Craniometaphyseal Dysplasia, Autosomal Dominant

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 as well as widening and radiolucency of metaphyses in long bones. Identification of a heterozygous pathogenic variant in ANKH by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Treatment for feeding and respiratory issues per craniofacial team; surgical intervention 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. Hearing aids; vision aids and surgical treatment for optic nerve impaction; speech therapy; surgical intervention for malocclusion.

Surveillance: Evaluation for feeding and respiratory issues at least annually. Neurologic evaluation for signs and symptoms of narrowing of the cranial foramina including the foramen magnum at least annually. Hearing and ophthalmologic assessment at least annually.

Genetic counseling.

By definition, AD-CMD is inherited in an autosomal dominant manner. Most individuals diagnosed with AD-CMD have an affected parent; the proportion of individuals with AD-CMD caused by a de novo pathogenic variant is thought to be very low. Each child of an individual with AD-CMD has a 50% chance of inheriting the pathogenic variant. Once the AD-CMD-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

AD-CMD should be suspected in individuals with the following clinical, radiographic, and laboratory features.

Clinical features

• Obstruction of the nasal sinuses
• Characteristic facial features. Wide nasal bridge, paranasal bossing, hypertelorism with an increase in bizygomatic width, and prominent mandible (see Figure 1)
• Dolichocephaly due to fronto-occipital hyperostosis

Figure 1.

Facial features of a girl age 13 years with AD-CMD Reprinted from Reichenberger et al [2001] with permission from Elsevier

Radiographic features

• Cranial base. Sclerosis may begin in infancy (see Figure 2). Increasing diffuse hyperostosis of the cranial base leads to narrowing of the foramen magnum.
• Skull. Diffuse hyperostosis of cranial vault, facial bones, and mandible increases as the condition progresses [Lamazza et al 2009] with obstruction of the cranial foramina.
• Long bones. Metaphyseal widening (described as Erlenmeyer flask- or club-shaped) with thinned cortex and decreased bony density in the metaphyses can be detected early in life. Metaphyseal changes typically develop during early childhood. The flaring is most prominent in the distal femur and tibia (see Figure 3). 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.
• Ribs and clavicles (medial portion [i.e., endochondral]) can be sclerotic in younger children but show normal bone density by age five years [Richards et al 1996].

Figure 2.

Increased thickness of craniofacial bones in a child age three years with AD-CMD

Figure 3.

Metaphyseal widening of long bones, specifically prominent at the knee joint

Laboratory features

• Blood calcium and phosphate concentrations are within normal limits [Cheung et al 1997] or decreased [Sheppard et al 2003].
• Serum alkaline phosphatase activity can be elevated [Sheppard et al 2003, Wu et al 2016].
• Parathyroid hormone level is normal or can be slightly/transiently elevated [Fanconi et al 1988, Cheung et al 1997, Sheppard et al 2003, Wu et al 2016].
• 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.

Establishing the Diagnosis

The diagnosis of AD-CMD is established in a proband with characteristic craniofacial hyperostosis and flaring and undertrabeculation of long bone metaphyses and/or a heterozygous pathogenic variant in ANKH identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous ANKH variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of AD-CMD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with hyperostosis are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by hyperostosis, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is most likely to establish the diagnosis. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of this disorder.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Craniometaphyseal Dysplasia

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, Taggart et al 2014].

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 [Tanaka et al 2013].

Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone [Chen et al 2014].

Malocclusion and anterior cross-bite can be caused by jaw overgrowth [Hayashibara et al 2000].

Life expectancy. Individuals with typical uncomplicated AD-CMD have normal life expectancy. Expressivity in simplex cases (i.e., single occurrence in a family) of CMD is highly variable.

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 100%. Males and females are equally affected.

Nomenclature

AD-CMD was previously referred to as "craniometaphyseal dysplasia-Jackson type."

Prevalence

CMD is very rare. No epidemiology has been established.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal dominant craniometaphyseal dysplasia (AD-CMD), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Craniometaphyseal Dysplasia

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with Autosomal Dominant Craniometaphyseal Dysplasia

Surveillance

Table 6.

Recommended Surveillance for Individuals with Autosomal Dominant Craniometaphyseal Dysplasia

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.

Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• Clinical evaluation and cranial and long bone radiographs if the pathogenic variant in the family is not known.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

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].

Calcitriol with a low-calcium diet to stimulate bone resorption by promoting osteoclast formation had been reported to improve facial paralysis but has no effect on metaphyseal deformity [Key et al 1988, Wu et al 2016].

Acetazolamide has been suggested for treatment of disorders with increased bone mineral density. González-Rodríguez et al [2016] reported acetazolamide use in an individual with a phenotype similar to CMD, but diagnosis of AD-CMD was not confirmed.

Mode of Inheritance

By definition, 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 AD-CMD have an affected parent.
• Some individuals diagnosed with AD-CMD have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with AD-CMD caused by a de novo pathogenic variant is thought to be very low; however statistical data are not available.

• If the proband appears to be the only affected family member (i.e., a simplex case) and has a known ANKH pathogenic variant, molecular genetic testing is recommended for the parents of a proband.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.* Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals diagnosed with AD-CMD may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because penetrance of AD-CMD is 100%, sibs who inherit a pathogenic variant will develop the phenotype although the severity of the phenotype may vary.
• If the proband has a known ANKH pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low but still increased over that of the general population because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with AD-CMD has a 50% chance of inheriting the causative pathogenic variant.

Other family members. 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the AD-CMD-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ANKH encodes the progressive ankylosis protein homolog, a multispan transmembrane protein located at the outer cell membrane that transports 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.

Progressive ankylosis protein homolog expressing a craniometaphyseal dysplasia-associated variant most likely has a reduced ability to transport intracellular pyrophosphate from osteoblasts to the bone matrix [Ho et al 2000].

Mechanism of disease causation. Most common pathogenic variants result in one-amino acid deletions, while others are missense or small in-frame deletions and insertions [Nürnberg et al 2001, Reichenberger et al 2001, Kornak et al 2010, Zajac et al 2010, Dutra et al 2012]. Most pathogenic variants occur in the nucleotide region encoding presumed intracellular domains of the transmembrane loop structure. Based on findings in knockout and knock-in mice studies, ANKH pathogenic variants are thought to result in a dominant negative gain of function as well as loss of function of pyrophosphate transport. The shared phenotype between these murine models is explained by the rapid degradation of pathogenic ANK protein [Kanaujiya et al 2018]. To date, no other information on mechanism is available.

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Revision History

• 11 June 2020 (sw) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 2 November 2010 (me) Comprehensive update posted live
• 27 August 2007 (me) Review posted live
• 25 May 2007 (er) Original submission