Achondroplasia

Hypochondroplasia

Pseudoachondroplasia

Description

Rhizomelic shortening secondary to short humeri, flexion contractures from flexion deformities of distal humerus, elbow abnormalities, and trident appearance of hand [extra space between third and fourth rays]. Short stature noticeable at birth, foramen magnum stenosis, thoracolumbar kyphosis, spinal stenosis, and genu varum [14, 17]

Defective conversion of cartilage to bone. Less severe form of achondroplasia—body changes milder and often overlooked. Normal trunk length, disproportionately short arms and legs, hands and feet are broad and short. Differentiated from achondroplasia by lack of facial dysmorphism, less severe short stature, less obvious skeletal disproportion, and milder radiologic findings [17, 20]

Moderate to severe disproportionate short stature, ligamentous laxity, and progressive degenerative joint disease. Short-limb dwarfism with epiphyseal and metaphyseal involvement. Moderate brachydactyly, joint hyperextensibility in hands, restricted extension at elbows, and overall joint pain. Osteoarthritis in early adulthood [21–23]

Radiographic findings: Rhizomelia, mesomelia, acromelia of extremities; brachydactyly, metacarpal metaphyseal cupping, phalangeal metaphyseal widening in hands; prominent deltoid insertion area in arms; third metacarpal shortening [18, 19]

Radiographic findings: Same as achondroplasia, but milder [18]

Radiographic findings: Brachydactyly proximally rounded and shortened metacarpals with small or cone-shaped epiphyses in hands, short phalanges, irregular metaphyses, and irregular carpals. Elbows may appear enlarged [18, 21]

Genetics

Autosomal dominant, fully penetrant, but 80 % of cases are sporadic. Locus—4p16.3; Gene—FGFR3; Protein—FGFR3 [14, 24]

Autosomal dominant; Locus—4p16.3; Gene—FGFR3; Protein—FGFR3 [24]

Autosomal dominant; Locus—19p12-13.1; Gene—COMP; Protein—Cartilage Oligomeric Matrix Protein (COMP) [24]

Natural History

Short stature is present at birth. Motor development may be delayed. Average height for adult male—131 cm (52 in.). Average height for adult female—124 cm (49 in.) [14, 25]

Same as achondroplasia, but milder [17, 20]

Normal length and facies at birth. Often presents at the onset of walking with a waddling gait. By 2 years of age, growth rate below the standard growth curve which leads to disproportionate short-limb short stature. Average adult heights: 116 cm for females and 120 cm for males [21]

Treatment

Growth hormone therapy. Upper extremity limb lengthening has been documented with an average arm length gain of 10.2 ± 1.25 cm. Surgical realignment may be performed as well [14, 25]

Growth hormone therapy and limb lengthening if necessary [26]

Evaluate for skeletal manifestations. Anterior/posterior radiographs of hands. Assess ligamentous laxity. Analgesics for joint pain [21]

Thanatophoric dwarfism/dysplasia type 1

Thanatophoric dwarfism/dysplasia type 2

Marfan syndrome

Description

Underdevelopment of the entire skeleton, short-curve long bones, metaphyseal flaring, underdeveloped pelvic bones, flat acetabular roof, flat and underdeveloped vertebral bodies, cloverleaf skull may or may not be present [27, 28]

In TD2, long bones not as short as in TD1, nor are they bent and/or bowed. Metaphyses are flared and cupped. Flat vertebral bodies—but not as flat as TD1, almost all fetuses have cloverleaf skull. Overall, less severe bone involvement than TDI [27, 28]

Characterized by tall stature, thin habitus, long and slender digits, ligamentous laxity, arachnodactyly, and camptodactyly. Reduced upper-to-lower segment ratio. Bones are typically osteopenic and fracture often [6, 19]

Radiographic findings: Generalized micromelia, long bones of extremities are short and have telephone receiver-like appearance; skeletal maturation and ossification centers are not altered on radiograph [18, 28]

Radiographic findings: Generalized micromelia, long bones of extremities are short and have telephone receiver-like appearance; skeletal maturation and ossification centers are not altered on radiograph [18, 28]

Genetics

Autosomal dominant; Locus—4p16.3; Gene—FGFR3; Protein—FGFR3 [24]

Autosomal dominant; Locus—15q21.1; Gene—FBN1; Protein—Fibrillin-1 [24]

Natural History

Most common type of lethal neonatal skeletal dysplasia; overall association with rhizomelic limb shortening, macrocephaly, and cloverleaf skull. Difficult to differentiate from other forms of short-limb dwarfism—most important difference is that TD has severe rib shortening, restricted lung volume, and respiratory distress leading to death within a few hours of birth. Most infants do not survive past a few hours or days due to respiratory insufficiency [27–29]

Children taller than average for age. By adulthood, may reach 7 ft tall [19]

Treatment

At birth, infant may require suboccipital decompression to alleviate craniocervical junction constriction. Joint contractures or joint hypermobility should be evaluated and followed [29]

Therapy with nighttime splinting in extension is often successful for treatment of camptodactyly. More severe cases may require tendon transfer, release of volar structures and PIPJ. Surgery outcomes are unpredictable [30]

Osteogenesis imperfecta

Nail–Patella syndrome

Diastrophic dysplasia

Description

Characterized by fragile bones, low bone mass, blue sclerae, dentinogenesis imperfecta, hearing loss, and scoliosis. Frequent fractures produce limb deformities. Bowing may occur without prior fracture. Non-accidental injury must be considered in differential diagnosis [3, 5, 31]

Abnormal development of tissue derived from mesenchyme. Nail dysplasia or absence and radial head dislocation may be seen in the upper extremity. Decreased muscle mass in proximal upper extremity [19, 32]

Endochondral ossification affected causing short stature from shortened limbs, progressive spinal deformities, foot deformities, frequent joint subluxation and dislocation, large joint contractures, ear pinnae deformities, and/or cleft palate. Hitchhiker thumb, shortened fingers, synostosis of the proximal interphalangeal joints, and ulnar deviation of fingers. Radial dislocation may also be seen clinically [33–35]

Radiographic findings: Osteopenia, bone fractures, and bone deformities [31]

Radiographic findings: Radial head and capitellum hypoplasia, elbow dislocation [18]

Radiographic findings: Micromelia; short, thick tubular bones; epiphyseal dysplasia; metaphyseal flaring of long bones; bifid or V-shaped distal humerus, may also be pointed and hypoplastic; radial bowing; proximal radial dislocation at birth; brachydactyly and short ovoid first metacarpal; irregular carpal bones; joint dislocations [18, 33]

Genetics

OI Types I–IV: Autosomal dominant; Gene—COL1A1 or COL1A + G42; Protein—type 1 collagen

Autosomal dominant; Locus—9q34.1; Gene—LMX1B; Protein—LIM homeobox transcription factor 1 [24]

Autosomal recessive; Locus—5q32-33; Gene—DTDST; Protein—SLC26A2 sulfate transporter [24]

OI Type V: Autosomal dominant; Gene—unknown

OI Type VI: Autosomal recessive; Gene—unknown

OI Type VII: Autosomal recessive; Protein—Cartilage-associated protein [CRTAP] [24]

Natural History

More severe forms of OI may experience bone fragility and fracture in utero and/or at birth. Milder forms may remain nearly absent in adulthood. Overall, fracture incidence decreases after puberty and increases after menopause and males in their 60s [1]

Non-progressive nail dystrophy and elbow deformities. Patellae may be absent or hypoplastic [19, 32]

Diagnosis can be made through ultrasound and molecular genetic testing prenatally or clinically at birth. Normal mental status. Growth and motor capabilities greatly affected by deformities. Disproportionate dwarfism with a mean height of 130–140 cm can be seen in affected adults [36]

Treatment

Bisphosphonates may be used to decrease fracture frequency, improve vertebral bone density, and strengthen grip. Surgical goal is to minimize fracture frequency, restore bone axis, and avoid bowing. Long bone internal fixation in children is common via multilevel osteotomies and telescopic intramedullary nail fixation. Long-term rod revision surgery may be required [3, 4]

Patient may be followed and regularly assessed. Surgery is sometimes necessary [19, 32]

Focus on improving mobility through casting to maintain joint positioning, physiotherapy, and other forms of therapy. Cervical spinal surgery only indicated with clinical or neurophysiological evidence of spinal cord impingement—otherwise, cervical kyphosis typically spontaneously corrects. In cases of premature degenerative arthrosis, arthroplasty is indicated. Early physical therapy may prevent joint contractures [33, 35]

Kniest’s dysplasia

Cleidocranial dysostosis/dysplasia

Niemann–Pick disease

Description

Damage to articular and epiphyseal cartilage leading to disproportionate dwarfism. Children present with enlarged elbow and wrist joints with restricted movement, abnormal hands with long, knobby fingers. Round faces and barrel-shaped kyphotic trunk [19, 37]

Abnormal development of membranous bones such as the clavicle. Characterized by drooping shoulders, elongated neck, and shoulder adduction anteriorly. Central clavicle may be absent and a small piece of bone articulating with the acromion [26, 38]

Lipid storage disease. Previously not known to have skeletal involvement. Joint and/or limb pain has been reported as well as decreased bone mineral density [BMD] in both affected pediatric and adult patients [39]

Radiographic findings: Generalized ossification delay; epiphyses becoming hypoplastic/dysplastic; cloudy effect in physeal plate in late childhood; metaphyseal flare and epiphyseal fragmentation; reduced joint space in small joints of hand [18, 37]

Radiographic findings: Multiple pseudoepiphyses of metacarpals and tapered distal phalanges in hands [18]

Genetics

Autosomal dominant; Locus—12q13.1; Gene—COL2A1; Protein—type 2 collagen [24]

Autosomal dominant; Locus—6p21; Gene—RUNX2; Protein—Run related transcription factor 2 [24]

Autosomal recessive; Gene—SMPD1; Locus—p11; Protein—Acid sphingomyelinase [24, 26]

Natural History

Bone formation in fetus and infant most affected. Slow growth. Normal milestones and intelligence [19, 37]

Mean adult height for males is 162 cm [26]

Patients with neurological involvement do not survive beyond 3 years. Patients without neurodegeneration usually survive into late childhood or adulthood [39]

Treatment

UE management not well documented

Orthopedic intervention may be necessary if severe impairment or disability occurs [38]

No definitive treatment. Early intervention for low BMD such as load-bearing activities and muscle strengthening exercises. Frequent pulmonary disease and chronic fatigue must be considered [39]

Mucopolysaccharidoses

Description

Defective endochondral and membranous growth. Presents with dysostosis multiplex—short stature, platyspondyly with anterior beaking, ‘bullet-shaped’ phalanges. Joint contractures and carpal tunnel syndrome are common. Osteopenia may occur in association with pathologic fractures

MPS I H—Hurler syndrome: Carpal tunnel syndrome, joint contractures, and dysostosis multiplex

MPS I S—Scheie syndrome: Carpal tunnel syndrome, joint contractures, and dysostosis multiplex

MPS II—Hunter syndrome: only X-linked MPS disorder, Carpal tunnel syndrome, joint contractures, and dysostosis multiplex

MPS IIIA-B—Sanfilippo Types A-B: Less severe than I, II, VI, and VII

MPS IVA—Morquio Type A: severe skeletal dysplasia, joint hypermobility, and dysplastic odontoid process

MPS IVB—Morquio Type B: severe skeletal dysplasia, joint hypermobility, and dysplastic odontoid process

MPS VI—Maroteaux–Lamy syndrome: Carpal tunnel syndrome, joint contractures, and dysostosis multiplex

MPS VII—Sly syndrome: Joint contractures and dysostosis multiplex [40–42]

Radiographic findings: Coarsened long bones, shortened ulna, Madelung deformity of distal radius, shortened metacarpals with proximal tapering, and broad clavicles [42]

Genetics

Autosomal recessive; Gene—varies by type of MPS [42]

Natural History

Affected infants may appear healthy at birth. MPS presents later—timeline varies by form. Often children have short stature and some have progressive mental deterioration [19, 42]

Treatment

Carpal tunnel release and deformity correction. Bisphosphonates may be used to help increase bone density. Palliative and supportive care such as physical and occupational therapy when indicated [40–42]

Hereditary multiple exostoses/multiple osteocartilaginous exostoses/diaphyseal aclasia

Fibrodysplasia ossificans progressiva

Chondroectodermal dysplasia/Ellis–van Creveld syndrome

Description

Multiple cartilage-capped boney protuberances, or osteochondromas, at metaphyses of long bones. Mild short stature and disproportionate short-limbs. Rarely, an enchondroma may undergo a malignant transformation into secondary chondrosarcoma. UE most commonly presents with length discrepancy between the radius and ulna—radial bowing, radial tilting, and radial head dislocation may occur [43]

Fibrous tissues, muscles, and periosteal regions undergo progressive ossification. Shortened and deformed thumbs [19]

Short stature, irregular bone growth ad structure. Polydactyly also occurs [19]

Genetics

HME–1: Autosomal dominant, Locus—8q23-24.1; Gene—EXT1; Protein—Exostosin-1

Autosomal dominant; Locus—4q27-31, 17q21-22, or 2q23-24 [19]

Autosomal recessive; Locus—4p16 [19]

HME–2: Autosomal dominant, Locus—11p12-11; Gene—EXT2; Protein—Exostosin-2

HME–3: Autosomal dominant, Locus—19p [24]

Natural History

Numerous osteochondromas develop near growth plates. During childhood and adolescence, osteochondromas create a pseudo-growth plate and cause deformity with growth [44]

At age five, patient starts developing large ectopic osseous collections in muscular regions. These osseous collections cause severe disability and limits joint movement [19]

Treatment

Growth deformity correction and removal of symptomatic osteochondromas. To manage impending or complete radial head dislocation: Ulnar collateral carpal ligament release at the wrist and radial head resection at skeletal maturity. Ulnar wrist deviations are usually asymptomatic. If not, acute and guided-growth interventions may be successful. Malignant transformation into chondrosarcoma must be resected. Typically low grade [43]

No known effective treatment. Surgery, corticosteroids, and radiotherapy have been used. Bisphosphonates have been used to decrease ectopic osseous masses but clinical benefits are not well established [45]

Surgical excision of polydactyly [30]

Ehlers Danlos syndrome (EDS)

Spondyloepiphyseal DYSPLASIA

Multiple epiphyseal dysplasia

Description

Connective tissue disorder characterized by congenital joint hypermobility, skin hyperextensibility, and tissue fragility. Joint dislocations due to little to no trauma are common as is chronic limb pain. Severity varies with type of EDS [46, 47]