Introduction

Acrodysostosis refers to a rare genetic disorder characterised by skeletal development malformation, such as abnormally small hands and feet with short, stubby fingers and toes.¹

It is inherited as an autosomal dominant as a mode of transmission.³ If a condition is autosomal, it indicates that the mutated gene is found on a numbered chromosome (not a sex chromosome). If a child inherits one copy of the mutant gene from either of their biological parents, the illness is considered dominant. A 50% probability exists for a person with an autosomal dominant disorder to pass on the mutant gene to their biological offspring.⁴

Individuals who have acrodysostosis may have trouble breathing because of abnormal bone development that affects the chest and rib cage. These problems may affect breathing and lung function.

This article will discuss the genetic causes of acrodysostosis, symptoms, and the diagnosis. In addition, it explains possible reasons regarding the respiratory issues in acrodysostosis.

Causes and mechanism

Genetic causes

Recent research has identified the causes of acrodysostosis as there are two genes responsible. These genes interfere with the cAMP signalling pathway, that are essential for various cellular processes.²

Mutations in PRKAR1A cause acrodysostosis (Type 1)

Acrodysostosis is associated with a protein called PRKAR1A that’s not fully formed. This protein normally interacts with other components (catalytic subunits) in the cell.²

Cells use a molecule called cAMP (cyclic adenosine monophosphate) as a messenger, which acts as a postman delivering messages within the cell.²

However, due to the mutation, the interaction between PRKAR1A and these subunits is affected. The mutated PRKAR1A has a problem in binding to cAMP. This altered function leads to skeletal abnormalities and hormonal resistance.²

Mutations in PDE4D cause acrodysostosis (Type 2)

In some people with acrodysostosis, there are mutations in a gene called PDE4D.

This gene encodes a protein called phosphodiesterase 4D (PDE4D).³

This protein regulates the availability of cyclic adenosine monophosphate, which is essential to the cognitive process. PDE4D aids in the patients' full development of memory and intellect by controlling cAMP.³

People with these mutations show similar bone abnormalities as those with PRKAR1A mutations in addition to cognitive impairment. 

Type 2 impacts a person's cerebral capacity, whilst type 1 is linked to physical perspective.³

Physical abnormalities impacting respiration

Individuals with acrodysostosis often have physical and anatomical abnormalities that play a role in the respiratory problems, as following:

Craniofacial malformations

• Midface hypoplasia (underdevelopment of the middle of the face) contains skeletal abnormalities of the mandible and skull^5,6
• A small nasal passage that obstructs normal airflow⁵

Thoracic cage deformities

A narrow chest that restricts lung expansion and function.⁶

Spinal malformations

• Abnormal curvature of the spine (e.g. scoliosis or kyphosis)⁵⁶
• A risk of spinal stenosis, a condition marked by narrowing (stenosis) of the spaces within the spinal canal, spinal nerve root canals, or bones of the spinal column

As a result, individuals with acrodysostosis are predisposed to respiratory difficulties, such as obstructive sleep apnea and chronic respiratory insufficiency.¹

Clinical presentation

Common symptoms

Skeletal malformations

• Small feet and hands with short, stubby fingers and toes
• Shortened long bones leading to short stature
• Abnormal curvature of the spine causing numbness or pain

Distinctive facial features

• Underdeveloped upper jaw and nasal bone
• Small, flattened nose with upturned nostrils
• Prominent lower jaw
• Widely spaced eyes
• Extra fold of skin beside the nose covering inner eye corners
• Misaligned teeth
• Low-set ears

Intellectual disability 

• Mild to moderate intellectual disability
• Delays in mental and motor skills development

Delayed growth

• Severe growth delay before birth
• Continued growth delay after birth affecting height

Hormonal resistance 

Hormone resistance such as: parathyroid hormone and thyroid-stimulating hormone

Additional symptoms

• Repeated middle ear infections
• Hearing loss
• Obesity
• Skin lesions
• Blue eyes and red or blonde hair
• Arthritic changes in hands and coordination problems
• High blood pressure
• Increased risk of blood vessel narrowing
• Male-specific: Urethra opening on underside of penis and undescended testes

Respiratory symptoms

Acrodysostosis is considered one of the skeletal dysplasias that are quite a heterogeneous group of disorders, characterised by bone and cartilage abnormalities. These abnormalities affect the respiratory function in multiple ways, such as:⁷

Breathing difficulties

Breathing difficulties are a primary respiratory symptom in acrodysostosis. These can appear as:

• Dyspnea (shortness of breath): individuals may experience difficulty breathing during exercise or even at rest. This is due to obesity and bony abnormalities that restrict lung expansion and reduce respiratory efficiency¹
• Stridor: a high-pitched wheezing sound resulting from turbulent airflow in the upper airway. It can be heard during inhalation. This can be caused by narrow nasal passages or other airway obstructions which is not commonly associated with specific abnormalities in larynx or trachea but, it can occur in acrodysostosis as a result of repeated chest infections⁹

Obstructive sleep apnea (OSA)⁸

The prevalence of obstructive sleep apnea is higher in kids who have acrodysostosis. OSA occurs when the muscles at the back of the throat relax massively during sleep. This makes breathing stop many times while one is asleep. Symptoms of OSA include:

• Loud snoring: loud and continuous snoring is a characteristic of sleep apnea
• Breathing pauses: one can experience pauses in breathing during sleep, which is followed by gasping or choking sound
• Restless sleep: frequent awakening and restlessness during sleep
• Daytime fatigue: though patients sleep for apparently sufficient amounts of time, they become excessively somnolent during the day due to poor quality sleep

Recurrent respiratory infections

Recurrent respiratory infections are another common symptom in individuals with acrodysostosis. These infections can include:¹⁰

• Upper respiratory infections: this includes the common cold, sinusitis, and pharyngitis, which may occur more frequently and with greater severity
• Lower respiratory infections: this includes bronchitis and pneumonia, that are more severe and lead to complications if not treated

Chronic respiratory insufficiency

Chronic respiratory insufficiency refers to the continuous inability of the respiratory system for a long time to meet the body's oxygen demands. In acrodysostosis, this can result from structural abnormalities that limit lung function, leading to:^9,11

• Hypoxia: low oxygen levels in the blood, which manifest as cyanosis (bluish discoloration of the skin), fatigue, and affect cognitive functions
• Hypercapnia: elevated levels of carbon dioxide in the blood, which can lead to headaches, dizziness, and confusion

Nasal obstruction

Nasal obstruction is a common issue in acrodysostosis due to craniofacial abnormalities. This can lead to:¹⁰

• Mouth breathing: difficulty breathing through the nose, resulting in chronic mouth breathing
• Nasal congestion: the feeling of nasal stuffiness or congestion, even in the absence of infection

Diagnostic methods for acrodysostosis

There are multiple steps that are provided by a team of  providers to help you get the right management in your rare disease journey, they include:¹

Clinical diagnosis of acrodysostosis

The healthcare provider will diagnose through the following:

• Identification of characteristic symptoms
• Detailed patient history
• Thorough clinical evaluation
• Specialised tests are requested, including X-rays

Molecular genetic testing

Genetic testing confirms the diagnosis by detecting mutations in the PRKAR1A or PDE4D genes.

Diagnosis of respiratory problems

The respiratory function tests, also known as a pulmonary function test, are used to assess lung volume, capacity, rates of flow, and gas exchange, helping to identify any abnormalities in respiratory function, they include:¹²

Spirometry

The volume and flow of air that can be breathed and expelled are measured by spirometry.

Plethysmography

Plethysmography calculates the residual volume—the amount of air in the lungs after a complete exhalation—and the total lung capacity, or the amount of air the lungs can contain.

Diffusing capacity of the lungs for carbon monoxide (DLCO)

DLCO measures how well gases such as oxygen move from the lungs to the blood. It assesses the efficiency of gas exchange in the lungs.

Peak expiratory flow (PEF)

PEF measures the highest speed at which air can be blown out of the lungs. 

Arterial blood gas (ABG) analysis

The blood's pH and amounts of carbon dioxide and oxygen are measured using an ABG analysis. It provides information on lung function and the efficiency of gas exchange.

Management methods

Early intervention is important to guarantee that kids and young people with acrodysostosis reach their full potential and have fulfilling lives.¹

Currently, treating acrodysostosis is tailored according to the symptoms that each patient experiences. A team of professionals may need to work together in order to provide treatment, including:¹

• Paediatricians
• Physiotherapists
• Orthopaedics 
• Paediatric endocrinologists, who focus on abnormalities of the hormones
• Orthodontists, who specialise on dental anomalies
• Neurologists (nervous system specialists)
• Ophthalmologists, who specialise in eye disorders

Intervention strategies¹

• Surgery: corrects specific anomalies, such as an underdeveloped jaw
• Physio-therapy: helps  in improving mobility
• Hormonal Supplements: such as thyroid hormone and vitamin D, to promote healthy development and manage obesity
• Support Services: social support, special education, and other medical, social, and professional assistance

Summary

Respiratory symptoms in acrodysostosis are a significant concern due to the structural abnormalities caused by the disorder. To properly address these respiratory difficulties, a multidisciplinary team and early diagnosis and comprehensive care are needed. For individuals who have acrodysostosis, comprehending and treating these breathing problems can greatly enhance health outcomes and quality of life.

FAQ`s

Is acrodysostosis a disability?

Yes, as it causes multiple challenges that need to be addressed and is characterized by bone and cartilage deformity.

What are the different types of acrodysostosis?

There are 2 identified types of acrodysostosis: type 1(mutations in PRKAR1A) and type 2(mutations in PDE4D).