Systemic Skeletal Dysplasias

Introduction and Classification

The systemic skeletal dysplasias are a large group of inherited disorders of bone and cartilage development that produce abnormal skeletal growth, shape, and integrity. More than 450 distinct entities are recognized in the International Nosology and Classification of Genetic Skeletal Disorders, the most recent revision (2019) of which categorizes the conditions by molecular pathology, clinical presentation, and radiographic features. Although individually rare, the skeletal dysplasias collectively affect approximately 1 in 5,000 live births and produce a substantial portion of pediatric and adult orthopedic practice. The orthopedic surgeon must be able to recognize the clinical features of the principal dysplasias, anticipate their characteristic complications (cervical spine instability, spinal stenosis, joint deformities, fractures, scoliosis, growth-plate problems), and coordinate care with the broader multidisciplinary team. This chapter, synthesizing content from Tachdjian’s Pediatric Orthopaedics, Apley & Solomon’s, Miller’s Review, and Netter’s Concise Orthopaedic Anatomy, addresses the principal categories of skeletal dysplasia: disproportionate short-stature disorders (achondroplasia, hypochondroplasia, diastrophic dysplasia), disorders affecting epiphyses (multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia), disorders affecting metaphyses (metaphyseal chondrodysplasias), disorders of bone density (osteogenesis imperfecta, osteopetrosis, Paget disease), the mucopolysaccharidoses, and a selection of other clinically important entities.

Achondroplasia

Genetics and Pathophysiology Achondroplasia is the commonest skeletal dysplasia producing disproportionate short stature, with an incidence of approximately 1 in 25,000-40,000 live births. The condition is autosomal dominant, with approximately 80% of cases representing new mutations (typically associated with advanced paternal age) and 20% inherited from an affected parent. The causative mutation is in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16, with the great majority of cases caused by a single specific point mutation (G1138A producing a glycine-to-arginine substitution at codon 380). The mutation produces a constitutively active FGFR3 receptor, which suppresses chondrocyte proliferation and differentiation in the cartilage growth plate, producing the characteristic rhizomelic (proximal limb) short stature. Clinical Features The classical features include: rhizomelic short stature (with the upper arms and thighs disproportionately shorter than the forearms and legs); macrocephaly with frontal bossing and depressed nasal bridge; trident hands (with separation of the third and fourth fingers); thoracolumbar kyphosis in infancy that improves with weight-bearing and resolves in most cases; lumbar hyperlordosis in childhood and adulthood; spinal stenosis (the principal long-term clinical problem, with progressive narrowing of the spinal canal producing

neurological symptoms in adulthood); foramen magnum stenosis (producing potentially life-threatening compression of the cervicomedullary junction in infancy, manifesting as central apnea, weakness, or sudden death); midface hypoplasia with potential airway problems; otitis media and hearing impairment; genu varum (in approximately 30%); and elbow contractures.

Orthopedic Management The orthopedic management of achondroplasia encompasses several specific issues. Foramen magnum stenosis must be assessed in every infant by neurological examination, polysomnography, and MRI; surgical decompression is required in the small fraction of infants with symptomatic compression. Thoracolumbar kyphosis is typically observed and managed conservatively with early weight-bearing and supportive seating; persistent kyphosis at age 5 years that exceeds 30° may require bracing or surgical correction. Spinal stenosis is the principal adult problem: progressive neurogenic claudication, leg pain, and weakness develop typically in the third to fifth decade. Surgical decompression — multilevel laminectomy with fusion in many cases — produces good results but the postoperative course is more complex than in non-achondroplastic patients because of the small spinal canal. Genu varum may require corrective osteotomy or guided growth (hemiepiphysiodesis). Limb-lengthening procedures (Ilizarov, modern motorized intramedullary devices) are an option for patients seeking increased stature and improved function, with typical gains of 10-15 cm achievable over 1-2 years of treatment.

Hypochondroplasia and Pseudoachondroplasia

Hypochondroplasia is also caused by FGFR3 mutations (typically at codon 540 rather than 380) and produces a milder phenotype than achondroplasia, with shorter stature and trident hands but without the dramatic facial features of full achondroplasia. The orthopedic implications are similar but generally less severe. Pseudoachondroplasia is caused by mutations in cartilage oligomeric matrix protein (COMP) and produces a phenotype superficially resembling achondroplasia but with normal facies and important cervical spine instability (atlantoaxial instability requiring careful management with avoidance of contact sports and consideration of fusion in symptomatic cases). The combination of short stature with normal facial features is the key distinguishing point.

Diastrophic Dysplasia

Diastrophic dysplasia is an autosomal recessive disorder caused by mutations in the SLC26A2 gene encoding a sulfate transport protein. The condition is endemic in Finland (where the carrier frequency reaches 1 in 70) and is rare elsewhere. The classical clinical features are: short stature; “hitchhiker thumb” (proximally placed thumb with characteristic deviation); cauliflower ear (from intrauterine inflammation of the auricular cartilage); cleft palate; clubfeet (typically severe, rigid, and resistant to standard treatment); cervical kyphosis; scoliosis; and joint contractures with multiple joint dysplasias. The orthopedic management includes serial casting and surgical correction of

clubfoot (notoriously resistant to Ponseti management in this condition), management of scoliosis and cervical kyphosis, and joint preservation through life.

Multiple Epiphyseal Dysplasia (MED)

Multiple epiphyseal dysplasia is a group of autosomal dominant disorders caused by mutations in cartilage oligomeric matrix protein (COMP), collagen IX, or matrilin-3. The condition affects principally the epiphyses of the long bones, producing characteristic irregular ossification of the epiphyses, with later development of premature degenerative arthritis particularly of the hips, knees, and shoulders. Clinical presentation is typically in middle childhood with joint pain, mild short stature, and waddling gait. Radiographs show small, fragmented, irregular epiphyses of the long bones, particularly the femoral heads and the distal femoral and proximal tibial epiphyses around the knee. The condition is often confused with Legg-Calvé-Perthes disease, particularly when presenting as bilateral synchronous changes of the femoral heads; the bilateral, symmetric, and multi-joint pattern, combined with the family history when present, distinguishes MED from Perthes. Treatment is principally protective: limitation of high-impact activities, weight management, and management of joint pain. Surgical management is reserved for established complications: corrective osteotomy for varus or valgus deformity, joint preservation procedures for hip dysplasia, and ultimately joint replacement for established arthritis (often in the fourth and fifth decades of life, decades earlier than for primary osteoarthritis).

Spondyloepiphyseal Dysplasia (SED)

Spondyloepiphyseal dysplasia exists in two principal forms: SED congenita (autosomal dominant, caused by mutations in type II collagen) presenting at birth with short stature, short trunk, flattened face, and characteristic vertebral and epiphyseal abnormalities; and SED tarda (X-linked recessive in many cases) presenting in late childhood with short stature, mild facial features, and progressive joint problems. The vertebral findings include flattened, irregular vertebral bodies with anterior beaking, atlantoaxial instability from odontoid hypoplasia (a critical orthopedic concern requiring careful cervical spine assessment and consideration of prophylactic cervical fusion in patients with mechanical or neurological signs), and progressive scoliosis. The epiphyseal findings parallel those of MED with hip and knee involvement leading to early arthritis. The orthopedic management combines cervical spine surveillance with fusion when needed, scoliosis management, and joint-preserving and joint-replacing surgery for the hip and knee arthritis. Retinal detachment is a recognized complication of the type II collagen mutations and requires ophthalmologic surveillance.

Metaphyseal Chondrodysplasias

The metaphyseal chondrodysplasias are a group of conditions characterized by abnormal metaphyseal ossification with sparing of the epiphyses. The principal forms are: Schmid form (autosomal dominant, type X collagen mutation): mild short stature, coxa vara, genu varum, waddling gait. The orthopedic management focuses on the coxa vara and varus deformities. Jansen form (autosomal dominant, PTH-related protein receptor mutation): severe short stature with hypercalcemia from constitutive PTH-receptor activation. Severe metaphyseal expansion produces dramatic radiographic features. McKusick form (cartilage-hair hypoplasia) (autosomal recessive, RMRP gene mutation): short stature, fine sparse hair, immunodeficiency, and characteristic metaphyseal abnormalities. The condition is enriched in the Old Order Amish population.

Osteogenesis Imperfecta (OI)

Genetics and Pathophysiology Osteogenesis imperfecta — “brittle bone disease” — is a group of inherited disorders of type I collagen, the principal structural protein of bone, with an overall incidence of approximately 1 in 15,000-20,000. The classical Sillence classification (1979) recognizes four principal types, supplemented by additional rarer types in modern classifications. Type I (mild): Autosomal dominant, caused by quantitative reduction in type I collagen. Mild bone fragility, blue sclerae, normal or near-normal stature, dentinogenesis imperfecta in approximately 50%. Multiple long-bone fractures in childhood, decreasing in frequency at puberty. Type II (lethal): Autosomal dominant new mutations (rarely autosomal recessive) producing severe qualitative collagen abnormalities. Multiple intrauterine fractures, severe deformity at birth, perinatal death from respiratory failure in most cases. Type III (severe, progressively deforming): Autosomal dominant new mutations (sometimes autosomal recessive). Severe bone fragility with progressive deformity, severely short stature, multiple fractures, severe scoliosis. Wheelchair-dependent in many cases. Type IV (moderate): Autosomal dominant. Moderate bone fragility, short stature, deformity, normal or near-normal sclerae. Additional types V (autosomal dominant, IFITM5 mutations with hyperplastic callus formation), VI through VIII (autosomal recessive forms with various collagen-processing defects), and additional rarer types have been added in modern classifications.

Clinical Features and Diagnosis The cardinal feature is bone fragility with multiple fractures from minor trauma. Other characteristic features include short stature (variable by type), bone deformity (typical bowing of the long bones from healed fractures and ongoing remodeling), blue sclerae (from the thin sclera allowing the underlying choroid to show through), dentinogenesis imperfecta with bluish-gray discolored brittle teeth (in approximately 50% of cases), hearing impairment (typically conductive in childhood, sensorineural in adulthood, from involvement of the small bones of the middle ear), joint hypermobility, easy bruising, and a number of additional features. The diagnosis is principally clinical, supported in many cases by molecular genetic testing (which can also assist in counseling and prenatal diagnosis). Orthopedic Management The orthopedic management has been transformed by bisphosphonate therapy and modern internal fixation techniques. Bisphosphonate therapy — typically intravenous pamidronate or zoledronate, with oral alendronate as an alternative — reduces fracture rates, improves bone density, and reduces bone pain in OI. The optimal duration and timing are debated; many centers use repeated courses through childhood and adolescence, with continued treatment into adulthood depending on response. Acute fracture management in OI follows the principles of routine fracture care: appropriate reduction, immobilization in the shortest required period (because of the risk of profound osteoporosis from immobilization), and rehabilitation. Multiple fractures occurring through previous fixation devices is a common challenge. Telescoping intramedullary nailing with devices such as the Bailey-Dubow rod (the original telescoping rod) and the modern Fassier-Duval rod, provide protective fixation that grows with the child. The principle is to insert a rod that extends through the metaphysis at each end, with telescoping components that elongate as the bone grows. The procedures address both the prevention of new fractures and the correction of established deformity by multiple osteotomies along the bone with intramedullary realignment. Scoliosis management in OI is complex because of the poor bone quality. Bracing is poorly tolerated and largely ineffective. Surgical fusion, when indicated for severe progressive curves, requires careful planning with attention to bone quality and instrumentation purchase. Basilar invagination and cranial settling — upward translation of the cervical spine into the cranium from soft cranial bone — is a recognized late complication of severe OI and requires careful management with the input of neurosurgical and skull-base specialists.

Osteopetrosis

Osteopetrosis — “marble bone disease” — is a group of inherited disorders of osteoclast function producing dense, brittle bone from failure of normal resorption. The principal forms are: Autosomal recessive (infantile, malignant) osteopetrosis: Severe form presenting in infancy with bone marrow failure (from obliteration of the marrow spaces by dense bone), recurrent infections, optic and other cranial nerve compression from foraminal narrowing, and severe bone fragility. Treatment is bone-marrow transplantation in selected cases. Autosomal dominant (Albers-Schönberg) osteopetrosis: Milder form presenting in adolescence or adulthood with multiple fractures, characteristic radiographic features (dense bones, “bone-within-bone” appearance of vertebrae, “rugger-jersey” spine with alternating bands of sclerotic and lucent vertebral endplates), and modest clinical impact. The orthopedic management focuses on fracture care, which is particularly challenging because of the dense bone that resists drilling, the increased risk of nonunion (the dense bone has limited vascularity), and the risk of intraoperative complications.

Mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of enzymes involved in glycosaminoglycan degradation. The accumulation of partially degraded glycosaminoglycans in lysosomes throughout the body produces multi- organ disease with characteristic skeletal manifestations. The principal types include: MPS I (Hurler syndrome, severe form; Scheie syndrome, mild form): alpha-L- iduronidase deficiency. Hurler patients have severe disease with progressive intellectual decline, corneal clouding, severe organ involvement, characteristic facial features, and multi-organ failure with death in childhood; modern treatment with hematopoietic stem cell transplantation has substantially improved outcomes. The orthopedic features include dysostosis multiplex (characteristic skeletal abnormalities including paddle-shaped ribs, J- shaped sella, bullet-shaped phalanges), thoracolumbar gibbus deformity, cervical spine instability, hip dysplasia, and hand contractures with the characteristic “claw hand.” MPS II (Hunter syndrome): X-linked recessive, iduronate sulfatase deficiency. Similar skeletal features without corneal clouding. MPS III (Sanfilippo syndrome): Several types, principally with neurological involvement; orthopedic features are mild. MPS IV (Morquio syndrome): Severe skeletal involvement with characteristic spondyloepiphyseal dysplasia. Atlantoaxial instability from odontoid hypoplasia is a critical concern, with risk of catastrophic cord injury; many centers recommend prophylactic cervical fusion at an early age. MPS VI (Maroteaux-Lamy syndrome): Similar to MPS I but with normal intelligence.

The orthopedic management of MPS includes cervical spine surveillance and fusion when indicated, management of the gibbus deformity and scoliosis, and joint replacement as the patients reach adolescence and adulthood with modern enzyme replacement and transplantation therapies extending life expectancy.

Other Notable Conditions

Cleidocranial Dysplasia Cleidocranial dysplasia, caused by RUNX2 (CBFA1) mutations, produces aplasia or hypoplasia of the clavicles (allowing the patient to bring the shoulders together anteriorly), delayed closure of cranial fontanelles and sutures, supernumerary teeth, short stature, and various other abnormalities. The orthopedic management is largely supportive.

Marfan Syndrome and Loeys-Dietz Syndrome These connective tissue disorders, discussed in detail in the chapter on joint hypermobility, produce significant skeletal features including tall stature, scoliosis, protrusio acetabuli, pes planus, and pectus excavatum or carinatum. The cardiovascular risks (aortic dilation and dissection) require coordinated care with cardiology. Stickler Syndrome Stickler syndrome, caused by mutations in collagen types II, IX, or XI, produces a characteristic phenotype of high myopia, retinal detachment, hearing loss, cleft palate, and progressive joint problems with epiphyseal dysplasia features. The condition overlaps with SED congenita. Camurati-Engelmann Disease Camurati-Engelmann (progressive diaphyseal dysplasia) is an autosomal dominant condition causing progressive cortical thickening of the diaphyses of the long bones, with bone pain and weakness as the principal symptoms. Trevor Disease (Dysplasia Epiphysealis Hemimelica) Trevor disease is a rare developmental disorder in which cartilaginous overgrowth occurs from one side of an epiphysis, producing a hemimelic mass and joint deformity. Surgical excision of the abnormal cartilage is the treatment.

General Principles of Management

The management of patients with skeletal dysplasia follows several unifying principles. First, accurate diagnosis is essential because of the wide variation in natural history and complications across the dysplasias; the diagnosis combines clinical features, radiographic features, family history, and increasingly molecular genetic testing. Second, the orthopedic surgeon must recognize the systemic and non-orthopedic features of each dysplasia and coordinate care with the appropriate specialists. Third, surveillance for specific complications — atlantoaxial instability in pseudoachondroplasia, SED, and Morquio;

foramen magnum stenosis in achondroplasia; basilar invagination in OI; obstructive sleep apnea in achondroplasia and Morquio — is essential and often requires lifelong follow-up. Fourth, the indications and risks of surgery in patients with skeletal dysplasia differ from those of patients without the underlying condition; bone quality, anesthetic considerations, and the underlying systemic complexity must all be considered in surgical planning.

Summary and Take-Home Points

The systemic skeletal dysplasias are a heterogeneous group of inherited disorders producing characteristic patterns of skeletal abnormality with associated systemic features. Achondroplasia, the commonest dysplasia of disproportionate short stature, results from FGFR3 mutations and produces rhizomelic short stature with foramen magnum stenosis in infancy and progressive spinal stenosis in adulthood. Multiple epiphyseal dysplasia and spondyloepiphyseal dysplasia produce epiphyseal abnormalities with early arthritis, with SED carrying the critical concern of atlantoaxial instability from odontoid hypoplasia. Osteogenesis imperfecta, the principal disorder of bone fragility, ranges from the lethal Type II to the mild Type I, and has been transformed by modern bisphosphonate therapy and telescoping intramedullary rod techniques. Osteopetrosis produces dense but brittle bone with characteristic radiographic features. The mucopolysaccharidoses, particularly Morquio syndrome, produce severe skeletal involvement requiring lifelong management. Across all of these conditions, the principles of accurate diagnosis, surveillance for specific complications, coordinated multidisciplinary care, and orthopedic intervention tailored to the underlying disorder determine successful outcomes.