Skeletal Dysplasia

Original Editor - Ayodeji Mark-Adewunmi

Top Contributors - Ayodeji Mark-Adewunmi  

Introduction

Skeletal dysplasias, also known as osteochondrodysplasias, constitute a diverse group of conditions characterized by anomalies in the growth or texture of bone and cartilage. These rare genetic disorders, collectively termed skeletal dysplasia, impact bone growth and development, leading to variations in bone size, shape, and structure, which manifest as short stature, limb deformities, and various other skeletal irregularities.

Skeletal dysplasias are caused by genetic mutations and their phenotypes evolve over a lifetime. This contrasts with dysostoses, which are malformations of single or multiple bones due to abnormal blastogenesis in utero and whose phenotypes do not change throughout life.

Epidemiology

Approximately 1 in 5,000 infants are born with a form of skeletal dysplasia. However, when considered together, genetic skeletal dysplasias, also known as osteochondrodysplasias, constitute a distinct group of genetic disorders characterized by widespread skeletal abnormalities.

Etiology

Skeletal dysplasia results from mutations in the genes that regulate bone growth and development. These mutations may be inherited from one or both parents, or they may arise spontaneously during the development of the fetus.

Clinical Signs and Symptoms

The symptoms of skeletal dysplasia can vary widely, depending on the specific disorder and its severity. Common symptoms include:

Short stature: Individuals with skeletal dysplasia often have a height that is below average for their age and gender.

Limb deformities: This condition can lead to limb size and shape abnormalities, such as bowed legs, knock-knees, and a curved spine.

Joint pain: People with skeletal dysplasia may experience joint pain and stiffness, especially in the hips and knees.

Breathing difficulties: Some individuals may have narrowed airways, resulting in breathing challenges.

Dental abnormalities: Certain skeletal dysplasia types can affect dental health, leading to missing or malformed teeth.

Skeletal dysplasia Classification

In the 2010 nosology, the first eight groups of conditions are categorized by the molecular basis of the disease: FGFR3, type 2 collagen, type 11 collagen, sulfation disorders, perlecan, aggrecan, filamin, and TRPV4.

The remaining 32 groups are classified based on their clinical and radiographic characteristics. The prefixes acro-, meso-, rhizo-, spondylo-, epi-, and meta- refer to different parts of the body: acro- to the extremities, meso- to the middle segments, rhizo- to the proximal segments, spondylo- to the spine, epi- to the epiphyses, and meta- to the metaphyses. For instance, if only the hands and feet are affected, the acromelic group of conditions would be relevant, while the spondylometaphyseal dysplasias would be consulted if the spine and metaphyses are involved.

Skeletal Dysplasia Groups Based on Molecular Bases	Skeletal Dysplasia Groups Based on Clinical Presentations
FGFR3 chondrodysplasia group	Short-rib dysplasias group (may include polydactyly)
Type 2 collagen group and similar disorders	Group comprising multiple epiphyseal dysplasia and pseudoachondroplasia
Type 11 collagen group	Metaphyseal dysplasias
Sulfation disorders group	Spondylometaphyseal dysplasias (SMD)
Perlecan group	Spondylo-epi-(meta)-physeal dysplasias (SE(M)D)
Aggrecan group	Severe spondylodysplastic dysplasias
Filamin group and related disorders	Acromelic dysplasias (affecting limb extremities)
TRPV4 group	Acromesomelic dysplasias (involving limb extremities and midsections)
	Mesomelic and rhizo-mesomelic dysplasias (affecting proximal and middle limb sections)
	Bent bone dysplasias
	Slender bone dysplasia group
	Dysplasias associated with multiple joint dislocations
	Chondrodysplasia punctata (CDP) group
	Neonatal osteosclerotic dysplasias
	Increased bone density group (without bone shape alteration)
	Increased bone density group with metaphyseal and/or diaphyseal involvement
	Osteogenesis imperfecta and decreased bone density group
	Group with abnormal mineralization
	Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)
	Osteolysis group
	Group with disorganized development of skeletal components
	Overgrowth syndromes with skeletal involvement
	Genetic inflammatory/rheumatoid-like osteoarthropathies
	Cleidocranial dysplasia and isolated cranial ossification defects group
	Craniosynostosis syndromes
	Dysostoses predominantly involving craniofacial regions
	Dysostoses predominantly involving vertebral and/or costal regions
	Patellar dysostoses
	Brachydactylies (may include extraskeletal manifestations)
	Limb hypoplasia-reduction defects group
	Polydactyly-Syndactyly-Triphalangism group
	Defects in joint formation and synostoses

Achondroplasia

Achondroplasia is an autosomal dominant genetic condition and the leading cause of dwarfism. It is also the most common type of non-lethal osteochondrodysplasia, or skeletal dysplasia, occurring in approximately 1 in 25,000 births. Those with achondroplasia generally have a shorter stature, with the average height for adult males being 131 cm (4 feet, 3 inches) and for females 123 cm (4 feet, 0 inches).

The condition is apparent at birth, as are craniofacial abnormalities like macrocephaly and mid-face hypoplasia. These clinical features differentiate achondroplasia from pseudoachondroplasia, where dwarfism is not evident at birth and craniofacial abnormalities are not typical. Plain radiography is essential for the differential diagnosis of achondroplasia.

Achondroplasia is the most prevalent form of short-limbed skeletal dysplasia. This condition arises from gain-of-function mutations in the FGFR3 gene, leading to a generalized disruption of endochondral bone formation, while intramembranous bone formation remains unaffected. Remarkably, nearly all individuals with achondroplasia share the same mutation, resulting in uniform clinical features among patients.

These features include a short stature due to rhizomelic shortening of the limbs, a "trident hand" characterized by the inability to oppose the third and fourth fingers, a disproportionately large head with a prominent forehead, mid-face recession, and relative prognathism. Children often exhibit thoracolumbar kyphosis with pronounced lumbosacral lordosis, and there is a rapid progression of foramen magnum stenosis after birth, which can lead to hydrocephalus, apnea, quadriplegia, and even sudden death in infancy and early childhood.

Radiologically, the hallmark findings are impaired endochondral bone formation coupled with intact intramembranous ossification. In tubular bones, this results in abnormal longitudinal growth and normal transverse growth, producing short, broad bones with metaphyseal cupping.

Pseudoachondroplasia

Pseudoachondroplasia is an osteochondrodysplasia made distinctive by disproportionate short stature, hip and knee deformities, brachydactyly (short fingers) and ligamentous laxity. It affects at least 1 in 20,000 individuals. Pseudoachondroplasia is inherited in an autosomal dominant manner and is caused solely by mutations in the cartilage oligomeric matrix protein COMP gene.

It’s distinguished by a moderate to severe form of disproportionate short-limb short stature. The limb shortening is fundamentally confined to the proximal limb segments i.e., Femurs and humeri. A known presenting feature is a waddling gait, noticed at the onset of walking.

A prompt diagnosis of a skeletal dysplasia in general and Pseudoachondroplasia in specific is still based upon a comprehensive clinical and radiographic correlation. A detailed radiographic examination of the axial and appendicular skeleton is invaluable for the differential diagnosis of Pseudoachondroplasia. Coxa vara (reduced neck shaft angle), broad femoral necks, short femurs and humeri, and bullet-shaped vertebrae are noticeable radiographic features. Additionally, the presence of metaphyseal broadening, cupping and dense line of ossification about the knee can simulate rachitic changes. These radiographic features are collectively known as rachitic-like changes. The presence of epiphyseal changes serves as an important differentiating feature from achondroplasia.

Osteogenesis imperfecta

COL1A1/2-related Osteogenesis Imperfecta is transmitted in an autosomal dominant pattern. A significant number of cases are due to de novo mutations in the COL1A1 or COL1A2 genes, which are responsible for most instances of perinatally lethal and progressively deforming osteogenesis imperfecta. In the classic non-deforming type with blue sclerae and the common variable type with normal sclerae, about 60% of cases arise de novo. This condition is characterized by frequent fractures from minor trauma, defective dentinogenesis imperfecta, and hearing loss.

The clinical manifestations of COL1A1/2-related osteogenesis imperfecta vary widely, from severe and life-threatening perinatal fractures to individuals with a minimal tendency for repeated fractures, skeletal deformities, and a normal stature and lifespan. The clinical spectrum also includes individuals with varying degrees of disabling skeletal deformities and short stature. Radiographic signs of osteogenesis imperfecta may show long bone deformities, such as bowing of the tibias and femurs, bones resembling pencils in shape and tapering, cortical thinning and rarefaction, pathological fractures in different stages of healing, bone shortening, and vertebral wedging. Consequently, COL1A1/2-related osteogenesis imperfecta is categorized into four sub-types (I, II, III, and IV), based on the variety of radioclinical features.

Osteogenesis imperfecta comprises a set of genetic disorders known as osteoporosis syndromes, marked by compromised intramembranous ossification due to abnormal type I collagen synthesis. Clinically, it presents with fragile bones, loose joints, delicate soft tissues, and blue sclerae, which result from scleral transparency. Sillence's classification system categorizes osteogenesis imperfecta into four subtypes. The more severe forms appear in utero, characterized by numerous fractures and limb deformities, while milder forms cause recurrent fractures following minor trauma. Radiologically, it is associated with widespread osteoporosis and frequent fractures. Additionally, defective ossification of the skull is evident through numerous Wormian bones and significantly open fontanels.

Mucopolysaccharidosis(Dysostosis Multiplex)

Mucopolysaccharidosis (MPS) represents a group of osteochondrodysplasias frequently encountered in clinical practice. MPS can lead to a broad range of clinical and radiological manifestations, from mild skeletal and systemic involvement to severe, life-threatening conditions. It results from a contiguous gene duplication or deletion syndrome involving multiple genes. All forms of MPS are inherited in an autosomal recessive manner, with the exception of MPS II, known as Hunter syndrome, which is X-linked. They are caused by an abnormal function of the lysosomal enzymes, which blocks degradation of mucopolysaccharides and leads to accumulation of harmful byproducts, namely, heparan sulfate, dermatan sulfate, and keratan sulfate. The resulting cellular malfunction can lead to a diverse array of skeletal and visceral manifestations. MPS have been subcategorized according to the type of enzyme inadequacy and glycoprotein accumulated.

Dysostosis multiplex refers to the skeletal abnormalities observed in mucopolysaccharidoses, a group of lysosomal storage disorders characterized by deficient or defective enzymes necessary for breaking down glycosaminoglycans, as seen in conditions like Hurler and Hunter diseases. This phenotype is common to all mucopolysaccharidoses, varying only in severity. Clinically, it presents with distinct coarse facial features, corneal clouding, short stature, and hepatosplenomegaly. Radiologically, dysostosis multiplex is identified by a large, thick skull, J-shaped sella turcica, robust clavicles, paddle- or oar-shaped ribs, hook-shaped vertebral bodies with posterior scalloping, comma-shaped ilia, broadened diaphyses and narrowed metaphyses of long bones, proximally pointed metacarpals, and bullet-shaped phalanges.

Cleidocranial dysostosis

Cleidocranial dysostosis, a general skeletal disorder, is characterized by deformities of the collarbone (cleido-) and skull (cranium), which are commonly present in affected individuals. Typical characteristics include underdeveloped or absent collarbones, allowing the shoulders to be brought close together, a delayed closure of the front of the skull, a prominent forehead, wide-set eyes, abnormal teeth, and a flat nose.:

• Partly or completely missing collarbones
• A soft spot or larger soft area in the top of the head where the fontanelle failed to close.
• Bones and joints are underdeveloped.
• The permanent teeth include supernumerary teeth.
• Permanent teeth not erupting
• Bossing (bulging) of the forehead.
• Hypertelorism

Cleidocranial dysplasia is usually marked by a clavicular defect (cleido-) and the late closure of cranial sutures (cranio-). Clinically, it presents with mild craniofacial dysmorphism, delayed fontanel closure, dental anomalies, and clavicular hypoplasia, which results in highly mobile shoulders that can meet at the midline. Generally, patients experience a benign course with no significant physical disabilities.

Radiologically, it is characterized by impaired calvarial ossification with numerous Wormian bones, delayed fontanel and suture closure. Clavicle aplasia or hypoplasia, typically in the middle and lateral thirds, may be symmetrical or asymmetrical. Additionally, the scapulae and glenoid fossa are undersized. Delayed ossification of the pubic, ischial bones, and sacrum leads to broad pubic symphyses and sacroiliac joints. Pseudoepiphyses are observed at the bases of metacarpals and metatarsals, and the distal phalanges tend to be underdeveloped.

Fibrous dysplasia(McCune-Albright syndrome)

Fibrous dysplasia leads to the thinning of bones and the development of growths or lesions within one or more bones in the human body. These lesions, resembling tumors, involve the replacement of medullary bone with fibrous tissue, resulting in the enlargement and weakening of the affected bone areas. Lesions, particularly when they affect the skull or facial bones, can lead to visible deformities. While the skull is frequently involved, it is not always the case, and fibrous dysplasia can affect any bone.

McCune–Albright syndrome is distinguished by a triad of café-au-lait spots, early onset puberty, and polyostotic fibrous dysplasia. Pain, pathological fractures, and bone deformities may accompany fibrous dysplasia in the limbs. Craniofacial involvement can lead to proptosis, facial asymmetry, as well as vision and hearing loss. The typical radiological sign of fibrous dysplasia is a "ground glass" appearance in the bone marrow, presenting as geographic, elongated, and expansile lesions. There should be no periostitis. The "shepherd’s crook deformity" often refers to a proximal femoral lesion with bowing.

Computed Tomography scans can more clearly reveal craniofacial lesions, which may appear both sclerotic and lytic. Mazabraud syndrome involves fibrous dysplasia along with single or multiple intramuscular myxomas near the bone lesions.

Langer–Giedion syndrome

Langer–Giedion syndrome, a rare genetic disorder, arises from the deletion of chromosomal material. Typically diagnosed at birth or during early childhood, it is characterized by mild to moderate intellectual challenges, short stature, distinctive facial features, a small head, and skeletal anomalies, including protruding bony growths.

Maffucci syndrome

Maffucci syndrome is an irregular condition marked by multiple enchondromas coupled with numerous simple or cavernous soft tissue hemangiomas. Lymphangiomas may also be present..

Patients appear normal at birth, with the syndrome manifesting during childhood and puberty. The enchondromas impact the extremities, and their distribution is asymmetrical..

Osteosclerosis

Osteosclerosis, characterized by an increase in bone density, is typically identified on an X-ray as a white area, indicating a significant elevation in bone density.

Differential diagnosis

Juvenile idiopathic arthritis can closely resemble the clinical presentation of certain osteochondrodysplasias or genetic skeletal dysplasias, as both conditions may present with swollen, stiff, and deformed joints.

Type II collagen disorders, caused by variants in the COL2A1 gene, can lead to mild or severe disease. The severe form can be lethal within weeks of birth, with infants presenting clear signs such as disproportionate short stature, skeletal dysplasia, distinctive eye abnormalities, and cleft palate. Infants with a mild form may exhibit only arthritis at birth, which can progress to a more severe condition later in life. Early diagnosis is challenging, and type II collagenopathies often show significant phenotypic overlap with conditions like MPS. Guidelines exist to help healthcare professionals recognize these conditions and their symptoms to support efficient diagnosis.

Management

The timely management of skeletal dysplasia is crucial for preventing functional decline. The rarity of the disorders causing skeletal dysplasia makes management challenging, especially when patients lack access to specialized physicians.

Comprehensive guidelines exist for managing various aspects of skeletal dysplasia, including craniofacial and spinal manifestations, type II collagen disorders, pregnancy in individuals with skeletal dysplasia, peri-operative care, and foramen magnum stenosis in achondroplasia. Additionally, written and video resources are available to support patients with skeletal dysplasia and their caregivers.

Emerging therapies for genetic skeletal dysplasias include enzyme replacement therapy, small molecule therapy, hematopoietic stem cell transplantation, and gene therapy. These therapies aim to prevent disease progression and improve quality of life. Enzyme replacement therapies are effective for some mucopolysaccharidoses and Gaucher disease. Studies have shown the effectiveness of enzyme replacement therapy. Hematopoietic stem cell transplantation can be life-saving for certain conditions, such as malignant infantile osteopetrosis.

Despite treatments like enzyme replacement therapy and stem cell transplantation, individuals with skeletal dysplasia often need orthopedic surgery and other disease management interventions. There is a scarcity of information to support these patients, as most physicians may encounter only one or two cases of skeletal dysplasia in their careers. However, guidelines exist to support best practices in managing various aspects of skeletal dysplasia, including craniofacial issues, spinal disorders, diagnosis and management of type II collagen disorders, pregnancy in individuals with skeletal dysplasia, peri-operative management, and foramen magnum stenosis in achondroplasia.