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Craniometaphyseal dysplasia, autosomal dominant(CMDD)

MedGen UID:
338945
Concept ID:
C1852502
Disease or Syndrome
Synonyms: CMDD; Craniometaphyseal dysplasia Jackson type
 
Gene (location): ANKH (5p15.2)
 
Monarch Initiative: MONDO:0007397
OMIM®: 123000

Disease 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. [from GeneReviews]
Authors:
Ernst Reichenberger  |  I-Ping Chen   view full author information

Additional descriptions

From OMIM
Craniometaphyseal dysplasia is an osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, which may finally result in hearing loss and facial palsy (summary by Nurnberg et al., 1997). The delineation of separate autosomal dominant and autosomal recessive (CMDR; 218400) forms of CMD by Gorlin et al. (1969) was confirmed by reports that made it evident that the dominant form is relatively mild and comparatively common, while the recessive form is rare, severe, and possibly heterogeneous.  http://www.omim.org/entry/123000
From MedlinePlus Genetics
Craniometaphyseal dysplasia is a rare condition characterized by thickening (overgrowth) of bones in the skull (cranium) and abnormalities in a region at the end of long bones known as the metaphysis. The abnormal bone growth continues throughout life. Except in the most severe cases, the lifespan of people with craniometaphyseal dysplasia is normal.

Bone overgrowth in the head causes many of the signs and symptoms of craniometaphyseal dysplasia. Affected individuals typically have distinctive facial features such as a wide nasal bridge, a prominent forehead, wide-set eyes (hypertelorism), and a prominent jaw. Excess bone formation in the jaw can delay teething (dentition) or result in absent (non-erupting) teeth. Infants with craniometaphyseal dysplasia may have breathing or feeding problems caused by narrow nasal passages. In severe cases, abnormal bone growth can pinch (compress) the nerves that extend from the brain to various areas of the head and neck (cranial nerves). Compression of the cranial nerves can lead to paralyzed facial muscles (facial nerve palsy), blindness, or deafness.

There are two types of craniometaphyseal dysplasia, which are distinguished by their pattern of inheritance and genetic cause. They are known as the autosomal dominant and autosomal recessive types.

The x-rays of individuals with craniometaphyseal dysplasia show unusually shaped long bones, particularly long bones in the legs. The ends of these bones are wider and appear less dense than usual in people with this condition.  https://medlineplus.gov/genetics/condition/craniometaphyseal-dysplasia

Clinical features

From HPO
Erlenmeyer flask deformity of the femurs
MedGen UID:
383796
Concept ID:
C1855895
Finding
Flaring of distal femur.
Club-shaped distal femur
MedGen UID:
346601
Concept ID:
C1857505
Finding
An abnormal conformation of the femur that becomes gradually enlarged towards the distal end. This feature affects the distal femoral metaphysis and epiphysis.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Tinnitus
MedGen UID:
52760
Concept ID:
C0040264
Disease or Syndrome
Tinnitus is an auditory perception that can be described as the experience of sound, in the ear or in the head, in the absence of external acoustic stimulation.
Mixed hearing impairment
MedGen UID:
102336
Concept ID:
C0155552
Disease or Syndrome
A type of hearing loss resulting from a combination of conductive hearing impairment and sensorineural hearing impairment.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Narrow internal auditory canal
MedGen UID:
868969
Concept ID:
C4023383
Finding
Reduction in diameter of the internal auditory canal.
Incus ankylosis
MedGen UID:
1054522
Concept ID:
CN378419
Finding
Incus ankylosis refers to congenital or acquired fixation of the incus, which is associated with conductive hearing resulting from impairment of the sound-conduction mechanism (the external auditory canal, tympanic membrane, and/or middle-ear ossicles).
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Prominence of the zygomatic bone
MedGen UID:
507285
Concept ID:
C0375511
Anatomical Abnormality
Large or prominent malar surface of the zygomatic bone of the skull, which is convex and forms the prominence of the 'cheek bones'.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Intervertebral disk calcification
MedGen UID:
451050
Concept ID:
C0410607
Disease or Syndrome
The presence of abnormal calcium deposition of the intervertebral disk.
Cranial hyperostosis
MedGen UID:
318629
Concept ID:
C1832451
Finding
Excessive growth of the bones of cranium, i.e., of the skull.
Thin bony cortex
MedGen UID:
318844
Concept ID:
C1833325
Finding
Abnormal thinning of the cortical region of bones.
Metaphyseal widening
MedGen UID:
341364
Concept ID:
C1849039
Finding
Abnormal widening of the metaphyseal regions of long bones.
Flared metaphysis
MedGen UID:
337976
Concept ID:
C1850135
Finding
The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.
Sclerosis of skull base
MedGen UID:
377095
Concept ID:
C1851714
Finding
Increased bone density of the skull base without significant changes in bony contour.
Calvarial osteosclerosis
MedGen UID:
340927
Concept ID:
C1855657
Finding
An increase in bone density affecting the calvaria (roof of the skull).
Thickened calvaria
MedGen UID:
346823
Concept ID:
C1858452
Finding
The presence of an abnormally thick calvaria.
Small foramen magnum
MedGen UID:
348813
Concept ID:
C1861217
Finding
An abnormal narrowing of the foramen magnum.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Abnormal pelvic girdle bone morphology
MedGen UID:
866545
Concept ID:
C4020847
Anatomical Abnormality
An abnormality of the bony pelvic girdle, which is a ring of bones connecting the vertebral column to the femurs.
Delayed pneumatization of the mastoid process
MedGen UID:
867257
Concept ID:
C4021617
Finding
An abnormally reduced degree of pneumatization (i.e., formation of air cells) in the mastoid process with respect to age-dependent norms.
Abnormality of the vertebral column
MedGen UID:
892426
Concept ID:
C4021789
Anatomical Abnormality
Any abnormality of the vertebral column.
Polyarticular chondrocalcinosis
MedGen UID:
870801
Concept ID:
C4025258
Disease or Syndrome
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Disease or Syndrome
An abnormally decreased phosphate concentration in the blood.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.
Nasal congestion
MedGen UID:
6523
Concept ID:
C0027424
Sign or Symptom
Reduced ability to pass air through the nasal cavity often leading to mouth breathing.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
Epiblepharon
MedGen UID:
488856
Concept ID:
C0344503
Congenital Abnormality
Redundant eyelid skin pressing the eyelashes against the cornea and/or conjunctiva.
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Choanal stenosis
MedGen UID:
108427
Concept ID:
C0584837
Finding
Abnormal narrowing of the choana (the posterior nasal aperture).
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Delayed eruption of primary teeth
MedGen UID:
341477
Concept ID:
C1849538
Finding
Delayed tooth eruption affecting the primary dentition.
Delayed eruption of permanent teeth
MedGen UID:
340353
Concept ID:
C1849540
Finding
Delayed tooth eruption affecting the secondary dentition.
Tooth malposition
MedGen UID:
377692
Concept ID:
C1852504
Finding
Abnormal alignment, positioning, or spacing of the teeth, i.e., misaligned teeth.
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Bony paranasal bossing
MedGen UID:
341786
Concept ID:
C1857499
Finding
Alveolar ridge overgrowth
MedGen UID:
400802
Concept ID:
C1865598
Finding
Increased width of the alveolar ridges.
Secondary hyperparathyroidism
MedGen UID:
9368
Concept ID:
C0020503
Disease or Syndrome
Secondary hyperparathyroidism refers to the production of higher than normal levels of parathyroid hormone in the presence of hypocalcemia.
Increased circulating osteocalcin level
MedGen UID:
1621520
Concept ID:
C4531126
Finding
An elevated level of osteocalcin in the blood.
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Visual fixation instability
MedGen UID:
1372887
Concept ID:
C4476760
Finding
A deficit in the ability to fixate eye movements in order to stabilize images on the retina

Recent clinical studies

Etiology

Prontera P, Rogaia D, Sobacchi C, Tavares VL, Mazzotta G, Passos-Bueno MR, Donti E
Am J Med Genet A 2011 May;155A(5):1106-8. Epub 2011 Apr 4 doi: 10.1002/ajmg.a.33826. PMID: 21465646

Diagnosis

Ou W, Chen Y, Ju Y, Ma M, Qin Y, Bi Y, Liao M, Liu B, Liu J, Zhang Y, Li L
J Affect Disord 2023 Oct 15;339:624-632. Epub 2023 Jul 17 doi: 10.1016/j.jad.2023.07.078. PMID: 37467793

Therapy

Ou W, Chen Y, Ju Y, Ma M, Qin Y, Bi Y, Liao M, Liu B, Liu J, Zhang Y, Li L
J Affect Disord 2023 Oct 15;339:624-632. Epub 2023 Jul 17 doi: 10.1016/j.jad.2023.07.078. PMID: 37467793

Recent systematic reviews

Ou W, Chen Y, Ju Y, Ma M, Qin Y, Bi Y, Liao M, Liu B, Liu J, Zhang Y, Li L
J Affect Disord 2023 Oct 15;339:624-632. Epub 2023 Jul 17 doi: 10.1016/j.jad.2023.07.078. PMID: 37467793

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