What Is Acromicric Dysplasia?

Acromicric Dysplasia is a genetic disorder caused by a mutation in the FBN1 gene, and people with it usually have joint stiffness and short heights due to a lack of bone development. The different types of treatments are only for symptoms but not for the genetic root of the disease.

Introduction to acromicric dysplasia 

Acromicric Dysplasia (AD) is a very rare genetic disorder that appears during the later stages of infancy. It can be detected through genetic testing during the pregnancy in order to prepare the parents for the symptoms that come along with the condition. AD is usually characterised by abnormal bone and cartilage development. However, the frequency of the condition is very low as there are just over 60 cases reported worldwide.

Causes and genetics

Mutation in the FBN1 gene

The FBN1 gene is located on the q arm (longer arm) of chromosome 15. Acromicric Dysplasia is a result of heterozygous mutations in the FBN1 gene, which is responsible for the production of a protein called ‘fibrillin-1’. This macromolecule is integral to the strength and function of connective tissues in our body. In the extracellular matrix, Fibrillin-1 combines with other proteins to form microfibrils that form elastic fibres. These are extremely important in the formation of ligaments and skin, allowing it to stretch and grow. Additionally, their added strength also provides support to bones and tissues in the eyes.

Microfibrils contain the growth factor TGF-𝛽. It is important in the regulation of the development and differentiation of cells. Due to mutations in the FBN1 gene, there is a lack of microfibrils to regulate the growth factor, making it atypically active. This leads to the physical abnormalities that are characteristic of acromicric dysplasia.

Inheritance pattern 

Those affected by this condition either inherit it from an affected parent or have a random mutation in the FBN1 gene in a family without its history. As this is inherited in an autosomal dominant pattern, even one parent having the mutated gene could cause the newborn to have the condition. Recently, there have been cases where the mutations are newly found without any family history.

Clinical features 

Physical characteristics

The condition causes prominent physical abnormalities like short stature and joint limitations. 

The average height of inflicted adults ranges around 4 feet 2 inches to 4 feet 5 inches, characterising them as dwarfs. Some other physical features like an abnormally round face, short nose and long philtrum are also frequently seen symptoms.

Skeletal abnormalities 

Bone mineralisation is slower, leading to delayed bone age. This means that the skeletal system has lower physiological maturity than a person of the same age without the disorder. This leads to bones being shorter, meaning that individuals possess short hands and legs. This makes everyday tasks like reaching cabinets much harder. Some patients also have unusual finger shapes due to abnormal bone growth, which is diagnosed via X-rays, as shown in the picture below. Subsequently, they are also prone to carpal tunnel syndrome (CTS), which is characterised by aching and numb hands as well as weak gripping skills.

Non-skeletal manifestations 

Apart from skeletal limitations, the condition also affects other bodily systems, mainly due to developmental issues. In terms of the respiratory system, some individuals have respiratory complications due to irregular tract formation. Additionally, the chances of asthma and tracheal infections are also higher than normal. 

Although rarely, some patients with acromicric dysplasia have mild heart abnormalities like atrial septal defect and blood vessel deformities. Blood vessel development is also dependent on this gene therefore this mutation could cause critical problems like making vessels prone to aneurysms. These are uncommon and milder compared to the skeletal abnormalities caused by AD. Unlike the condition itself, cardiac difficulties have procedures in place to alleviate these problems.

Diagnosis

Clinical examination 

The first method of checking includes a physical examination in which a physician checks for the previously mentioned symptoms. If an individual exhibits those features, then they are referred to specialists for either genetic testing or radiological imaging.

Radiological imaging 

X-rays are a common method of identifying delayed bone age and other abnormal features. Through the scan, specialists look out for short metacarpals, coning of phalanges and broad bones that are a result of acromicric dysplasia.

Genetic testing (FBN1 gene mutation analysis)

Since this is a genetic condition, genetic testing would be an absolute way of confirming the presence of the mutated FBN1 gene. PCR (Polymerase Chain Reaction) is used to amplify the extracted exons of the FBN1 gene from the individual. It is then sequenced and compared to understand if there have been any mutations leading to Acromicric Dysplasia.

Management and treatment 

Multidisciplinary approach 

This method involves addressing the physical and psychological effects of the disorder. Psychologists and support groups are particularly helpful for the affected individuals and their families. This allows them to learn more about the disorder and the challenges it poses as one grows into an adult. 

On the other hand, physical therapists and orthopaedic surgeons can help improve joint mobility through exercises or personalised treatments. Furthermore, a dietician could help by providing information on the nutrients essential for optimum growth to reduce some of the developmental issues that might arise. A culmination of these efforts can prove to be very useful for affected individuals.

Symptomatic treatment 

Slow development of bones and joints leads to stiffness, which can be improved with stretching exercises. The exercises also improve mobility and strength of joints. However, if these pains are not manageable by physiotherapy, then medications are prescribed to alleviate pain.

Regular monitoring of symptoms is necessary to prevent the escalation of pain, which could cause severe damage to the body. It is advised that individuals immediately visit their doctor when they experience any symptoms that are a result of this condition.

Supportive care for respiratory and cardiovascular concerns

The respiratory and cardiovascular issues that are caused by this disorder are specific to every individual. Cardiologists assess the cardiovascular system of the individual. If the individual has any treatable defects, then they are referred to cardiac surgeons. 

For respiratory issues, specialists monitor and help to manage breathing difficulties. Symptoms can be managed through appropriate breathing exercises and techniques, but in severe cases, individuals are sent to pulmonologists who suggest treatments based on the individual's level of deformity.

Prognosis 

It is a lifelong condition that has varied severity in individuals. There is no absolute treatment for the condition as of now. Therefore, once diagnosed, the various treatments mentioned above can be implemented, which will allow patients to participate in daily activities to the best of their abilities.

Current research and future directions 

Genetic studies and gene therapies 

There are no specific therapies developed for treating Acromicric Dysplasia (AD), but with advancements in genetic medicine, there will likely be upcoming research. Currently, there are gene editing and gene silencing technologies that could be implemented on the FBN1 gene of the affected individuals to correct the mutated gene. 

In 2022, base editing technology has been tested on embryos to correct Marfan syndrome, which is also caused by mutation in the same gene. This was possible by sequencing and doing a whole-genome analysis of the chosen embryo. Hence, there is a high possibility of this newly discovered therapy being a feasible treatment for embryos with AD.

Recently, recombinant human growth hormone (rhGH) was used to treat a child with AD, and the patient showed a significant increase in development. Human growth hormone (HGH) is produced by the pituitary gland and is necessary for growth in children and adults. rhGH is produced using recombinant DNA technology, making it easier to produce for medical purposes. This novel technique could help alleviate quite a few symptoms associated with AD, but the long-term effects of the therapy need to be assessed to continue the use of this therapy.

Advancements in orthopaedic interventions 

Individuals who have acute physiological symptoms have access to orthotics, which help improve leg stability. This is an efficient alternative, especially for those with knee joint stiffness who find walking challenging. There has also been the invention of adaptive equipment such as reachers and mobility aids that help individuals carry out daily tasks with ease. 

Some patients also undergo limb lengthening procedures to alleviate joint pain and allow them to carry out everyday tasks without difficulty.

Support networks and patient advocacy

There are plenty of online and physical support groups available to patients and their families. This allows experienced individuals to share their stories with others and help them cope with the disorder as well as possible. Some genetic consultants can help provide you with information on how the disease would affect your lineage.

Summary

• Acromicric Dysplasia is a genetic disorder caused by a mutation in the FBN1 gene.
• It mostly manifests physically in the form of short stature, joint stiffness and mobility difficulties. The non-physical symptoms mostly develop in the cardiovascular and respiratory systems. In almost all cases, AD does not have any effect on intellectual development.
• It currently has no outright treatment, but scientists are researching ways to implement genetic therapies to correct the mutated gene at the embryo stage.
• Its treatment needs to be well-rounded, especially tackling the physical and mental aspects.
• Patients require regular medical checkups to ensure no new symptoms of the condition have developed.