Atelosteogenesis type 3

Alternate Names

AOIII; AO3

Summary

Atelosteogenesis type 3 is a disorder that affects the development of bones throughout the body. Affected individuals are born with inward- and upward-turning feet (clubfeet) and dislocations of the hips, knees, and elbows. Bones in the spine, rib cage, pelvis, and limbs may be underdeveloped or in some cases absent. As a result of the limb bone abnormalities, individuals with this condition have very short arms and legs.

Epidemiology

The prevalence of AOIII is unknown. Less than 25 affected patients have been reported.

Cause

Mutations in the FLNB gene cause atelosteogenesis type 3. The FLNB gene provides instructions for making a protein called filamin B. This protein helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. Filamin B attaches (binds) to another protein called actin and helps the actin to form the branching network of filaments that makes up the cytoskeleton. It also links actin to many other proteins to perform various functions within the cell, including the cell signaling that helps determine how the cytoskeleton will change as tissues grow and take shape during development.

Filamin B is especially important in the development of the skeleton before birth. It is active (expressed) in the cell membranes of cartilage-forming cells (chondrocytes). Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone (a process called ossification), except for the cartilage that continues to cover and protect the ends of bones and is present in the nose, airways (trachea and bronchi), and external ears. Filamin B appears to be important for normal cell growth and division (proliferation) and maturation (differentiation) of chondrocytes and for the ossification of cartilage.

FLNB gene mutations that cause atelosteogenesis type 3 change single protein building blocks (amino acids) in the filamin B protein or delete a small section of the protein sequence, resulting in an abnormal protein. This abnormal protein appears to have a new, atypical function that interferes with the proliferation or differentiation of chondrocytes, impairing ossification and leading to the signs and symptoms of atelosteogenesis type 3.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Signs and symptoms

Affected individuals are born with inward- and upward-turning feet (clubfeet) and dislocations of the hips, knees, and elbows. Bones in the spine, rib cage, pelvis, and limbs may be underdeveloped or in some cases absent. As a result of the limb bone abnormalities, individuals with this condition have very short arms and legs. Their hands and feet are wide, with broad fingers and toes that may be permanently bent (camptodactyly) or fused together (syndactyly). Characteristic facial features include a broad forehead, wide-set eyes (hypertelorism), and an underdeveloped nose. About half of affected individuals have an opening in the roof of the mouth (a cleft palate.)

Individuals with atelosteogenesis type 3 typically have an underdeveloped rib cage that affects the development and functioning of the lungs. As a result, affected individuals are usually stillborn or die shortly after birth from respiratory failure. Some affected individuals survive longer, usually with intensive medical support. They typically experience further respiratory problems as a result of weakness of the airways that can lead to partial closing, short pauses in breathing (apnea), or frequent infections.

People with atelosteogenesis type 3 who survive past the newborn period may have learning disabilities and delayed language skills, which are probably caused by low levels of oxygen in the brain due to respiratory problems. As a result of their orthopedic abnormalities, they also have delayed development of motor skills such as standing and walking.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 30%-79% of people have these symptoms

• Coronal cleft vertebrae
• Distal tapering femur(Tapering of outermost end of thighbone)
• Elbow dislocation(Dislocations of the elbows)
• Hip dislocation(Dislocated hips)
• Knee dislocation
• Patellar dislocation(Dislocated kneecap)
• Respiratory insufficiency(Respiratory impairment)
• Short tubular bones of the hand
• Talipes equinovarus(Club feet)
• Vertebral hypoplasia(Underdeveloped vertebrae)

5%-29% of people have these symptoms

• Abnormal cervical curvature(Abnormal neck curve)
• Absent humerus(Absent long bone in upper arm)
• Absent radius(Missing outer large bone of forearm)
• Club-shaped distal femur(Club-shaped outermost end of thighbone)
• Epiphyseal stippling of the humerus
• Fibular aplasia(Absent calf bone)
• Global developmental delay
• Hand clenching(Clenched hands)
• High palate(Elevated palate)
• Laryngotracheomalacia
• Micrognathia(Little lower jaw)
• Polyhydramnios(High levels of amniotic fluid)
• Short tibia(Short shinbone)
• Thoracic hypoplasia(Small chest)
• Thoracolumbar kyphosis(Ulnar deviation of the wrist)

Diagnosis

The diagnosis is established after a full skeletal x-ray survey and confirmed with genetic testing. AOIII demonstrates less delay of normal ossification compared to AOI.

Antenatal diagnosis Prenatal diagnosis is possible by ultrasound from 20 weeks onward and by prenatal genetic testing in case of family history.

Treatment

Cervical spine instability

• Asymptomatic infants: Early intervention to improve cervical spine stability using posterior arthrodesis is successful.
• Infants w/myelopathic signs: Function can be stabilized &/or improved by combination of anterior decompression & circumferential arthrodesis.
• Care must be taken to minimize extension of cervical spine intraoperatively.

Scoliosis

• Medical treatment per orthopedist
• No effective surgical intervention has been described.

Large joint dislocations

• Operative reduction is usually required.
• Conservative, nonsurgical management of hip dislocation in Larsen syndrome is often unsuccessful.

Clubfeet

• Routine management per orthopedist

Laryngotrach-eomalacia

• Anesthetic agents that exhibit more rapid induction & recovery are preferred.
• Due to ↑ risk for airway complications in individuals w/Larsen syndrome

Cleft palate

• Treated by multidisciplinary craniofacial team when possible

Hearing loss

• Possible treatments incl: hearing aids, vibrotactile devices, & cochlear implantation (see Hereditary Hearing Loss and Deafness Overview).

NIH genetic and rare disease info

• NIH info on Atelosteogenesis type 3

Atelosteogenesis type 3 is a rare disease.

Atelosteogenesis type 3 Resources
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