Craniometaphyseal dysplasia is an extremely rare genetic disorder characterized by distinctive abnormalities of the head and facial (craniofacial) area, impairment of certain nerves (cranial nerves) that emerge from the brain, and malformations of the long bones of the arms and legs. In infants and children with craniometaphyseal dysplasia, there may be overgrowth and/or abnormal hardening of certain bones of the skull (cranial hyperostosis and/or sclerosis) and overgrowth (hypertrophy) of craniofacial bones, resulting in widely-spaced eyes (ocular hypetelorism), an abnormally wide nasal bridge, an enlarged lower jaw (mandible), and a "leonine" facial appearance (leontiasis ossea). Compression of certain nerves emerging from the brain (cranial nerves) may result in loss of some motor function (paralysis) in the facial area (cranial nerve palsy) and hearing loss (conductive and/or sensorineural hearing impairment). In addition, in individuals with the disorder, the long bones of the arms and legs may develop abnormally, resulting in unusual "club-like" flaring or broadening of the end portions (metaphyses) of the bones (metaphyseal dysplasia). In some cases, craniometaphyseal dysplasia may be inherited as an autosomal dominant genetic trait; in other cases, the disorder may have an autosomal recessive mode of inheritance.
Craniometaphyseal dysplasia is a genetic disorder that is usually evident at birth. This disorder is characterized by the abnormal growth (hyperostosis) or hardening of the bones of the forehead and back of the head. The facial bones may show thickening, especially at the bridge area of the nose and lower jaw bone (mandible). The nasal passages may be abnormally narrow, and affected individuals may experience inflammation of the mucous membranes (rhinitis). The eyes are widely spaced and bulging (proptosis). If cranial pressure is not relieved there may be facial paralysis, deafness and loss of vision due to compression of the brain and cranial nerves. The limbs may be affected by a hardening (sclerosis) or broadening of the shaft of the long bones close to the growth center (metaphyseal splaying). Intelligence is usually normal.
Craniometaphyseal dysplasia may be inherited either as an autosomal dominant trait, in which case the mutant gene has been tracked to the short arm of chromosome 5 (5p15.2-p14.1), or it may be inherited as an autosomal recessive trait, in which case the mutant gene has been tracked to the long arm of chromosome 6 (6q21-q22). The recessive form is the more rare of the two, and tends to have a more severe impact on those affected. People with the dominant form have milder symptoms.
The gene on chromosome 5 controls the production of a protein involved in the transport of pyrophosphate into the bone matrix. The concentration of pyrophosphate in the bone matrix is key to regulating the mineralization of the bone. The gene located at chromosome 6q21-q22 deals with an entirely different process in the development of bone.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 5p15.2-p14.1” refers to a region between bands 15.2 and 14.1 on the short arm of chromosome 5. In a like manner the term “chromosome 6q21-q22” refers to a region between bands 21 and 22 on the long arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Craniometaphyseal dysplasia is a very rare disorder that affects males and females in equal numbers. Little is known about the incidence or prevalence of this disorder.
Early surgical treatment of Craniometaphyseal Dysplasia to relieve cranial pressure and correct the facial deformities may help eliminate the sight and hearing complications associated with this disorder. Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Reichenberger E, Mulliken JB. Craniometaphyseal Dysplasia. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:184.
Gorlin RJ, Cohen MMJr, Levin LS. eds. Syndromes of the Head and Neck. 3rd ed. Oxford University Press, London, UK; 1990:229.
Jones KL., ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:395.
Puri P, Chan J. Craniometaphyseal dysplasia: ophthalmic features and management. J Pediatr Ophthalmol Strabismus. 2003;40:228-31.
Sheppard WM, Shprintzen RJ, Tatum SA, et al. Craniometaphyseal dysplasia: a case report and review of medical and surgical management. Int J Pediatr Otorhinolaryngol. 2003;67:687-93.
Reichenberger E, Tiziani V, Watanabe S, et al. Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane transport protein ANK. Am J Hum Genet. 2001;68:1321-26.
Iughetti P, Alonso LG, Wilcox W, et al. Mapping of the autosomal recessive (AR) craniometa-physeal dysplasia locus to chromosome region ^q21-22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia. Am J Med Genet. 2000;95:482-91.
Feingold M. 28-year follow-up of the craniofacial findings in a patient with craniometaphyseal dysplasia. Am J Med Genet. 1999;86:501-02.
Tinschert S, Braun HS. Craniometaphyseal dysplasia in six generations of a German kindred. Am J Med Genet. 1998;77:175-81.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Craniometaphyseal Dysplasia, Autosomal Dominant; CMDD. Entry Number; 123000: Last Edit Date; 7/2/2001.
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Craniometaphyseal Dysplasia, Autosomal Recessive; CMDR. Entry Number; 218400: Last Edit Date; 3/18/2004.
Skeletal Dysplasias. Orthoteers. Updated on: 27 January 2001. 5pp.
The Osteopetroses (Marble Bones). The Merck Manual. 2004.
Craniometaphyseal dysplasia. Encyclopedia of Medical Imaging III:1. Amersham Health. nd. 1p.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100