Introduction

Acrodysostosis, also known as Maroteaux-Malamut syndrome, is a rare genetic disorder that includes a group of skeletal dysplasias (abnormal growth of cells). The disorder is characterised by severe short fingers and toes, facial dysostosis, and nasal hypoplasia (underdevelopment of an organ/tissue).¹

Peripheral dysostosis, nasal hypoplasia, and mental retardation, or the syndrome of pug-nose and peripheral dysostosis, were previous names for the condition.¹

Knowing how this disorder leads to developmental growth and delay is very important to ensure proper care for the sufferers. This article will thus provide a detailed overview of the causes, symptoms, diagnosis, treatment, and prognosis of growth and developmental delays in acrodysostosis.

Causes of acrodysostosis

Genetic Factors

The genetics of the condition are pointing out what may be called the complex molecular network of our development. There are two gene mutations that are detected.

• PRKAR1A Mutations (ADOHR)

One of the genetic factors causing acrodysostosis is mutations in the PRKAR1A gene. The gene is of high importance for the cAMP-PKA signalling pathway involved in a number of biological processes, including bone formation.²

The mutation in this gene is associated with hormone resistance, called as acrodysostosis with hormone resistance, or ADOHR, is a subtype of acrodysostosis caused by this gene mutation.²

Patients with ADOHR often have resistance to some hormones, such as PTH and TSH, added to the list of their conditions.²

• PDE4D Mutations (ADOP4)

The PDE4D gene is another important element. Another kind of acrodysostosis called ADOP4 (Acrodysostosis without Hormone Resistance) is caused by gene mutations.²

Additionally linked to the cAMP-PKA pathway, its malfunction results in severe malformations of the skeleton. Unlike ADOHR, most ADOP4 individuals usually do not show signs of hormone resistance, yet the skeletal symptoms can be as severe.²

The cAMP-PKA Signalling Pathway

The cAMP-PKA signalling pathway is considered one of the most important pathways involved in how the cells respond to various hormones and neurotransmitters.³

The functions and mechanism of cAMP-PKA signalling pathway

cAMP: The key messenger

cAMP is at the core of cellular responses. It affects the cell through three main effectors: PKA, EPAC, and cyclic-nucleotide-gated ion channels.³

Adenylyl cyclase and phosphodiesterase: Countering cAMP levels

cAMP is synthesised due to adenylyl cyclase (AC) and degraded by phosphodiesterase; the balance between the activities of these two enzymes ultimately determines the final levels of cAMP.³

These enzymes are controlled by different signals, which provide for appropriate cellular responses.³

Activation by G-protein-coupled receptors (GPCRs)

The majority of ACs are activated by G-protein-coupled receptors, such as the β adrenoceptor. When a ligand, for example, epinephrine, binds to the GPCR, this causes the release of a Gs protein subunit αs, which in turn activates AC to produce cAMP.³

PKA (which phosphorylates numerous metabolic enzyme): The main effector

It is the critical target of cAMP and consists of two regulatory and two catalytic subunits.

When cAMP binds to the regulatory subunits, this releases the catalytic subunits, thereby activating PKA.³

Subsequently, PKA goes ahead to phosphorylate a host of proteins; this event eventually affects various metabolic pathways, including glycogen and lipid metabolism.³

Regulation and cross-talk

The cAMP-PKA pathway is tightly regulated through a number of other signalling pathways  including calcium signalling, protein kinases, and receptor tyrosine kinases.

The activity of PKA is counterbalanced by protein phosphatases, which dephosphorylate PKA targets to provide an excellent control of cellular activities.³

Transcriptional Regulation

PKA exerts effects on gene expression by phosphorylating some transcription factors, one of which is CREB (cAMP-response element-binding protein).³

Subsequently, CREB gets phosphorylated itself and then binds to CREs (cAMP-response elements) in DNA, stimulating the transcription of target genes.³

EPAC and Ion Channels

Another effector of cAMP, EPAC (a guanine-nucleotide-exchange factor), activates small GTPases such as Rap1 and is known to be involved in the regulation of cell adhesion.³

cAMP also acts on the cyclic-nucleotide-gated ion channels, which are involved in the regulation of ion flux and membrane potential in a wide variety of cells.³

Feedback Mechanisms

The pathway contains feedback loops that allow PKA to shut off its own activity through actions on PDEs and ACs. This will ensure that a fine-tuned cAMP signal, suitable for its cellular context, exists.³

The cAMP-PKA signalling pathway is a complex process of coordinating a variety of cellular processes into the integration of signals from multiple sources.

Symptoms of acrodysostosis

While researchers have identified a syndrome with distinct core symptoms, there is a lot we don’t fully understand about the disorder. It’s crucial to recognize that affected individuals may not exhibit all the symptoms.

Skeletal Malformations

1. Hands and Feet

Malformed shortening of bones leading to small hands and feet with extremely short, stubby fingers and toes (severe brachydactyly). Sometimes, only one or two fingers/toes may be involved. Big toes may either not be affected or unusually large.⁴

2. Long Bones

Shortening of long bones leading to short stature.⁴

3. Spine

Abnormal curvature (scoliosis or kyphosis) and risk of spinal stenosis, causing numbness or pain in the lower back and legs.⁴

Distinctive Facial Features

Jaw and Nose⁴

• Underdeveloped upper jaw (maxillary hypoplasia)
• Underdeveloped nasal bone (nasal hypoplasia) leading to a small nose with a flattened bridge
• Rounded nose tip and upward-pointing nostrils
• Prominent lower jaw (mandible) 

Other facial features⁴

• Widely-spaced eyes (hypertelorism)
• Epicanthal folds (extra skin folds on the nose sides)
• Misaligned teeth (malocclusion) and low-set ears

Intellectual and developmental issues⁴

Cognitive and motor skills

• Mild to moderate intellectual disability
• Delays in learning and motor skills (psychomotor delays), such as walking and talking
• Learning disabilities

Growth delays⁴

Before Birth

• Severely affected growth, leading to small size at birth.

After Birth

• Ongoing growth delays and short stature due to the lack of a pubertal growth spurt.
• Hormone Resistance.

Multiple Hormones

• Resistance to hormones like parathyroid and thyroid-stimulating hormones
• Hormones are present but tissues do not respond fully, though higher levels may still have some effects

Additional Physical Findings⁴

Common Issues

• Repeated middle ear infections (otitis media), hearing loss, obesity, and pigmented skin lesions.
• Blue eyes and red or blond hair.

Arthritic Changes

Arthritic changes in the hands affecting manual dexterity.

Male Genitalia

Hypospadias (urethral opening on the underside of the penis) and undescended testes (cryptorchidism).

Metabolic and Cardiovascular Manifestations⁴

• Hypertension: High blood pressure.
• Vascular Stenosis: Increased risk of blood vessel narrowing.

Diagnosis

Diagnosis of acrodysostosis is made based on its typical symptoms, obtaining a good history, detailed clinical examination, and investigations like X-rays.⁴

Clinical Work-up and Testing⁴

Prenatal Testing

The ultrasound examination with foetal ultrasound, that produces pictures of the foetus made by passing sound waves through the abdomen of the mother, may show several signs which point to the acrodysostosis, such as slowed growth and short long bones. 

There are no specific prenatal markers for the presence of acrodysostosis on the other hand.

Postnatal Indicators

• At birth itself, various indications like evident facial features and growth retardation can be seen
• X-rays can exhibit very short bones in the hands and feet, with very early fusion of growth plates, or epiphyses, of these areas
• Stippling at epiphyses may also appear in the X-rays

Genetic Testing 

• Genetic testing is available in some cases to confirm this diagnosis by identifying mutations in one of two specific genes causing this disorder
• Testing of this nature is only accessible through specialised laboratories

Management of acrodysostosis

Treatment for acrodysostosis is not standardised. It depends on the patient's symptoms, multiple therapies may be used, such as physical therapy or surgery to repair certain problems. In many cases, a multidisciplinary medical team is needed. Hormone resistance should be assessed in patients with acrodysostosis and treated appropriately.⁵

This team may include: 

• Paediatricians
• Orthopedists 
• Paediatric endocrinologists 
• Other medical doctors such as an orthodontist or a dentist to address dental issues. 

Currently, treatment of acrodysostosis is largely symptomatic and supportive such as:

• Surgery: This would correct all the physical abnormalities, such as jaw and dental irregularities^6,4
• Physical therapy: to manage joint pain and improve mobility⁴
• Thyroid and vitamin D supplementation: for growth support and prevention of obesity⁴
• Hearing aids and regular auditory checkups: in mitigating hearing loss⁶
• Early Intervention and Support Services for Children: with the purpose of realising the potential through directed educational and social care training⁴

Summary

Acrodysostosis is described by characteristic skeletal abnormalities, facial traits, and potential developmental delay. Mutations in the PRKAR1A or PDE4D genes, which control important biological processes, are the cause of this.

Clinical history, imaging analysis, and genetic testing are used to make the diagnosis. In addition to physical therapy, and surgery, symptomatic treatment is administered through a multidisciplinary approach, with the goal of improving the quality of life for individuals afflicted with the illness.

FAQ’s

Is acrodysostosis a disability?

Yes, it can be said that acrodysostosis is a kind of disability.

What are the different types of acrodysostosis?

There are two major kinds of acrodysostosis, mainly based on genetic mutations and hormone resistance: Type 1 (Acrodysostosis with hormone resistance (ADOHR)), type 2 (Acrodysostosis without Hormone Resistance (ADOP4)).