What Is Achondrogenesis

Introduction

Achondrogenesis describes a group of genetic disorders that causes severe underdevelopment of the bone and cartilage in unborn babies. This condition increases the risk of babies being stillborn or prematurely born. Achondrogenesis causes 1 in 650 perinatal deaths.¹ It also results in severe underdevelopment of the lungs, which means that babies that survive birth will die within a few days.¹

Achondrogenesis, derived from the Greek meaning “not producing cartilage”, is characterized by extreme shortening of the limbs compared to the trunk as well as skeletal abnormalities, including abnormal development of the vertebrate and the ribs.³

Achondrogenesis is usually diagnosed during pregnancy using ultrasound.³ Skel dysplasia can usually be detected from weeks 14-17 of gestational age.1 There are three major forms of achondrogenesis, but all of them are caused by a genetic defect. Each different form varies slightly in the associated symptoms. The specific type of achondrogenesis can be determined using genetic testing.

Types of achondrogenesis

All forms of achondrogenesis are genetic conditions. All the forms are associated with an increased risk of stillbirth or premature birth.¹

There are three main types of achondrogenesis - these are divided based on the severity of limb shortening and bone formation of the skull and spine:¹ 

• Type IA (Houston-Harris)
• Type IB (Fraccaro)
• Type II (Langer-Saldino)

Causes

Achondrogenesis is caused by genetic mutations. The gene that is mutated varies amongst the different types of achondrogenesis. 

Genes are important because they create proteins. Proteins help the body to function in a normal way. When a gene is mutated or faulty, it can create a protein that cannot function properly. Therefore, a faulty gene can result in the body functioning abnormally. This can cause a problem that stops the body from working normally - a genetic disorder.

Type IA achondrogenesis is caused by genetic mutations in the TRIP11 gene, and Type IB achondrogenesis is caused by genetic mutations in the SLC26A2 gene. The TRIP11 and the SLC26A2 genes make proteins that help transport materials to make the skeleton and cartilage, respectively.³ Therefore, it makes sense that if these genes were mutated, the skeleton and cartilage may not develop properly - and that is what happens!

Type IA achondrogenesis and Type IB achondrogenesis are inherited conditions. They are both autosomal recessive, which means that the faulty gene must be inherited from both the mother and the father. Type IA achondrogenesis and Type IB achondrogenesis can be distinguished using genetic testing. Type IA achondrogenesis is caused by genetic changes to the TRIP11 gene, whilst Type IB achondrogenesis is caused by genetic changes to the SLC26A2 gene - these differences can be picked up during genetic testing.³

Type II achondrogenesis is caused by genetic mutations in the COL2A1 gene. The COL2A1 gene encodes for the protein called collagen type II, which is most prevalent in cartilage and is used to give cartilage strength and form.³

Type II achondrogenesis is an autosomal dominant disorder. This is not, generally, an inherited disorder. Type II achondrogenesis is caused by new genetic changes in the COL2A1 gene - this means that the genetic change happens at conception rather than is transferred from the parents to the baby - so it manifests in babies who have no family history of achondrogenesis.²

Symptoms

Generally, achondrogenesis is characterized by an abnormally shaped and thin head, abnormal accumulation of fluid in the body, and premature birth.³ In infants that survive birth, the thorax is small, resulting in underdeveloped lungs with abnormal function - the head also looks disproportionately large.³

The symptoms associated with achondrogenesis manifest during pregnancy and as a newborn, although the age at which the disease begins to manifest differs between the types of achondrogenesis.³ When the symptoms manifest, it may guide a medical professional to propose and further investigate a possible diagnosis. Similarly, the severity of the symptoms and the combination of the symptoms themselves may vary among people with achondrogenesis.³

The symptoms can usually be seen on a prenatal ultrasound from 14 weeks of gestational age.³

Very frequent symptoms:³ 

• Abnormal chondral ossification (this is a process where the cartilage is turned into bone - this is very important for the prenatal baby)
• Abnormal bone mineral density (may affect all bones)
• Anteverted nares (upturned nostril)
• Aplasia/Hypoplasia of the lungs (absent or underdeveloped lungs)
• Flat face
• Long philtrum (long distance between the nasal base and the midline of the upper lip)
• Macrocephaly (large head circumference)
• Micrognathia (decreased size of the lower jaw)
• Micromelia (smaller/shorter limbs)
• Narrow chest
• Severe short stature (dwarfism)
• Short neck
• Short nose
• Short thorax
• Skeletal dysplasia (abnormal development of bones and connective tissues)

Frequent symptoms:³

• Inguinal hernia (contents of the abdominal cavity come through the inguinal canal)
• Polyhydramnios (excess amniotic fluid in the uterus during pregnancy)
• Umbilical hernia (contents of the abdominal cavity protrude around the umbilicus)

Occasional symptoms:³ 

• Abnormality of cardiovascular system morphology (structure of heart and vessels is not normal)
• Cystic hygroma (cystic lymphatic lesion of the neck)

The different forms of achondrogenesis have unique symptoms that help distinguish between them.

Type IA achondrogenesis is the most severe form. Characteristic symptoms include a thin, underdeveloped skull, facial abnormalities such as protruding eyes and tongue or a flat face, and short beaded ribs that easily fracture short trunk and limbs.^1,3 The small thorax results in under developed lungs resulting in respiratory failure and death after birth.³

Type IB achondrogenesis is characterized by a short trunk and limbs, narrow chest, umbilical and inguinal hernia, poor skull formation, and a prominent abdomen. ^2,3

Moreover, these individuals may have short fingers and toes with inward-pointing feet, a flat face, and a short neck.³ The associated SLC26A2 gene can have many different mutations, but only some of the mutations cause Type IB achondrogenesis. Other mutations in SLC26A2 can cause other disorders, such as dystrophic dysplasia or recessive multiple epiphyseal dysplasias, but the type of disorder within the individual is permanent and cannot change between these different types.^3,6

Type II achondrogenesis is characterized by a prominent forehead, small chin, cleft palate, club feet, narrow chest, abnormally small or short bones in the limbs, abnormally developed vertebrae and pelvis, and thin ribs.^2,3

Treatment

There is no treatment to cure or manage achondrogenesis. The only associated treatments are supportive. These treatments may help the baby reduce pain, stress, or symptoms associated with the disorder despite only living a few days.^2,3  Genetic counselling is recommended during family planning for families with an affected child and for those families with a known mutation to help them make informed decisions. Guidance in finding a psychologist, therapist, or psychiatrist for the affected families may help them come to terms with and further understand what they are going through.

Diagnosis 

From 14 weeks gestational age, a doctor may be able to detect signs of achondrogenesis on a routine ultrasound scan. If this is the case, additional tests can be performed to confirm the diagnosis if a specific achondrogenesis mutation is identified in the mother or father of the baby: ^2,5

• Amniocentesis - a thin needle is used to extract amniotic fluid from the uterus. This test is a genetic test that looks for genetic disorders such as achondrogenesis. This is performed at 15-18 weeks of gestational age.
• Chorionic villus sampling (CVS) - a small sample of placental tissue is extracted using a needle through the belly or tube through the vagina. This test is a genetic test which looks for genetic disorders such as achondrogenesis. This is performed at 10-12 weeks of gestational age.
• Fetal ultrasound - targeted ultrasound looking for bone and cartilage problems.

In the case that achondrogenesis is undiagnosed during pregnancy, after birth, the baby may undergo testing to confirm achondrogenesis:²

• Physical examination
• X-rays
• Genetic testing

FAQs

How common is achondrogenesis?

Less than 1 in 50,000 people in the United States have achondrogenesis.³ Achondrogenesis affects males and females equally and is present in 1 in 40,000 births.^2,7 Type II achondrogenesis occurs in 1 out of 40,000 to 60,000 births.²

What is the prognosis?

Achondrogenesis is the second most common lethal skeletal dysplasia.⁷ It is lethal due to the underdevelopment of the lungs; because of this, babies who survive birth do not survive more than a few days.² All types of achondrogenesis have an increased risk of premature birth and stillbirth, with Type IA achondrogenesis having a stillbirth rate of 50%.¹ Type II achondrogenesis babies generally are heavier, have longer limbs, and survive a longer period post-birth.¹

Advocacy and support groups 

Many organizations offer support and aim to increase awareness about achondrogenesis. Some are run by healthcare professionals, others by patients and their families, and some offer some sort of collaboration. 

For example, there are patient organizations within the US that specifically help individuals who have been impacted by achondrogenesis. One such is called the Little People of America, Inc.³ 

Did I do something to give my baby achondrogenesis?

No. You are not in control of giving your baby achondrogenesis.

Summary 

Achondrogenesis is a genetic disorder causing the severe underdevelopment of the bone and cartilage in unborn babies. This disorder increases the risk of premature birth and stillbirth, and babies that do survive birth will only survive a few days due to underdevelopment of the lungs. There is no curative treatment for achondrogenesis and no treatment that can help manage this disorder either. Support to the families that this disorder affects is crucial, including genetic counselling.