What is acrodysostosis?

Acrodysostosis is an extremely rare genetic disorder present at birth, characterised by distinct facial features and craniofacial abnormalities. When discussing facial features, it refers to the face’s characteristics contributing to a person’s appearance and expression, such as, the mouth, cheeks, eyes, nose, etc. Whereas, craniofacial features refers to facial features, but also the relationship between the facial structure and the cranial vault, including other congenital abnormalities. Acrodysostosis is categorised into two types: acrodysostosis type 1 and acrodysostosis type 2, it is important to note there are also likely other forms of acrodysostosis to exist too, but little is known about them.¹

Overview of acrodysostosis

This condition affects both male and females equally at birth, but may go unnoticed until years after birth, due to cases going undiagnosed and misdiagnosed. Moreover, acrodysostosis is believed to be hereditary, caused by a genetic mutation in the PRKAR1A gene (type 1) or the PDE4D gene (type 2). It is also an autosomal dominant disease, indicating that the presence of only one copy of the mutated gene is required to be inherited by the child from either parent, so there is a 50% chance of passing on the mutated gene to the child.² However, a lot of people with acrodysostosis do not have a family history of acrodysostosis, as it typically occurs randomly when cells divide during mitosis.

Symptoms of Acrodysostosis

Symptoms of acrodysostosis are prevalent during pregnancy and childbirth. It is important to be informed of what features to be aware of in a new-born (aged between 0-4 weeks old), so the disease does not go undiagnosed or misdiagnosed.³

Facial features in Acrodysostosis:³

Very Common:

• Retruded and wide nasal bridge: Positioning of the nasal root in relation to the overall facial profile for age
• Depressed nasal ridge: Lack of prominence of the nose resulting from a posteriorly placed nasal ridge
• Decreased length of nose: Distance from nasion to sub-nasal more than two standard deviations below the mean
• Hypoplasia of the maxilla (Upper jaw deficiency): Creating a misalignment between the upper and lower teeth, causing a deficient amount of projection of the base of the nose and lower midface region
• Underdevelopment of midface
• Open mouth: Characterised by a permanently or nearly permanently opened mouth

Common:

• Upturned nose
• Short and broad skull: A cephalic index greater than 81%
• Wide-set eyes: With a Interpupillary distance more than 2 SD above the mean
• Increased projection of lower jaw

Less common:

• Prominent eye folds
• Open bite between upper and lower teeth

Craniofacial features in Acrodysostosis:³

Very Common:

• Abnormally shaped vertebrae
• Abnormally shaped long bones of the hand and feet
• Early bone maturation
• Brachydactyly syndrome (Short fingers of the toes)
• Cone-shaped end part of bone

Common:

• Abnormal female external genitalia
• Undescended testes
• Delayed tooth eruption: Defined as tooth eruption more than 2 standard deviation beyond the mean eruption age

Additional features

Furthermore, besides presenting physical characteristics, some children with acrodysostosis may display mild to moderate intellectual disability alongside delays in mental and motor skills development, however these are not necessarily universal symptoms.¹ These symptoms usually often affect those with acrodysostosis type 2. Delayed growth is another common symptom severely affecting babies, where babies with acrodysostosis are usually born abnormally small. So, this growth delay transcends through their life, affecting the child’s height and growth spurt in puberty, in comparison to children their age.¹ 

Although, not all, some individuals can develop resistance towards hormones, such as the parathyroid hormone and thyroid-stimulating hormones. Resistance towards hormones refers to when the tissues of the body are not effectively responding to the presence or effect of hormones that are present in normal to high levels. This symptom often affects those with acrodysostosis type 1.⁴

Lastly, the following symptoms have also been noticed in some individuals with acrodysostosis: repeated middle ear infections; hearing loss; obesity; skin lesions that are flesh-coloured, brown or black; blue eyes, and red or blond hair; and high blood pressure, due to an increased risk of narrowing of the blood vessel.⁴

Diagnostic approaches

Diagnosing an individual with acrodysostosis depends on identifying physically presenting characteristics, a detailed patient history, a thorough clinical evaluation and a range of specialised tests including X-Rays.

Physical examination

Individuals with acrodysostosis can usually be diagnosed with a physical exam. These individuals will display any of the following facial and craniofacial abnormalities:⁵

• Advanced bone age
• Bone deformities in hands and feet
• Delays in growth
• Short limbs including small hands and feet
• Short stature
• Small, upturned broad nose with flat bridge
• Distinct features of the face (short nose, open mouth, jaw that sticks out)
• Wide-spaced eyes, sometimes with prominent eye folds

Examination

Traditional x-ray studies would reveal unusually short bones in the hands and feet and premature fusion of the end portions (epiphyses) of specific bones of the hands, feet, and elbows. The appearance of spots on the epiphyses (stippling) may also be detected by traditional x-ray during the first months of life.⁴

Prenatal foetal ultrasonography is another method of examination in which reflected sound waves create an image of the developing foetus, potentially revealing intrauterine growth retardation (IUG) and short long bones that would confirm the diagnosis of acrodysostosis.⁴

For some cases, molecular genetic testing can confirm a diagnosis, but this is only available at specific specialised laboratories. This can be done by detecting mutations in one of the two specific genes known to cause the disorder, PRKAR1A gene (type 1) or the PDE4D gene (type 2).⁴

Treatment

Due to the rarity of acrodysostosis, no treatment trials have been conducted on large groups of patients that have been tested and proven to be effective. Hence, there are no typical treatments for acrodysostosis, as each individual presents with different symptoms, requiring different treatment tailored to the individual’s need. 

Treatment for acrodysostosis often requires a multi-disciplinary team, rather than one specialist, including:¹

• Paediatricians
• Physical therapists
• Orthopaedics (specialising in skeletal abnormalities)
• Paediatric endocrinologists (specialising in hormonal imbalances)
• Orthodontists (specialising in abnormalities of the teeth)
• Neurologists (specialising in the nervous system)
• Ophthalmologists (eye disease specialist)

Corrective surgeries may also be performed to correct underdeveloped or abnormally prominent jaws. Additionally, thyroid hormone supplementation and vitamin D supplements can support bone growth.

Summary

Understanding and becoming aware of what craniofacial abnormalities and physical characteristics to spot out during early stages can contribute heavily to the diagnosis of an individual with acrodysostosis. It is also crucial to educate ourselves with more extremely rare diseases and bring more awareness to acrodysostosis. This is so that early intervention can happen, to ensure the children can reach their full potential and receive the full support they need to live their life to the fullest.