Atelosteogenesis type 1

Other Names: AOI; Giant cell chondrodysplasia; Spondylohumerofemoral hypoplasia

Atelosteogenesis type 1 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.

Epidemiology

Atelosteogenesis type 1 is a rare disorder; its exact prevalence is unknown. Only a few dozen affected individuals have been identified.

Cause

Mutations in the FLNB gene cause atelosteogenesis type 1. 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. Filamin B 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 1 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 1.

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. Almost all 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 neonates are stillborn or die rapidly after birth and present clinically with severe short-limbed dwarfism, dislocated hip, knee and elbow joints, club feet and if born alive have cardiorespiratory failure. Craniofacial dysmorphism describes a prominent forehead, hypertelorism, a depressed nasal bridge with a grooved tip, micrognathia and frequently a cleft palate. There is a continuum with overlapping clinical findings between atelosteogenesis I, atelosteogenesis III and boomerang dysplasia.

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

• Abnormal ossification involving the femoral head and neck
• Abnormality of fibula morphology(Abnormality of the calf bone)
• Absent or minimally ossified vertebral bodies
• Brachydactyly(Short fingers or toes)
• Coronal cleft vertebrae
• Midface retrusion(Decreased size of midface)
• Narrow chest(Low chest circumference)
• Pulmonary hypoplasia(Small lung)
• Rhizomelia(Disproportionately short upper portion of limb)
• Short femur(Short thighbone)
• Talipes equinovarus(Club feet)

5%-29% of people have these symptoms

• Abnormal pancreatic duct morphology
• Cleft palate(Cleft roof of mouth)
• Enlarged cisterna magna
• Hypertelorism(Wide-set eyes)
• Joint dislocation(Joint dislocations)
• Laryngotracheal stenosis
• Low-set ears(Low set ears)
• Malrotation of colon
• Micrognathia(Little lower jaw)
• Multiple renal cysts(Multiple kidney cysts)
• Neonatal short-trunk short stature
• Platyspondyly(Flattened vertebrae)
• Polyhydramnios(High levels of amniotic fluid)
• Proptosis(Bulging eye)
• Retinal dysplasia
• Scoliosis
• Telecanthus(Corners of eye widely separated)

Diagnosis

Diagnosis can be confirmed from skeletal radiographs, chondro-osseous histopathology and genetic testing. Distinctive radiographic findings comprise severe platyspondyly, distally tapered; shortened, incomplete or absent humeri and femurs; shortened or bowed radii, ulnas, and tibias; hypoplastic pelvis and fibulas; and deficient ossification of the metacarpals, middle and proximal phalanges.

Differential diagnosis Differential diagnosis comprises other skeletal dysplasias with severe short-limbed dwarfism such as campomelic dysplasia, Ellis-van Creveld syndrome, achondroplasia, metatropic dysplasia, Roberts syndrome, short rib-polydactyly syndrome, and thanatophoric dysplasia. Other, differential diagnosis includes achondrogenesis, hypophosphatasia, and osteogenesis imperfecta.

Antenatal diagnosis Prenatal ultrasound can detect bone dysplasia and other manifestation and plays an important role in early detection and diagnosis. Prenatal ultrasound findings for AOI may include severe limb shortening and deficient ossification of the long bones, shortened flaring or absent humeri and femurs from 18 weeks onwards. Other skeletal abnormalities as well as some facial dysmorphic features may be detectable.

Treatment

Palliative care is offered to newborns suffering from AOI.

Prognosis

Prognosis is poor. Death is often due to a combination of pulmonary hypoplasia and tracheobronchomalacia early in life.

NIH genetic and rare disease info

• NIH info on Atelosteogenesis type 1

Atelosteogenesis type 1 is a rare disease.

Atelosteogenesis type 1 Resources
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