Skeletal dysplasias

Skeletal dysplasias are a group of genetic disorders that affect the development of bone and cartilage. The disorders may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Some skeletal dysplasias can be detected as early as the prenatal period, while others manifest later in life, typically during childhood or adolescence. Achondroplasia, characterized by disproportionate short stature and craniofacial abnormalities, is the most common type of skeletal dysplasia. Osteogenesis imperfecta is a bone disease characterized by impaired osteogenesis that results in brittle bones that fracture easily, while osteopetrosis is a high-density bone disease that results in increased sclerotic thickening of the skeleton on radiological examination. Campomelic syndrome is a life-threatening disorder characterized by skeletal dysplasia, abnormal sex development, and other congenital defects due to SOX9 gene mutations.

• Definition: a genetic disorder characterized by impaired longitudinal bone growth that results in disproportionate short stature
• Epidemiology
  • Most common type of skeletal dysplasia
  • Most common cause of disproportionate short stature
  • 1:15,000–40,000 children affected in the US ^[1]
• Etiology
  • Gain of function mutation in fibroblast growth factor receptor 3 gene (FGFR3) on chromosome 4
  • New (sporadic) mutations in ∼ 80% of cases ^[2]
  • The probability of new mutations increases with the father's age at the time of conception.
  • Autosomal dominant inheritance in ∼ 20% of cases (homozygosity is lethal perinatally)
• Pathophysiology
  • Defective FGFR3 → continuous receptor stimulation by FGF → inhibited chondrocyte proliferation → ↓ endochondral ossification → impaired longitudinal bone growth
  • Normal intramembranous ossification of the craniofacial bones → disproportionately large head in relation to the limbs
• Clinical features
  • Stature
    • Disproportionate short stature
    • Normal-sized torso
    • Short, plump extremities
  • Craniofacial abnormalities
    • Macrocephaly
    • Prominent brows
    • Midface retrusion
    • Flattening of the nose
    • Middle ear deformation: recurrent otitis media
  • Other skeletal abnormalities
    • Small foramen magnum: compression of the cervical medulla
    • Lumbar lordosis and kyphoscoliosis
    • Spinal canal stenosis: lower back and leg pain, paresthesias, dysesthesia, incontinence
    • Small chest wall
    • Trident hand: a deformity of the hand that is characterized by short stubby fingers of equal size and increased separation between the middle finger and ring finger, which gives the hand the three-pronged appearance of a trident
  • Normal intellectual development
• Diagnostics
  • Physical examination
  • X-ray findings
    • Lateral skull: frontal prominence, midface hypoplasia
    • Spine: spinal canal stenosis, scoliosis
    • Extremities: short, thick bones
  • CT/MRI head: indicated in patients with signs of cervicomedullary compression
    • Assessment of brain stem compression
    • Measurement of the size of the foramen magnum
• Therapy ^[3]
  • Daily s.c. vosoritide injections (C-type natriuretic peptide analog): increases linear growth in children 5 years of age and older with open epiphyses (growth plates)
  • Surgical correction of spinal stenosis, secondary scoliosis, genu varum, brain stem compression

Osteogenesis imperfecta is a genetic disorder characterized by defective synthesis, structure, and/or processing of type 1 collagen resulting in skeletal deformities and brittle bones that fracture easily. ^[4]

Epidemiology

• 1 in 15,000–20,000 births ^[4]
• Osteogenesis imperfecta type I is the most common form in populations of European origin. ^[5]

Etiology ^[4]

• Various genetic defects
  • Most commonly autosomal dominant mutations in COL1A1 or COL1A2 genes that affect collagen synthesis, structure, and/or processing
  • Rare variants: usually recessive or X-linked ^[4]

Pathophysiology ^[6]

The most common mutations affecting collagen synthesis: ↓ formation of hydrogen and disulfide bonds between type I preprocollagen molecules → ↓ triple helix formation → ↓ synthesis of normal type I collagen → impaired bone matrix formation (osteogenesis)

Clinical features of osteogenesis imperfecta ^[5][6][7]

The severity of skeletal features and presence of extraskeletal features vary by type of osteogenesis imperfecta.

• Skeletal features
  • Brittle bones
  • Recurrent fractures from minimal trauma (including during birth)
  • Secondary skeletal deformities from fractures, e.g.: ^[5]
    • Scoliosis
    • Bowing of long bones (e.g., tibial bowing)
    • Chest wall deformities
  • Growth delay and short stature
  • Facial and skull anomalies (e.g., macrocephaly, triangular-shaped face, flat midface)
• Extraskeletal features
  • Blue sclerae
  • Dentinogenesis imperfecta (due to a lack of dentin); : dental abnormalities, including brittle, opalescent teeth
  • Joint hypermobility
  • Muscle weakness
  • Progressive hearing loss ^[6]
  • Pulmonary complications ^[6][7]
  • Cardiovascular complications (e.g., valvular disease, aortic root dilation)
  • Chronic pain

The fractures caused by osteogenesis imperfecta may be mistaken for nonaccidental injury. ^[4]

Clinical features of classical types

• Osteogenesis imperfecta was originally classified into four types based on clinical features; this classification may still be used for treatment decisions.
• A classification based on genetics is often preferred, as it allows genetic counseling and prognostication; clinical features are also not exclusive to type. ^[7]

Individuals with osteogenesis imperfecta can't BITE: Bones (recurrent fractures), I (“eye” = blue sclerae), Teeth (dental abnormalities), Ears (hearing loss).

Diagnostics ^[4][5][6]

• Diagnosis is based on clinical features and radiological findings.
  • Skeletal survey shows characteristic changes (e.g., fractures, bone anomalies).
  • DEXA scan may be used to confirm low bone density and exclude differential diagnoses. ^[9]
  • Severe forms can be detected with prenatal diagnostics (e.g., fetal anatomy scan).
• Diagnosis is confirmed with genetic testing.
• Bone biopsy and histology are rarely needed for diagnosis. ^[9]

X-ray findings

• Fractures in various stages of healing
• Osteopenia
• Long bone anomalies, e.g.:
  • Bowing
  • Shortened crumpled long bones (accordion appearance)
  • Metaphyseal flaring
• Rib anomalies (e.g., thin ribs, narrow thorax)
• Vertebral compression fractures
• Skull anomalies (e.g., intrasutural bones, basilar invagination)

Prenatal diagnostics

• More severe forms may be detected on routine fetal anatomy scan based on:
  • Long bone anomalies (e.g., fractures, bowing, shortening)
  • Rib anomalies (e.g., fractures, thickened, thinned)
  • Decreased mineralization of the bones
  • Fetal growth restriction
• Diagnosis may be confirmed with invasive prenatal genetic testing.

Differential diagnoses ^[9]

• Nonaccidental injury
• Nutritional deficiencies (e.g., rickets) ^[11]
• Fractures secondary to malignancy
• Inherited disorders (e.g., chondrodysplasia, hypophosphatasia)
• Early-onset osteoporosis ^[4]

Management ^[4][6][7]

General principles

• Refer to a multidisciplinary team for management of skeletal and extraskeletal manifestations.
• Advise adequate calcium and vitamin D intake to optimize bone health. ^[9]
• Offer genetic counseling to affected patients and family members.
• Offer support to caregivers. ^[6]
• Screen regularly for complications.

If a severe or lethal form is diagnosed prenatally, pregnancy termination may be offered in accordance with patient preferences and applicable laws. ^[6]

Management of skeletal manifestations

• Acute fracture management
• Bisphosphonates to improve bone density ^[12]
• Orthopedic surgery to reduce deformities and improve mobility (e.g., osteotomy, intramedullary rods, spinal fusion)
• Physical therapy and occupational therapy
• Orthotics and mobility aids ^[9]
• Pain management (see "Chronic noncancer pain management" and "Pain management in children")

Management of extraskeletal manifestations

• Interventions to improve hearing (e.g., hearing aids, stapedotomy, and/or cochlear implants)
• Oral hygiene; capping of teeth and mandibular surgery to prevent malocclusion ^[9]
• Management of cardiac and pulmonary complications

Screening for complications

• Regular audiologic evaluation to assess for hearing loss
• Oral health checks
• Regular spirometry ^[13]
• Echocardiography every 3–5 years if asymptomatic; more frequently for patients with murmurs, cardiac or pulmonary symptoms, or thoracic deformities ^[6][9]
• CT skull base to assess for basilar invagination every 3–5 years if height Z-score is below -3 ^[9]

• Definition: an inherited, diffuse bone disease that results in sclerotic thickening of the skeleton on radiological examination
• Epidemiology
  • Type I osteopetrosis: 2–5 per 1,000,000 live births
  • Type II osteopetrosis: 2–10 per 1,000,000 live births
• Etiology
  • Type I osteopetrosis (malignant osteopetrosis): autosomal recessive disease
    • Age of onset: infancy
    • Clinical course: severe
  • Type II osteopetrosis (benign osteopetrosis, Albers-Schonberg disease): autosomal dominant disease
    • Age of onset: early adulthood
    • Clinical course: mild
  • Rare cause: carbonic anhydrase II deficiency
    • Autosomal recessive condition associated with inability of osteoclasts to generate an acidic environment for bone resorption
    • Leads to renal tubular acidosis, osteopetrosis of intermediate severity, and cerebral calcification resulting in intellectual disability
• Pathophysiology: gene mutations → inability of osteoclasts to generate acidic environment in the bone matrix → impaired bone resorption with preserved osteoblastic function → overgrowth of bone with pathological bone composition
• Clinical features
  • Recurring pathological fractures (osteopetrotic bone tissue is very dense but brittle)
  • Cranial nerve disorders (e.g., palsies) due to hyperostosis and stenosis of the cranial nerve foramina
  • Pancytopenia due to reduced marrow space
  • Hepatosplenomegaly due to extramedullary hematopoiesis
• Diagnostics
  • X-ray: symmetrical, homogenous, sclerotic thickening of both cortical and trabecular bone (stone bone)
  • Laboratory findings: See “Laboratory evaluation of bone disease.”
    • Calcium levels may be normal or low (especially in severe form, e.g., type I osteopetrosis).
    • ↑ CK-BB
    • ↑ Tartrate-resistant acid phosphatase (TRAP)
• Therapy
  • Bone marrow transplant (potentially curative treatment): Functional osteoclasts may develop from unimpaired monocytes deriving from transplanted stem cells.
  • Surgical decompression is required in the case of optic and/or auditory nerve compression.

References:^[14]

• Definition: a potentially lethal disorder characterized by skeletal dysplasia, abnormal sex development, and other congenital defects due to SOX9 gene mutations ^[15][16]
• Etiology
  • SOX9 gene mutations on chromosome 17
  • Autosomal dominant inheritance
  • Results from missense mutations, frameshift mutations, or chromosomal rearrangements
• Clinical features
  • Skeletal abnormalities
    • Bowing of long bones (particularly the legs)
    • Short legs
    • Dislocated hips
    • Club feet
    • Underdeveloped shoulder blades
    • Short stature
    • Characteristic facial features (e.g., small chin, prominent eyes, flat face, large head)
    • Pierre Robin sequence (cleft palate, glossoptosis, micrognathia)
  • Abnormalities of the reproductive system
    • In most affected individuals with 46,XY karyotype, the external genitalia will either be ambiguous or female.
    • Internal reproductive organs may not correspond with the external genitalia and individuals can have testes, ovaries, or both.
  • Other defects
    • Life-threatening laryngotracheomalacia
    • Respiratory distress syndrome
    • Hearing loss
• Diagnosis
  • Clinical and radiographic findings
  • Genetic testing
• Treatment
  • Airway protection
  • Surgical repair of congenital anomalies