Other Skeletal Dysplasias

Natural History

Conductive hearing loss typically presents in childhood and may worsen later. Many cases are amenable to surgical correction. Hyperopia can be severe and should be looked for early in life. Symphalangism is not always present in childhood. Bony fusions are progressive and lead to increasing stiffness and limitation of movement of the spine and/or limbs, which is sometimes painful. Neurologic complications secondary to spinal canal stenosis occur frequently. Vertebral fusion, particularly in the cervical spine, can be debilitating.

Etiology

This disorder has an autosomal dominant inheritance pattern with appreciable variance in expression. Mutations in the NOG gene that encodes noggin are responsible for the majority of cases. Noggin is an antagonist of bone morphogenetic protein (BMP). Mice lacking noggin fail to initiate joint development, which suggests that excess BMP leads to enhanced recruitment of cells into cartilage, resulting in oversized growth plates and failure of normal joint development. Genetic heterogeneity is present as mutations in three other genes, GDF5 , FGF9 , and GDF6 have been reported in a small number of families. Although the clinical phenotype is similar in individuals with all four genotypes, those with mutations in FGF9 lack hearing loss, and those with GDF6 mutations lack the dysmorphic facial features as well as symphalangism, humeroradial synostosis, and vertebral fusion defects.

Comment

The term NOG-related symphalangism spectrum disorder has been proposed to include the many different phenotypes related to NOG mutations, which include proximal symphalangism, multiple synostoses syndrome, stapes ankylosis with broad thumbs and toes, tarsal-carpal coalition syndrome, and brachydactyly type B2.

Occasional Abnormalities

Cleft palate; preauricular skin tag; ocular hypertelorism; short nose, with broad, square nasal tip; enamel hypoplasia; missing permanent teeth; decreased range of motion at elbows; odontoid hypoplasia, basilar invagination, platybasia, and stenosis of the foramen magnum; delayed ossification of many epiphyses as well as in carpal ossification; rib anomalies; broad humerus; femoral epiphyseal dysplasia; postaxial polydactyly; clinodactyly; sacral anomaly; clubfoot; renal cyst and other kidney anomalies; mild developmental delay.

Natural History

Failure of normal spinal segmentation—which, when symmetric, leads to block vertebrae and when asymmetric, leads to unsegmented bars—causes most of the morbidity. Progressive scoliosis and lordosis, which are the major complications, are sometimes associated with restrictive lung disease. Cervical vertebral instability has been described. The unsegmented bar is difficult to identify on radiographs in early life because it is cartilaginous. Tomography is often helpful.

Etiology

This disorder has an autosomal recessive inheritance pattern in most cases. Mutations in the gene encoding filamin B ( FLNB ) are responsible. FLNB seems to have an important role in vertebral segmentation, joint formation, and endochondral ossification. A few autosomal dominant families in which heterozygous mutations of MYH3 , which encodes the heavy chain of embryonic myosin, have been reported. MYH3 is also responsible for some cases of distal arthrogryposis 1 (DA1), DA2, DA2B, and multiple pterygium syndrome.

Occasional Abnormalities

Intellectual disability; cleft lip; hypodontia; supernumerary teeth; gingival hyperplasia; periodontitis; conductive and sensorineural hearing loss; hypoplastic humerus; entropion of lower eyelids; anterior cortical lens opacities; simian crease; cardiovascular defect; mobile, infolding arytenoid cartilage; tracheomalacia; bronchomalacia; tracheal stenosis; cryptorchidism; malignant hyperthermia.

Natural History

Prognosis is relatively good with aggressive orthopedic management. Many patients begin walking late. Osteoarthritis involving large joints and progressive kyphoscoliosis are potential complications. Airway obstruction caused by tracheomalacia and bronchomalacia may be life-threatening. All affected individuals should be evaluated for cervical spine instability. Particular care should be exercised during anesthesia because of the mobile arytenoid cartilage as well as the potentially dangerous spinal anomalies.

Etiology

Autosomal dominant is the most commonly reported mode of inheritance. Mutations in the gene encoding filamin B ( FLNB ) have been reported in multiple families and in sporadic cases. FLNB seems to have an important role in vertebral segmentation, joint formation, and endochondral ossification. Mutations in FNLB also cause spondylocarpotarsal synostosis syndrome, atelosteogenesis types I and III, and Boomerang dysplasia.

Comment

Three different autosomal recessive forms of LS have been described. Larsen of Reunion Island was described in 1975. Clinical features of it include short stature, dislocation of large joints, ligamentous hyperlaxity, and characteristic facies, including a round flat face, prominent forehead, bulging eyes, and microstomia. Imaging studies reveal multiple joint dislocations, advanced carpal ossification, widened metaphysis and radio-ulnar-synostosis. Mutations in B4GALT7 are responsible.

In 2008, a second autosomal recessive form was identified, which is caused by deficiency of carbohydrate sulfotransferase 3 (also called chondroitin-6-sulfatransferase ) as a result of homozygous or compound heterozygous mutations in CHST3 . Clinical features include multiple joint dislocations, club feet, genu recurvatum, hip dislocations, and degeneration of the intervertebral discs. Neither the facial features of the autosomal dominant type nor cleft palate have occurred.

A third autosomal recessive type was described in two consanguineous Saudi Arabian families. Mutations in GZF1, which encodes GDNF1 -inducible zinc finger protein 1, are responsible. The clinical phenotype includes short stature, large joint hyperextensibility and dislocations, pectus carinatum, severe myopia, and retinal detachment.

Natural History

Lesions are usually not present at birth but become obvious between 2 and 10 years of age. A slowing of lesion growth occurs at adolescence and then ceases in adults. Remodeling defects caused by disruption of normal epiphyseal growth plate of the long bones lead to limb discrepancy and angular deformities. Involved bone may be relatively short, especially the ulna. Excessive growth or intense pain in the lesion should raise concern with respect to malignant transformation to osteosarcoma, less commonly other sarcomas, which occurs in 3% to 5% with an age ranging from 11 to 64 years. The majority of malignant transformations occur between 20 and 40 years of age; 56.2% are located in the pelvis and proximal femur. The issue of screening for malignant transformation is controversial. In one recent publication it was suggested that all patients between 20 and 40 years with Multiple Exostoses syndrome be screened annually with an MRI. However, there was no recommendation regarding an anatomic site to target. Two-thirds of patients have surgery for removal of at least one exostosis. For adults the mean number of exostoses removed is 3.5. Compression of peripheral nerves occurs in 22.6%, of blood vessels in 11.3%, and of the spinal cord rarely. Arthritis with mean age of onset of 36 years occurs in 14%. During pregnancy, changes in the exostoses occur in 10.5%. Other complications include bursa formation, usually presenting as a painful enlarging mass simulating malignant transformation, osteomyelitis, muscle impingement, hemarthrosis, pneumothorax, and hemothorax. More severe disease occurs in males than females, and in those with EXT1 as opposed to EXT2 mutations. Serial imaging to evaluate centrally located osteochondromas has been suggested, but the benefits do not clearly outweigh the risks of irradiation, in the absence of symptoms. This condition may significantly impact daily activities, as well as social and psychologic well-being. Bisphosphonate therapy has been tried for pain relief and to improve functioning.

Etiology

This disorder has an autosomal dominant inheritance pattern. Three loci for hereditary multiple exostoses (HME) have been identified; EXT1 at 8q23-24, EXT2 at 11p11-p12, and EXT3 at 19p. This last locus may reflect a false–positive linkage result. A combination of sequencing and deletion analysis of the entire coding regions of both EXT1 and EXT2 detects mutations in 70% to 95% of affected individuals, more frequent in EXT1 (56% to 78%) than in EXT2 (19% to 44%). When multiple exostoses occur with intellectual disability and behavioral problems, two microdeletion syndromes should be considered: Langer-Giedion syndrome at 8q24 that includes EXT1 and TRPS1 , the gene for tricho-rhino-phalangeal syndrome type I; and Potocki-Shaffer syndrome or proximal 11p deletion syndrome, which includes EXT2 .

Comment

Some chondrosarcomas have demonstrated loss of heterozygosity of chromosomes 8q and 11p, which is consistent with the two-hit model of tumor development. EXT1 and EXT2 are tumor-suppressor genes.