How early during pregnancy can atelosteogenesis type 1 be detected?

The condition can typically be suspected during a detailed second-trimester anatomy ultrasound, usually between weeks 18 and 22 of pregnancy. Sonographers look for characteristic signs such as severely shortened limb bones (severe micromelia), absence or hypoplasia of the fibula and humerus, a narrow thorax, and fixed joint dislocations or clubfeet. A definitive diagnosis requires prenatal genetic testing via amniocentesis to detect mutations in the FLNB gene. What is the recurrence risk for parents who have had a child with atelosteogenesis type 1?::Because atelosteogenesis type 1 is inherited in an autosomal dominant manner and is almost always caused by a new, spontaneous (de novo) mutation in the FLNB gene, the chance of having a second affected child is generally low (around 1 percent). However, the risk is slightly higher than the general population due to the possibility of germline mosaicism, where some egg or sperm cells carry the mutation without the parent showing symptoms. What causes the severe respiratory failure in infants born with this condition?::Respiratory failure occurs primarily due to severe pulmonary hypoplasia. The infant's rib cage and thoracic vertebrae are profoundly underdeveloped, creating a chest cavity that is far too small and rigid to allow the lungs to grow normally during fetal development or to expand mechanically after birth. How do geneticists distinguish atelosteogenesis type 1 from other severe skeletal dysplasias?::Atelosteogenesis type 1 shares features with conditions like thanatophoric dysplasia and campomelic dysplasia, but it is clinically distinguished by a unique combination of specific absent limb bones (often missing fibulae or distal humeri), distinct vertebral anomalies (coronal clefting), and specific facial dysmorphisms. Definitive differentiation is accomplished through molecular sequencing of the FLNB gene.

Atelosteogenesis type 1

Atelosteogenesis type 1 is a rare, lethal skeletal disorder caused by mutations in the FLNB gene, leading to severe bone underdevelopment and respiratory failure in newborns.

Overview

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 and dislocations of the hips, knees, and elbows. Bones in the spine, rib cage, pelvis, and limbs may be underdeveloped or absent. As a result of the limb bone abnormalities, individuals with this condition have very short arms and legs. Characteristic facial features include wide-set eyes, an upturned nose with a grooved tip, and a very small lower jaw and chin. Affected individuals may also have an opening in the roof of the mouth. Males with this condition can have undescended testes.

Individuals with atelosteogenesis type 1 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.

Frequency

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

Causes

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 that gives structure to cells and allows them to change shape and move. Filamin B attaches 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 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, 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.

Learn more about the gene associated with Atelosteogenesis type 1

FLNB

Inheritance

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 de novo mutations in the gene and occur in people with no history of the disorder in their family.

Other Names for This Condition

AOI
Atelosteogenesis type I
Giant cell chondrodysplasia
Spondylohumerofemoral hypoplasia

Additional Information & Resources

Genetic Testing Information

Genetic Testing Registry: Atelosteogenesis type I

Genetic and Rare Diseases Information Center

Atelosteogenesis type I

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

ATELOSTEOGENESIS, TYPE I; AO1

Scientific Articles on PubMed

PubMed

References

Farrington-Rock C, Firestein MH, Bicknell LS, Superti-Furga A, Bacino CA, Cormier-Daire V, Le Merrer M, Baumann C, Roume J, Rump P, Verheij JB, Sweeney E, Rimoin DL, Lachman RS, Robertson SP, Cohn DH, Krakow D. Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat. 2006 Jul;27(7):705-10. doi: 10.1002/humu.20348. Citation on PubMed
Krakow D, Robertson SP, King LM, Morgan T, Sebald ET, Bertolotto C, Wachsmann-Hogiu S, Acuna D, Shapiro SS, Takafuta T, Aftimos S, Kim CA, Firth H, Steiner CE, Cormier-Daire V, Superti-Furga A, Bonafe L, Graham JM Jr, Grix A, Bacino CA, Allanson J, Bialer MG, Lachman RS, Rimoin DL, Cohn DH. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet. 2004 Apr;36(4):405-10. doi: 10.1038/ng1319. Epub 2004 Feb 29. Citation on PubMed
Sawyer GM, Clark AR, Robertson SP, Sutherland-Smith AJ. Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains. J Mol Biol. 2009 Jul 31;390(5):1030-47. doi: 10.1016/j.jmb.2009.06.009. Epub 2009 Jun 6. Citation on PubMed

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