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Craniometaphyseal Dysplasia, Autosomal Dominant

Synonym: Craniometaphyseal Dysplasia, Jackson Type

, PhD and , DDS, MS, PhD.

Author Information
, PhD
Associate Professor, Department of Reconstructive Sciences
Center for Regenerative Medicine and Skeletal Development
UConn Health (UCH)
Farmington, Connecticut
, DDS, MS, PhD
Assistant Professor, Department of Oral Health and Diagnostic Sciences
UConn Health (UCH)
Farmington, Connecticut

Initial Posting: ; Last Update: January 15, 2015.

Summary

Clinical characteristics.

Autosomal dominant craniometaphyseal dysplasia (designated AD-CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, widely spaced eyes with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. 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). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum.

Diagnosis/testing.

Diagnosis is based on clinical and radiographic findings that include diffuse hyperostosis of the cranial base, cranial vault, facial bones, and mandible and metaphyseal widening and radiolucency in the long bones. ANKH is the only gene known to be associated with AD-CMD. Pathogenic variants in other as-yet unknown genes may also be causative.

Management.

Treatment of manifestations: Treatment consists primarily of surgery to reduce compression of cranial nerves and the brain stem/spinal cord at the level of the foramen magnum. Severely overgrown facial bones can be contoured; however, surgical procedures can be technically difficult and bone regrowth is common.

Prevention of secondary complications: Delayed tooth eruption should be considered when planning orthodontic treatment.

Surveillance: Regular neurologic evaluation, hearing assessment, and ophthalmologic examination, at intervals determined by the individual's history and severity of skeletal changes.

Genetic counseling.

AD-CMD is inherited in an autosomal dominant manner. Many individuals with AD-CMD caused by a pathogenic variant in ANKH have an affected parent, but de novo mutations are frequent in simplex cases (i.e., a single occurrence in a family). Each child of an individual with AD-CMD has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk for AD-CMD is possible if the pathogenic variant in the family is known.

Diagnosis

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, widely spaced eyes (ocular hypertelorism) with an increase in bizygomatic width, and prominent mandible (Figure 1).

Figure 1.

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 2.

Figure 2.

Increased thickness of craniofacial bones in three-year-old with AD-CMD

Other findings variably present:

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 3.

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. Pathogenic variants 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) [Nürnberg et al 2001, Reichenberger et al 2001].

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Autosomal Dominant Craniometaphyseal Dysplasia (AD-CMD)

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
ANKHSequence analysis 2~90% 3
Deletion/duplication analysis 4Not reported
Unknown 5NA
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Proportion of affected individuals meeting diagnostic criteria for AD-CMD in whom a pathogenic variant in ANKH is usually found [Nürnberg et al 2001, Reichenberger et al 2001]

4.

Testing that identifies exonic or whole-gene deletions/duplications not 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), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

Some simplex cases of CMD did not have identifiable pathogenic variants in ANKH, suggesting possible locus heterogeneity.

Testing Strategy

To confirm/establish the diagnosis in a proband

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

One genetic testing strategy is molecular genetic testing of ANKH. Sequence analysis of ANKH may be used to confirm the diagnosis.

An alternative genetic testing strategy is use of a multi-gene panel that includes ANKH and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If serial single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of AD-CMD, genomic testing may be considered. Such testing may include whole exome sequencing (WES), whole genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Notes regarding WMitoSeq. (1) Pathogenic mtDNA variants present at low levels of heteroplasmy in blood may not be detected in DNA extracted from blood and may require DNA extracted from skeletal muscle; (2) mtDNA deletions/duplications may not be detected effectively.

Clinical Characteristics

Clinical Description

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 (midface retrusion) 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.

Differential Diagnosis

Autosomal recessive craniometaphyseal dysplasia (AR-CMD) (OMIM 218400) A homozygous pathogenic variant (c.716G>A, p.Arg239Gln) in GJA1, which codes for connexin 43 (CX43), has been identified in seven individuals from four families with the autosomal recessive form of CMD [Hu et al 2013]. A severe form of CMD has been reported in the literature with presumed autosomal recessive inheritance; however, molecular genetic testing in these reported cases, including exome sequencing in some cases, has not definitively identified an etiology.

Pyle disease (OMIM 265900) 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 (OMIM 605946) is inherited in an autosomal dominant manner. The gene(s) in which mutation is causative are unknown [Braun et al 2001].

Craniodiaphyseal dysplasia (CDD) (OMIM 218300). 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 cylindric in shape. CDD may be associated with intellectual disability. Pathogenic variants for an autosomal dominant form of CDD have been identified in SOST [Kim et al 2011].

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 mutation of FLNA. Inheritance is X-linked.

Osteopathia striata with cranial sclerosis (OSCS) (OMIM 300373). 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 pathogenic variants in AMER1 [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 retrusion are usually apparent by mid-childhood. Hyperostosis of the skull results in narrowing of the foramina, causing 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. Pathogenic variants 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 (OMIM 607634), characterized by cranial sclerosis and high bone mass without increased fragility, may be caused by pathogenic variants in LRP5.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Medical genetics consultation

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.

Prevention of Secondary Complications

Delayed tooth eruption should be considered when planning orthodontic treatment [Chen et al 2014].

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.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Early diagnosis of at-risk relatives may be beneficial for management of complications from progressive hyperostosis.

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, clinical evaluation and cranial and long bone radiographs can be used to clarify the disease status of at-risk relatives.

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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 de novo mutation. The proportion of cases caused by de novo mutation is very low. Statistical data are not available.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include sequence analysis of ANKH.
  • The family history of some individuals diagnosed with autosomal dominant craniometaphyseal dysplasia may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant 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 ANKH pathogenic variant.

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

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 ANKH pathogenic variant, the diagnosis of AD-CMD is established.

Considerations in families with apparent de novo mutation. When neither parent of a proband with autosomal dominant CMD has the pathogenic variant or clinical evidence of the disorder, the ANKH mutation is likely de novo. 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.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the ANKH pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like AD-CMD) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu

Molecular Genetics

Information 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 Databases

GeneChromosome LocusProteinLocus SpecificHGMD
ANKH5p15​.2Progressive ankylosis protein homologANKH @ LOVDANKH

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)

123000CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT; CMDD
605145ANK, MOUSE, HOMOLOG OF; ANKH

Gene structure. ANKH has 12 exons and an mRNA transcript encompassing 8.2 kb (NM_054027.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. At least 12 pathogenic variants in exons 7, 8, 9, and 10 affecting seven amino acids are known [Nürnberg et al 2001, Reichenberger et al 2001, Kornak et al 2010, Zajac et al 2010, Dutra et al 2012]. Most common pathogenic variants result in one-amino acid deletions. Other pathogenic variants are one-amino acid insertions, single nucleotide variants, and deletions of several amino acids. Most pathogenic variants occur in nucleotide region encoding presumed intracellular domains of the transmembrane loop structure.

Normal gene product. ANKH encodes a 492-amino acid protein (NP_473368.1), 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 with 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, Chen et al 2011].

References

Literature Cited

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Chapter Notes

Revision History

  • 15 January 2015 (me) Comprehensive update posted live
  • 2 November 2010 (me) Comprehensive update posted live
  • 27 August 2007 (me) Review posted to live Web site
  • 25 May 2007 (er) Original submission
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