Acromesomelic dysplasia (AMD) is a genetic disorder that interferes with bone and cartilage development, resulting in the shortening of the long bones of the forearms, lower legs, hands and feet. There are four different types of AMD resulting from mutations in different genes encoding proteins involved in bone formation and growth.¹ To prevent, diagnose and treat acromesomelic dysplasia, it is fundamental to understand the underlying dysfunctions in biochemical pathways and how they alter the behaviour of bone cells. 

Introduction

Acromesomelic dysplasia is an extremely rare disorder affecting less than 1000 people in the United States. It causes skeletal abnormalities, including short forearms, lower legs, hands and feet and progressive development of abnormal spinal curvatures.² These features are usually present from the first years of life when it is typically diagnosed based on clinical evaluation and potentially subsequent genetic testing. Treatment usually involves supportive techniques to improve the posture of the spine, such as physical therapy, braces, casts and corrective surgery. 

Acromesomelic dysplasia can be caused by one or more mutations in any of the genes encoding the proteins NPRB, GDF5 and BMPR1B, giving rise to distinct AMD types. These are all involved in skeletal growth and development. For each gene, an individual inherits two copies, one from each parent. In autosomal recessive diseases like AMD, both copies must be mutated to develop the condition. If the two parents have only one abnormal gene copy, however, they have a 25% chance of passing it to their offspring, making consanguinity a possible risk factor.¹

Acromesomelic dysplasia can worsen the quality of life by interfering with body appearance, posture and gait. This can result in difficulties with daily motor activities and low self-esteem or poor mental health. In order to overcome these challenges, research has focused on grasping the molecular and biochemical abnormalities involved in the pathophysiology of AMD. This article will provide an overview of these mechanisms and how they can be targeted in future treatments. 

Symptoms and diagnosis of acromesomelic dysplasia

The most defining feature of acromesomelic dysplasia is an abnormal shortening of the lower portions of the limbs, including the forearms, lower legs, hands and feet. During childhood, patients also develop progressive abnormalities in spinal curvature, particularly low thoracic 

kyphosis (giving the appearance of a hump in the central portion of the spine) and hyperlordosis (the lower spine curving inwards). Depending on the type of AMD, other characteristics may also be present, including:

• Cranial features such as an enlarged head (macrocephaly), prominence of the forehead and occipital (back) portion and an abnormally small nose
• Dislocation of the elbow joint (Madelung deformity) and associated difficulties in forearm movement
• Short stubby fingers (brachydactyly)
• Progressive development of osteoarthritis resulting in joint pain and tenderness 
• Delayed puberty (rarely)¹
• Genital abnormalities in individuals affected by a mutation in the BMPR1B gene³

Diagnosis of acromesomelic is typically through clinical observation of distinctive skeletal features; in addition, providers may order genetic testing to confirm the diagnosis and determine the subtype.¹

Genetic basis of acromesomelic dysplasia

AMD can result from a mutation in different genes, encoding proteins that either function as signalling hormones or hormone receptors, which regulate bone development. These are:

• Natriuretic peptide receptor B (NPRB) - Maroteaux subtype
• Growth Differentiation Factor 5 (GDF5) - Hunter-Thompson or Grebe subtypes, depending on severity and presence of genital abnormalities
• Bone Morphogenetic Protein Receptor Type 1B (BMPR1B), which GDF5 binds to - Demhirran subtype

Acromesomelic dysplasia is an autosomal disease, which means it affects genes that are not present in the sex-linked chromosomes (X and Y). In addition, it has a recessive inheritance pattern, meaning a person must inherit two copies of the mutated gene, one from each parent, to exhibit symptoms. Individuals that have only one mutated copy are known as “carriers”, they have a normal phenotype themselves, but a child of two carrier parents has a 1 in 4 chance of inheriting two mutated copies and developing AMD.¹

Biochemical mechanisms 

Research has provided insights into the molecular and cellular interactions between different proteins and bone function and growth. 

Natriuretic peptides are a family of proteins that regulate different systems and functions across the body, including renal sodium excretion, vascular tone and cardiac stroke volume.⁴ Type C natriuretic peptide (NP-C), which binds to NPRB, is involved in long bone growth. Studies in rats show that the loss of NP-C or NPRB shrinks areas of new bone tissue formation and reduces the proliferation of osteo- and chondrocytes (cells that make up bone and cartilage, respectively).⁵ This results in a shortening of the lower limbs similar to that seen in acromesomelic dysplasia of the Moreaux type. 

Growth differentiation factor 5 (GDF5) is another protein with important roles in bone growth and regeneration that is expressed by cartilage from embryonic development to adulthood.⁶ GDF5 binds to BMPR1B, which stimulates the formation of new bone and cartilage components. It is believed signalling at this receptor upregulates osteo- and chondrogenic genes and increases the expression of Cadheri, which helps bone cells stick together and plays an important role in bone integrity. In addition, GDF5/BMPR1B signalling is involved in joint cartilage repair, with poor function resulting in an increased risk of osteoarthritis, which occurs when cartilage shrinks, leading to joint inflammatory processes. This may underlie the symptoms and abnormalities seen in Hunter-Thompson, Gerber and Demhirran subtypes of AMD.⁷

Current and emerging treatments

Current treatments for acromesomelic dysplasia primarily focus on managing symptoms and improving quality of life, as there is no cure for the condition. Orthopaedic interventions, such as corrective surgeries or braces, are often employed to address skeletal deformities and improve mobility. Physiotherapy also plays an important role in enhancing joint function and muscle strength, which can help individuals adapt to the physical challenges posed by AMD.¹

Emerging treatments are exploring genetic and molecular approaches. Researchers are investigating the potential of CRISPR technology and other gene-editing tools to correct genetic mutations at the DNA level. By understanding the biochemical processes involved in bone growth and taking advantage of rational drug design, researchers can also develop future targeted pharmacotherapies, such as NPRB and BMPR1B agonists, which correct the molecular abnormalities in acromesomelic dysplasia.

Conclusion

Acromesomelic dysplasia is a rare genetic disorder that interferes with bone and cartilage development, resulting in characteristic features, particularly shortening of the lower legs and arms, abnormal curvature of the spine and propensity for osteoarthritis. There are four subtypes associated with different genetic alterations and/or severity, but they are all passed down through autosomal recessive inheritance, which means individuals must have two mutated copies of the genes in question to express symptoms. 

Understanding the genetic and biochemical basis of AMD can provide useful information for the development of new treatment strategies. It appears that loss of type C natriuretic peptide signalling at the NPRB orGDF-5 signalling at the BMPR1B disturbs bone and cartilage formation, growth and repair. As such, targeting these genes and molecules could be promising therapeutic interventions.

FAQs

Q1: What is acromesomelic dysplasia (AMD)? 

Acromesomelic dysplasia is a rare skeletal disorder characterised by the disproportionate shortening of the limbs and short stature. It involves abnormalities in bone growth and development, leading to skeletal deformities.¹

Q2: What are the genetic causes of AMD? 

AMD is caused by mutations in genes involved in bone growth and development. Specific mutations in the GDF5, NPRB and BMPR1B genes, which disrupt normal cartilage and bone formation, have been linked to different forms of AMD.¹

Q3: How are natriuretic peptides linked to AMD?

Natriuretic peptides are a family of proteins that can regulate different homeostatic functions. Type C NP, particularly, is involved in bone growth. Moreaux type AMD is characterised by loss of function of the NPRB receptor, which type C natriuretic peptide binds to to stimulate the proliferation of bone and cartilage cells.⁵

Q4: What is growth differentiation factor 5, and how is it associated with AMD?

GDF5 is a signalling molecule which upregulates genes involved in bone formation and plays important roles in bone and cartilage growth and repair. Different types of AMD are associated with either an inability to produce GDF5 or loss of function of the receptor it binds to (BMPR1B), affecting these processes and resulting in a characteristic shortening of the limbs, as well as increased predisposition to osteoarthritis.⁷

Q5: How is AMD treated?

There is no known cure for AMD, instead, management involves supportive interventions to ameliorate symptoms such as abnormal spinal curvature and poor mobility.¹ These include physiotherapy, casts, braces and corrective surgery. New research, however, has shown the 

possibility of future disease-modifying therapies such as gene editing and drugs targeting biochemical abnormalities.