Craniometaphyseal Dysplasia

What is Craniometaphyseal Dysplasia?

This rare disease is a genetic condition that leads to the overgrowth of the bones in the head, arms and legs.

When this overgrowth causes the bones to push against each other, or together, many of the symptoms of this syndrome are triggered.

Syndrome Synonyms:
Cmd; Craniometaphyseal Dysplasia, Jackson Type; Cmdj

What gene changes cause Craniometaphyseal Dysplasia?

Mutations to the ANKH, GJA1 genes are responsible for causing the syndrome.

The syndrome may be inherited in an autosomal dominant and recessive pattern respectfully. This form of the condition leads to more severe symptoms, including those that may be life threatening.

When inherited in an autosomal dominant pattern the symptoms of the syndrome tend to be much less severe.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

What are the main symptoms of Craniometaphyseal Dysplasia?

The overgrowth of bones in the head, arms and legs causes many symptoms including widely spaced eyes, a wide nasal bridge, eyes that stick out further than the average, a long head. Many individuals have different shaped bones in the legs and arms. A hardening of the bones is also a symptom.

These abnormalities in the development and growth of the bones can make eating and breathing difficult, especially in infants

Possible clinical traits/features:
Autosomal dominant inheritance, Macrocephaly, Sclerosis of skull base, Abnormality of the vertebral column, Abnormality of pelvic girdle bone morphology, Abnormality of the nasopharynx, Bony paranasal bossing, Calvarial osteosclerosis, Misalignment of teeth, Mixed hearing impairment, Metaphyseal widening, Mandibular prognathia, Nasal obstruction, Hypertelorism, Short stature, Facial palsy, Erlenmeyer flask deformity of the femurs, Club-shaped distal femur

How does someone get tested for Craniometaphyseal Dysplasia?

The initial diagnosis of Craniometaphyseal Dysplasia can begin with facial genetic analysis screening, as offered by FDNA Telehealth, which can identify the key markers of the syndrome and outline the need for further testing. If further testing is recommended what will follow is a consultation with a genetic counselor and then a geneticist. These consultations will usually involve a comprehensive review of the patient’s medical history, a generational family history documenting health issues and genetic conditions, and a detailed physical examination. Based on this clinical consultation, the options and recommendations for genetic testing will be shared with the individual’s parents/guardians and consent will be sought for further testing. This process may take place over the course of several clinic visits. Genetic testing will involve a blood sample. Results from the testing will then be sent back to the geneticist who will explain the resulting report in detail with the parents/guardians of the individual being tested.

Medical information on Craniometaphyseal Dysplasia

Autosomal dominant inheritance, Macrocephaly, Sclerosis of skull base, Abnormality of the vertebral column, Abnormality of pelvic girdle bone morphology, Abnormality of the nasopharynx, Bony paranasal bossing, Calvarial osteosclerosis, Misalignment of teeth, Mixed hearing impairment, Metaphyseal widening, Mandibular prognathia, Nasal obstruction, Hypertelorism, Short stature, Facial palsy, Erlenmeyer flask deformity of the femurs, Club-shaped distal femur

"This craniotubular bone dysplasia is characterised by sclerosis of the skull, which includes the vault and the base, combined with abnormal metaphyseal modelling of the long bones. The initial symptoms are often progressive nasal obstruction and mouth breathing in childhood. In familial cases, the facial distortion might be the earliest complaint. Clinically there is broadening of the nasal base with paranasal bossing, telecanthus and a prominence of the facial bones, especially the jaw. Bilateral facial weakness and progressive deafness might be other childhood signs. Patients with optic nerve compression have also been reported (Puri and Chan, 2003). Intelligence is usually normal. Richards et al., (1996) reported surgical management of the craniofacial abnormalities. Most families have shown autosomal dominant inheritance although autosomal recessive inheritance has been occasionally observed, (Penchaszadeh et al., 1980; Tinschert and Braun 1998). The main differential diagnosis is craniodiaphyseal dysplasia. Elcioglu and Hall (1998) provide a follow up of an autosomal recessive case. Feingold (1999) provide a 28 year follow up of a case.
Nurnberg et al., (1997) mapped the gene to 5p14.1-p15.2 in a dominant family. Nurnberg et al., (2001) and Reichenberger et al., (2001) demonstrated mutations in the ANKH gene, This is homologous to the gene responsible for progressive ankylosis (ank) in the mouse. This gene codes for a protein spanning the outer cell membrane and shuttles inorganic pyrophosphate, a major inhibitor of physiologic and pathologic calcification, bone mineralisation, and bone absorption. The mutations were gain of function.
Iughetti et al., (2000) reported an inbred Brazilian family with an autosomal recessive form of the disorder and mapped the gene to 6q21-22. The patient reported by Frontera et al., (2011) whose Moroccan parents were first cousins also showed homozygosity at 6q21-q22. The phenotype was severe and included optic atrophy and mental retardation
Sheppard et al., (2003) provide a good review of medical and surgical management. Their case had hypocalcemia and secondary hyperparathyroidism, which returned to normal after calcium supplementation. The alkaline phosphatase remained markedly elevated.
Note that the ANKH gene is also responsible for chondrocalcinosis (see elsewhere) and a family with both was reported by Baynam et al., (2009). The recessive form linked to 6q21 is caused by mutations in GJA1 (Hu et al., 2013).
Singh et. al. (2016) reviewed the differential diagnoses of cranial sclerosis and appendicular involvement in children. They also reported a male with ANKH mutation with a history of diminishing vision and hearing loss. Cranial CT scan showed diffuse calvarial and skull base hyperostosis and narrowing internal auditory canals. X-rays showed metaphyseal widening, cortical thinning of all long bones (mostly distal femur that resembled an Erlenmeyer flask), cranial vault sclerosis, prominent mandible, widening of the metacarpal and phalangeal shafts, and diffuse broadening of the ribs and clavicles.
A review of oral manifestations was published by Martin et. al. (2017). The authors described a case with hypercementosis in a family with Craniometaphyseal Dysplasia. Clinical characteristics included pain and recurrent swelling associated with the upper left posterior teeth.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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