Clinical Diagnosis

Diagnosis 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 Manifestations

Facial features include wide nasal bridge, paranasal bossing, wide-set eyes (ocular hypertelorism) with an increase in bizygomatic width, and prominent mandible (Figure 1).

Figure

Figure 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 Manifestations

Cranial 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]

Figure

Figure 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).

Figure

Figure 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.

Testing

Blood 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 Testing

Gene. 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 testing

• Sequence 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)

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
ANKH	Sequence analysis	Sequence variants 2	~90% 3	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 Strategy

To confirm/establish the diagnosis in a proband

• Clinical examination and cranial and long bone radiographs (distal third of the femur) to identify characteristic findings

• Molecular genetic testing of ANKH to confirm the diagnosis

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Calcium 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].

Natural History

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].

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.

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been reported.

The phenotypic severity (expressivity) in AD-CMD is variable even among affected members of the same family.

Penetrance

Penetrance is close to 100% in both genders. Males and females are equally affected.

Prevalence

CMD is very rare. No epidemiology has been established.

Evaluations Following Initial Diagnosis

To 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 Manifestations

Treatment 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.

Surveillance

Because 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.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Treatment 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.

Other

Calcitonin 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].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Autosomal dominant craniometaphyseal dysplasia (AD- CMD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant CMD have an affected parent.

• A proband with autosomal dominant CMD may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is very low. Statistical data are not available.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The risk to the sibs of the proband depends on the probability of germline mosaicism in a parent of the proband and the spontaneous mutation rate of ANKH. Although no instances of germline mosaicism have been reported, it remains a possibility.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include mutation analysis of the ANKH gene. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with autosomal dominant CMD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with autosomal dominant CMD has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Mode of inheritance in simplex cases (i.e., a single occurrence in a family) cannot be determined by phenotype alone. If molecular genetic testing identifies a heterozygous disease-causing ANKH mutation, the diagnosis of AD-CMD is established.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Revision History

• 2 November 2010 (me) Comprehensive update posted live

• 27 August 2007 (me) Review posted to live Web site

• 25 May 2007 (er) Original submission