What is acrodysostosis ?

Acrodysostosis is an extremely rare genetic disorder caused by sporadic mutations. It causes short stature, growth delays, skeletal malformations and underdeveloped facial bones at birth.¹ These symptoms are caused by hormonal and endocrine abnormalities triggered by genetic mutations.

Parathyroid hormone (PTH) resistance and thyroid-stimulating hormone (TSH) resistance in acrodysostosis 

Individuals with Acrodysostosis experience resistance to hormones that act through a particular signalling pathway which when inhibited leads to the acceleration of the normal differentiation process of growth plate chondrocytes( cells that make and maintain cartilage) which causes advanced skeletal maturation,² specifically parathyroid hormone (PTH) and thyroid stimulating hormone (TSH).²

Resistance to a hormone means that despite the body producing the hormone normally, it can no longer exert its normal effects within the body.

 PTH is responsible for synthesising active vitamin D and calcitriol in the kidneys as well as regulating calcium and phosphate.³ TSH stimulates thyroid hormone secretion by enhancing iodine uptake, thyroglobulin the protein used to make thyroid hormone) synthesis and thyroid peroxidase activity. Thyroid peroxidase is an enzyme that catalyses iodine oxidation to form iodine atoms, which are then added onto protein residues on thyroglobulin for the production of thyroid hormones.⁴ It also increases blood flow to the thyroid gland and stimulates hypertrophy and hyperplasia of thyroid follicular cells, resulting in the growth of the thyroid gland. 

Resistance is evident in individuals suffering from acrodysostosis as they have increased circulating PTH levels in the presence of low or normal serum calcium and normal or increased serum phosphate and the absence of vitamin D deficiency or kidney insufficiency. They will also have increased basal urinary cAMP levels, which will sharply rise when they are infused with PTH due to a defect in the pathway it is involved.² PTH hormone resistance is less prominent compared to similar disorders, evidenced by the absence of hypocalcemia (low levels of calcium in the blood) after 10-24 years of diagnosis.¹¹

Individuals with Acrodysostosis may also show resistance to:

• Calcitonin: a hormone produced in the C-cells of the thyroid which lowers blood calcium levels by exerting different effects on the bones, kidneys and gut cells
• Growth hormone-releasing hormone: a hormone produced in the hypothalamus which functions to promote human growth hormone production. Human growth hormone induces growth in nearly every tissue and organ in the body, especially in adolescents¹²
• Gonadotropins: peptide hormones that regulate ovarian and testicular function, as well as being essential for normal growth, sexual development and reproduction. This includes follicle-stimulating hormone and luteinising hormone, which are both made in the pituitary and chronic gonadotrophin, which is made in the placenta. These hormones are under the control of gonadotropin-releasing hormone¹³

The genetic basis of acrodysostosis 

This resistance arises due to gain-of-function mutations (producing a new trait or causing a trait to appear in inappropriate tissues or at inappropriate times in development) (5) in the gene PRKAR1A, which produces a type of protein which is the most common effector of cyclic AMP. Cyclic AMP is a nucleotide that acts as a second messenger to mediate various biological responses inside cells (8) and loss-of-function mutations (preventing the normal gene from being produced or causing it to become inactive) (6) in the insulin-responsive gene PDE4D. This gene codes for a phosphodiesterase that hydrolyses cAMP and controls the specificity and temporal/spatial compartmentalisation of cAMP induced protein kinase A (PKA) signalling. These genes are involved in the PTH signalling pathway. Mutations in PRKAR1A cause a decreased PKA activation rate after cAMP binding which causes skeletal dysplasia and hormonal resistance (7). Nine nonsense PRKAR1A mutations have been associated with acrodysostosis. Some of them cause a decreased affinity for domain A or B for cAMP and suppressed PKA activity. There are also loss-of-function mutations in PRKAR1A that lead to unrestrained PKA activity and degradation of mRNA by nonsense mediated decay. 12 missense PDE4D mutations are associated with acrodysostosis all of which are located on the main functional domains of the gene. The mutations cause defects in PKA activation. PKA activation is impaired via PTHrP due to these mutations(2). The impairment of actions mediated by PTH related proteins is the most likely cause of the skeletal phenotype of acrodysostosis.

Different types of acrodysostosis

Patients with PRKAR1A variants tend to have less characteristic facial dysostosis, normal intelligence and resistance to multiple hormones. Whereas, patients with PDE4D variants who present with characteristic facial dysostosis, intellectual disability and subtle or complete absence of hormonal resistance.¹⁴ This has led to characterising the disease in two forms: Acrodysostosis 1, where there is hormone resistance and short stature and Acrodysostosis 2, where there is no hormone resistance. 

Inheritance of acrodysostosis 

Acrodysostosis can be inherited in an autosomal dominant manner, which means that inheriting just one copy of the mutated gene is enough to cause the disease, therefore, only one parent would need to have the altered gene. Despite most cases being reported as random and not being passed down from a relative,¹⁰ there is evidence that the advanced age of a patient's father can cause a de novo mutation that leads to Acrodysostosis.

FAQs

What facial features do people with Acrodysostosis have?

People who have Acrodysostosis will have a small, upturned, broad nose with a flat bridge, an open mouth, a jaw that sticks out and wide-spaced eyes, sometimes with an extra skin fold at the corner of the eyes.⁹

Is Acrodysostosis a disability?

Acrodysostosis can lead to intellectual disability and developmental delays.⁹

What are the symptoms of Acrodysostosis?

Common signs and symptoms are very short fingers and toes, underdeveloped facial bones, a small nose and short stature.¹⁰ Advanced skeletal maturation, decreased vertebral interpedicular distance (reduction in measurement between the bony structures that connect the vertebral body to the posterior arch of a spinal vertebra) and obesity are also frequently observed.¹¹ Frequent middle ear infections as well as hearing problems, are also a symptom.¹⁷

What is PDE4-related Acrodysostosis?

Acrodysostosis type 2, which is caused by mutations in cAMP specific phosphodiesterase 4D (PDE4D)

How do you treat Acrodysostosis?

Due to the rarity of the disease, there are currently no standard treatments available. However, certain interventions may be proposed based on the specific needs of the patient. Surgeries may be performed to treat specific abnormalities like an underdeveloped jaw and dental braces may be necessary to correct the shape of misaligned teeth. Thyroid hormone supplementation as well as vitamin D supplements may help to improve a patient's growth as well as preventing the onset of obesity. Physical therapy may also be helpful to patients to help them with mobility. Treatment may require corroboration from specialists like paediatricians, ophthalmologists, neurologists and orthopaedics.¹⁵

How do you diagnose acrodysostosis?

Acrodysostosis is diagnosed based on the identification of its characteristic features, studying a patient's familial history to see if the condition may have been passed down, clinical evaluation to make a differential diagnosis and a wide variety of specialised tests, including x-rays. X-rays will reveal if a patient has abnormally short bones in their hands and feet or the appearance of spots on the rounded end of their long bone. Many symptoms will be evident at birth, such as, the characteristic facial features and limited growth. These features can also be identified prior to birth via a foetal ultrasound; this technique has the potential to reveal underdeveloped growth in the foetus as well as short long bones.¹⁵

In some cases, molecular genetics can be used to confirm a diagnosis of acrodysostosis. This involves analysing a patient's DNA in order to find out if they have mutations in the PRKAA1 or PDE4D genes.¹⁶

What is acrodysostosis of the hands?

Acrodysostosis causes a shortening of the interphalangeal joints of the hands and feet, which causes the fingers to be anomalously short, small and stubby.¹⁵

Summary

Acrodysostosis is a rare genetic disorder that causes abnormalities in skeletal formation from birth. It is caused by a resistance to various hormones that are important in development and growth, including parathyroid hormone (PTH) and thyroid-stimulating hormone. This occurs due to mutations in the genes PDE4D and PRKAR1A.