Achondrogenesis is a rare genetic disorder that affects the bone growth of babies when they develop in the womb. This can result in severe disability, stillbirth, premature birth or even death in the first few days of life. This article will explain about achondrogenesis and why the survival rate of this condition is so low.

Understanding achondrogenesis

When a baby develops in the womb, their bones are not made of the same strong material as adult bones. Instead, the developing skeleton is made of a floppy material called cartilage, which is the same material that makes up your nose and ears. Its elastic nature allows the developing bones to grow rapidly during gestation (pregnancy) to eventually form a recognisable skeleton.

Achondrogenesis means a lack of cartilage development during this process, meaning that the skeleton lacks a base on which to build. It is part of a larger group of genetic disorders affecting the developing skeleton known as skeletal dysplasia, which includes conditions such as achondroplasia. 

In achondrogenesis, the basic skeleton cannot form properly, causing several developmental issues that result in short limbs and a lack of development of the chest wall, which causes breathing difficulties after birth.

This condition is rare and affects approximately 1 in 15,000 births.¹   

What are the causes of achondrogenesis?

It is a genetic disorder caused by changes (mutations) in the genes that are involved in cartilage development.

These mutations are inherited (passed down) from parents. Every cell in your body has two copies of every gene, and a baby inherits one copy from each parent. Some conditions, like achondrogenesis, require both copies of the gene to be mutated to cause symptoms of the disease in the affected person. If a parent themselves has one normal copy of a gene and one mutated copy, but they don’t have any symptoms of the disease, then they are called a carrier for the disease. If a child has two parents who are carriers for a disease that requires two mutated copies to cause the disease (like achondrogenesis), then they have a 1 in 4 chance of having the disease. Some genetic disorders are dominant, which means that just having one copy of the mutated gene will cause the disorder to be present in the child. On the other hand, achondrogenesis is a recessive disorder, which means both parents need to pass on a mutated gene for the child to be affected with the condition.

Types of achondrogenesis

There are several different types of genetic mutations in achondrogenesis, which cause different subtypes of the condition.²

Type 1A

The Houston-Harris variant is an autosomal recessive form which is caused by the inheritance of a mutation from each parent, so that the baby has two mutated copies of the gene. The mutation affects the TRIP11 gene, which is responsible for producing essential components of cells that modify proteins for growth and development.³

Type 1B

The Fraccaro variant is an autosomal recessive form caused by the inheritance of one genetic mutation from each parent. The mutation affects the SLC26A2 gene, which is responsible for transporting sulphate molecules in and out of cells.

Type 2

The Langer-Saldino variant is caused by a spontaneous mutation in the COL2A1 gene at a very early stage of the baby’s development, meaning that it is not inherited from the parents. This is the most common form and is responsible for 80% of cases of achondrogenesis.⁴ This is an autosomal dominant mutation, which means that even if only one of the child’s two gene copies is affected, the child will still go on to develop achondrogenesis.

If I have the affected gene, does that mean my child will have achondrogenesis?

It is important to note that both parents need to pass on a copy of the affected gene for a child to have either form of Type 1 achondrogenesis. As Type 1 achondrogenesis is an autosomal recessive condition, if a child just has one mutated gene copy, the body will use the other, non-mutated gene to function normally. This means the child will be unaffected by the condition. So, both parents need to be carriers of a mutated copy of the gene for there to be a chance that the child is affected.⁵

Will my future children be affected?

If you have already had a child affected by achondrogenesis, this will depend on the form of achondrogenesis that the previous child had. If they had a Type 1 disorder, it would indicate that both parents carry one mutated copy of the gene. In this instance, there is a 1 in 4 chance of another child having the disorder.

Type 2 achondrogenesis arises by chance in the developing baby, and the risk of future children being born with the disorder in this case is very low.

What are the physical changes seen in achondrogenesis?

Changes that are often seen on an ultrasound scan of the baby in the womb include:

• Abnormal growth of the developing skeleton (skeletal dysplasia)
• Short arms and legs
• Narrow chest
• Underdeveloped lungs (pulmonary hypoplasia)
• Changes to the head and face
  • Large head (macrocephaly)
  • Small chin (micrognathia)
  • Flattened nose and face
• Increased amounts of water surrounding the baby (polyhydramnios)
• A generally swollen appearance of the baby (hydrops fetalis)
• Umbilical hernia and inguinal hernia
• Cystic hygroma  (swelling around the neck)
• Problems affecting the heart and blood vessels 

How is achondrogenesis diagnosed?

Usually, it becomes apparent at the 20-week ultrasound scan of the baby, when some of the features described above can be identified. Some other genetic tests may also be used, including amniocentesis and chorionic villus sampling.

If a baby is born with achondrogenesis, the diagnosis can be confirmed by examination, x-ray imaging and genetic testing. In the majority of cases, the baby will sadly pass away in the womb or shortly after birth, and in this instance, a post-mortem may be offered to the family.

Prognosis in achondrogenesis

A prognosis is a medical means of describing whether an individual is likely to have a good or bad outcome from their condition. Unfortunately, the prognosis for achondrogenesis is very poor, with up to 85% of babies affected by skeletal dysplasia such as achondrogenesis passing away in the womb or within hours to days after birth.

There are rare cases of survival for more than a few days. These infants require intensive medical intervention to keep them alive, requiring round-the-clock input from neonatal specialist teams. These infants have severe disabilities and are unlikely to survive into later childhood.⁶

Why does achondrogenesis have poor survival rates?

Several factors can affect how likely a baby is to survive with the diagnosis of achondrogenesis:

• Breathing difficulty – This is typically the main cause of death. The problems with developing cartilage cause deformity to the chest wall, which restricts the lungs from properly forming (pulmonary hypoplasia). When an affected baby is born, they cannot breathe deeply enough to get enough oxygen to survive, resulting in respiratory failure
• Issues with the developing bones – this often has a knock-on effect on other organ systems that use the developing skeleton as a template, including the cardiovascular and digestive systems
• The limitations of medical intervention - treatment options for this condition are supportive rather than curative, due to the severity of the way the disease affects the baby’s vital organ systems

How does the type of achondrogenesis affect life expectancy?

• Type 1A and 1B – The Type 1 variants often result in death inside the womb or shortly after birth
• Type 2 – This variant has a slightly higher chance of survival beyond the first few hours, but life expectancy remains short

The role of supportive care

Making decisions around life support for a child is one of the hardest decisions a parent can make. In the majority of cases of achondrogenesis, the baby will pass away in the womb or during birth. Some babies may survive the birth, but the methods that can be used to keep an infant alive are incredibly invasive and, in all likelihood, are very distressing to the child. The medical team overseeing care may discuss moving away from these interventions and towards palliative care methods instead, which focus on making the child comfortable and withdrawing any unnecessary medical devices or treatments that may be causing distress. Family counselling and psychological support are available for parents in such situations.⁷

Are there any gene therapy options?

Current research trials into achondrogenesis are limited. Although gene therapies are listed as a potential treatment for rare genetic disorders, there is no treatment currently licensed for achondrogenesis.

If parents have had a child affected with achondrogenesis, it is recommended that they undergo genetic testing. This can assess if they are carriers of the genes that can cause type 1 variants of achondrogenesis. If you have had a baby born with congenital defects, your future pregnancies will be closely monitored by the foetal medicine team, who can help to support your decision-making during pregnancy.⁵

Summary

Achondrogenesis is a rare yet severe form of genetic disorder that affects a baby as it develops in the womb. The developing skeleton is particularly affected, causing short limbs and growth restriction. The chest wall is also affected and develops abnormally, causing affected babies to be born with underdeveloped lungs and an inability to breathe properly. Sadly, there is no cure for babies born with this condition, and clinical management focuses on avoiding unnecessary distress or harm to the baby. It is not expected that the majority of children born with achondrogenesis to survive beyond the first few days of life.