#achondrogenesis

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Achondrogenesis is a number of disorders that are the most severe form of congenital chondrodysplasia (malformation of bones and cartilage).

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Achondrogenesis: 1A, 1B, & 2

Hey guys, we’re back with another disease of the day! Today we’re going to be talking about achondrogenesis. Achondrogenesis is an extremely dangerous disease that affects infants. Due to the severity of the condition, most infants die before or shortly after birth.

Achondrogenesis is a group of disorders that affect the cartilage and bone development. Infants with achondrogenesis usually die before birth or die soon after due to respiratory failure. It is rare that some infants live for a short time after birth. This is normally only with the help of medical support. The characteristics of achondrogenesis are a small body, short limbs, and other skeletal abnormalities. Achondrogenesis is usually diagnosed during pregnancy with further testing to distinguish between the three types. These different types are distinguished by the sign and symptoms.

The three types of achondrogenesis are type 1A, type 1B, and type 2. Type 1A and 1B are the more similar of the three. Type 1A causes infants to have extremely short limbs, narrow chest, short ribs, and a lack of normal bone formation in the skull and spine. The TRIP11 gene provides the instructions for the making of a protein called GMAP-210. This protein plays an important role in the Golgi apparatus. Mutations in the TRIP11 alter the GMAP-210 and therefore alter the structure and function of the Golgi apparatus. This is what could lead to problems with bone formation as commonly seen in type 1A.

Type 1B causes extremely short limbs, a narrow chest, and rounded abdomen. The fingers and toes are often short and the feet may turn in and upward. Type 1B is caused by mutations in the SLC26A2 gene. This gene is responsible for making proteins that aid in the development of cartilage and its conversion to bone. This is what causes the skeletal problems that is seen in type 1B. This mutation prevents bones from properly forming.

Type 2 causes short arms and legs, narrow chest with short ribs, and underdeveloped lungs. There is also a lack of ossification in the spine and pelvis as well as an enlarged abdomen. Facial features include a prominent forehead, and small chin. Type 2 is a combination of 1A and 1B and is caused by mutations in the COL2A1 gene. This gene makes a protein that forms type II collagen. This collagen is what is found in cartilage. Cartilage is essential for the development of bones and connective tissues that support the body. Without COL2A1 working properly, bones and other connective tissues do not form properly.

Achondrogenesis type 1A and type 1B have an autosomal recessive inheritance. This means that a person would need both copies of the TRIP11 or SLC26A1 gene in order to have the mutations. Achondrogenesis type 2 is an autosomal dominant inheritance because they only need one copy of the mutant gene. There are no treatments that can cure achondrogenesis. Rather, treatments focus on relieving pain. It is recommended that families affected by achondrogenesis seek genetic counseling.

Due to the sensitivity of this disease, I will not be including a picture of the characteristics. Achondrogenesis causes serious deformations and complications in infants. Achondrogenesis type 2 occurs in approximately 40,000 to 60,000 newborns.

Sources: https://ghr.nlm.nih.gov/condition/achondrogenesis#diagnosis, https://rarediseases.info.nih.gov/diseases/2882/achondrogenesis

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An infant with achondrogenesis type II. Note the protuberant abdomen and extremely short lower extremities.

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This posteroanterior (PA) view radiograph of an infant with achondrogenesis type II shows the relatively large calvaria with normal cranial ossification, short and flared thorax, bell-shaped cage and shorter ribs without fractures, relatively well ossified iliac bone with long crescent-shaped medial and inferior margins, and short tubular bones. The sacrum, pubis, and ischium are not visible.

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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.

Background

Marco Fraccaro first described achondrogenesis in 1952. He used the term to describe a stillborn female with severe micromelia and marked histological cartilage changes. The term was later used to characterize the most severe forms of chondrodysplasia in humans, which were invariably lethal before or shortly after birth. By the 1970s, researchers concluded that achondrogenesis was a heterogeneous group of chondrodysplasias lethal to neonates; achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria.

In 1983, a new radiological classification of achondrogenesis (types I-IV) by Whitley and Gorlin was adopted in the McKusick catalog. According to this classification, type I and type II have the same femoral cylinder index (CIfemur; calculated as length of femur divided by width of femur) range (1-2.8). Both types have crenated ilia and stellate long bones. Multiple rib fractures are characteristic of type I but not type II. Type III has nonfractured ribs, halberd ilia, mushroom-stem long bones, and a CIfemur of 2.8-4.9. Type IV has nonfractured ribs, sculpted ilia, well-developed long bones, and a CIfemur of 4.9-8. This radiological classification based on the CIfemur was later abandoned. Researchers suggested that achondrogenesis type III probably corresponds to type II and that type IV probably corresponds to mild type II (hypochondrogenesis).

In the late 1980s, structural mutations in collagen II were shown to cause achondrogenesis type II, which thus constitutes the severe end of the spectrum of collagen II chondrodysplasias. Achondrogenesis type I was subdivided further in 1988 on the basis of convincing histological criteria. It was subdivided into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB, which has an abnormal cartilage matrix. Classification of type IB as a separate group has been confirmed by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DDST) gene, making it allelic with diastrophic dysplasia.

Currently, 3 variants of achondrogenesis have been defined based on radiologic and histopathologic features: type IA (Houston-Harris), type IB (Parenti-Fraccaro), and type II (Langer-Saldino). Achondrogenesis IA appears to be autosomal recessive, but the mutant gene is still unknown. Type IB is caused by recessive mutations of the diastrophic dysplasia sulfate transporter gene (SLC26A2), and type II is caused by autosomal dominant mutations of the type II collagen gene (COL2A1).

Achondrogenesis II results from heterozygosity for a new dominant mutation in the COL2A1 gene at the chromosomal locus 12q8.11–q13.2. Intramolecular heterogeneity has been recognized, and genotype–phenotype correlations have been demonstrated.

Several heritable osteochondrodysplasias have now been recognized as members of the family of type II collagen disorders, all of which result from dominant mutations in the COL2A1 gene. Phenotypes within this group range from severe lethal dwarfism at birth to relatively mild conditions with precocious osteoarthrosis and little or no skeletal growth abnormality. Achondrogenesis II-hypochondrogenesis and lethal spondyloepiphyseal dysplasia congenita (SEDC) represent the more severe end of the spectrum.These entities are characterized by severe disproportionate short stature of prenatal onset. The distinction between these phenotypes is mainly based on clinical, radiographic, and morphological features but considerable phenotypic overlap often hampers proper classification.

Mutations within the COL2A1 gene also cause hypochondrogenesis (OMIM 200610), spondyloepiphyseal dysplasia (SED) congenita (OMIM 183900), SED Namaqualand type (OMIM 142670), mild SED with precocious osteoarthritis, spondyloepimetaphyseal dysplasia Strudwick type (OMIM 184250), Kniest dysplasia (OMIM 156550), multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia (OMIM 271700), and Stickler dysplasia type I (OMIM 108300)

Epidemiology Frequency

United States

Lethal achondrogenesis types I and II are both rare.

Their respective frequencies are unknown; however, the overall frequency has been estimated at 1 in 40,000 births.

Mortality/Morbidity

Achondrogenesis type I results in stillbirth more frequently than type II.

Babies with achondrogenesis type I who are not stillborn typically have a shorter gestation and survive for a shorter time than those with type II. They are also smaller with much shorter limbs, which supports the general view that type I is the more severe form.

Race

Achondrogenesis has no racial predilection.

Sex

Males and females are equally affected.

Age

Achondrogenesis is detected prenatally or at birth because of typical clinical, radiological, histological, and molecular findings.

Causes

Type IA is an autosomal recessive disorder with an unknown chromosomal locus. In the current International Nomenclature of Constitutional Disorders of Bone, type IA is classified under spondylodysplastic and other perinatally lethal groups of osteochondrodysplasias.

Type IB is an autosomal recessive disorder resulting from mutations of the diastrophic dysplasia sulfate transporter (DDST) gene (SLC26A2), which is located at 5q32-q33.

Type II is an autosomal dominant type II collagenopathy resulting from mutations in the COL2A1 gene, which is located at 12q13.1-q13.3.