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Pathology of Metabolic Bone Disease in Children

This page was last updated on April 8th, 2024


  • Heterogeneous group of disorders: The skeletal dysplasias are an extensive and pathologically heterogeneous group of disorders. For many of these conditions the underlying genetic anomaly and the metabolic basis of the disease have been discerned.
  • Spinal involvement: In the axial skeleton bone, cartilage, and ligaments are affected. Vertebrae are typically small or malformed, and ligaments are thickened. Together these result in short stature, spinal deformity, instability, or neuraxial compression.


Texts of syndromes, genetics, and heritable diseases should be consulted for more detailed descriptions of these disorders (10). Those conditions with particular neurosurgical relevance can be broadly classified as follows:

Chondrodysplasias: The chondrodysplasias include a large number of bone dysplasias typified by short limbs or a short trunk. The following list includes those that may present with spinal complications:

  • Achondroplasia: Implications for the spine include foramen magnum stenosis with brainstem compression (childhood) and generalized spinal canal stenosis due to short vertebral pedicles (adolescence and adulthood).
  • Hypochondroplasia: Hypochondroplasia is a clinically milder disease than achondroplasia, with a similar predilection to cause spinal canal stenosis.
  • Spondyloepiphyseal dysplasia: Vertebral involvement is common in this group of disorders. The underlying abnormality is a defect in type II collagen due to a mutation in the COL2A1 gene. The epiphyses are preferentially involved, the vertebrae are flattened (platyspondyly), and the ligaments are lax, resulting in a high incidence of instability and deformity. Affected individuals are dwarfed, the neck is short, and the thoracic cage is frequently underdeveloped. Craniovertebral instability with myelopathy occurs in up to 35% of affected individuals and is associated with worse prognosis (25).
  • Other rare chondrodysplasias: Other rarer forms that may result in spinal instability, deformity, and myelopathy include chondrodysplasia punctate and diastrophic dysplasia, which are associated with cervical instability and deformity (such as kyphoscoliosis) (20, 36); Kniest dysplasia, which is associated with atlantoaxial instability and cervical deformity; and metatropic dysplasia, which is associated with atlantoaxial instability.

Osteogenesis imperfecta: The underlying pathophysiological defect in osteogenesis imperfecta is a disorder of type I collagen. Mutations in the COLIA1 and COLIA2 genes are responsible for more than 90% of cases (18).

  • Eight types: Currently, eight different types of osteogenesis imperfecta are described. Type I constitutes 50% of cases, while type II is the most severe form and is usually lethal in infancy. Individuals with type I and type IV osteogenesis imperfecta have a more benign natural history with normal life expectancy in a large number of cases. The neurosurgical implications of osteogenesis imperfecta include macrocrania, bleeding diatheses, spinal fractures and deformity, and basilar invagination (28). Type III and type IV osteogenesis imperfecta are the forms most likely to develop basilar invagination and require surgery for craniovertebral compression (23). Respiratory impairment and neurological complications of basilar invagination contribute to early death in patients with type III (19).

Mucopolysaccharidoses: The mucopolysaccharidoses are a group of metabolic disorders characterized by lysosomal enzyme deficiency. Lysosomal enzymes are required for the breakdown of a group of chemicals that include dermatan sulfate, heparin sulfate, and keratan sulfate; together theses chemical are known as glycosaminoglycans (or mucopolysaccharides).

  • Eight types: The clinical syndrome is determined according to which particular lysosomal enzyme is defective. Many of the mucopolysaccharidoses have neurosurgical implications, summarized in the table below.
MPS* Type Synonym Bone dysplasia Neurosurgical
I-H Hurler syndrome Severe Communicating
I-HS Hurler-Scheie
Moderate Cervical stenosis
I-S Scheie syndrome Mild Atlantoaxial
II Hunter syndrome Moderate


Cervical stenosis

III Sanfilippo syndrome Minimal Rare
IV Morquio syndrome Severe Atlantoaxial 
VI Maroteaux-Lamy
Severe Craniovertebral
VII Sly syndrome Severe Craniosynostosis

*MPS, mucopolysaccharidosis.

Larsen syndrome: Larsen syndrome is a condition characterized by congenital joint dislocations and is thought to occur in response to a mutation in the filamin B (FLNB) gene. With respect to the spine, this condition is characteristically associated with ligamentous laxity rather than primary bony anomaly. Severe hypermobility and mid-cervical deformity with resultant spinal cord injury are well recognized (27).

Hajdu-Cheney syndrome: This syndrome is an autosomal dominant disorder of connective tissue. It results in focal bone destruction (particularly acroosteolysis of the phalanges) as well as generalized osteoporosis. Features include micrognathia, dental abnormalities, short neck, and ligamentous laxity. In the skull vault there is persistence of the cranial sutures along with multiple wormian bones. The characteristic craniovertebral anomaly is progressive basilar invagination (23).

Molecular/Genetic Pathology

The approximate incidence and mode of inheritance of the metabolic bone diseases are shown in the table below.

Disease Incidence Inheritance*
Achondroplasia 1:16,000–1:35,000


Spondyloepiphyseal dysplasia 1:100,000 AD
Hurler syndrome 1:80,000 AR
Hunter syndrome 1:250,000 X-linked
Morquio syndrome 1:80,000 AR
Morateaux-Lamy syndrome 1:300,000 AR
Osteogenesis imperfecta 1:20,000 AD
Larsen syndrome 1:100,000 AR and AD forms
Hajdu-Cheney syndrome Unknown AD

*AD, autosomal dominant; AR, autosomal recessive.


Achondroplasia is the commonest of the chondrodysplasias.

  • Autosomal dominant inheritance: The majority of cases arise, however, from spontaneous mutations in the affected gene. Advanced paternal age is a risk factor in these sporadic cases.
  • FGFR3: These conditions result from mutations in the FGFR3 gene.

Osteogenesis Imperfecta

  • Autosomal dominant inheritance
  • Disorder of collagen: These conditions are inherited disorders of type I collagen.
  • COLIA1 and COLIA2 genes: Two genes are implicated, COL1A1 and COL1A2, both of which encode for the production of type 1 collagen. Eight subtypes of osteogenesis imperfecta are described; they are distinguished by their clinical features and nature of the COLIA mutations.


MPS* Type Synonym Genetics*
I-H Hurler syndrome AR
I-HS Hurler-Scheie syndrome AR
I-S Scheie syndrome AR
II Hunter syndrome X-linked
III Sanfilippo syndrome AR
IV Morquio syndrome AR
VI Maroteaux-Lamy syndrome AR
VII Sly syndrome AR

*MPS, mucopolysaccharidosis; AR, autosomal recessive.

Miscellaneous metabolic syndromes affecting the spine

Larsen syndrome: This syndrome is thought to occur in response to a mutation in the filamin B (FLNB) gene.

  • Spondyloepiphyseal dysplasia: This condition is thought likely to be a disorder of type II collagen due to a mutation in the COL2A1 gene. 


The histopathological features of the metabolic bone diseases do not usually impact on clinical practice.

  • Chondrodysplasias (including achondroplasia): The ossification centers in the vertebrae are underdeveloped. The epiphyses of long bones are markedly enlarged. Histologically, the cartilage and bone appear relatively normal.
  • Osteogenesis imperfectas: The histopathological hallmark is a lack of bone bulk, and this is common to most types of osteogenesis imperfecta. Bone trabeculae are thin; there is reduced osteoid matrix and thinning of the bone cortices. Pathological fractures are common with exuberant callus formation.
  • Mucopolysaccharidoses: Common to these disorders is impaired metabolism of the glycosaminoglycans in the extracellular matrix of connective tissues. Cartilage is particularly affected, resulting in damage to articular surfaces, growth plates, and costal cartilages.