Overview

Acrodysostosis is a rare heterogeneous group of skeletal dysplasia resulting from a mutation in a specific gene. The disease is often presented with underdevelopment of facial bones, abnormally short fingers and toes and other systemic symptoms such as hormone resistance, cardiovascular complications and intellectual disabilities. There are two subtypes of acrodysostosis: type 1 and type 2. Type 1 acrodysostosis is caused by a mutation in the PRKAR1A gene while type 2 results from mutation in the PDE4D gene. Treatments and management strategies of acrodysostosis focus on controlling the multisystemic symptoms via a pharmacological approach or by performing corrective surgeries for facial skeletal abnormalities. Regular monitoring and assessments are also conducted to monitor the progression of the disease. The lack of clinical data on this disease calls for more extensive research in developing specialised treatment, thus contributing to more effective management of the disease with the ultimate goal of improving the patient’s quality of life.

Understanding acrodysostosis 

Acrodysostosis is a type of skeletal dysplasia disease caused by genetic mutations in either the PRKAR1A or PDE4D gene. These two genes are responsible for coding different proteins in the cAMP signalling cascade. The PRKAR1A gene encodes for type 1 a regulatory subunit of the cAMP-dependent enzyme, protein kinase A (PKA).¹ PKA is a crucial signalling enzyme, activated by 3′5′cyclic adenosine monophosphate (cAMP), that is responsible for the regulation of cellular metabolisms and gene expressions which ultimately contributes to the regulation of bone homeostasis.^{2 3} A mutation in this gene disrupts the normal functioning of the regulatory subunit, causing reduced sensitivity of PKA to cAMP, subsequently affecting the downstream signalling effects of PKA.⁴ PRKAR1A mutations are usually presented with hormonal resistance and are referred to as type 1 Acrodysostosis.² 

Mutation in the PDE4D gene leads to type 2 Acrodysostosis. The effect of this mutation remains elusive, but it is proposed that the PDE4D mutation disrupts the activity of PKA by increasing the degeneration rate of cAMP, subsequently resulting in decreased interaction between PKA and cAMP.⁵ This form of Acrodysostosis is rarely associated with hormonal resistance.⁴ Both mutations are heterozygous and are mostly sporadic. However, a few type 2 acrodysostosis cases with autosomal-dominant inheritance were reported.⁵ 

The manifestations of the disease often involve skeletal abnormalities. Both types of acrodysostosis share similar symptoms including:⁶ 

• Brachydactyly
• Facial dysostosis
• Nasal hypoplasia
• Maxillary hypoplasia
• Short stature
• Peripheral dysostosis
• Endocrine abnormalities (hormonal resistance) 
• Hypertension
• Obesity 

Despite the similar clinical features, both type 1 and type 2 acrodysostosis possess slightly indifferent characteristics that could help healthcare professionals distinguish between the two. For instance, cone-shaped epiphyses and short-stature are more often associated with type 1 acrodysostosis, whereas type 2 acrodysostosis patients usually present more distinctive facial dysostosis, intellectual defects and cryptorchidism.^{5 6} Initially, the presence of hormonal resistance towards parathyroid hormone (PTH) and thyroid-stimulating hormone (TSH) was reported only in type 1 acrodysostosis patients.¹ However, recent studies demonstrated substantial PTH and TSH resistance in some type 2 acrodysostosis patients. Hence, the initial assertion of hormonal resistance being an exclusive clinical feature for type 1 acrodysostosis no longer holds true.⁵ 

Diagnostic strategies 

Initial assessment

The initial diagnosis of the disease is based on its visibly apparent clinical characteristics including facial dysostosis and retardation of growth. Your healthcare provider will also consider your medical history and, in some cases, your family history. However, an accurate diagnosis of the disease can be challenging due to a few factors. Firstly, the clinical, biochemical, and radiological characteristics of acrodysostosis highly resemble those of pseudohypoparathyroidism type 1a (PHP1a) or pseudopseudohypoparathyroidism (PPHP)- related disorders that affect the cAMP signalling pathway.⁷ Besides, the high phenotypic variability trait of the disease causes the presentation of acrodysostosis to be greatly variable and unspecific even among patients with mutation in the same gene. Hence, a clear picture of the symptoms or clinical features associated with each subtype of acrodysostosis has not been established.⁵ Therefore, further genetic testing is required to obtain a spot-on diagnosis of acrodysostosis. 

Genetic testing

Molecular genetic analyses can identify mutations in the specific genes causing the disease. After the molecular cause is detected, healthcare professionals can confirm the diagnosis, either PHP1a, type 1, or type 2 acrodysostosis, thus reducing the risks of misdiagnosis. Also, the test results are crucial for genetic counselling in cases where the patient’s family members or future offspring are at risk of inheriting the disease.⁷ 

Radiological and other diagnostic tools

X-ray studies can observe radiological features of acrodysostosis, such as abnormally short toes and fingers (brachydactyly) and other skeletal abnormalities. When a familial history of acrodysostosis is present, prenatal screening (prenatal fetal ultrasonography) will be performed to screen for prenatal growth retardation.⁶ Patients are also screened for hormonal resistance, especially to PTH and TSH. Frequent monitoring of symptoms associated with PTH and TSH resistance, including hypothyroidism, hypocalcaemia and hyperphosphatemia, is required so management strategies can be executed efficiently.⁴  

Treatment options 

Pharmacological treatments

As acrodysostosis is a congenital genetic disease, there is no cure. Treatment protocols are targeted at managing symptoms by a team of specialists, including paediatricians, endocrinologists, orthopaedists, physical therapists, neurologists, physiotherapists etc. Oral supplementation of activated vitamin D and calcium is given to ensure calcium, phosphate and vitamin D levels are maintained at the optimum range.⁷ Appropriate dosage of thyroid hormone replacement tablets, levothyroxine can be given to patients with TSH resistance-related hypothyroidism. A recent study reported a successful administration of growth hormone to a type 2 acrodysostosis patient, demonstrating positive results of increased growth velocity after one and a half years of growth hormone therapy.⁸  

Surgical interventions

Orthopaedic surgeries are sometimes performed to amend skeletal abnormalities such as abnormal development of facial features (facial dysplasia) or abnormal protrusion of the jaws (prognathism). Protrusion of the jaws might also contribute to misalignments of teeth, which may require dental braces procedures. These surgical procedures are paramount for the normal functioning of the jaws (chewing, speech, etc.) whilst enhancing the aesthetic appearances of patients.⁶ 

Physical and occupational therapy

Skeletal malformations, such as the underdevelopment of phalanges and metacarpals (brachydactyly), can be diagnosed at a relatively young age. Affected patients often experience a compromised ability to perform precise movements such as writing, tying shoe laces, cutting, etc. To enhance their mobility, a multidisciplinary approach combining physical and occupational therapy will be introduced to patients, thus enabling them to perform daily activities with ease.⁷ 

Management strategies 

Multidisciplinary approach

The symptoms of acrodysostosis affect multiple systems of the body, including the skeletal and endocrine systems. Therefore, joint efforts from a range of specialists, such as endocrinologists, orthopaedists, orthodontists, neurologists, physical therapists, and paediatricians, are needed to devise a comprehensive plan to provide patients with long-term treatment for their life-long condition of acrodysostosis. 

Long-term monitoring and follow-up

Regular screenings and follow-ups for hormone resistance are needed to ensure hormone levels are maintained at normal levels, especially in symptomatic patients, to effectively manage symptoms associated with increased levels of PTH or TSH. The high-variability nature of acrodysostosis raises the need for regular follow-ups in case of the emergence of potential complications or new hormonal resistance.⁵ Cognitive and behavioural assessments are also conducted to monitor their intellectual development and for the diagnosis of intellectual disabilities.⁷

Supportive care

As acrodysostosis is a life-long condition, supportive care from various parties is crucial to providing mental and psychological support for patients as they go through the hardships of receiving life-long treatments and assessments which could be rather daunting, especially when the affected patient could be very young. Psychological support from patient support groups, friends and social groups is beneficial for the mental well-being of patients.⁷ Nutritional guidance on their dietary intakes and lifestyle modifications are also provided to curb cardiovascular and metabolic disorders.⁴ Genetic counselling is also given to the patient’s family members, especially those with autosomal dominant inheritance, to educate them on the potential risks of their offspring inheriting the disease. Patients with cognitive disabilities might also require educational assistance.⁷

Summary 

There is no definitive cure for acrodysostosis. Current treatments are aimed at treating the multisystemic symptoms associated with the disease such as hormonal resistance and skeletal abnormalities. Management strategies are planned systematically by a group of healthcare professionals of different specialisations to provide long-term treatment and regular assessments to effectively control the symptoms of the disease. Due to the rarity of the disease, there is a lack of clinical trials conducted on large groups of patients. As a result, no standardised treatment protocols are available, and the long-term efficacy of drugs for the treatment of acrodysostosis is not well defined.⁶ Also, the lack of clinical data and studies, as well as the highly variable nature of acrodysostosis, makes the specific diagnosis and prognosis of the disease rather challenging.⁵ Therefore, more clinical trials and more attention from international health organisations are indispensable to enhance treatment intervention and patients’ quality of life.⁹