Achondrogenesis: Causes, Symptoms, Complications, And Treatment

Achondrogenesis, also known as osteochondrodysplasias, can be described as rare skeletal dysplasia in which the patient shows extreme shortening of the arms and legs as compared to the trunk, ribs, vertebra, and overall skeletal. Due to the nature of the disorder, it can be extremely life-threatening to the individual, especially at the infancy stage as the newborns die shortly after birth due to respiratory failure. The subdivision of Achondrogenesis are:

• Achondrogenesis type IA (Houston-Harris type).
• Achondrogenesis type IB (Fraccaro type).
• Achondrogenesis type II (Langer-Saldino type).

Achondrogenesis type IA and type IB are autosomal recessive, on the other hand, Achondrogenesis type II autosomal dominant disorder makes all three types distinct from each other. Al three types of Achondrogenesis are usually detected by prenatal ultrasound examination within 14-17 weeks of gestational age.

Autosomal dominant is a pattern of inheritance where affected individuals possess one copy of a mutant gene (autosomal chromosomes) and one copy of the normal gene. An individual with autosomal dominant diseases has a 50-50 chance of passing the mutant gene to their offspring.

On the other hand, the autosomal recessive disease is a pattern of inheritance where the affected individual possesses two copies of the mutant gene. This disorder is only passed when both of the parents have the same genetic mutation. This can also happen if one copy of the gene is dominant and one copy is recessive.

The chances of getting affected by the genetic mutation can be different, for example, there is a 25% chance that a child may turn out to be normal with no mutation whatsoever or become get affected with two recessive genes, but in this case, there is a 50% chance that the offspring will become a carrier of the disease with no such medical condition.

Each type of Achondrogenesis is distinct from each other as the root cause of the mutation in every case is different. The key role of the genes in an individual body is to provide instructions to cells for creating proteins that play an important role in many functions of the body. So when there is any fault in the overall development of the gene, the instruction that your default gene sends also creates defaults in the body which may create life-threatening abnormalities for the rest of your life.

As mentioned above, the Achondrogenesis type IA and type IB can only be inherited in an autosomal recessive manner. So the root cause of the mutation is the inheritance of the same in one of the parents of the patient.

The abnormal gene which is responsible for Achondrogenesis type IA is the TRIP11 gene and the gene responsible for Achondrogenesis type IB is the abnormality of the SLC26A2 gene. These two genes play an important role when it comes to the cellular transport of certain cartilage proteins which are required to build an efficient skeleton and other tissues in the human body.

Mutation in the TRIP11 gene and SLC26A2 gene results in the deficiency of the Golgi microtubule which is associated with protein 210 and sulfate transporter which is responsible for the appropriate development and function of cartilage. Furthermore, type IB Achondrogenesis can also be sub-classified as a sulfation disorder as the medical condition is also associated with mutations in the gene SLC26A2.

Cartilage is a special kind of tissue that acts as a cushion between all joints of the body. In the early stages of the structural development of the bones, the embryo of a skeleton consists of fragile structured cartilage which later develops into bones. Abnormal development of the cartilage causes friction between the bones making it difficult to move or in this case hinder the overall growth of the skeletal system.

Other than type IA and type IB, Achondrogenesis type II is also caused by inheritance of the genetic mutation but in this case, the mutation is developed in an autosomal dominant manner. The malfunctioned gene triggers the type II Achondrogenesis in the COL2A1 gene, which is responsible for encoding the collagen type II in the body.

Collagen is one of the important proteins in the body as it has a major contribution to the production of connective tissue. It is found in abundance which makes the medical condition more lethal and life-threatening. The role of the connective tissue is to give the cells of the body more strength and a durable structure. There are different types of collagen that can be found in different sections of the body, but type II is the type of collagen that is mostly found in cartilage, bones, and the vitreous ( or center of the eye).

Interestingly, the presence of type II Achondrogenesis is quite rare in the siblings of the affected infant. This happens because the presence of germline mosaicism is often found in only one cell line in the egg or sperm of the parent. The germline mosaicism or the germ cells is carried by only a few of the COL2A1 genes while others carry mosaicism or normal COL2A1 genes.

If one of the parents does not infuse a mutated gene with another COL2A1 mutated gene the abnormality does not affect the offspring but they become a carrier of the mutated gene making it more prone to the development of Achondrogenesis II in future generations. Even though there is no test to detect the presence of germline mutation in the parents, there is one test available that can detect the presence of germline mutation in the fetus during the early stages of pregnancy.

Some of the medical conditions that may mirror the signs of Achondrogenesis are:

• Skeletal dysplasias (osteochondrodysplasias): Is the main term used to characterize the group of disorders that develops an abnormal growth of the cartilage and bones. Some of them are life-threatening complications as they start to affect the infant shortly after birth, while other dysplasias are serious in their symptoms but may not cause early death or life-threatening complications in infancy. There are over 450 types of skeletal dysplasias with more than 360 causative genes that are known by scientists around the world which can cause short-limbed stature and shortening of trunk and limbs. Some of the skeletal dysplasias that mimic the signs of Achondrogenesis are:
  • Kniest dysplasia: It is quite identical to Achondrogenesis as both of the illnesses are caused by the mutation in the COL2A1 gene. The only difference they have is in the case of Achondrogenesis the signs like short stature, enlarged knees, and cleft palate are fatal and life-threatening which cause early death in infants but in the case of kniest dysplasia, the symptoms are not life-threatening and usually develop with age.
  • Campomelic syndrome: Another form of dysplasia that is rare which resembles the signs of Achondrogenesis. It is very distinctive as the cause of the congenital disorder is the mutations in the SOX9 gene. Also apart from identical skeletal abnormalities, other symptoms like bowing and angular shape leg bones, underdevelopment of the trachea, multiple anomalies of the face, and absence of one pair of ribs make it different from Achondrogenesis.
  • Hypophosphatasia: It is an inborn metabolic disorder of the bones which have skeletal defects identical to rickets and Achondrogenesis. Due to the abnormal activity of alkaline phosphatase in the blood serum, the amount of bone cells in the body starts to degrade resulting in various skeletal complications like epiphyses and osteoid during the early stages. Even though the nature of the illness is different from Achondrogenesis, it has been seen that initially, they both show the same set of symptoms.
  • Thanatophoric dysplasia: One of the most common yet known to be the most lethal form of skeletal dysplasias mirror the same set of signs like enlarged head followed by short and more bowed bones in the arms, ribs, and legs with narrow thorax and flattened vertebrae. The root cause of the disorder makes it different from Achondrogenesis as it is caused due to the mutation of the FGFR3 gene leading to abnormal production of amniotic fluid in the body.
  • Short-rib-polydactyly syndrome: More than an individual disease, SRPS is known as a group of different skeletal dysplasias possessing the same effects. Other than the skeletal deformations, the patient may have deformed ears, cleft lip, and palate, and a narrow chest with short ribs along with the absence of a gallbladder, kidney and genital cystic, and brain malformations.

General symptoms of Achondrogenesis may include:

• Premature birth
• Cleft palate - Incomplete closure of the roof of the mouth
• Abnormal or ossified head shape
• The short size of neck, limbs, and ribs
• Flat vertebrae
• Hydrops fetalis - Abnormal accumulation of fluid in the body
• Small thoracic cage
• Ear deformities
• Corneal clouding

Other symptoms that are associated with Achondrogenesis are specific to its type, here are some other signs of this medical condition.

• Achondrogenesis type IA symptoms:
  • Flat face
  • Protruding eyes and tongue
  • Short trunk and limbs
  • Short beaded ribs
  • Ossification of the skull
  • Abnormality of spine, pelvis, and extremities
  • Small thorax which may lead to early death
• Achondrogenesis type IB symptoms:
  • Short trunk and limbs
  • Narrow chest
  • Prominent abdomen
  • Umbilical or inguinal hernia
  • Inward turned feet with short fingers and toes
  • Flat face with short neck and cleft palate
  • Abnormal thickening of the soft tissue in the neck
• Achondrogenesis type II symptoms:
  • Narrow chest
  • Smaller arms or legs
  • Thin ribs
  • Flat vertebra
  • Underdeveloped lungs
  • Small chin
  • Cleft palate
  • Clubfeet
  • Abnormal formation of spine and pelvis
  • Hydrops fetalis
  • Enlarged abdomen

To diagnose Achondrogenesis, your medical professional may conduct a series of tests to assist the physical features. Tests like X-ray (radiography), a study of tissue samples via histology, and molecular genetic tests to confirm the mutations in the SLC26A2 gene. Which will further help your doctor to confirm the type of Achondrogenesis in the infant.

Furthermore, Achondrogenesis can also be diagnosed in the prenatal stages by conducting an ultrasound, amniocentesis, and a chorionic villus sampling within 14-15 weeks gestation. The amniocentesis and a chorionic villus sampling test are only suggested in case gene mutations have also been detected in other members of the family.

Treatment of Achondrogenesis is designed by a team of specialists in a symptomatic and supportive manner. It involves the overall palliative care where your physicians will try to minimize pain, discomfort, stress, and all other associated symptoms.

Along with physiotherapy, genetic counseling and psychosocial support are also recommended for the patient and its families.

Summary: Achondrogenesis, also known as osteochondrodysplasias, can be characterized as rare skeletal dysplasia where the patient shows extreme shortening of the arms and legs as compared to the trunk, ribs, vertebra, and overall skeletal. Depending upon the type it can be caused by a mutation in different genes.