Skeletal Dysplasia

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Introduction

Skeletal dysplasias also termed as osteochondrodysplasias are a large heterogeneous group of disorders comprising of abnormalities of bone or cartilage growth or texture. Skeletal dysplasia is a group of rare genetic disorders that affect bone growth and development. These disorders are characterized by abnormalities in the size, shape, and structure of bones, resulting in short stature, limb deformities, and other skeletal abnormalities.

They occur due to genetic mutations and their phenotype continues to evolve throughout life. Skeletal dysplasias thus differ from dysostoses which are malformations of single or multiple bones in combination, are due to abnormal blastogenesis in-utero and phenotypically remain static throughout life.

Epidemiology

About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection.

Etiology

Skeletal dysplasia is caused by mutations in genes that are responsible for bone growth and development. These mutations can be inherited from one or both parents, or they can occur spontaneously during fetal development.

Clinical Signs and Symptoms

The symptoms of skeletal dysplasia can vary widely depending on the specific type of disorder and the severity of the condition. However, some common symptoms include:

Short stature: Individuals with skeletal dysplasia are typically shorter than average for their age and gender.

Limb deformities: Skeletal dysplasia can cause abnormalities in the size and shape of the limbs, including bowed legs, knock-knees, and curved spine.

Joint pain: Skeletal dysplasia can cause joint pain and stiffness, particularly in the hips and knees.

Breathing difficulties: In some cases, skeletal dysplasia can cause narrowing of the airways, leading to breathing difficulties.

Dental abnormalities: Some types of skeletal dysplasia can cause abnormalities in the teeth, including missing or misshapen teeth.

Skeletal dysplasia Classification

The first 8 groups of conditions in the 2010 nosology are separated according to the molecular basis of the disease: FGFR3, type 2 collagen, type 11 collagen, sulfation disorders, perlecan, aggrecan, filamin, and TRPV4.

The other 32 groups are organized according to their clinical and radiographic presentation. The prefix acro- refers to the extremities (hands and feet), meso- to the middle portion (ulna and radius, tibia and fibula), rhizo- to the proximal portion (femur and humerus), spondylo- to the spine, epi- to the epiphyses, and meta- to the metaphyses. For example, if only the hands and feet are shorter, one would consult the acromelic group of conditions, whereas if the spine and metaphyses are affected, one would consult the spondylometaphyseal dysplasias.

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;

1. Short-ribs dysplasias (with or without polydactyly) group

2. Multiple epiphyseal dysplasia and pseudoachondroplasia group

3. Metaphyseal dysplasias

4. Spondylometaphyseal dysplasias (SMD)

5. Spondylo-epi-(meta)-physeal dysplasias (SE(M)D)

6. Severe spondylodysplastic dysplasias

7. Acromelic dysplasias (extremities of the limbs)

8. Acromesomelic dysplasias (extremities and middle portion of the limbs)

9. Mesomelic and rhizo-mesomelic dysplasias (proximal and middle portions of the limbs)

10. Bent bones dysplasias

11. Slender bone dysplasia group

12. Dysplasias with multiple joint dislocations

13. Chondrodysplasia punctata (CDP) group

14. Neonatal osteosclerotic dysplasias

15. Increased bone density group (without modification of bone shape)

16. Increased bone density group with metaphyseal and/or diaphyseal involvement

17. Osteogenesis imperfecta and decreased bone density group

18. Abnormal mineralization group

19. Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)

20. Osteolysis group

21. Disorganized development of skeletal components group

22. Overgrowth syndromes with skeletal involvement

23. Genetic inflammatory/rheumatoid-like osteoarthropathies

24. Cleidocranial dysplasia and isolated cranial ossification defects group

25. Craniosynostosis syndromes

26. Dysostoses with predominant craniofacial involvement

27. Dysostoses with predominant vertebral with and without costal involvement

28. Patellar dysostoses

29. Brachydactylies (with or without extraskeletal manifestations)

30. Limb hypoplasia-reduction defects group

31. Polydactyly-Syndactyly-Triphalangism group

32. Defects in joint formation and synostoses

Achondroplasia

Main article: Achondroplasia

Achondroplasia is a type of autosomal dominant genetic disorder that is the most common cause of dwarfism. It is also the most common type of non-lethal osteochondrodysplasia or skeletal dysplasia. The prevalence is approximately 1 in 25,000 births. Achondroplastic dwarfs have short stature, with an average adult height of 131 cm (4 feet, 3 inches) for males and 123 cm (4 feet, 0 inches) for females. In achondroplasia the dwarfism is readily apparent at birth. likewise, craniofacial abnormalities in the form of macrocephaly and mid-face hypoplasia are present at birth. The previous clinical findings differentiate between achondroplasia and pseudoachondroplasia in which dwarfism is not recognizable at birth and craniofacial abnormalities are not considered a disease feature. Plain radiography plays an additional and important role in 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.