Craniometaphyseal dysplasia is an osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve ... Craniometaphyseal dysplasia is an osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial palsy (summary by Nurnberg et al., 1997). The delineation of separate autosomal dominant and autosomal recessive (CMDR; 218400) forms of CMD by Gorlin et al. (1969) was confirmed by reports that made it evident that the dominant form is relatively mild and comparatively common, while the recessive form is rare, severe, and possibly heterogeneous.
Beighton (1995) pointed out that Peter Jackson, an English physician on the staff of Groote Schuur Hospital, University of Cape Town, collaborated with Fuller Albright at the Massachusetts General Hospital, Boston, in the disorders of osseous modeling (Jackson ... Beighton (1995) pointed out that Peter Jackson, an English physician on the staff of Groote Schuur Hospital, University of Cape Town, collaborated with Fuller Albright at the Massachusetts General Hospital, Boston, in the disorders of osseous modeling (Jackson et al., 1954) and identified a specific syndrome that comprised dysplasia of the metaphyses, sclerosis of the base of the skull, and overgrowth of the craniofacial bones. They culled 5 previously reported cases and added 2 of their own, and they termed the condition craniometaphyseal dysplasia. Podlaha and Kratochvil (1963) and Lejeune et al. (1966) observed that craniometaphyseal dysplasia differs from Pyle disease (metaphyseal dysplasia; 265900) in the presence of conspicuous involvement of the craniofacial bones. Widening of the bridge of the nose develops and eventually leonine facies. Pressure on cranial nerves is responsible for a considerable part of the disability (facial palsy and mixed hearing loss). The cases in the family reported by Rimoin et al. (1969) and those reported by Spranger et al. (1965) should be considered dominant craniometaphyseal dysplasia, reserving the term Pyle disease for the recessive disorder which is more nearly a 'pure' metaphyseal dysplasia with little or no craniofacial involvement. Spranger (1970) reviewed the skull x-ray of Pyle's original case and failed to find the intense increase in bone density characteristic of craniometaphyseal dysplasia. Furthermore the metaphyseal flare is notably abrupt in Pyle disease, producing the 'Erlenmeyer flask' deformity, and is milder ('club-like') in craniometaphyseal dysplasia. The same family was reported by Rimoin et al. (1969) and by Gladney and Monteleone (1970). Stool and Caruso (1973) observed affected father and 15-month-old daughter. Both had peripheral facial palsy and the father was profoundly deaf. Taylor and Sprague (1989) described an Australian kindred with 9 affected persons in 4 generations. Kornak et al. (2010) reported 3 unrelated patients with craniometaphyseal dysplasia and no family history of the disorder. All had typical features of the disorder, with macrocephaly, hypertelorism, skull hyperostosis, paranasal bossing, teeth crowding, and metaphyseal flaring. The first patient, who was the most severely affected, was a French boy who developed hearing loss and bilateral facial palsy soon after birth. He had severe sclerosis of the skull base, orbits, maxilla, and mandible, with almost complete obstruction of the sinuses. There was rapid worsening of the bone phenotype in the first years of life. The second patient was a 24-year-old man from the Netherlands who presented with progressive conductive and sensorineural hearing loss and was found to have typical features of the disorder, with unilateral facial palsy apparent in infancy, macrocephaly, and teeth crowding. The third patient was a 43-year-old Italian man with typical manifestations of CMD, including sclerosis of the skull base and maxilla, hyperostotic but not sclerotic mandible, and partially obstructed sinuses, but without cranial nerve compression. He also had narrowing of the middle ear cavities with bilateral fixation of the body of the incus to the lateral attic, resulting in conductive deafness and tinnitus. These middle ear manifestations were similar to those observed in postinflammatory ossicular fixation secondary to acute or chronic otitis media.
Nurnberg et al. (2001) tested ANKH (605145) as a positional candidate in 9 unrelated families and demonstrated 6 different mutations in 8 of the families (e.g., 605145.0001-605145.0003). In 5 different families and in isolated cases, Reichenberger et al. ... Nurnberg et al. (2001) tested ANKH (605145) as a positional candidate in 9 unrelated families and demonstrated 6 different mutations in 8 of the families (e.g., 605145.0001-605145.0003). In 5 different families and in isolated cases, Reichenberger et al. (2001) described mutations in the ANKH gene. In 3 unrelated patients with craniometaphyseal dysplasia and no family history of the disorder, Kornak et al. (2010) identified 3 different heterozygous mutations in the ANKH gene (605145.0011-605145.0013). In a large 4-generation Australian family with craniometaphyseal dysplasia, originally described by Taylor and Sprague (1989) and in which Nurnberg et al. (2001) identified a heterozygous missense mutation in the ANKH gene (G389R; 605145.0002), Baynam et al. (2009) found evidence for chondrocalcinosis segregating with CMDD in affected female family members. Although a chance association of chondrocalcinosis with CMDD could not be excluded, Baynam et al. (2009) suggested that the lack of joint symptoms in affected male family members might be due to involvement of sex-dependent mechanisms or to the fact that only mutation-positive women in the pedigree had reached the age at which the chondrocalcinosis phenotype typically expresses.
Diagnosis of autosomal dominant craniometaphyseal dysplasia (AD-CMD) is based on clinical and radiographic findings [Jackson et al 1954, Gorlin et al 2001]. ...
DiagnosisClinical DiagnosisDiagnosis of autosomal dominant craniometaphyseal dysplasia (AD-CMD) is based on clinical and radiographic findings [Jackson et al 1954, Gorlin et al 2001]. Obstruction of the nasal sinuses, sclerosis of the cranial base, and flaring of long bone metaphyses may be observed within the first weeks of life. Clinical ManifestationsFacial features include wide nasal bridge, paranasal bossing, wide-set eyes (ocular hypertelorism) with an increase in bizygomatic width, and prominent mandible (Figure 1). FigureFigure 1. Facial features of a 13-year-old girl with AD-CMD Reprinted from Reichenberger et al [2001], with permission from Elsevier Long skull shape (dolichocephaly) resulting from fronto-occipital hyperostosis has been reported in a number of individuals. Radiographic ManifestationsCranial radiographs. Typical findings: Beginning sclerosis of the cranial base at early stages, sometimes detected in infants [Taylor & Sprague 1989] (Figure 2)Increasing diffuse hyperostosis of the cranial base, cranial vault, facial bones, and mandible as the condition progresses [Lamazza et al 2009]FigureFigure 2. Increased thickness of craniofacial bones in three-year-old with AD-CMD Other findings variably present: Obstruction of cranial foramina Narrowing of the foramen magnum [Millard et al 1967, Puliafito et al 1981, Day et al 1997] Long bone radiographs. The long bone phenotype, consisting of metaphyseal widening (described as Erlenmeyer flask- or club-shaped) with thinned cortex and decreased bony density (radiolucency) in the metaphyses, can be detected early in life. Metaphyseal changes typically develop during early childhood. The flaring is most prominently seen in the distal femur and tibia (Figure 3).FigureFigure 3. Metaphyseal widening of long bones, specifically prominent at the knee joint Ribs and the medial (endochondral) portion of the clavicles can be sclerotic in younger children but show normal bone density by age five years [Richards et al 1996]. Diaphyseal sclerosis/hyperostosis can be present in infancy but disappears with age. Bone density of the diaphyses is normal in children and adults; cortical thickness can be increased. TestingBlood calcium and phosphate concentrations are within normal limits [Cheung et al 1997] or decreased [Fanconi et al 1988, Sheppard et al 2003].Serum alkaline phosphatase activity can be elevated [Fanconi et al 1988, Cheung et al 1997, Sheppard et al 2003]. Parathyroid hormone level is normal or can be slightly/transiently elevated [Fanconi et al 1988, Cheung et al 1997, Sheppard et al 2003]. Osteocalcin is decreased [Yamamoto et al 1993].Note: Findings are based on very limited data. Variability of the described parameters can be expected. Abnormal parameters may be transient. Molecular Genetic TestingGene. Mutations have been found in the human ankylosis gene (ANKH) for autosomal dominant CMD and some simplex cases (i.e., a single occurrence in a family) [Nurnberg et al 2001, Reichenberger et al 2001]. Other loci. Some simplex cases of CMD did not have identifiable mutations in ANKH, suggesting possible locus heterogeneity. Clinical testingSequence analysis detects mutations in about 90% of individuals meeting diagnostic criteria for AD-CMD [Nurnberg et al 2001, Reichenberger et al 2001].Table 1. Summary of Molecular Genetic Testing Used in Autosomal Dominant Craniometaphyseal Dysplasia (AD-CMD)View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityANKHSequence analysisSequence variants 2~90% 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Proportion of affected individuals in whom a mutation in ANKH is usually found [Nurnberg et al 2001, Reichenberger et al 2001] Interpretation of test results. For issues to consider in interpretation of sequence analysis results. click here.Testing StrategyTo confirm/establish the diagnosis in a probandClinical examination and cranial and long bone radiographs (distal third of the femur) to identify characteristic findings Molecular genetic testing of ANKH to confirm the diagnosisPrenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersCalcium pyrophosphate dihydrate deposition disease (CPPDD, chondrocalcinosis). Mutations in ANKH identified in CPPDD include an insertion of four amino acids (which creates a new translation start site) or one amino acid substitution caused by missense mutations in the N-terminal portion of ANKH [Pendleton et al 2002, Williams et al 2003]. One family with an ANKH mutation was described with cosegregating AD-CMD and chondrocalcinosis [Baynam et al 2009].Other. Polymorphisms in ANKH have been associated with ankylosing spondylitis [Tsui et al 2003, Tsui et al 2005] and bone size [Malkin et al 2006].
Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is often detected within the first few weeks of life because of breathing or feeding problems resulting from choanal stenosis (narrowing of nasal sinus) [Haverkamp et al 1996, Cheung et al 1997]. ...
Natural HistoryAutosomal dominant craniometaphyseal dysplasia (AD-CMD) is often detected within the first few weeks of life because of breathing or feeding problems resulting from choanal stenosis (narrowing of nasal sinus) [Haverkamp et al 1996, Cheung et al 1997]. Early stages of AD-CMD can be radiographically recognized as sclerosis of the cranial base. Hyperostosis of the cranial base, cranial vault, facial bones, and mandible occurs gradually. Overgrowth of the lower jaw (mandibular hyperostosis) and recessed midface are often seen [Hayashibara et al 2000]. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss) as cranial hyperostosis and sclerosis progress [Beighton et al 1979, Richards et al 1996]. Nasal obstruction and mandibular hyperostosis affect speech modulation. Associated Chiari I malformation can lead to severe headaches [Day et al 1997].Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone.Malocclusion and anterior cross-bite can be caused by jaw overgrowth [Hayashibara et al 2000]. Life expectancy. Autosomal dominant CMD has typically a less severe prognosis than the autosomal recessive form (see Differential Diagnosis). Expressivity in simplex cases (i.e., single occurrence in a family) of CMD is highly variable. Individuals with typical uncomplicated AD-CMD have normal life expectancy. Individuals with severe forms of CMD (mostly attributed to autosomal recessive inheritance) can have reduced life expectancy as a result of compression of the foramen magnum.
No genotype-phenotype correlation has been reported. ...
Genotype-Phenotype CorrelationsNo genotype-phenotype correlation has been reported. The phenotypic severity (expressivity) in AD-CMD is variable even among affected members of the same family.
Autosomal recessive craniometaphyseal dysplasia (AR-CMD). A potential locus for the autosomal recessive form of CMD is at chromosome 6q21-q22 [Iughetti et al 2000]. This localization is based on one family only. Individuals with severe forms of CMD (mostly attributed to autosomal recessive inheritance) can have reduced life expectancy as a result of compression of the foramen magnum. ...
Differential DiagnosisAutosomal recessive craniometaphyseal dysplasia (AR-CMD). A potential locus for the autosomal recessive form of CMD is at chromosome 6q21-q22 [Iughetti et al 2000]. This localization is based on one family only. Individuals with severe forms of CMD (mostly attributed to autosomal recessive inheritance) can have reduced life expectancy as a result of compression of the foramen magnum. Pyle disease is an autosomal recessive form of metaphyseal dysplasia with little or no involvement of the cranial bones. The gene(s) in which mutation is causative are unknown. Braun-Tinschert type of metaphyseal dysplasia is inherited in an autosomal dominant manner. The gene(s) in which mutation is causative are unknown [Braun et al 2001]. Craniodiaphyseal dysplasia (CDD). Cranial and facial thickening are generally more severe than in CMD. Diaphyses of long bones are generally expanded; flaring of the metaphyses is mild or not observed. The long bones are cylindrical in shape. CDD may be associated with intellectual disability. The mode of inheritance is thought to be autosomal recessive; the gene(s) in which mutation is causative are unknown. Frontometaphyseal dysplasia (FMD). Skeletal findings are frontal bone hyperostosis and metaphyseal dysplasia similar to those seen in Pyle disease (metaphyseal dysplasia). FMD is one of the otopalatodigital spectrum disorders, caused by mutations in FLNA. Inheritance is X-linked. Osteopathia striata with cranial sclerosis (OSCS). Longitudinal striations of sclerotic long bones in combination with osteosclerosis of cranial and facial bones are characteristic. Inheritance is X-linked dominant, with likely genetic heterogeneity. OSCS is caused by mutations in WTX [Jenkins et al 2009]. SOST-related sclerosing bone dysplasias (including sclerosteosis and van Buchem disease) are allelic disorders that share progressive skeletal overgrowth. Distinctive facial features including asymmetric mandibular hypertrophy, frontal bossing, and midface hypoplasia are usually apparent by mid-childhood. Hyperostosis of the skull results in narrowing of the foramina causes entrapment of the seventh cranial nerve often leading to facial palsy and entrapment of the eighth cranial nerve often resulting in deafness in mid-childhood. In sclerosteosis, hyperostosis of the calvarium reduces intracranial volume, increasing the risk for potentially lethal elevation of intracranial pressure in adulthood. Survival of individuals with sclerosteosis into old age is unusual. The manifestations of van Buchem disease are generally milder than sclerosteosis and syndactyly is absent. Mutations in SOST, the gene encoding sclerostin, the bone morphogenetic protein (BMP) antagonist, are causative. Inheritance of both disorders is autosomal recessive. Autosomal dominant osteopetrosis type 1, characterized by cranial sclerosis and high bone mass without increased fragility, may be caused by mutations in LRP5.
To establish the extent of disease in an individual diagnosed with autosomal dominant craniometaphyseal dysplasia (AD- CMD), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with autosomal dominant craniometaphyseal dysplasia (AD- CMD), the following evaluations are recommended:Radiologic assessment Audiologic assessment Ophthalmologic examination Neurologic examination Otolaryngologic evaluation Endocrinologic tests to assess bone metabolism Dental evaluation Craniofacial teams, often associated with pediatric hospitals, may offer a full evaluation of a patient including psychological assessment and speech therapy.Treatment of ManifestationsTreatment consists primarily of surgical intervention. Compression of a nerve canal or narrowed foramen magnum can be surgically treated. Severe bony overgrowth of facial bones and nasal, forehead, and cranial regions can be contoured. However, surgical procedures can be technically difficult and bone regrowth is common. As severe complications have occurred, surgery is considered for conservative purposes to relieve severe symptoms caused by cranial nerve compression.SurveillanceBecause progressive thickening of craniofacial bones continues throughout life, regular neurologic evaluation, hearing assessment, and ophthalmologic examination are required for early diagnosis and management of complications of narrowing of the cranial foramina, including the foramen magnum. The frequency of neurologic evaluations depends on the individual's history of skeletal changes. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationTreatment with calcitriol, a stimulator of bone resorption, has not demonstrated long-term success. Calcitriol with a low-calcium diet to stimulate bone resorption by promoting osteoclast formation has been reported to improve facial paralysis but has no effect on metaphyseal deformity [Key et al 1988].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherCalcitonin has been thought to be effective because of its inhibitory effect on bone turnover. However, previous case reports found calcitonin therapy to be ineffective in treating hyperplasia of craniofacial bones in persons with CMD [Fanconi et al 1988, Haverkamp et al 1996].
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. Craniometaphyseal Dysplasia, Autosomal Dominant: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDANKH5p15.2Progressive ankylosis protein homologANKH @ LOVDANKHData 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 Craniometaphyseal Dysplasia, Autosomal Dominant (View All in OMIM) View in own window 123000CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT; CMDD 605145ANK, MOUSE, HOMOLOG OF; ANKHNormal allelic variants. ANKH has 12 exons and an mRNA transcript encompassing 8.2 kb. Pathologic allelic variants. At least 12 mutations in exons 7, 8, 9, and 10 affecting seven amino acids are known [Nurnberg et al 2001, Reichenberger et al 2001, Kornak et al 2010, Zajac et al 2010]. Most common mutations are one-amino acid deletions. Other mutations are one-amino acid insertions, point mutations, and deletions of several amino acids. Most mutations occur in presumed intracellular domains of the transmembrane loop structure. Normal gene product. ANKH encodes a 492-amino acid protein, the progressive ankylosis protein homolog, which is a multi-span transmembrane protein located at the outer cell membrane. Its primary known function is the transport of intracellular pyrophosphate into the extracellular matrix. Pyrophosphate is a regulator of matrix (bone) mineralization. The protein sequence of the progressive ankylosis protein homolog is highly conserved among vertebrate animals. Abnormal gene product. Progressive ankylosis protein homolog carrying an ANKH mutation known to cause craniometaphyseal dysplasia most likely has a reduced ability to transport intracellular pyrophosphate from osteoblasts to the bone matrix [Ho et al 2000]. An animal model for CMD has been generated to study the function of mutant ANKH. The model suggests that the function of osteoblasts and osteoclasts are affected [Chen et al 2009].