Skeletal Dysplasias

Skeletal dysplasia is a generalized structural abnormality of bone growth and modelling. Bone modelling is a consequence of osteoblast and osteoclast activity and growth / morphogenetic factors are important in development. The main structural protein of bone and cartilage is collagen. Mutations in collagen genes cause generalized dysplasia.

The skeletal dysplasias are genetically heterogenous and can be inherited as autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant disorders, and rarer genetic mechanisms of disease including chromosomal deletions/duplications, germline mosaicism, and uniparental disomy have been seen.

Although each skeletal dysplasia is relatively rare, collectively the birth incidence of these disorders is almost 1/5000. Skeletal dysplasia can be associated with variety of orthopedic, neurologic, auditory, visual, pulmonary, cardiac, renal complications, usually referred with deformity or short stature.

Skeletal Dysplasias short stature and deformities of limbs and spine 01/21/98 Skeletal Dysplasias short stature and deformities of limbs and spine respiratory problems chest wall or upper airway abnormalities central nervous system problems hydrocephaly spinal stenosis spinal cord injury from cervical spine and/or cervicovertebral junction instability muscle hypotonia, contractures, intrinsic muscle disease hearing loss, dental problems, myopia, retinal detachment are also more common with some of the skeletal dysplasias 8

Achondroplasia most common short limbed bone dysplasia. Diagnosed at birth rhizomelic limb shortening large head with broad, prominent forehead fingers are short, tapered and splayed

Achondroplasia - X-ray findings Pelvis is abnormal with small, square iliac wings Horizontal acetabular roots and narrowing of the greater sciatic notch long bones are short and the metaphyses slope because of narrow chest - respiratory problems are frequent translucent area at proximal ends of the femora in neonatal period

Achondroplasia if both parents affected - homozygotes can occur Autosomal dominant Gene maps to chromosome 4p mutation identified in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene most cases are denovo mutations in these cases recurrence risk is small germ-line mosaicism - small risk to normal parents of having recurrence if both parents affected - homozygotes can occur infants more severely affected and usually die early from compression of foramen magnum and respiratory failure

Hypochondroplasia Diagnosis might be difficult in the neonatal period Clinical features include: presence of mild rhizomelic limb shortening less severe than in achondroplasia / some bossing of the forehead fibula seem to be disproportionately long Interpedicular distance in the spine narrows caudally Findings may not be present or noted until second or third year of life Autosomal dominant inheritance - FGFR3 receptor mutations

Thanatophoric Dysplasia characterized by extreme rhizomelia, bowed long bones, normal trunk length but narrow thorax, and a relatively large head Most cases of thanatophoric dysplasia are sporadic. Some cases in the same sibship have been reported, and therefore an autosomal recessive pattern of inheritance has been suggested. The limbs show rhizomelic shortening. The femurs are extremely short and bowed, and, in the most severe forms, may be shaped like a telephone receiver. The thorax is narrow in the anteroposterior dimension, with short ribs.

Thanatophoric Dysplasia Limbs are very short (extreme rhizomelia) Chest is narrow bowed long bones Most infants die within a few hours of birth from respiratory failure Clinical features: head is large with prominent forehead depressed nasal bridge

Thanatophoric Dysplasia - X-ray feature shortening of the long bones with metaphyseal flaring and cupping characteristically curved femurs (“telephone receiver”) Iliac wings are hypoplastic Severe flattening of vertebral bodies gives an inverted “H” or inverted “U” shape Incidence - 1/20,000 live births

ThanatophoricDysplasia Autosomal dominant Mutations in FGFR3 receptor Most cases are sporadic Condition probably caused by a lethal AD gene

Achondrogenesis (AR )Lethal chondrodystrophy characterized by extreme micromelia, short trunk, and a disproportionately large cranium disorder of both endochondral and membranous ossification (partial or complete lack of ossification of the calvarium and spine as well as extremely short long bones and, frequently, multiple rib fractures )

Achondrogenesis Types I and II Type 1 - Parenti-Fraccaro - Autosomal recessive Type 2 - Langer - Saldino - Autosomal dominant Difficult to distinguish clinically Both result in stillbirth or neonatal death

Achondrogenesis - Clinical Features severe micromelia relatively large head, short neck, short trunk and protuberant abdomen flat nasal bridge nose is short with anteverted nostrils

Hypochondrogenesis Most AD - New mutations Clinical features: mutations in Type II collagen genes Clinical features: flat face, depressed nasal bridge, small thorax, relatively large head Limbs are short Infant seems edematous

Diastrophic Dysplasia Autosomal recessive Severe Limb Dysplasia Short limbs, severe talipes equinovarous hitch-hiker thumbs (abducted thumbs) cleft palate in many cauliflower ear characteristic swelling of the pinnae occasional dislocations of joints

Diastrophic Dysplasia respiratory problems due to narrow chest and micrognathis can be the cause of death X-rays - marked shortening of the first metacarpals Epiphyses and metaphyses are irregular V-shaped deformity at distal ends of the femora and tibiae vertebral bodies are irregular

Camptomelic Dysplasia Hallmark bowing of long bones particularly the femur and tibia Large head, small jaw, cleft palate and flat nasal bridge Ears may be malformed and low set Chest narrow - respiratory distress is common

Camptomelic Dysplasia Interesting Associations: 1/3 cardiac defects (VSD, ASD, Fallot Tetrology) 1/3 hydronephrosis - unilaterally medullary cystic disease Ambiguous Genitalia occur in the majority of patients with XY karyotype Other frequent malformation include hydrocephalus, arrhinencephaly

Camptomelic Dysplasia Genetics: Autosomal dominant Some with balanced translocations in the 17q12-25 region Mutations in Sox 9 gene have been demonstrated Most cases are sporadic

Fibrodysplasia Ossificans Progressiva Clue to dx in neonatal period is hypoplasia of great toe Absent skin crease - single phalanx - deviation laterally Progressive ossification - birth to 10 years Baldness and deafness Synovial osteochondromatosis Autosomal dominant ACVR1 gene

Craniometaphyseal Dysplasia Progressive nasal obstruction and mouth breathing in childhood Later - craniotubular bone dysplasia can be seen on skeletal X-ray sclerosis of skull, vault and base abnormal metaphyseal modeling of the long bones

Craniometaphyseal Dysplasia Bony overgrowth involving the supraorbital ridges giving visor-like appearance Tibia are curved backwards with mild valgus deformity of knees Extension and rotation is limited at elbows Deafness and cranial nerve entrappment occur

Short rib polydactyly syndrome AR lethal characterized by extremely narrow thorax, limbed dwarfism,and polydactyly 4 types

Chondroectodermal dysplasia (Ellis van Creveld syndrome) characterized by short limbed dwarfism, polydactyly, and nail and tooth abnormalities. It is inherited as autosomal recessive. Congenital heart disease is present in over half of the cases.

Asphyxiating thoracic dysplasia – Jeune Syndrome The main manifestation of this condition is a small thorax which results in respiratory distress. In the neonate this disorder may be difficult to differentiate from chondroectodermal dysplasia since occasionally polydactyly may be present.

OSTEOGENESIS IMPERFECTA Osteogenesis imperfecta is a heritable disorder caused by mutations in the gene for type I collagen. The classification of osteogenesis imperfecta (types I through IV) is based on clinical characteristics Type I osteogenesis imperfecta is associated with an increased risk of fracture but is usually not deforming. Type II osteogenesis imperfecta is lethal in the perinatal period, owing to severe fractures and deformity. Patients with type III or type IV osteogenesis imperfecta survive fractures in infancy and childhood but have progressive deformity.

Osteogenesis Imperfecta Type I Commonest form of OI Affected Individuals have: blue sclera and tendency to fracture the long bones Infants are of normal weight and length at birth and do not have multiple fractures deafness Healing occurs without deformity X-ray may reveal wormian bones of the skull and mild osteoporosis

Osteogenesis Imperfecta Type I Autosomal dominant inheritance Cells from individuals with OI type I secret about half the normal amount of Type I procollagen Gene linked to one of the Type I collagen loci 7 q 21-22 17 q 21-22

Osteogenesis Imperfecta Type II Severe, usually lethal form of OI Chest narrow, sclera blue, nose beaked Marked reduction of ossification of cranial vault and facial bones Beading of the ribs - indicates multiple fractures

Hypophoshatasia Two forms - early and late Both have reduced chondro-osseous mineralization low levels of alkaline phospatase in blood, cartilage and bone Infantile form: stillbirth, early death due to respiratory insufficiency

Hypophosphatasia Long bones - deformed and sometimes fractured Differential diagnosis - OI bones are very poorly mineralized and irregular ossification of the metaphyses which are widened and frayed Skull is poorly ossified Concentration of phosphoethanolamine is elevated in urine Late onset - AD Early onset - AR