Table 3. [Genes of Interest in the Differential Diagnosis of Autosomal Dominant Craniometaphyseal Dysplasia]. - GeneReviews®

Gene	Disorder	MOI	Clinical Characteristics	Distinguishing Features
AMER1	Osteopathia striata with cranial sclerosis	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 (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	Progressive overgrowth of craniofacial bones w/deafness, facial palsy, & visual disturbance due to nerve entrapment Choanal stenosis is a clinically significant complication. Radiologically, cranial & facial bones are hyperostotic while diaphyses of limb bones are expanded, w/thin cortices.	Cranial & facial thickening are generally more severe in CDD than in CMD.
Sclerosteosis (See SOST Sclerosing Bone Dysplasias.)	AR	Progressive skeletal overgrowth (most pronounced in skull & mandible) & variable syndactyly Facial distortion due to bossing of forehead & mandibular overgrowth becomes apparent in early childhood w/progression into adulthood. Hyperostosis of skull → narrowing of foramina & entrapment of 7th cranial nerve (→ facial palsy) w/other, less common nerve entrapment syndromes. Hyperostosis of calvarium ↓ intracranial volume, ↑ risk for potentially lethal elevation of intracranial pressure. Survival into old age is unusual but not unprecedented.	Sclerosis in spine & pelvis, 2-3 finger syndactyly, nail dysplasia, no metaphyseal flaring, gigantism
Van Buchem disease (See SOST Sclerosing Bone Dysplasias.)	AR	Progressive skeletal overgrowth Van Buchem disease is generally milder than sclerosteosis; no syndactyly. Life span appears normal.	Osteosclerosis incl 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.

Gene

Disorder

MOI

Clinical Characteristics

Distinguishing Features

AMER1

Osteopathia striata with cranial sclerosis

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 (See Otopalatodigital Spectrum Disorders.)

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)

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)

Cranial sclerosis & high bone mass w/o ↑ fragility

Diffuse osteosclerosis, no metaphyseal flaring

SFRP4

Pyle disease (OMIM 265900)

Metaphyseal dysplasia

Little or no involvement of cranial bones in Pyle disease

SOST

Craniodiaphyseal dysplasia (CDD) (OMIM 218300)

Progressive overgrowth of craniofacial bones w/deafness, facial palsy, & visual disturbance due to nerve entrapment
Choanal stenosis is a clinically significant complication.
Radiologically, cranial & facial bones are hyperostotic while diaphyses of limb bones are expanded, w/thin cortices.

Cranial & facial thickening are generally more severe in CDD than in CMD.

Sclerosteosis (See SOST Sclerosing Bone Dysplasias.)

Progressive skeletal overgrowth (most pronounced in skull & mandible) & variable syndactyly
Facial distortion due to bossing of forehead & mandibular overgrowth becomes apparent in early childhood w/progression into adulthood.
Hyperostosis of skull → narrowing of foramina & entrapment of 7th cranial nerve (→ facial palsy) w/other, less common nerve entrapment syndromes.
Hyperostosis of calvarium ↓ intracranial volume, ↑ risk for potentially lethal elevation of intracranial pressure.
Survival into old age is unusual but not unprecedented.

Sclerosis in spine & pelvis, 2-3 finger syndactyly, nail dysplasia, no metaphyseal flaring, gigantism

Van Buchem disease (See SOST Sclerosing Bone Dysplasias.)

Progressive skeletal overgrowth
Van Buchem disease is generally milder than sclerosteosis; no syndactyly.
Life span appears normal.

Osteosclerosis incl clavicles & ribs; hyperphosphatasemia.

TGFB1

Progressive diaphyseal dysplasia

Hyperostosis of skull results in narrowing of foramina, causing facial palsy & deafness.

Diaphyseal hyperostosis of long bones is pronounced.

From: Craniometaphyseal Dysplasia, Autosomal Dominant

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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