Skeletal Dysplasia

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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.

Groups of conditions organized according to their molecular bases;

• FGFR3 chondrodysplasia group
• Type 2 collagen group and similar disorders
• Type 11 collagen group
• Sulfation disorders group
• Perlecan group
• Aggrecan group
• Filamin group and related disorders
• TRPV4 group

Conditions can be grouped based on their clinical presentations;

• Short-rib dysplasias group (may include polydactyly)
• Group comprising multiple epiphyseal dysplasia and pseudoachondroplasia
• Metaphyseal dysplasias
• Spondylometaphyseal dysplasias (SMD)
• Spondylo-epi-(meta)-physeal dysplasias (SE(M)D)
• Severe spondylodysplastic dysplasias
• Acromelic dysplasias (affecting limb extremities)
• 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 disorder and the most common cause of dwarfism. It's also the most prevalent form of non-lethal osteochondrodysplasia or skeletal dysplasia, with a frequency of about 1 in 25,000 births. Individuals with achondroplasia typically have short stature, with adult males averaging 131 cm (4 feet, 3 inches) and females 123 cm (4 feet, 0 inches) in height.

The condition is evident at birth, as is craniofacial abnormalities such as macrocephaly and mid-face hypoplasia. These clinical features distinguish achondroplasia from pseudoachondroplasia, where dwarfism isn't apparent at birth and craniofacial abnormalities aren't a characteristic of the condition. Plain radiography is crucial for the differential diagnosis of achondroplasia.

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[edit]

COL1A1/2-related osteogenesis imperfecta is inherited in an autosomal dominant manner. The proportion of cases caused by a De novo COL1A1 or COL1A2 mutations are the cause of osteogenesis imperfecta in the vast majority of perinatally lethal osteogenesis imperfecta, and progressively deforming osteogenesis imperfecta. In classic non-deforming osteogenesis imperfecta with blue sclerae or common variable osteogenesis imperfecta with normal sclerae, nearly 60% of cases are de novo. COL1A1/2-related osteogenesis imperfecta is identified by repeated fractures with trivial trauma, defective dentinogenesis imperfecta (DI), and hearing loss. The clinical features of COL1A1/2-related osteogenesis imperfecta can be highly variable ranging from severe and lethal perinatal fractures to individuals with minimal tendency to repeated fractures and skeletal deformities and with a normal stature and life span. In between the clinical spectrum may include individuals with various degrees of disabling skeletal deformities and short stature. The radiographic findings of osteogenesis imperfecta include; long bone deformations such as bowing of the tibias and femurs, pencil-like deformity and tapering of bones, cortical thinning and rarefaction, pathologic fractures at various degrees of healing, bone shortening and vertebral wedging. Accordingly, COL1A1/2-related osteogenesis imperfecta has been classified into four sub-types (I, II, III, and IV) built upon the diversity of the radioclinical features.

Mucopolysaccharidosis

Mucopolysaccharidoses (MPS) constitute a commonly seen group of osteochondrodysplasias. Mucopolysaccharidosis can cause a wide spectrum of clinical and radiologic manifestations ranging from mild skeletal and systemic involvement to severe life-threatening manifestations. It is caused by a contiguous gene duplication or deletion syndrome in which multiple genes are involved. All forms of MPS are inherited in an autosomal recessive pattern, except fir of MPS II; 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.

Cleidocranial dysostosis

Main article: Cleidocranial dysostosis

Cleidocranial dysostosis is a general skeletal condition named for the collarbone (cleido-) and cranium deformities which people with it often have. Common features include:

• 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

Fibrous dysplasia

Main article: Fibrous dysplasia

Fibrous dysplasia causes bone thinning and growths or lesions in one or more bones of the human body.

These lesions are tumor-like growths that consist of replacement of the medullary bone with fibrous tissue, causing the expansion and weakening of the areas of bone involved. Especially when involving the skull or facial bones, the lesions can cause externally visible deformities. The skull is often, but not necessarily, affected, and any other bones can be involved.

Langer–Giedion syndrome

Main article: Langer–Giedion syndrome

Langer–Giedion syndrome is a very rare genetic disorder caused by a deletion of chromosomal material. Diagnosis is usually made at birth or in early childhood. The features associated with this condition include mild to moderate learning difficulties, short stature, unique facial features, small head and skeletal abnormalities including bony growths projecting from the surfaces of bones.

Maffucci syndrome

Main article: Maffucci syndrome

Maffucci syndrome is a sporadic disease characterized by the presence of multiple enchondromas associated with multiple simple or cavernous soft tissue hemangiomas. Also lymphangiomas may be apparent.

Patients are normal at birth and the syndrome manifests during childhood and puberty. The enchondromas affect the extremities and their distribution is asymmetrical.

Osteosclerosis

Osteosclerosis, an elevation in bone density, is normally detected on an X-ray as an area of whiteness and is where the bone density has significantly increased.