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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.—ED.
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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Craniometaphyseal dysplasia (designated CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, wide-set 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 CMD life expectancy is normal; however, in those with severe 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 CMD. Mutations in other as-yet unknown genes may also be causative. Sequence analysis of ANKH detects mutations in about 90% of individuals with CMD.
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. Surveillance: regular neurologic evaluation, hearing assessment, and ophthalmologic examination, at intervals determined by the individual's history and severity of skeletal changes.
Genetic counseling. CMD is usually inherited in an autosomal dominant manner. Rarely, autosomal recessive inheritance is suspected. Most individuals with autosomal dominant CMD have an affected parent. Each child of an individual with autosomal dominant CMD has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk for CMD may be available through laboratories offering custom prenatal testing if the disease-causing mutation(s) in the family is known.
Diagnosis of craniometaphyseal dysplasia (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.
Facial features include wide nasal bridge, paranasal bossing, wide-set eyes (ocular hypertelorism) with an increase in bizygomatic width, and prominent mandible.
Long skull shape (dolichocephaly) resulting from fronto-occipital hyperostosis has been reported in a number of individuals.
Cranial radiographs. Typical findings:
Beginning sclerosis of the cranial base at early stages, sometimes detected in infants [Taylor & Sprague 1989]
Increasing diffuse hyperostosis of the cranial base, cranial vault, facial bones, and mandible as the condition progresses
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.
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 is present in infancy but disappears with age. Bone density of diaphyses is normal in children and adults; cortical thickness can be increased.
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.
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.—ED.
Gene. Mutations have been found in the human ankylosis gene (ANKH) for the autosomal dominant form and some isolated cases of CMD [Nurnberg et al 2001, Reichenberger et al 2001].
Other loci. Some simplex cases (i.e., a single occurrence in a family) of CMD did not have identifiable mutations in ANKH, suggesting possible locus heterogeneity.
A potential locus for the recessive form of CMD is chromosome 6q21-q22 [Iughetti et al 2000]. Localization is based on one family only.
Clinical testing. For clinical confirmation of mutations identified in research laboratories, see
.
Research testing
Sequence analysis detects mutations in about 90% of individuals meeting diagnostic criteria for CMD [Nurnberg et al 2001, Reichenberger et al 2001]
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|
| Sequence analysis | Mutations in exons 9 and 10 | ~90% | Research only 2 |
1. Proportion of affected individuals with a mutation(s) as classified by test method [Nurnberg et al 2001, Reichenberger et al 2001]
2. No laboratories offering clinical molecular genetic testing for this disease are listed in the GeneTests Laboratory Directory. However, clinical confirmation of mutations identified in research laboratories may be available for families in which a disease-causing mutation has been identified in a research laboratory. For laboratories offering such testing, see
.
To 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 to confirm mutations identified in a research laboratory (see
)
Calcium pyrophosphate dihydrate deposition disease (CPPDD, chondrocalcinosis). Mutations in ANKH identified in CPPDD include an insertion mutation 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].
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].
Craniometaphyseal dysplasia (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 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. The autosomal dominant form of CMD has typically a less severe prognosis than the autosomal recessive form. Expressivity in simplex cases (i.e., single occurrence in a family) of CMD is highly variable.
Individuals with typical uncomplicated autosomal dominant 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.
The phenotypic severity (expressivity) in autosomal dominant CMD is variable even among affected members of the same family.
Penetrance is close to 100% in both genders. Males and females are equally affected.
Anticipation is not observed.
CMD is very rare. No epidemiology has been established.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Metaphyseal dysplasia
Pyle disease is an autosomal recessive form of metaphyseal dysplasia with little or no involvement of the cranial bones. The causative gene(s) is unknown.
Braun-Tinschert type of metaphyseal dysplasia is inherited in an autosomal dominant manner. The cusative gene(s) is 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 mental retardation. The mode of inheritance is thought to be autosomal recessive; the causative gene(s) is 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. 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. The causative gene(s) is unknown.
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, 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. 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 craniometaphyseal dysplasia (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 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.
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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
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.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
In the majority of instances, craniometaphyseal dysplasia (CMD) results from heterozygosity for mutations in the ANKH gene and is inherited in an autosomal dominant manner. A rare and more severe autosomal recessive form is suspected by segregation pattern (unaffected parents have more than one child with CMD).
This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.
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 upon 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 upon the status of the proband's parents. If a parent is found to be affected, his or her family members may be at risk.
This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with autosomal recessive CMD are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing using molecular genetic techniques is not offered because it is not clinically available.
Mode of inheritance in simplex cases (i.e., a single occurrence in a family) cannot be determined by phenotype alone.
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 (i.e., with assisted reproduction) or undisclosed adoption could also be explored.
Family planning. The optimal time for determination of genetic risk 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. 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. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.
No laboratories offering molecular genetic testing for prenatal diagnosis for CMD are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering custom prenatal testing, see
.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
|---|---|---|---|
| ANKH | 5p15.2-p14.1 | Progressive ankylosis protein homolog | ANKH |
| Unknown | 6q21-q22 | Unknown |
| 123000 | CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT; CMDD |
| 218400 | CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL RECESSIVE; CMDR |
| 605145 | ANK, MOUSE, HOMOLOG OF; ANKH |
Normal allelic variants: The ANKH gene has 12 exons and an mRNA transcript encompassing 8.2 kb.
Pathologic allelic variants: At least seven mutations in exons 9 and 10 affecting seven amino acids are known [Nurnberg et al 2001, Reichenberger et al 2001]. Most common mutations are one-amino acid deletions. One-amino acid insertions and point mutations are also found. Most mutations occur in presumed intracellular domains of the transmembrane loop structure.
Normal gene product: The ANKH gene encodes a 492-amino acid protein, the progressive ankylosis protein homolog, which is a multispan 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].
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. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
27 August 2007 (me) Review posted to live Web site
25 May 2007 (er) Original submission
