252 Craniometaphyseal dysplasia (CMD) is a rare craniotubular bone dysplasia in which sclerosis of the skull is associated with abnormal modeling of the metaphyses of the long bones.
GENETICS/BASIC DEFECTS
1. Genetic heterogeneity
a. Autosomal dominant form [also called CMD, Jackson type (CMDJ)]:
i. CMDJ locus mapped to 5p15.2–p14.1 within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene ii. ANK protein: spans the outer cell membrane and
shuttles inorganic pyrophosphate, a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption
b. Autosomal recessive form i. Rare
ii. Ill-defined
iii. Probably heterogeneous
iv. Often difficult to diagnose with precision v. Autosomal recessive CMD locus mapped to
6q21–22 2. Basic defects
a. Autosomal dominant form: caused by mutations in the human homolog of the mouse progressive ankylo- sis gene (ANKH)
b. Autosomal recessive form
i. May involve dysfunctional osteoclasts because reported metabolic responses of affected chil- dren to therapy with calcitonin and clacitrol ii. Osteoclast-like cells derived from the bone mar-
row shown to lack expression of the osteoclast vacuolar proton pump
CLINICAL FEATURES
1. Autosomal dominant form a. General features
i. Good general health ii. Normal intelligence iii. Normal stature
b. Bony overgrowth of the facial bone resulting in the typical facies:
i. Frontal bossing ii. Hypertelorism
iii. Paranasal bossing (30% of cases in childhood) a) May be present during infancy
b) Tends to regress with age
c) Virtually absent by adolescence and early adulthood
d) May be associated with some degree of nasal obstruction and frequent mouth breathing
iv. Mild to moderate mandibular prognathism v. An open mouth secondary to bony encroachment
of the nasal passages vi. Malalignment of the teeth
vii. Grotesque hyperostosis of the facial bones viii. Decreased facial movement
c. Bony overgrowth of the cranial foramina resulting in the following features:
i. Cranial nerve paralysis ii. Nystagmus
iii. Optic atrophy
iv. Facial palsy (30% of cases) a) Common but variable b) May be unilateral or bilateral c) May occur at any age
d) The involvement often fluctuant in early childhood
e) May be permanent in adulthood v. Deafness (50% of cases)
a) Due to compromised auditory nerve and inner ear by bone overgrowth
b) May be unilateral or bilateral
c) Often “mixed” in type due to chronic otitis media and upper respiratory tract infection secondary to minor anatomical abnormali- ties of the airway and sinuses
d) Usually partial and rarely profound vi. Less commonly reported conditions
a) Compression of the cerebellar tonsils and medulla secondary to a narrowed foramen magnum
b) Obstruction of Eustachian tube c) Obstruction of nasolacrimal duct d) Obstruction of nasal passages
e) Raised intracranial pressure: rare instances of a potentially lethal rise in intracranial pressure due to hyperostosis of the calvarium d. Abnormal modeling of the metaphyses of the long
bones
i. Metaphyseal widening of the long and short tubular bones
ii. Thin cortical layer iii. Coarse trabeculations
e. Clinical and radiographic features improved in later childhood in the dominant form
2. Autosomal recessive form
a. Similar to, but more severe than, those seen in the dominant form
b. An increasing severity with age
c. Progressive overgrowth and craniofacial deformity i. Very severe facial distortion
ii. A thick bony wedge over the bridge of the nose iii. Dystopia canthorum
Craniometaphyseal Dysplasia
CRANIOMETAPHYSEAL DYSPLASIA 253
iv. Ocular hypertelorism
v. Enlarged malar prominences and mandible (marked prognathism)
vi. Wide alveolar ridge
vii. Narrowed nasal passages leading to mouth breathing
viii. Dental abnormalities
d. Abnormal modeling of the metaphyses of the long bones
i. Gradual, club-shaped widening of the metaphyses ii. Thin cortex and undermineralized medullary
bone 3. Differential diagnosis
a. Pyle disease (metaphyseal dysplasia)
i. Frequently confused with craniometaphyseal dys- plasia. In Pyle disease, metaphyseal flaring occurs but there is minimal involvement of the skull ii. Autosomal recessive inheritance
b. Craniodiaphyseal dysplasia
i. Most severe thickening, distortion, and enlarge- ment of the craniofacial region
ii. Characterized by diaphyseal endostosis iii. Does not exhibit metaphyseal flaring
iv. Inheritance likely autosomal recessive c. Frontometaphyseal dysplasia
i. A pronounced bony supra-orbital ridge ii. Hirsutism
iii. Long-bone alterations iv. Conductive deafness
d. Camurati-Engelmann disease (progressive diaphyseal dysplasia)
i. Presence of excess subperiosteal bone in the dia- physes of the long bone
ii. Normal metaphyses
iii. Rare craniofacial involvement
e. Van Buchem disease (hyperostosis corticalis general- isata)
i. Dense and thickened craniofacial skeleton ii. Generalized cortical thickening of the long
bones mainly due to endosteal bone apposition
DIAGNOSTIC INVESTIGATIONS
1. Normal serum calcium, phosphorous and alkaline phos- phatase
2. Radiographic features
a. Autosomal dominant form: age-related radiographic features
i. Characteristic hyperostosis and sclerosis of the skull ii. Paranasal bony bossing, most evident in early
childhood
iii. May be present with prognathism and asymmetry iv. Characteristic nonsclerotic widening of the metaphyses of the tubular bones: a major radi- ographic feature
a) Most obvious at the lower end of the femur b) An “Erlenmeyer flask” configuration in
childhood
c) A “club” shape in adulthood
b. Autosomal recessive form: severe radiographic mani- festations
i. Increasing severity with age
ii. Sclerosis and hyperostosis of the calvarium, the base of the skull, and the facial bones and mandible
iii. Increased bone deposition on the walls of the paranasal sinuses
iv. Underpneumatization of mastoid cells
v. Gradual, club-shaped widening of the metaphyses vi. Thin cortex and undermineralized medullary
bone
3. Gross pathological features
a. Thickened “ivory-hard” facial and cranial bones b. Narrow cranial foramina
c. Narrowing of the nasal chambers and posterior choanae
4. Histological features
a. Compact laminar cortical bone with dilated Haversian canals containing osteoblasts
b. No osteoclasts identified in the periosteal or endosteal layers
c. An increased amount of ground substance and exces- sive formation of subperiosteal and subendosteal bone
5. Molecular genetic analysis for mutations in the human homolog of the mouse progressive ankylosis gene (ANKH)
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal dominant form: 50% risk if one par- ent is affected, otherwise risk not increased ii. Autosomal recessive form: 25%
b. Patient’s offspring
i. Autosomal dominant form: 50%
ii. Autosomal recessive form: not increased unless the spouse is also a carrier in which case there is 50% recurrence risk
2. Prenatal diagnosis: has not been reported 3. Management
a. Medical treatment attempted with the following two hormones
i. Calcitonin: has an inhibitory effect on bone for- mation
ii. Calcitriol
a) Stimulates resorption of bone by promoting osteoclast formation
b) Partial resolution of facial nerve paralysis, increased size of the cranial nerve foramina, and demineralization of the cranial base dur- ing treatment of one patient with high doses of calcitriol
b. Hearing aids for hearing loss
c. Psychological support for facial disfigurement
254 CRANIOMETAPHYSEAL DYSPLASIA
d. Surgical treatment with mixed results
i. Resection of dysplastic bone arduous because it is highly mineralized with a consistency like thick ivory
ii. Craniofacial reduction performed with some dif- ficulty
iii. Optic canal decompression for progressive visual loss
iv. Facial nerve decompression
v. Middle ear exploration and implantation of total ossicular replacement prosthesis for conductive hearing loss
vi. Foramen magnum decompression for cervi- comedullary encroachment
REFERENCES
Beighton P: Craniometaphyseal dysplasia (CMD), autosomal dominant form. J Med Genet 32:370–374, 1995.
Beighton P, Hamersma H, Horan F: Craniometaphyseal dysplasia—variability of expression within a large family. Clin Genet 15:252–258, 1979.
Boltshauser E, Schmitt B, Wichmann W, et al.: Cerebellomedullary compres- sion in recessive craniometaphyseal dysplasia. Neuroradiology 38 Suppl 1:S193–S195, 1996.
Bricker SL, Langlais RP, van Dis ML: Dominant craniometaphyseal dysplasia.
Literature review and case report. Dentomaxillofac Radiol 12:95–100, 1983.
Carnevale A, Grether P, del Castillo V, et al.: Autosomal dominant craniometa- physeal dysplasia. Clinical variability. Clin Genet 23:17–22, 1983.
Chandler D, Tinschert S, Lohan K, et al.: Refinement of the chromosome 5p locus for craniometaphyseal dysplasia. Hum Genet 108:394–397, 2001.
Cheung VG, Boechat MI, Barrett CT: Bilateral choanal narrowing as a presen- tation of craniometaphyseal dysplasia. J Perinatol 17:241–243, 1997.
Cole DE, Cohen MM Jr: a new look at craniometaphyseal dysplasia. J Pediatr 112:577–579, 1988.
Cooper JC: Craniometaphyseal dysplasia: a case report and review of the liter- ature. Br J Oral Surg 12:196–204, 1974.
Day RA, Park TS, Ojemann JG, et al.: Foramen magnum decompression for cervicomedullary encroachment in craniometaphyseal dysplasia: case report. Neurosurgery 41:960–964, 1997.
Fanconi S, Fischer JA, Wieland P, et al.: Craniometaphyseal dysplasia with increased bone turnover and secondary hyperparathyroidism: therapeutic effect of calcitonin. J Pediatr 112:587–591, 1988.
Gorlin RJ, Spranger J, Koszalka MF: Genetic craniotubular bone dysplasias and hyperostoses: a critical analysis. Birth Defects Orig Art Ser V(4):79–95, 1969.
Gorlin RJ, Koszalka MF, Spranger J: Pyle’s disease (familial metaphyseal dysplasia). A presentation of two cases and argument for its separation from craniometaphyseal dysplasia. J Bone Joint Surg Am 52:347–354, 1970.
Iughetti P, Alonso LG, Wilcox W, et al.: Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21–22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia. Am J Med Genet 95:482–491, 2000.
Jackson WPU, Albright F, Drewry G, et al.: Metaphyseal dysplasia, epiphyseal dysplasia, diaphyseal dysplasia, and related conditions. I. Familial meta- physeal dysplasia and craniometaphyseal dysplasia: their relation to leon- tiasis ossea and osteopetrosis: disorders of ‘bone remodeling’. Arch Intern Med 94:871–885, 1954.
Key LL Jr, Volberg F, Baron R, et al.: Treatment of craniometaphyseal dyspla- sia with calcitriol. J Pediatr 112:583–587, 1988.
Kietzer G, Paparella MM: Otolaryngological disorders in craniometaphyseal dysplasia. Laryngoscope 79:921–941, 1969.
Martin FW: Otorhinological aspects of craniometaphyseal dysplasia. Clin Otolaryngol 4:67–76, 1979.
Millard DR Jr, Maisels DO, Batstone JH, et al.: Craniofacial surgery in cran- iometaphyseal dysplasia. Am J Surg 113:615–621, 1967.
Nürnberg P, Thiele H, Chandler D, et al.: Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet 28:37–41, 2001.
Nürnberg P, Tinschert S, Mrug M, et al.: The gene for autosomal dominant craniometaphyseal dysplasia maps to chromosome 5p and is distinct from the growth hormone-receptor gene. Am J Hum Genet 61:918–923, 1997.
Penchaszadeh VB, Gutierrez ER, Figueroa E: Autosomal recessive craniometa- physeal dysplasia. Am J Med Genet 5:43–55, 1980.
Puri P, Chan J: Craniometaphyseal dysplasia: ophthalmic features and manage- ment. J Pediatr Ophthalmol Strabismus 40:228–231, 2003.
Reichenberger E, Tiziani V, Watanabe S, et al.: Autosomal dominant cran- iometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Am J Hum Genet 68:1321–1326, 2001.
Shea J, Gerbe R, Ayani N: Craniometaphyseal dysplasia: the first successful surgical treatment for associated hearing loss. Laryngoscope 91:1369–1374, 1981.
Yamamoto T, Kurihara N, Yamaoka K, et al.: Bone marrow-derived osteoclast- like cells from a patient with craniometaphyseal dysplasia lack expres- sion of osteoclast-reactive vacuolar proton pump. J Clin Invest 91:362–367, 1993.
Fig. 1. A girl with craniometaphyseal dysplasia showing characteris- tic craniofacial features consisting of hypertelorism, broadening nasal base with paranasal bossing, short nose, and prominent facial bones.
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