General Discussion

Summary

Achondrogenesis is a group of rare skeletal dysplasias characterized by extreme shortening of the arms and legs in relation to the trunk, abnormal development of ribs, vertebra and other skeletal abnormalities. The health problems associated with these conditions are life-threatening and most affected infants are stillborn or die shortly after birth due to respiratory failure. All types of achondrogenesis are genetic conditions; type IA and type IB, are autosomal recessive disorders, whereas achondrogenesis type II is an autosomal dominant disorder. All types of achondrogenesis are very severe skeletal dysplasias usually detected by prenatal ultrasound examination as early as week 14-17 of gestational age.

Introduction

The term achondrogenesis was first used in the medical literature in 1952 by an Italian pathologist named Marco Fraccaro. Achondrogenesis is derived from Greek and means “not producing cartilage.” Achondrogenesis belongs to group of skeletal dysplasias, (also called osteochondrodysplasias), a broad term for a group of disorders (about 450 clinical diagnoses) characterized by abnormal growth or development of cartilage and bone.

Signs & Symptoms

Achondrogenesis is characterized by premature birth, abnormal accumulation of fluid in the body (hydrops fetalis), and a head that may be abnormal in shape and less ossified. The head may look disproportionately large, because the body is small. In addition, affected individuals have extremely short limbs and ribs, short neck, flat vertebrae and many other bones of the skeleton are not properly developed. In infants born with this disorder the abdomen is prominent and the thoracic cage is small. Other abnormalities are incomplete closure of the roof of the mouth (cleft palate), corneal clouding, and ear deformities. The disorder is life-threatening either before birth or shortly after birth usually due to underdeveloped thorax and small lungs.

Achondrogenesis type IA (Houston-Harris type) is characterized by varying facial abnormalities (flat face, protruding eyes and protruding tongue or only minor facial anomalies), short trunk and limbs, short beaded ribs and thin skull bones (deficient ossification of the skull). Bone formation is abnormal in the spine, pelvis and extremities, but the degree of the severity of skeletal involvement may be variable. However, small thorax leads to underdevelopment of lungs and death soon after birth.

Achondrogenesis type IB (Fraccaro type) is characterized by short trunk and limbs, narrow chest, and prominent abdomen. Affected infants may have a protrusion around the belly-button (umbilical hernia), or near the groin (inguinal hernia), and have short fingers and toes with feet turned inward. The face may be flat, the palate may be cleft and the neck is usually short. In some cases, the soft tissue of the neck may be abnormally thickened. Achondrogenesis type IB is sub-classified as a sulfation disorder, a small group of disorders associated with mutations in the gene SLC26A2. This group includes diastrophic dysplasia and recessive multiple epiphyseal dysplasia, which are milder conditions. It is important to note that one diagnosis does not change to another while the baby is developing, even if the genetic changes are located in the same gene.

Achondrogenesis type II (Langer-Saldino type) is characterized by a narrow chest, abnormally small or short bones in the arms and/or legs, thin ribs, flat vertebra or deficient ossification of vertebral bodies, underdeveloped lungs, small chin, cleft palate and club feet. Bone formation is abnormal in the spine and pelvis. Abnormal accumulation of fluid may occur (hydrops fetalis) and the abdomen may be enlarged.

Causes

Each type of achondrogenesis is caused by a mutation in a specific gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

The gene mutations that cause achondrogenesis type IA and type IB are inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person is a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than non-consanguineous parents to carry the same abnormal gene, which increases the risk to have children with a rare recessive genetic disorder.

Achondrogenesis type IA is caused by mutations in the TRIP11 gene. Achondrogenesis type IB is caused by mutations in the SLC26A2 gene. These two genes are required for the efficient cellular transport of certain cartilage proteins needed to build skeleton and other tissues. Mutations of the TRIP11 gene results in deficiency of the Golgi microtubule associated protein 210. This protein is found in most cell types of the body. The protein product of the SLC26A2 gene is a sulfate transporter that is involved in the proper development and function of cartilage. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted into bone.

The gene mutation that causes achondrogenesis type II is caused by so called autosomal dominant change in the COL2A1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Most cases of achondrogenesis type II are caused by a new (de novo) mutation in the COL2A1 gene, which means that risk for the parents of an affected infant to get another child with the same disease is not higher then 1%. This gene encodes collagen type II. Collagen is one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength. There are many different types of collagen, which are indicated by Roman numerals. Collagen type II is most prevalent in cartilage and the jelly-like fluid that fills the center of the eye (vitreous). Collagen is also found in bone.

There are very rare cases where siblings of infants with achondrogenesis type II have been affected. This is most likely due to the presence of more than one cell line in the egg or sperm from a parent (germline mosaicism). In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the COL2A1 gene mutation, while other germ cells contain normal COL2A1 genes (“mosaicism”). The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene COL2A1 mutation, leading to the development of achondrogenesis II, while the parent does not have this disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same autosomal dominant genetic condition. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during early pregnancy may be available and is best discussed directly with a genetic specialist.

Affected Populations

Achondrogenesis affect males and females in equal numbers. Achondrogenesis type IA and type IB are very rare disorders and prevalence for them is unknown. Achondrogenesis type II occurs in approximately 1/40,000-1/60,000 newborns.

Related Disorders

Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others are only may or may not cause life-threatening complications. Some forms do not cause life-threatening complications early in life. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities may be present depending upon the specific disorder. There are approximately 450 types of skeletal dysplasias with more than 360 causative genes. Several forms are discussed below; the differentiation among them is made by radiographic and molecular means.

Kniest dysplasia is one of several forms of skeletal dysplasias that are caused by a change (mutation) in the COL2A1 gene. This gene is involved in the production of a particular protein that forms collagen type II, which is essential for the normal development of bones and other connective tissue. Changes in the composition of collagen type II lead to abnormal skeletal growth and, thus, to a variety of congenital skeletal diseases known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other symptoms develop with age. (For more information on this disorder, choose “Kniest” as your search term in the Rare Disease Database.)

Campomelic syndrome is a rare congenital disorder in which multiple anomalies are present. It is caused by mutations in the SOX9 gene and characterized by bowing and angular shape of the long bones of the legs, especially the tibiae; multiple minor anomalies of the face; cleft palate; other skeletal anomalies such as abnormalities of the shoulder and pelvic area and eleven pairs of ribs instead of the usual twelve; underdevelopment of the trachea; developmental delay in some cases and incomplete development of genitalia in males such that they appear to be females. (For more information on this disorder, choose “campomelic” as your search term in the Rare Disease Database.)

Hypophosphatasia is an inborn metabolic disorder of the bones characterized by skeletal defects resembling those of rickets. The symptoms result from a failure of bone mineral to be deposited in young, uncalcified bone (osteoid), and in the cartilage at the end of the long bones (epiphyses) during early years. The activity of the enzyme alkaline phosphatase in blood serum and bone cells is lower than normal. Urinary excretion and blood plasma concentrations of phosphoethanolamine and inorganic pyrophosphate are abnormally high. Hypophosphatasia does respond to treatment with Strensig (For more information on this disorder, choose “hypophosphatasia” as your search term in the Rare Disease Database.)

Thanatophoric dysplasia is one of the most common forms of lethal skeletal dysplasias. It is characterized by an enlarged head, short and eventually bowed bones in the arms and legs, small, short ribs, narrow thorax and flattened vertebrae. There is an abnormally large amount of amniotic fluid. Thanatophoric dysplasia is caused by mutations in the FGFR3 gene.

Short-rib-polydactyly syndrome includes several types of skeletal dysplasias. The infant may have cleft lip and palate, deformed ears, and a narrow chest with short ribs. The kidneys are often deformed (cystic), as are the sex organs. There may be brain malformations and an absence of a gallbladder. This disorder is often life-threatening as a result of insufficient lung development.

Diagnosis

Achondrogenesis is diagnosed by physical features, X-ray (radiographic) findings and examination of tissue samples under a microscope (histology). Molecular genetic tests for mutations in the SLC26A2 gene can be used to confirm the diagnosis of achondrogenesis type 1B.

Prenatal diagnosis of achondrogenesis by ultrasound is possible after 14-15 weeks gestation. Prenatal diagnosis by chorionic villus sampling (10-12 weeks gestation) or amniocentesis (15-18 weeks gestation) is possible if the specific gene mutations have been identified in a family member.