Craniometaphyseal Dysplasia, Autosomal Dominant
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 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.
Diagnosis
Formal diagnostic criteria for autosomal dominant craniometaphyseal dysplasia (AD-CMD) have not been established.
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 1
When the phenotypic and laboratory findings suggest the diagnosis of AD-CMD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of ANKH is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. Note: To date such variants have not been identified as a cause of this disorder.
- A multigene panel that includes ANKH and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
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
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ANKH | Sequence analysis 3 | ~90% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 6 | |
| Unknown 7 | NA | ~10% |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Nürnberg et al [2001], Reichenberger et al [2001]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Since AD-CMD occurs through a gain-of-function/dominant negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
- 7.
Some simplex cases of CMD did not have identifiable pathogenic variants in ANKH, suggesting possible locus heterogeneity.
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, 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.
Differential Diagnosis
Table 3.
Genes of Interest in the Differential Diagnosis of Autosomal Dominant Craniometaphyseal Dysplasia
| Gene | Disorder | MOI | Clinical Characteristics | Distinguishing Features |
|---|---|---|---|---|
| AMER1 | Osteopathia striata with cranial sclerosis (OSCS) (OMIM 300373) | XL | Longitudinal striations of sclerotic long bones in combination w/osteosclerosis of cranial & facial bones | Short stature, delayed closure of anterior fontanelle, micrognathia, linear striations in long bones of females |
| FLNA | Frontometaphyseal dysplasia type 1 (FMD1) (see Otopalatodigital Spectrum Disorders) | XL | Skeletal findings are frontal bone hyperostosis & metaphyseal dysplasia (similar to those seen in Pyle disease). | Urogenital defects, contractures in hands, elbows, knees, & ankles |
| GJA1 | Autosomal recessive craniometaphyseal dysplasia (AR-CMD) (OMIM 218400) | AR | Hyperostosis of cranial base & cranial vault w/metaphyseal flaring similar to AD-CMD | Skeletal phenotype may be less severe than in typical AD-CMD. |
| LRP5 | Autosomal dominant osteopetrosis type 1 (OMIM 607634) | AD | Cranial sclerosis & high bone mass w/o ↑ fragility | Diffuse osteosclerosis, no metaphyseal flaring |
| SFRP4 | Pyle disease (OMIM 265900) | AR | Metaphyseal dysplasia | Little or no involvement of cranial bones in Pyle disease |
| SOST | Craniodiaphyseal dysplasia (CDD) (OMIM 218300) | AD |
| Cranial & facial thickening are generally more severe in CDD than in CMD. |
| Sclerosteosis (see SOST Sclerosing Bone Dysplasias) | AR |
| Sclerosis in spine & pelvis, 2-3 finger syndactyly, nail dysplasia, no metaphyseal flaring, gigantism | |
| Van Buchem disease (see SOST Sclerosing Bone Dysplasias) | AR |
| Osteosclerosis includes clavicles & ribs; hyperphosphatasemia. | |
| TGFB1 | Progressive diaphyseal dysplasia | AD | Hyperostosis of skull results in narrowing of foramina, causing facial palsy & deafness. | Diaphyseal hyperostosis of long bones is pronounced. |
AD = autosomal dominant; AD-CMD = autosomal dominant craniometaphyseal dysplasia; AR = autosomal recessive; CMD = craniometaphyseal dysplasia; MOI = mode of inheritance; XL = X-linked
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].
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 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
| System/Concern | Evaluation | Comment |
|---|---|---|
| Respiratory & feeding problems in infancy | Referral for craniofacial team eval incl otolaryngologic eval | Incl eval for choanal stenosis |
| Skeletal hyperostosis |
| |
| Cranial nerve compression | Neurologic exam | |
| Otolaryngologic eval | To evaluate auditory system | |
| Audiologic assessment | To evaluate for hearing loss | |
| Ophthalmologic exam | To evaluate for vision loss | |
| Endocrine / Bone metabolism |
| To evaluate bone turnover |
| Speech | Eval by speech therapist | In early childhood; progressive hearing loss, facial palsy & hyperostosis can lead to speech issues. |
| Delayed eruption & malocclusion | Eval by dentist | From the time of primary tooth eruption to identify tooth impaction or delay in tooth eruption |
| Genetic counseling | By genetics professionals 1 | To inform individuals & families re nature, MOI, & implications of AD-CMD to facilitate medical & personal decision making |
AD-CMD = autosomal dominant craniometaphyseal dysplasia; CTX = carboxy-terminal collagen crosslinks; MOI = mode of inheritance; P1NP = procollagen type 1 N-terminal propeptide
- 1.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations
Table 5.
Treatment of Manifestations in Individuals with Autosomal Dominant Craniometaphyseal Dysplasia
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Feeding & respiratory issues in newborns & infants | Per craniofacial team | |
| Cranial nerve compression | Surgical intervention | To relieve severe symptoms caused by cranial nerve compression |
| Narrowed foramen magnum | Surgical intervention | To relieve headaches & risks assoc w/Chiari malformation |
| Hyperostosis of facial bones | Severe bony overgrowth of facial bones & nasal, forehead, & cranial regions can be contoured. |
|
| Hearing loss | Hearing aids | Cochlear implant may be possible. |
| Vison loss |
| In anticipation of progressive vision loss, children may learn Braille. |
| Speech issues | Consider speech therapy. | |
| Malocclusion | Surgical intervention for severe malocclusion | Delayed tooth eruption should be considered when planning orthodontic treatment [Chen et al 2014]. |
Surveillance
Table 6.
Recommended Surveillance for Individuals with Autosomal Dominant Craniometaphyseal Dysplasia
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Feeding & respiratory issues in newborns & infants | Craniofacial team | Annually, or more frequently if needed |
| Narrowing cranial foramina, incl foramen magnum | Neurologic eval | |
| Hearing loss | Hearing assessment | |
| Vision loss | Ophthalmologic exam |
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.