyotypeFull skeletal survey including views of the cervical spine to identify cervical vertebral abnormalitiesHearing screeningMedical genetics consultationTreatment of ManifestationsIn children with CD and cleft palate, care by a craniofacial team and surgical closure are recommended.In individuals with a 46,XY karyotype and female genitalia, gonadectomy is recommended because of the increased risk of gonadoblastoma. (No data regarding the appropriate age for this procedure are available.) Most survivors with CD require orthopedic care. Club feet require surgical correction. The hips should be checked for luxation.Cervical fusion surgery is sometimes needed for cervical vertebral instability resulting from vertebral malformations.Surgery is often required in childhood for progressive cervico-thoracic kyphoscoliosis that compromises lung function [Thomas et al 1997]. Bracing is usually not helpful.Prevention of Secondary ComplicationsRisk associated with use of anesthesia prior to imaging or surgery. If a cervical spine abnormality is identified, special care should be exercised for any surgical procedure.SurveillanceMost long-term survivors require annual monitoring of growth and spinal curvature by clinical and radiographic measurements.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Campomelic Dysplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSOX917q24.3Transcription factor SOX-9SOX9 homepage - Mendelian genesSOX9Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Campomelic Dysplasia (View All in OMIM) View in own window 114290CAMPOMELIC DYSPLASIA 608160SRY-BOX 9; SOX9Molecular Genetic PathogenesisMutations within the SOX9 coding region lead to an altered SOX9 protein with impaired activity to function as a transcription factor. In contrast, chromosomal rearrangements (translocations, inversions) with breakpoints as far as approximately 1 Mb upstream of SOX9 as well as SOX9 upstream deletions leave the SOX9 coding region intact but most likely lead to reduced expression of SOX9 by interrupting its extended cis-regulatory domain. In either case, SOX9 function as a developmental regulator is compromised.SOX9 is a proven key regulator at various steps of chondrocyte differentiation , regulating expression of the collagen genes COL2A1 and COL11A2 as well as of CD-RAP and ACAN (also known as AGGRECAN) [Akiyama & Lefebvre 2011].Regulation of COL2A1 by SOX9 may explain some of the phenotypic overlap of campomelic dysplasia (CD) with spondyloepiphyseal dysplasia congenita.SOX9 functions as a testis-determining gene downstream of SRY, inducing the formation of Sertoli cells and production of the anti-müllerian hormone AMH (also known as MIS) [Vidal et al 2001]. Of note, duplication or deletion of a common region ~0.5 Mb upstream of SOX9 causing isolated disorders of sexual development in the absence of any CD symptoms have been reported [Benko et al 2011, Cox et al 2011, Vetro et al 2011].Studies in the mouse provide evidence that the murine ortholog of human SOX9 also plays a role during formation of the pancreas, heart, gut, and inner ear.Thus, the wide spectrum of pathologic symptoms seen in CD including the skeletal defects, XY sex reversal, pancreatic defects (size reduction of islets of Langerhans and reduced insulin secretion), heart defects, and sensorineural and conductive hearing impairment can be attributed directly to impaired ability of the pleiotropic developmental regulator SOX9 to activate target genes during organogenesis.Normal allelic variants. The coding sequence of 5.4-kb SOX9 is distributed over three exons separated by introns of 0.9 kb and 0.6 kb. There are no known normal allelic variants at the amino acid level. At the nucleotide level, one frequent synonymous variant within codon 169 leaves the encoded amino acid histidine unchanged (see Table 2).Table 2. SOX9 Allelic Variants Discussed in This GeneReviewView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference SequencesNormalc.507C>T (879C>T)p.(=) 2(His169His)NM_000346.3 NP_000337.1Pathologicc.1320C>A (1692C>A)p.Tyr440*c.1320C>G (1692C>G)p.Tyr440*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions. For SOX9 these numbers correspond to the first base position of the reference sequence NM_000346.3.2. The designation p.(=) means that protein has not been analyzed but no change is expected.Pathologic allelic variants. Numerous pathogenic nonsense and frameshift mutations of SOX9 are distributed over the entire coding region; there is no mutation hot spot with the exception of the recurrent nonsense mutation p.Tyr440* [Pop et al 2005]. Missense mutations cluster in the HMG domain (a DNA-binding domain) or in the dimerization domain and are occasionally recurrent. A few splice mutations and deletions of part of SOX9 or all of SOX9 and of flanking genes have been described [Olney et al 1999, Pop et al 2004, Smyk et al 2007]. Translocation and inversion breakpoints that interrupt the 1-Mb cis-regulatory domain upstream of SOX9 are all unique but concentrate within a proximal and a distal breakpoint cluster [Leipoldt et al 2007]. Approximately 90% of the pathogenic mutations are found in the SOX9 coding region and approximately 5% are SOX9 deletions, translocations, or inversions upstream of SOX9.Normal gene product. The SOX9 protein consists of 509 amino acids and functions as a transcription factor. Like all SOX proteins, it contains a DNA-binding domain (the HMG domain) encompassing 79 amino acids (residues 103-181) by which it binds to regulatory sites at target genes. The activation of these target genes is mediated by a C-terminal transactivation (TA) domain (residues 402-509) and an adjacent auxiliary TA domain (residues 339-379) [McDowall et al 1999]. A fourth functionally relevant domain is a dimerization domain, located N-terminal to the HMG domain [Bernard et al 2003, Sock et al 2003].Abnormal gene product. Nonsense and most frameshift mutations in SOX9 predict a prematurely truncated protein that misses all or part of the TA domain and, when the mutation is located toward the N terminus, all or part of the HMG domain as well. Resultant mutant proteins missing both domains constitute loss-of-function alleles, whereas mutant proteins retaining the HMG domain may function as dominant-negative alleles. More C-terminally located frameshift mutations are predicted to encode an extended SOX9 protein with a mutant C terminus in place of the TA domain. Missense mutations are exclusively located in the HMG domain, affecting the DNA-binding capacity of SOX9 [Meyer et al 1997, McDowall et al 1999], or in the dimerization domain, causing loss of SOX9 dimer formation [Bernard et al 2003, Sock et al 2003].