Introduction

Acromicric dysplasia (AMD) is a rare autosomal dominant bone disorder which is characterised by short stature, short hands and feet, stiff joints, and mild facial dysmorphism with normal intelligence.¹ Unlike other skeletal dysplasias, acromicric dysplasia has a mild clinical phenotype, mainly characterised by short stature. These facial features can include a small jaw, prominent eyes, and a sunken nasal bridge. The incident rate is less than 1/1 000 000, and only approximately 60 cases are reported worldwide. Acromicric dysplasia is caused by heterozygous mutations in the FBN1 gene, missense mutations clustered in exons 41 and 42 in the transforming growth factor-beta (TGF-β) binding protein-like domain 5 (TB5) of FBN1.^2,3 

This article explores the role of the FBN1 gene in the development of acromicric dysplasia, delving deeper into how mutations within this gene can disrupt the formation of essential structures and signalling pathways, ultimately leading to the characteristic features of AMD.

First incidence record and its clinical observation 

In 1986, Maroteaux et al described a new entity bone dysplasia in six unrelated children presenting with short stature, markedly shortened hands and feet, growth retardation, normal intelligence and mild facial dysmorphic features.¹ The metacarpal and phalanges were short, stubby, notch in the radial slide of the second metacarpal and a notch in the ulnar side of the fifth metacarpal. In further descriptions, both sexes were affected, and acromelic dysplasia was found in the birth parent and the child assigned male at birth (AMAB).

FBN1 gene and microfibrils

The FBN1 gene, located on the long arm of chromosome 15, comprises 66 exons and encodes a 2,871-amino acid structural protein called fibrillin-1. The FBN1 gene provides instructions for making a large protein called fibrillin-1.^4,5 Fibrillin-1 is a cysteine-rich glycoprotein, and it is the primary structural component of extracellular matrix microfibrils present in the connective tissues. These microfibrils are a complex network of molecules that provide support and structure to various tissues throughout the body. In the growth plate extracellular matrix, the microfibrillar network regulates the activity and bioavailability of the TGF-β, which itself has a significant impact on chondrogenesis and osteogenesis.⁶ TGF-β affects the development by helping to control the proliferation, differentiation, motility and apoptosis of the cells.

What will the mutation do?

The mutations within the FBN1 gene impact microfibril formation and function. These disruptions can have a profound effect on the signalling pathway of TGF-β. By this specific mutation, the protein produced by the FBN1 gene may present:

• Reduced quantity: Fewer microfibrils are available, affecting the structural integrity of tissues
• Abnormal structure: The mutated protein may not assemble properly into functional microfibrils, and its ability to provide support and interact with TGF-β is affected

FBN1 mutations and acromicric dysplasia

The mutations in the FBN1 gene can lead to a spectrum of skeletal disorders with opposite skeletal features, resulting in Marfan syndrome and acromicric dysplasia. Marfan syndrome is characterised by excessive bone growth resulting in tall stature, elongated limbs, and other connective tissue issues.^7,8  

Acromicric dysplasia is the opposite of Marfan syndrome, identified with short stature, shortened limbs, and joint limitations. In people with acromicric dysplasia, at least nine FBNI mutations have been identified. Researchers have identified a hotspot for these mutations within exons 41 and 42 of the FBN1 gene. These exons encode a specific region of the fibrillin-1 protein known as the TGFβ-binding protein-like domain 5 (TB5). 

Mutations in this domain likely disrupt the interaction between microfibrils and TGF-β in a way that differs from mutations causing Marfan syndrome. This mutation results in a reduction and structural variance of the microfibrils. Without enough normal microfibrils to store TGF-β, the growth factors are abnormally active, which includes:

• Disrupted regulation of TGF-β: The FBN1 mutations in the TB5 domain may hinder the ability of microfibrils to store TGF-β – this could lead to chronically elevated levels of active TGF-β in tissues crucial for bone growth and development
• Altered signaling: Excessive signalling can disrupt normal communication between cells in the growth plates, which may lead to premature closure, hindering bone elongation and contributing to short stature and shortened limbs. The abnormal TGF-β signalling may also influence the development and function of cartilage and connective tissues around joints. This can contribute to the stiffness and limited mobility often observed in acromicric dysplasia

The exact mechanism of the mutated gene remains under investigation, and the link between FBN1 mutations, disrupted TGF-β signalling, and the characteristic features is becoming increasingly well-established.

Unanswered questions and future directions

Due to the heterogeneity of the FBN1 gene variation, the genotype-phenotype association is still unclear. The mutation causes a significant impact on the microfibrillar network and TGF-β signalling, which in turn triggers either Marfan syndrome or acromelic dysplasia.⁹ 

A study found that FBN1 missense variants involving a cysteine were likely to cause heart valve disease and other life-threatening complications.⁷ Probably unknown disease-modifying factors caused the phenotypic divergence.¹⁰ Currently, there is no surveillance or management of patients with acromelic dysplasia. A coordinated multidisciplinary approach involving genetic, paediatric, cardiac, pulmonary, orthopaedic, and ophthalmic specialists and organised follow-up may be needed throughout life. There are no large cohort studies that have been conducted to evaluate the therapeutic response to recombinant Human Growth Hormone (rhGH) in patients with acromelic dysplasia. Only a few cases with conflicting outcomes have been reported; some patients show a good response to rhGH therapy, reporting improved growth rate and height.^11,12,13 The other set of patients shows limited benefit from rhGH and no significant degree of catch-up growth. As outcomes of the rhGH therapy are insufficient and contradictory, the clinical effect of rhGH therapy remains insignificant.¹⁴

Recent case report

A case report of two different acromelic dysplasia phenotypes in a Chinese family caused by a missense mutation in the FBN1 gene, described by Fengyan Tian et al. notes that the proband presented with facial features and extremity abnormalities with radiological confirmations.¹⁵ 

The report further states that the proband’s elder sibling, assigned female at birth (AFAB), and their birth parent had similar physical features. Mutation analysis demonstrated a heterozygous missense mutation in exon 42 of FBN1. The proband and mother were diagnosed with acromicric dysplasia, and the elder sibling AFAB, with geleophysic dysplasia. The proband was therapeutically treated with rhGH with a positive outcome of body length gain of 0.72 SDS in half a year. The efficacy of rhGH therapy is controversial, and more research on its long-term efficiency is needed. 

Summary

A deeper understanding of how specific mutations within the FBN1 gene influence TGF-β signalling and, ultimately, the skeletal phenotype is crucial. There is a reasonable probability to show that other genetic or environmental factors may play a role in modifying the effects of FBN1 mutations. Identifying these factors could provide insights into the investigation of the genotype-phenotype discrepancy and the exact mechanism of mutations. Developing accurate animal models of acromicric dysplasia caused by FBN1 mutations is essential. This knowledge could help to explain the spectrum of severity observed in acromicric dysplasia cases. 

By addressing the unanswered questions, researchers may actively understand the link between FBN1 mutations and acromicric dysplasia. A deeper understanding of the mechanisms will pave the way for the development of more effective diagnostic tools and targeted therapies for individuals suffering from rare genetic disorders.

FAQs

How common is acromicric dysplasia?

Acromicric dysplasia is a rare disorder, and its prevalence is unknown. The incident rate is less than 1/1 000 000, and only approximately 60 cases are reported worldwide.

What is another name used for acromicric dysplasia?

Acromicric dysplasia is also known as Acromicric Skeletal Dysplasia.

When is the symptom-onset of acromicric dysplasia?

The symptoms may appear in newborns.

Is the disease hereditary, passed down from parent to child?

Yes, it is possible that the disease can be passed down from a biological parent to the child in an autosomal dominant manner.

What is the life expectancy of an individual with acromicric dysplasia?

Life expectancy is generally normal, and no major complications are commonly reported.