Overview

Achondrogenesis defines a group of severe and rare genetic disorders affecting the development of the human skeleton. Achondrogenesis is considered a life-threatening condition, usually detected prenatally, and unfortunately leading to stillbirth, or death soon after birth. They have underdeveloped lungs, and the extreme shortening of the limbs (micromelia), skeletal abnormalities of the trunk, vertebrae, skull, and ribs build a characteristic clinical aspect. These conditions are caused by mutations in the TRIP11, SLC26A2, and COL2A1 genes.

A genetic mutation is a genetic error. The DNA sequence is changed in a particular gene location. The genetic basis of a condition refers to the affected genes, the specific gene mutation, the normal role of these genes in the body, and how it is modified by the mutation, causing the symptoms of the disorder. The inheritance patterns refer to the way the genetic error happens and how it is transmitted from parents to the offspring. 

Understanding the genetic basis and inheritance patterns of achondrogenesis is the key to providing an early, accurate diagnosis and proper case management. This also represents a starting point for an efficient genetic counselling process for families who have an affected child.

What is achondrogenesis?

Achondrogenesis refers to a group of rare and fatal genetic conditions, affecting between 1 in 40 000, and 1 in 60 000 newborns. Achondrogenesis as a term, refers to the lack of cartilage production. The bone and cartilage formation is severely altered in affected foetuses, causing a characteristic appearance – extreme micromelia, and other skeletal abnormalities, such as a narrow chest, a short trunk, and an apparently disproportionately large head, detectable on the prenatal ultrasound examination as early as weeks 14–17 of pregnancy.

The life-threatening complications are frequently leading to death before or shortly after birth. There are many other disorders caused by abnormalities of the cartilage and bones, called “Osteochondrodysplasias”, and Achondrogenesis is included in this wider group.^1,2

What is the genetic basis of achondrogenesis?

There are three forms of Achondrogenesis: type 1A and 1B, and type 2. All forms are lethal (deadly) skeletal dysplasias causing severe and disproportionate dwarfism and clinically present similar symptoms, but they have a different genetic basis: the affected gene is different in each case. 

Classification 

• Achondrogenesis type 1A - Houston-Harris type
• Achondrogenesis type 1B - Parenti-Fraccaro type  
• Achondrogenesis type 2 - Langer-Saldino type 

Genes

Table 1. The mutated gene and the corresponding type of achondrogenesis. 

Achondrogenesis type 1A (ACG1A) is caused by genetic mutations in the TRIP11 gene (thyroid hormone receptor interactor 11). This gene encodes the protein called GMAP-210 (Golgi microtubule-associated protein 210), and this protein seems to interact with the ends of the microtubules inside the cells and is involved in the “trafficking of proteins”.

The gene mutation causes the loss of the encoded protein’s function: moving proteins from the endoplasmic reticulum, known as “the cell’s protein factory”, to the Golgi apparatus – an important part of the cell responsible for “cargo sorting/processing" and other cellular processes involving metabolism, cell signaling, and cell fate. Because the proteins are not transported to the Golgi complex, they remain and accumulate in the endoplasmic reticulum, causing it to enlarge and leading to the death (apoptosis) of those cells. This happens in the cells of the bones and cartilage, and these changes impact the skeletal formation in foetuses, causing severe micromelia, intrauterine growth restriction, and absent ossification (bone formation) in the skull and the vertebral bodies of the spine.^3,4,5,6

Achondrogenesis type 1B (ACG1B) is caused by mutations in the SLC26A2 gene (solute carrier family 26 member 2), located on chromosome 5. The genetic mutation affects the protein called “sulphate transporter” and has consequences on hyaline cartilage (smooth connective tissue) formation in the foetuses. Cartilage is very important in the development of the human skeleton. Inside the womb, the skeleton of humans is initially made of cartilage, and then it slowly converts into bone.

The gene mutation determines the clinical appearance given by the disproportion between a normal-size head and an abnormally shorter body and severe micromelia. The soft tissue appears to be abundant, compared to a very small, short skeleton.^3,7

Achondrogenesis type 2 (ACG2) is caused by mutations in the COL2A1 gene (collagen type II alpha 1 chain), located on chromosome 12. This gene is involved in the collagen type II production, impacting its function within the body. It is necessary for the formation of hyaline cartilage and a type of ossification called endochondral ossification – this is how most of the body’s bones are formed—by replacing hyaline cartilage with bone during fetal development.

Collagen type II is also important for the eye and inner ear development. The severity of ACG2 is variable. There are perinatal lethal cases, but also mild forms diagnosed in adulthood when the patient presents premature arthrosis. ACG2 is less severe than ACG type 1A and B, but most clinical traits overlap.^1,2,3,6,8,9

The clinical effects of the gene mutations

The achondrogenesis symptoms are the clinical effects of the gene mutations that cause the different types of the disorder. Although the genetic cause is different, the symptoms are very similar. The traits of the ACG types are shown in Table 2.^1,2,3,4,7,8

Table 2. The clinical features given by the genetic mutations corresponding to each type of achondrogenesis. 

What are the inheritance patterns of achondrogenesis?

Autosomal recessive inheritance

Achondrogenesis type 1A and 1B are autosomal recessive disorders. The mutated gene is on one of the numbered chromosomes (autosomes), not on the sex chromosomes (X and Y). Recessive disorder means that two copies of the mutated gene are required in order to develop the condition. Therefore, both parents are “carriers” of one copy of the mutated gene. They are not affected because each has only one copy of the gene, which is not enough to develop the disorder. Therefore, in the case of ACG1A and ACG1B, the mutated genes, TRIP11 gene, and the SLC26A2 gene, are transmitted from the parents in an autosomal recessive inheritance pattern to their offspring. The carrier parents have a 25% chance with each pregnancy of having an affected child. This child will have the disorder. They also have a 25% chance of having an unaffected child who is not a carrier and has 2 normal gene copies, one from each parent. They also have a 50% chance that their child will be a gene mutation carrier (like themselves), but unaffected by the disorder.⁷

Autosomal dominant inheritance 

Achondrogenesis type 2 is an autosomal dominant disorder. The mutated COL2A1 gene is inherited in a “dominant” way. This means that the presence of just a single copy of the mutated gene is sufficient to cause the condition. If just one of the parents has the mutation, they have a 50% chance on each pregnancy that their child (regardless of gender) will have the disorder. But in ACG2, most of the cases are caused by a “de novo mutation” in the COL2A1 gene, meaning that the disorder appears for the first time in that family, in the affected member. In this case, if a couple already has an affected child, they would have a risk not higher than 1% to have another affected baby.  

When a family has more than one of their children affected by ACG2, it can be the case of germline mosaicism inheritance. Because the mutation of the COL2A1 gene is inherited in an autosomal dominant way, just one of the parents can be an asymptomatic carrier of the gene and transmit the genetic error to all of their offspring. It is called “germline” because the asymptomatic parent carries the defect only in their eggs or sperm (germ cells, or reproductive cells), and it is called "mosaicism" because some of these germ cells have the gene mutation, and some don’t have the gene mutation. This makes it impossible to detect or test before the pregnancy. These cases are more rare and require the guidance and assistance of the genetic specialist. 

Diagnosis

Achondrogenesis can be diagnosed prenatally, via ultrasound examination, as early as week 14–15 of pregnancy. Further more invasive investigations, such as chorionic villus sampling, and amniocentesis, can be performed in order to test the DNA of the foetus and identify the mutation. Depending on the clinical presentation of the case, single or multipanel gene testing can be performed when the symptoms are more characteristic to a disorder, and genomic testing (exome or genome sequencing) can be performed when the symptoms are variable and non-specific.^1,4,7 

Because the cases are usually lethal, the diagnosis can be established after birth, post-mortem, by X-ray examination of the body, and histology of the tissues. When already having a baby suffering from achondrogenesis, or when the parents are aware of being carriers of a recessive mutation of the genes involved in achondrogenesis, a clear diagnosis is helpful for the genetic counsel for their family’s reproductive perspectives.^3,8 

Management and treatment

Considering the severity of all the types of Achondrogenesis, usually, the cases require palliative care of the newborn. This means treating specific symptoms and various complications while caring for the patient’s needs and ensuring they experience no pain or discomfort. Genetic counselling and psychological support are very important.

Summary

Achondrogenesis defines a group of rare and life-threatening genetic disorders affecting the development of the human skeleton. There are three types of achondrogenesis: 1A and 1B, and type 2, all skeletal dysplasias causing severe and disproportionate dwarfism. Clinically, the symptoms are similar, but the genetic basis is different, and the affected genes are TRIP11, SLC26A2, and COL2A1, playing an important role in the diagnostic process.  

The inheritance patterns are different for the three types. Achondrogenesis types 1A and B are transmitted in an autosomal recessive way, and achondrogenesis type 2 is transmitted in an autosomal dominant way. The genetic basis and inheritance patterns of achondrogenesis are the key elements to ensuring an early, accurate diagnosis, management, and treatment, and provide the necessary information for the genetic counsel.