Skeletal dysplasia

Overview

Skeletal dysplasias are a collection of over 450 heritable bone abnormalities. They frequently show with disproportion, radiographic abnormalities, and, on rare occasions, other organ system abnormalities throughout the newborn period. It is critical to get a specific diagnosis to aid in management, family recurrence, and identifying those illnesses that are highly related with mortality in order to provide better therapeutic care.

Long-term management of these illnesses is dependent on an awareness of the associated skeletal system anomalies, and these children benefit most from a team approach to health care surveillance.

 

What is skeletal dysplasia?

Skeletal dysplasias, also known as osteochondrodysplasias, are a category of heritable illnesses defined by anomalies in cartilage and bone formation, resulting in aberrant skeleton shape and size, as well as disproportion of the long bones, spine, and skull. Natural histories, prognoses, inheritance patterns, and etiopathogenetic processes differ.

Skeletal dysplasias, characterized by short stature (height three or more standard deviations below the mean height for age), can be accompanied by involvement of other systems, including the neurologic, respiratory, and cardiac systems.

The molecular foundation for the vast majority of these illnesses is now understood. Achondroplasia, osteogenesis imperfecta, thanatophoric dysplasia, campomelic dysplasia, and hypochondroplasia are all common skeletal dysplasias. 

 

Embryology

The skeletal system develops through two separate processes: endochondral and membraneous ossification. Most of the mammalian appendicular skeleton is formed by endochondral ossification, which includes a series of carefully regulated developmental processes. These include embryonic limb bud start and expansion from lateral plate mesoderm, specification of mesenchymal cells for future limb parts, mesenchymal condensations initiating cartilage differentiation, ossification of growing bones, and lastly, normal postnatal growth and maturation.

Membraneous ossification is the process through which condensing mesenchymal cells transform nearly directly into bone cells. The skull, lateral clavicle, and pubis bones are formed through mesenchymal ossification. Postnatal growth continues through the cartilage growth plate, where resting chondrocytes proliferate, hypertrophy, and finally apoptose to become the building framework of bone. Skeleton formation is governed by a number of biological pathways (genes), and disruptions to these intricately coordinated processes can result in skeletal dysplasias.

 

Pathophysiology

Until skeletal maturity, cartilage remains at the ends of bone in the growth plate, which is in charge of longitudinal bone formation. Bone finally replaces the cartilaginous template. Many of the genes that are altered in skeletal dysplasias encode proteins that are essential in the growth plate.

Understanding the involvement in growth plate function provides vital clues into the molecular pathophysiology of skeletal dysplasia and makes it simple to understand how a certain mutation creates a specific phenotype. The following are some examples of genes that are involved in growth plate chondrocytes and skeletal dysplasia :

Mutations in type II collagen produce a wide range of spondyloepiphyseal dysplasia diseases (ie, spondyloepiphyseal dysplasia congenita, Kniest dysplasia, Stickler syndrome, and achondrogenesis). Multiple epiphyseal dysplasia is caused by mutations in the smaller matrix components, such as type IX collagen and cartilage oligomeric protein.

 

Epidemiology

  • Skeletal dysplasias account for about 5% of all congenital abnormalities.
  • Skeletal dysplasias occur at a rate of about one in every 4000-5000 births. Because many skeletal dysplasias do not emerge until low stature, joint complaints, or other difficulties arise throughout childhood, the true prevalence may be twice as high.
  • The incidence of lethal skeletal dysplasias is predicted to be 0.95 per 10,000 deliveries.
  • Thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta, and achondrogenesis are the four most frequent skeletal dysplasias. Thanatophoric dysplasia and achondroplasia are responsible for 62% of all deadly skeletal dysplasias.
  • The most prevalent nonlethal skeletal abnormality is achondroplasia.

 

Types of skeletal dysplasia

A brief overview of the most common skeletal dysplasias is included below.

Achondroplasia

This is the most prevalent nonlethal skeletal dysplasia, affecting 250,000 people globally and occuring in 1:26,000-1:28,000 live births.

A G380R mutation in the FGFR3 transmembrane region is the genetic mechanism underlying achondroplasia. It is a gain-of-function mutation that is present in 99 percent of affected people. Inheritance is autosomal dominant, with de novo mutations accounting for 80% of instances.

 

Major characteristics of achondroplasia include the following:

  • Disproportionate short stature with proximal shortening of the arms and legs and large head with frontal bossing
  • Trident hand configuration
  • Average final height: 130 cm for men and 125 cm for women
  • Normal intelligence and lifespan

 

Major complications include the following:

  • Craniocervical junction compression
  • Middle ear infections
  • Obstructive apnea
  • Spinal stenosis

Osteogenesis imperfecta

Osteogenesis imperfecta (OI), a heterogeneous collection of heritable connective tissue abnormalities, is another prevalent skeletal dysplasia, with an incidence of 1:15,000-1:20,000 newborns.

Mutations in the type 1 collagen genes COLA1 and COLA2 are the molecular pathways underlying OI types I-IV. Types V-XII are the rarer varieties.

 

Inheritance in OI is as follows:

  • Types I-IV (Sillence classification, 85% of cases): Autosomal dominant
  • Types V-XII: Autosomal recessive, except for type V (autosomal dominant)

Major characteristics of the most common forms of OI are as follows.


OI type I - mild form with diagnosis in early childhood

This is characterized by the following:

  • Sclera may be blue
  • Dentinogenesis imperfecta (subtype IB)
  • Normal stature reached
  • Hearing loss in 50% of patients

OI type II - perinatal lethal form

The condition is characterized as follows:

  • Patients may survive the neonatal period
  • Later mortality can occur secondary to pneumonia and respiratory insufficiency

 

OI type III - progressive deforming form

This form is characterized as follows:

  • Moderate deformity at birth
  • Development of chest wall deformities
  • Most patients are wheelchair dependent
  • Very short stature
  • Variable sclera
  • Dentinogenesis imperfecta and hearing loss are common. 

OI type IV - moderately severe form

Characteristics include the following:

  • Mild to moderate bone deformity
  • Variable short stature
  • Hearing loss occurs in some families
  • Variable sclera

 

Symptoms of skeletal disorders

Newborns with established skeletal abnormalities present with disproportion throughout the newborn phase. There are several common symptoms depending on the skeletal disease, such as relative macrocephaly, a narrow chest appearance relative to the abdomen, rhizomelia (short upper portion extremity), mesomelia (short mid-portion extremity), and usually brachydactyly (short hands, including phalanges).

Many of the deadly skeletal abnormalities, achondroplasia, campomelic dysplasia, chondrodysplasia punctate (all types), type II collagen disorders, Larsen syndrome, and the mucopolysaccharidoses, are associated with a flat nasal bridge, frontal bossing, and midface hypoplasia (most forms).

Type II collagen diseases, acrofacial dysostoses, Robinow syndrome, and many of the deadly skeletal dysplasias are among the conditions associated with micrognathia. The Robin-Pierre Robin sequence (small mandible and posterior cleft palate) is connected with these conditions and must be considered.

Because of the mandibular anomaly and the safety of the airway, few of these babies are delivered using EXIT techniques, but some of these children require post-delivery intubation and recurrent tracheostomies until final surgery for jaw retraction or time, awaiting facial growth. If the infant has the Pierre-Robin sequence, the cleft palate repair should be postponed to the craniofacial surgery team or plastic surgeons.


Skeletal dysplasia symptoms in the arms and legs

Skeletal dysplasia often causes irregular growth in a child’s arms and legs. A child with skeletal dysplasia may have:

  • Short arms and legs 
  • Stiff or immobile joints
  • Hips and other joints that become easily dislocated
  • One leg shorter than the other (leg-length discrepancy)
  • legs that bow outward (bowlegs) or inward (knock knees)
  • One or both feet that curve inward (clubfoot)

 

Skeletal dysplasia symptoms in the spine and torso

Skeletal dysplasia can cause problems in the development of the spine, neck, and chest. Complications may include:

  • Small chest cavity and missing or fused ribs 
  • Extra bone growth in the spinal column that presses against the spinal cord 
  • Spinal curvatures that grow too large (kyphosis, lordosis), or curve in the wrong direction 
  • Cervical spine instability

Skeletal dysplasia symptoms in other parts of the body

Skeletal dysplasia can interfere with the healthy development of other areas of the body. These symptoms can include:

  • Disproportionately huge head in comparison to the rest of the body prominent forehead undeveloped facial features
  • An accumulation of fluid surrounding the brain (hydrocephalus)
  • Frequent ear infections, which may result in hearing loss

 

Diagnosis 

Skeletal dysplasias necessitate a multidisciplinary approach that includes radiologic and genetic testing. This method is necessary for correct diagnosis and the selection of the appropriate treatment alternatives, as well as accurate counseling on results and the risk of recurrence.

The most helpful method of investigating the dysplastic skeleton is still conventional radiography evaluation. The skull, chest , spine and lateral views, including a specialized lateral view of the cervical spine), pelvis , tubular bone, and/or hands and feet should all be included in the skeletal survey 

Furthermore, genetic testing is important in the diagnosis and therapy of skeletal dysplasias. Molecular diagnostic approaches have identified the underlying gene abnormalities in around two-thirds of recognized skeletal dysplasias.


Diagnostic Considerations 

These include the following:

  • Cardiopulmonary diseases include dysgammaglobulinemia, familial dysautonomia, severe recurring pneumonias with bronchiectasis or intractable asthma, and congenital heart problems, particularly cyanotic variants.
  • Chromosomal abnormalities
  • Pituitary skeletal dysplasia, growth hormone insufficiency, Mauriac syndrome, and Shwachman syndrome are examples of endocrine abnormalities.
  • Inborn metabolic defects, such as lysosomal storage disorders
  • Intrauterine growth retardation caused by medications, ethanol, infections such as rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency caused by chromosomal defects; and placental insufficiency
  • Nutritional illnesses caused by insufficient calorie intake, such as cleft palate, anorexia, deprivation, eating difficulties, and severe malnutrition, such as kwashiorkor or marasmus.
  • Primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome are examples of primary growth disorders.

 

Prenatal Diagnosis of Osteochondrodyslasias

Rapid developments in both imaging modalities and the aforementioned molecular diagnostics have increased our ability to detect osteochondrodysplasias during pregnancy. In families where one parent has an autosomal dominant condition, molecular diagnostics by invasive procedures or ultrasound imaging can help determine if the unborn will be similarly afflicted.

The same strategy described above can be used for at-risk families with a previously afflicted kid with an autosomal recessive condition. However, afflicted newborns with skeletal dysplasias are frequently the first children in their families to be impacted.

Many pregnant women are offered a variety of noninvasive tests to identify whether or not their babies are at risk for genetic diseases. These molecular screening panels are for autosomal recessive and X-linked illnesses, including skeletal dysplasias like diastrophic dysplasia; however, many genes and mutations that might cause skeletal dysplasias are currently not included in these panels.

If one parent tests positive for a disorder, the other parent is usually tested as well, establishing a baseline risk for a problem. First trimester ultrasound analysis, which is often used to detect aneuploidy, is also useful in detecting severe, generally fatal skeletal dysplasias such as osteogenesis imperfecta, thanatophoric dysplasia, and short-rib polydactyly syndromes, to name a few.

If a newborn with a skeletal disease shows aberrant ultrasound results in the first trimester, such as a short crown-rump length for gestational age and increased nuchal fold thickness, the fetus has a severe, perhaps deadly skeletal dysplasia.

Many prenatal skeletal dysplasias are discovered in the late second trimester, when many pregnant women are checked for congenital defects by ultrasonography. Early detection (with and without a clear diagnosis) allows for preparation before to birth.

This covers a discussion of aggressive resuscitation, correct consultant assembly, cord blood collection for molecular diagnosis, and a smoother transition for the fetus from the prenatal to newborn era. This is especially critical if the newborn is expected to have a serious but non-fatal bone condition.

 

Management

Medical Care

  • The diagnosis of skeletal dysplasias during pregnancy may have an impact on the obstetric and perinatal management of afflicted newborns. A fetus with achondroplasia, for example, should have a cesarean birth to reduce the risk of CNS issues from vaginal delivery due to cephalopelvic disproportion induced by a big fetal head and instability of the fetal spine at the C1-C2 level.
  • The treatment is helpful. Individuals with skeletal dysplasia should get medical treatment aimed at avoiding neurologic and orthopedic consequences caused by spinal cord compression, joint instability, and long bone deformity.
  • Neonatal resuscitation and ventilatory support should be administered. The vast majority of newborns born with deadly skeletal dysplasias are stillborn or die within hours of delivery. Some newborns with severe respiratory distress (e.g., asphyxiating thoracic dysplasia) may survive if they are given breathing assistance.
  • In severe cases, adenotonsillectomy, weight loss, continuous airway pressure via nasal mask, and tracheostomy may be used to treat obstructive sleep apnea.
  • It is critical to keep track of a child's height, weight, and head circumference if he or she has skeletal dysplasia. Specific growth charts, such as those for achondroplasia, are available. Obesity should be avoided at all costs.
  • Some patients with skeletal dysplasia have been treated with recombinant human growth hormone. Because the abnormality is created by faulty bone development in response to the stimulus growth hormone secreted at normal levels, growth hormone is not a plausible therapy for the low height associated with skeletal dysplasia. Short-term therapy in patients with achondroplasia and hypochondroplasia resulted in an increase in growth velocity that lasted for up to 4-6 years. More research is required to prove any long-term positive benefits.

Surgical Care

Surgical intervention depends on the signs and symptoms of skeletal dysplasia as follows:

  • To avoid advancement to thoracic kyphosis, a Milwaukee brace equipped with kyphosis cushions can be used to regulate thoracolumbar kyphosis.
  • Anterior and posterior fusion is the best treatment for progressive kyphosis, which can lead to spinal cord compression and spastic paraparesis. Extensive lumbar laminectomy is used to treat lumbar lordosis with spinal stenosis. To alleviate edema of the cervicomedullary cord caused by bone compression, surgical decompression is necessary.
  • Progressive scoliosis requires spinal fusion.
  • The Ilizarov operation, often known as a bone-lengthening technique, is an osteogenetic distractive osteotomy used to mechanically stimulate diaphyseal bone development. In rare cases, the surgery can stretch limbs, rotate, angulate, and straighten bent or malformed long bones, and give reparative hope. Although recent experience has been more beneficial (reduced incidence of discomfort, infections, and neurologic/vascular damage), such surgical surgery is recommended to be postponed until the young person is ready to make an educated decision.
  • Patients with skeletal dysplasia caused by congenital immune deficiencies, mucopolysaccharidosis, lipidosis, osteopetrosis, or Gaucher disease may benefit from bone marrow transplantation.
  • Because of a narrow pelvis, moms with certain skeletal dysplasias (for example, achondroplasia) must have a cesarean birth (cephalopelvic disproportion secondary to marked pelvic contracture). In the case of achondroplasia, general anesthesia should be considered since the mother is likely to have spinal stenosis, which increases the risk of spinal or epidural anesthesia.

 

Complications

  • Polyhydramnios and fetal hydrops are common intrauterine consequences in individuals with deadly chondrodystrophy, such as achondrogenesis or thanatophoric dysplasia. Polyhydramnios is occasionally encountered in individuals with nonlethal chondrodystrophy, such as achondroplasia.
  • Respiratory complications: Patients with several kinds of chondrodystrophy, such as asphyxiating thoracic dystrophy, have respiratory discomfort due to a tiny chest, small lungs, a small or collapsing trachea, or a small upper airway. Infants can snore, have upper airway blockage, or have hypoxic episodes.
  • Hydrocephalus can arise in numerous kinds of skeletal dysplasia, most notably achondroplasia, metatropic dysplasia, and other diseases that impair the base of the skull, resulting in a tiny foramen magnum and jugular foramen.
  • Skeletal complications: In individuals with chondrodystrophys such as achondroplasia, SED congenita, and Morquio syndrome, instability of the C1-C2 cervical spine can lead to spinal cord compression or nerve injury. Vertebral anomalies, hip dysplasia, tight and loose joints, osteoarthritis, bent legs, and fractures are all possible.
  • Truncal hypotonia may result in kyphoscoliosis in newborns with achondroplasia or mucopolysaccharidoses. In achondroplasia, thoracolumbar kyphosis may return to significant lordosis.
  • Otolaryngologic complications: In individuals with diastrophic dysplasia and achondroplasia, persistent middle ear infections are linked with progressive deafness. Hearing loss can be either conductive or neurosensory in nature.
  • Ophthalmologic complications: In Kniest dysplasia and SED congenita, myopia may predispose the patient to retinal detachment.
  • Malocclusions, dental crowding, and structural abnormalities of teeth can occur in people with numerous kinds of chondrodystrophy.
  • Obesity is a common concern in people with several kinds of chondrodystrophy, particularly achondroplasia.

 

Other complications

  • In individuals with certain chondrodysplasias, anesthesia can be a concern.
  • Unstable cervical vertebrae must be ruled out.
  • Malignant hyperthermia under anesthesia can develop in individuals with certain kinds of chondrodysplasia, such as osteogenesis imperfecta.
  • Women with excessively small height are prone to a variety of obstetric and gynecologic issues. Because of the mother's constricted pelvis, a cesarean birth may be necessary.

 

Prognosis

Although certain skeletal dysplasias are fatal during the birth or infancy periods, individuals with other kinds of skeletal dysplasia have normal or near-normal life expectancy. The prognosis of individuals with nonlethal skeletal dysplasias is determined by the degree of skeletal abnormalities and accompanying anomalies.

  • Some patients may have problems finding a spouse.
  • Men with skeletal dysplasia had less psychological problems and are less stigmatized than women.
  • Medical and social elements of an adult's life with skeletal dysplasia include the following:
  1. Overall, there is substantial evidence that some impediments to equal opportunity in education and work exist, and that they, together with greater social isolation, are extremely likely to have a significant impact on financial condition and, hence, quality of life. Because of the abnormality, all people with skeletal dysplasia are physically limited. Only people with significant physical disabilities face barriers to education and work.
  2. There is a significant vacuum in understanding about the medical and social experiences of people with skeletal dysplasias.
  3. Many persons with debilitating conditions are concerned about the meaning of the disability designation. To qualify for benefits such as Disability Living Allowance, it may be essential to "come out" as handicapped 
  4. Only by taking a more severe methodological approach to future research will it be feasible to provide the solid evidence-base required to influence future health and social service provision, as well as material for education and training.

 

Conclusion 

Skeletal dysplasia is a term used to describe a group of uncommon genetic illnesses that damage bones and joints and impair children's growth and development. The condition results in unusually formed bones, particularly in the skull, spine, and long bones of the arms and legs. Skeletal dysplasia causes limbs that are excessively short in comparison to the rest of the body in children.

Your child's treatment team may include specialists from our Maternal Fetal Care Center, Division of Genetics and Genomics, Orthopedic Center, Department of Neurosurgery, Division of Endocrinology, and Social Work, depending on when skeletal dysplasia is discovered and its severity. Our doctors from throughout the hospital work together on uncommon and challenging cases on a regular basis to ensure that our patients receive quality treatment that is tailored to their unique requirements.