Overview

Are you interested in genetic disorders? What about cartilage and bone health? In this article, we will tackle a genetic condition known as achondrogenesis. 

So, what exactly is achondrogenesis? It is a set of rare skeletal disorders – also known as skeletal dysplasias – that can cause severe shortening of arms and legs compared to the torso and irregular development of the vertebrae or ribs, among other skeletal issues.¹ The term achondrogenesis was first introduced in 1952 by the Italian pathologist Marco Fraccaro, who was describing a stillborn baby with significant micromelia and severe cartilage changes.² The term ‘Achondrogenesis’ comes from the Greek language meaning “not producing cartilage” and is a general term for a group of illnesses.^1,2,3

There are three subdivisions of achondrogenesis:

• Type IA, also known as the Houston-Harris type, is a rare autosomal recessive skeletal dysplasia. It is characterised by having different facial abnormalities such as protruding eyes and tongue, flat face, thin skull bones, short limbs/trunk or short beaded ribs. This type can lead to underdeveloped lungs due to the small thorax which can cause death right after birth^2,3
• Type IB, also known as Fraccaro type, is characterised by a short trunk/limbs, a prominent abdomen, a narrow chest and short fingers/toes and feet turned inwards.^2,3 Babies may have an umbilical hernia (protrusion around the belly button), or an inguinal hernia (protrusion close to the groin). This type may also cause a flat face, a short neck that is abnormally thickened and a cleft palate^2,3
• Type II, also known as Langer-Saldino type, is characterised by short limbs, narrow chest, thin ribs and flat backbones. This type can also lead to small chins, cleft palates, clubbed foot (turned inwards), and underdeveloped lungs^5,6

To further delve into this topic, we will discuss normal cartilage and bone development and how it is affected in achondrogenesis.

Normal cartilage and bone development

The human skeleton starts forming during the first couple of weeks after conception. The process of bone formation is known as osteogenesis and ossification. Most of our bones are formed through endochondral ossification.^1,4 

So, what is this process? It involves the change of hyaline cartilage (the precursor in bone development) to bony tissue which are known as endochondral bones. Upon reaching the third month of pregnancy, the membrane surrounding the cartilage, known as perichondrium, becomes vascularised which allows osteoblasts (cells that form the bone) to come in and change the area into periosteum. These cells start forming a collar of compact bone around the diaphysis (the long part of a long bone), while the cartilage at the centre of this diaphysis starts to disintegrate at the same time.^1,4

Osteoblasts enter the diminishing cartilage and start switching it to spongy bone. This is then the primary ossification centre, with the process continuing from the centre towards the ends of the bones. The secondary ossification occurs when the cartilage changes to articular cartilage while the rest is changed into bones; this means that bones continue to grow during childhood and adolescence, until the growth of cartilage slows down and eventually stops (usually early 20s). This growth is influenced by the growth process and the sex hormones (reproductive hormones).^1,4

Pathophysiology of achondrogenesis

As mentioned previously, achondrogenesis is a rare and critical defect that can affect the bones and cartilage of infants.² This can rise due to genetic mutations:

• Type IA results due to the mutation in the gene TRIP11, which causes a dysfunctional GMAP-210 or even its complete absence. This GMAP-210 is an important protein for the normal function of the Golgi apparatus. Once the Golgi apparatus is affected, this can impair the synthesis and secretion of extracellular matrix components that are important for cartilage and bone development^2,3
• Type IB is caused by the mutation in the SLC26A2 gene that leads to inadequate sulphate transport, which can lead to impaired sulfation of the proteoglycans that are important for cartilage formation. This type is an autosomal recessive disorder, meaning that you need two copies of the faulty genes to cause the disease. Hence, the risk for parents, who are both carriers of the gene, to have an affected child is 25% with each conception³
• Type II is caused by the mutation of the COL2A1 gene that leads to a defective type II collagen. This mutation can be caused by a change in the COL2A1 gene that is inherited in an autosomal dominant manner, meaning that the illness can occur if only one copy of the affected gene is present in the offspring. Type II achondrogenesis is most commonly due to new mutations in the COL2A1 gene (known as de novo mutations). This reduces the likelihood of having another child with the same disease to 1% or less, in the case of families that already have an affected child^5,6

Symptoms

Symptoms of achondrogenesis include: ^2,3,5,6

• Short limbs 
• Abnormalities in the spine bone formation 
• Short trunk 
• Narrow chest with a prominent belly 
• Fluid build-up in the foetus’ skin or scalp and around the heart or lungs (known as hydrops foetalis) 
• Excess amounts of amniotic fluid 

Diagnosis

Diagnosis of achondrogenesis is done through multiple steps: ^2,3,5,6

• Examining physical features 
• Using radiographic techniques like X-rays to evaluate the skull, spine and other skeletal areas 
• Microscopic analysis of the tissue samples 
• Genetic testing is also an option to identify the type of mutation and root cause, such as testing for the SLC26A2 gene for type IB
• Prenatal diagnosis can also be done by ultrasound after 14 to 15 weeks of gestation
• Amniocentesis (15-18 weeks of gestation) can be done for specific mutations if there is a family history of this disorder. It is done through the insertion of a thin needle into the belly of the pregnant woman into the uterus, to take a sample of the amniotic fluid. This sample is then further tested for genetic mutations 
• Chorionic villus sampling, shortened as CVS, (10-12 weeks of gestation) is done by taking a sample from the placenta by inserting a needle or a thin tube through the vagina and cervix, or through the belly. This sample is then tested for genetic and chromosomal abnormalities 

Treatment, therapy and management

Currently, there are no treatment options for this condition, as babies with this illness either pass away shortly after conception or soon after birth. However, healthcare professionals provide symptomatic treatment and supportive care as needed. Hence, the need for research and therapy approaches are necessary in this area.

FAQs

Is it possible to have a second child affected by achondrogenesis?

This depends on the achondrogenesis type – types IA and IB have a 25% chance of inheriting the disorder, type II doesn’t typically occur in more babies in the same family.^3,5,6 

Do I need to have amniocentesis or CVS sampling in the pregnancy?

It is not mandatory to have these tests, and some people have genetic testing after their baby is born. However, having these tests done early is highly recommended if a skeletal dysplasia is suspected, and can help your healthcare provider develop an adequate care plan during pregnancy, delivery and the postpartum period.^1,2

Can parents prevent achondrogenesis from affecting their children?

The parents can’t prevent achondrogenesis in their child – they do not choose which genes they pass on to their child and they do not control when and where the mutations occur.³

Summary

Achondrogenesis is a group of rare skeletal dysplasias that are characterised by severe bone deformities that can affect the arms, legs and even the trunk. It can lead to irregular rib development and underdeveloped lungs. This condition has multiple types like type IA, type IB and type II, with all of them being genetic disorders linked to different genes. The likelihood of a child surviving this illness is very low, with their lifespan ending very shortly after birth. Therefore, medical research is vital for gaining a better understanding of the disease and finding new treatments and management strategies.