Overview

Achondrogenesis is a group of rare disorders (1 in 40,000 births), that affect the skeletal system and disrupt bone and cartilage development in unborn babies. The condition often causes several types of severe skeletal abnormalities due to which babies with achondrogenesis often die before birth, or shortly after. Three categories of the disorder are distinguished based on several factors characteristic for each of the types, namely achondrogenesis type 1A (Houston-Harris type), 1B (Parenti-Fraccaro type), and 2 (Langer-Saldino type).^1,2,3

Understanding achondrogenesis

Skeletal abnormalities are developed because of genetic mutations, which can be hereditary or occur due to exposure to certain environmental factors. The disorder causes shortening of limbs in proportion to the trunk, commonly known as dwarfism. Moreover, the underdevelopment of ribs, lungs, vertebrae, and other key organs often leads to the death of the baby affected by achondrogenesis before birth, or shortly after.²

The severity of the skeletal abnormalities often results in an inability of the affected infant to sustain life, making early mortality a characteristic of achondrogenesis. Moreover, no treatment exists for achondrogenesis. The disorder is divided into three categories, namely achondrogenesis type 1A, 1B, and type 2 which differ in symptoms, genetic cause of the condition, and its inheritance pattern.³

Three types of achondrogenesis

The three types of achondrogenesis are distinguished based on the characteristics of each category, namely the symptoms, specific genetic causes, and an inheritance pattern.

Achondrogenesis type 1A (Houston-Harris type)

• The signs of type 1A achondrogensis include various facial development abnormalities, short limbs, and a small trunk. A small chest, in turn, causes underdevelopment of the lungs and death from respiratory failure shortly after birth
• Inheritance: This type of achondrogenesis is inherited in an autosomal recessive pattern, in other words, the parents pass down the genetic mutations developed in the baby
• Genetic cause: It has been discovered that type 1A achondrogenesis is caused by a mutation in the TRIP11 gene, which codes information about the synthesis of a certain protein. The mutation prevents its production. Scientists suggest that chondrocytes (the cells cartilage originates from, and the cells of which the skeleton in the early development stages consists and later converted to bones) require the protein for proper functioning. It was proposed that the disruption of the process of its production causes the development of type 1A achondrogenesis^3,4

Achondrogenesis type 1B (Parenti-Fraccaro type)

• Babies affected by type 1B achondrogenesis usually have short limbs, a short trunk, and a narrow chest compared to the prominent rounded abdomen. Moreover, the toes and fingers are short and the feet might turn inward or upward. The infants often have a cleft palate or soft outpouching near the groin or around the belly button
• Inheritance: As in the case of type 1A, type 1B is inherited in an autosomal recessive pattern
• Genetic cause: Achondrogenesis type 1B is caused by a mutation in the SLC26A2 gene, which possesses information about the production of another protein involved in the development of the skeletal system. The mutations in this gene disrupt the synthesis of the protein, which in turn leads to problems with the development of cartilage and its conversion to bone. Malfunctions of this key protein cause the skeletal abnormalities characteristic of type 1B achondrogenesis.^3,5

Achondrogenesis type 2 (Langer-Saldino type)

• As in the case of types 1A and 1B achondrogenesis, the common signs of achondrogenesis type 2 are short limbs and trunk, and a narrow chest, causing underdevelopment of the lungs. The characteristics that distinguish this type from types 1A and 1B are a prominent forehead and a small chin
• Inheritance: This type of achondrogenesis is developed in babies with no family history of the disorder. The mutation causing the condition is not hereditary; it occurs spontaneously
• Genetic cause: The genetic cause of type 2 achondrogenesis is a mutation in the COL2A1 gene, necessary for the synthesis of type II collagen. Collagen type II is essential for the development of the skeleton and other connective tissues. Mutation of the COL2A1 gene prevents proper formation of collagen type II, and thereby, disrupts the process of the development of the skeleton resulting in skeletal abnormalities characteristic of type 2 achondrogenesis.^3,6

The importance of understanding achondrogenesis

Understanding the disorder and the causes of its development is important for several reasons. The knowledge and awareness of achondrogenesis can lead to early diagnosis. Moreover, it helps future mothers make informed decisions regarding parental care, potential interventions, and preparations for the birth and care of a child with achondrogenesis.^1,4 

Being prepared for the challenges associated with achondrogenesis including the possibility of losing the baby very soon after birth is crucial for emotional readiness and planning appropriate medical and psychological support. Awareness of the condition allows parents and families to connect with support groups, healthcare professionals, and resources that provide guidance, emotional support, and practical advice.¹

In the case of people who have a family history of achondrogenesis, knowledge about the condition is crucial for genetic counselling. It helps them understand the risks of recurrence in future pregnancies and explore reproductive options. Additionally, this knowledge can guide them in making informed decisions about prenatal testing and potential interventions.¹

Identification of achondrogenesis and its type

The disorder is usually detected during pregnancy. The healthcare provider usually notices the signs of achondrogenesis during a routine ultrasound examination. It often reveals skeletal abnormalities of the unborn baby, such as short limbs, and a small and narrow chest in proportion of the developing body. Additional tests will be conducted to confirm the diagnosis.¹

• Fetal ultrasound: A targeted and more detailed ultrasound examination can be performed if the doctor suspects achondrogenesis
• Amniocentesis: The doctor takes a sample of amniotic fluid (the liquid that surrounds the fetus in the uterus). A needle is inserted into the abdomen of a pregnant woman, and carefully directed into the amniotic sac to extract a small sample of fluid for testing. Using amniotic fluid genetic disorders of the fetus can be detected
• Chorionic villus sampling (CVS): This procedure involves taking a sample of the placenta (the organ inside the uterus which provides the baby with nutrients and oxygen necessary for growth) by puncturing the belly, or inserting a thin tube through the vagina. The sample, similar to amniotic fluid, can be utilised for genetic testing

Amniotic fluid and the sample of the placenta can be used to conduct genetic tests to determine if the baby is affected by achondrogenesis, and which type of disorder it is. The genetic tests most often involve either chromosome analysis or molecular genetic testing. Molecular genetic testing focuses on identifying the genetic mutation linked to the development of a particular type of achondrogenesis. Additionally, chromosomal analysis might be performed to exclude chromosomal abnormalities as a cause of skeletal malformations.^1,3

If the disorder is not detected during pregnancy, the doctors can diagnose it after the baby is born. Physical examination of the body of the newborn is the first step of the process, next, an X-ray is performed to evaluate the condition of the skeleton in the body of the newborn. Additionally, genetic tests facilitate the determination of the type of the disorder.^1,3

Summary

Achondrogenesis is a rare genetic disorder which causes skeletal abnormalities in fetuses. No cure for achondrogenesis exists and the severity of the skeletal abnormalities most often leads to a baby’s death during the pregnancy or shortly after delivery.

Three types of achondrogenesis are distinguished: achondrogenesis type 1A, 1B, and type 2, which differ in the disorder's signs, and its genetic cause. All three types are a result of genetic mutations in their respective genes. Type 1A and 1B achondrogenesis are hereditary, whereas type 2 develops in babies with no family history of the disorder. 

Understanding achondrogenesis is crucial for providing early diagnoses and helps future mothers and their partners make informed decisions about prenatal care and potential interventions. Being aware of the genetic cause for its development might help with emotional preparation and getting help from support groups and other resources, which are important for coping with the challenges associated with the condition.