Achondrogenesis

Achondrogenesis is a group of severe disorders that affect cartilage and bone development. These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of serious health problems, infants with achondrogenesis usually die before birth, are stillborn, or die soon after birth from respiratory failure. Some infants, however, have lived for a short time with intensive medical support.

Researchers have described at least three forms of achondrogenesis, designated as type 1A, type 1B, and type 2. The types are distinguished by their signs and symptoms, inheritance pattern, and genetic cause; however, types 1A and 1B are often hard to tell apart without genetic testing.

Achondrogenesis type 1A, which has also been called the Houston-Harris type, is the least well understood of the three forms. Affected infants have extremely short limbs, a narrow chest, short ribs that fracture easily, and soft skull bones. They also lack normal bone formation (ossification) in the spine and pelvis.

Achondrogenesis type 1B, also known as the Parenti-Fraccaro type, is characterized by extremely short limbs, a narrow chest, and a prominent, rounded abdomen. The fingers and toes are short and the feet may be rotated inward. Affected infants frequently have a soft out-pouching around the belly-button (an umbilical hernia) or near the groin (an inguinal hernia).

Infants with achondrogenesis type 2, which is sometimes called the Langer-Saldino type, have short arms and legs, a narrow chest with short ribs, and underdeveloped lungs. This condition is also associated with a lack of ossification in the spine and pelvis. Distinctive facial features include a prominent forehead, a small chin, and, in some cases, an opening in the roof of the mouth (a cleft palate). The abdomen is enlarged, and affected infants often have a condition called hydrops fetalis in which excess fluid builds up in the body before birth.

Achondrogenesis types 1A and 1B are rare genetic disorders; their incidence is unknown. Combined, achondrogenesis type 2 and hypochondrogenesis (a similar skeletal disorder) occur in 1 in 40,000 to 60,000 newborns.

Mutations in the SLC26A2 and COL2A1 genes cause achondrogenesis types 1B and 2, respectively. The genetic cause of achondrogenesis type 1A is unknown.

Achondrogenesis type 1B is the most severe skeletal disorder caused by mutations in the SLC26A2 gene. This gene provides instructions for making a protein that is essential for the normal development of cartilage and for its conversion to bone. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears. Mutations in the SLC26A2 gene disrupt the structure of developing cartilage, preventing bones from forming properly and resulting in the skeletal problems characteristic of achondrogenesis type 1B.

Achondrogenesis type 2 is one of several skeletal disorders that result from mutations in the COL2A1 gene. This gene provides instructions for making a protein that forms type II collagen. This type of collagen is found mostly in cartilage and in the clear gel that fills the eyeball (the vitreous). It is essential for the normal development of bones and other tissues that form the body's supportive framework (connective tissues). Mutations in the COL2A1 gene interfere with the assembly of type II collagen molecules, which prevents bones and other connective tissues from developing properly.

Based on a few infants with achondrogenesis type 1A, researchers believe that this form of the disorder is inherited in an autosomal recessive pattern. Achondrogenesis type 1B also has an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Achondrogenesis type 2 is considered an autosomal dominant disorder because one copy of the altered gene in each cell is sufficient to cause the condition. It is almost always caused by new mutations in the COL2A1 gene and typically occurs in people with no history of the disorder in their family.