bone fragility

Spondyloocular Syndrome

Clinical Characteristics
Ocular Features: 

Cataracts have been noted in several patients in the first and second decades of life.  Nystagmus and ‘amblyopia’ have also been reported.  Several individuals have had retinal detachments.

Systemic Features: 

Only a small number of families have been reported.  Poor bone mineralization with frequent fractures in long bones and vertebral compression seem to be consistent features often noted in the first and second decades of life.  Moderate osteoporosis and advanced bone age with platyspondyly may be present.  The vertebral fractures lead to abnormal spinal curvature and may result in shortened stature. 

Some sensorineural hearing loss is sometimes detected in the first decade.  The ears have been described as low-set and posteriorly rotated.  A variety of cardiac defects have been reported including mitral valve prolapse, septal defects, and anomalies of the aortic valve. 

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in the XYLT2 gene located at 17q21.33. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pamidronate given intravenously seems to have little therapeutic value.  Hearing aids can be beneficial.  Lensectomy may be of benefit although no reports of cataract surgery have been reported.  Fractures need immediate attention.  Patient may become wheelchair-bound by the second decade.  Special education may be helpful for those with learning difficulties.

References
Article Title: 

Cole-Carpenter Syndrome 1

Clinical Characteristics
Ocular Features: 

The bony orbits are shallow and the eyes appear prominent as part of the facial and skull bone deformities.  The proptosis may be progressive and eventually interfere with blinking and normal surface wetting of the cornea. 

Systemic Features: 

This condition may superficially resemble osteogenesis imperfecta with osseous deformities and frequent fractures.  However, the occurrence of craniosynostosis and hydrocephalus helps to distinguish it.  Cranial sutures may be slow to fuse and macrocephaly has been described.  Communicating hydrocephalus can be a feature and may require shunting.  Some patients have osteopenia of the long bones that fracture easily.

The facial features are said to be distinctive with midface hypoplasia, low-set ears, micrognathia, and, of course, prominent globes.  Growth may be subnormal and a variety of limb bone and digital anomalies have been described.  Intelligence is normal, however.

Genetics

This condition is the result of heterozygous mutations in the P4HB gene (17q25.3) (PDI family).

See Cole-Carpenter Syndrome 2 (616294) for a somewhat similar disorder that is recessively inherited.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A frontal craniectomy may be necessary during early childhood to relieve the proptosis particularly when blinking is impaired.  Patients must be followed for the development of communicating hydrocephalus.  Long bone fractures require prompt treatment. 

References
Article Title: 

Osteogenesis Imperfecta, Type VII

Clinical Characteristics
Ocular Features: 

Shallow orbits sometimes lead to severe and even progressive proptosis.  Bluish sclerae are sometimes present.

Systemic Features: 

Infants may be born with multiple fractures and adults are often short in stature.  Hypoplasia of the midface, frontal bossing, sutural craniosynostosis, hydrocephalus, and shallow orbits are frequently present and contribute to what is sometimes considered a distinctive facial dysmorphism.  Dentinogenesis imperfecta and hearing loss are variable features.  Neurological development is normal.

Multiple fractures occur and may result in marked long bone deformities, scoliosis, and short stature.  When the ribs are involved, respiratory insufficiency may result and can be responsible for early death.  Type VII osteogenesis imperfecta is sometimes considered a lethal form of OI. 

Genetics

Homozygous mutations in the CRTAP gene (3p22.3) are responsible for this condition.  This gene codes for a cartilage-associated protein and in mice is highly expressed in chondrocytes at growth plates and around the chondroosseous junction.  

This condition has been confused with Cole-Carpenter 1 syndrome (112240) but the latter is due to heterozygous mutations in P4HB (17q25.3) (PDI gene family).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Fractures require stabilization and hydrocephalus, if present, needs to be treated promptly.  Extreme proptosis can lead to inadequate hydration of the eye (especially the cornea) that may require lid surgery or orbital reconstruction.

References
Article Title: 

CRTAP mutation in a patient with Cole-Carpenter syndrome

Balasubramanian M, Pollitt RC, Chandler KE, Mughal MZ, Parker MJ, Dalton A, Arundel P, Offiah AC, Bishop NJ. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A. 2015 Jan 21. doi: 10.1002/ajmg.a.36916. [Epub ahead of print].

PubMed ID: 
25604815

New case of Cole-Carpenter syndrome

Amor DJ, Savarirayan R, Schneider AS, Bankier A. New case of Cole-Carpenter syndrome. Am J Med Genet. 2000 Jun 5;92(4):273-7. Review.

PubMed ID: 
10842295

Osteogenesis Imperfecta

Clinical Characteristics
Ocular Features: 

Blue sclerae, especially at infancy, is the most visible ocular sign in osteogenesis imperfecta but it is not always present.  It is also often present in normal infants.  In some patients, it is present early but disappears later in life. Some patients have significantly lower ocular rigidity, corneal diameters, and decreased globe length.  Interestingly, the intensity of the blue color in the sclerae does not seem to be correlated with scleral rigidity.

Systemic Features: 

A defect in type I collagen leading to brittle bones and frequent fractures is the systemic hallmark of this group of disorders.  Clinical and genetic heterogeneity is evident. The nosology is as yet not fully established and will likely require more molecular information.  Type I is considered the mildest of the several forms that have been reported.  Relatively minor trauma during childhood and adolescence can lead to fractures while adults have less risk.  Fractures generally heal rapidly without deformities  and with good callous formation in patients with milder disease.  However, those with more serious disease often end up with deformities and bowed bones.

Short stature, hearing loss, easy bruising, and dentinogenesis imperfecta are often seen as well.

Type II is more severe and fractures often occur in utero.  Fractures may involve long bones, skull bones and vertebrae.  At birth the rib case appears abnormally small and the underdeveloped pulmonary system may lead to severe respiratory problems and even death in some newborns.

Genetics

A number of conditions are associated with fragile bones and the classification of these in the early literature is confusing.  More confusion arises from classification schemes based solely on clinical degrees of severity.   

The designation ‘osteogenesis imperfecta’ is most accurately applied to disorders caused by construction defects in type I collagen fibers which are responsible in 90% of affected individuals.  The defect may occur in either the pro-alpha 1 or pro-alpha 2 chains which together form type I collagen.  The responsible genes are COL1A1 (17q21.31) and COL1A2 (7q22.1).  Clinical types I (166200), IIA (166210), III (259420), and IV (166220) map to these two loci.  The inheritance pattern is autosomal dominant.

Mutations in the CRTAP gene (610854; 3p22) cause an autosomal recessive OI-like phenotype classified as type VII while type VIII is an autosomal recessive OI-like disorder secondary to mutations in LEPRE1 (610915; 1p34).  However, these disorders, while clinically sharing some features of true OI, are better designated as separate conditions based on their unique molecular etiologies.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Avoidance of trauma is paramount.   Periodic intravenous administration of pamidronate can increase bone density and reduce the risk of fractures. Oral bisphosphonates do not seem to be beneficial.  Prompt reduction of fractures is important to the prevention of deformities. A multidisciplinary team is important for the treatment and rehabilitation of patients.

References
Article Title: 
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