Acrodysostosis - Types, Causes, Signs, and Treatment

Introduction

Acrodysostosis, also known as Arkless-Graham syndrome or Maroteaux-Malamut syndrome, is a rare genetic disorder caused due to mutations in two different genes presenting two different outlooks of the same condition. The condition is characterized by skeletal abnormalities, stunted physical and mental growth, and underdeveloped facial features.

What Causes Acrodysostosis?

Acrodysostosis is caused due to mutations in PRKAR1A (long arm of chromosome 17 - 17q24.2) and PDE4D genes (long arm of chromosome 5 - 5q11.2-q12.1), which present themselves as two different phenotypes. Although constitutionally different, both variants show similar physical characteristics.

Both PRKAR1A and PDE4D genes aid in GPCR–Gsα–cAMP–PKA signaling but show changes in different tissues of the body. GPCR (G-protein-coupled receptors) are receptors present on the plasma membranes of the cells and receive external signals producing secondary messengers to regulate various body functions like sensation, growth, and hormone responses.

What Are the Types of Acrodysostosis?

Based on the gene, acrodysostosis is phenotypically classified as:

1. ADOHR: Acrodysostosis with hormonal resistance (due to PRKAR1A defects).

2. ADOP4: Acrodysostosis due to PDE4D defects (no hormonal resistance).

Who Is More Susceptible to Acrodysostosis?

Acrodysostosis is a very rare disorder, with less than 100 cases reported globally. The disease has not reported any gender, race, or group affiliation. Due to the small sample size, acrodysostosis prevalence in a population is poorly understood as the condition is mostly misdiagnosed as a different condition.

What Are the Signs and Symptoms of Acrodysostosis?

• Abnormal short height.

• Malformed bones in the hands and feet.

• Short, stubby fingers and toes; big toes are unaffected.

• Scoliosis or kyphosis (abnormal curvature of the spine).

• Spinal stenosis (narrowing spaces within the spinal canal).

• Numbness of back and lower limbs.

• Hypoplastic maxilla and nasal bone (underdeveloped maxilla and nasal bone).

• The nose is abnormally small with a flattened bridge.

• Prognathic mandible (forwardly placed lower jaw).

• Hypertelorism (widely spaced eyes ).

• Epicanthal folds (extra folds of skin covering the inner corners of the eyes).

• Malocclusion.

• Low-set ears.

• Mild to moderate intellectual disability.

• Delays in acquiring mental skills.

• Psychomotor delays (delays in motor coordination).

• Learning disabilities.

• Delays in learning to walk and talk.

• Babies are born small for gestational age.

• Lack of the pubertal growth spurt.

• Resistance to hormones such as PTH, TSH, etc.

• Middle ear infections.

• Hearing loss.

• Obesity.

• Flesh-colored, brown, or black (pigmented nevi) skin lesions.

• Blue eyes.

• Red or blond hair.

• Arthritic changes hampering manual dexterity.

• Hypertension.

• Vascular stenosis (narrowing of the blood vessels).

• Pain in the lower limbs and back.

What Is the Pathophysiology of Acrodysostosis?

Mutation of the PRKAR1A and PDE4D genes alters the physiological process of cAMP-induced PKA signaling. Various mutations of the genes are responsible for the variations.

• PRKAR1A Gene: It is the most common effector of cAMP. About nine different mutations are seen in this gene, reflecting different types of defects in the cAMP-induced PKA signaling.

• Functional Defect: All of the mutated genes are expressed to form mutant proteins. Accumulation of these mutant proteins causes a defect in PKA activation by cAMP, leading to decreased responsiveness of PKA to cAMP, thus a decrease in phosphorylation through the Krebs cycle.

• Gain-of-Function Defect: Several point mutations in the PRKAR1A gene lead to increased affinity of regulatory proteins to cAMP, which suppresses PKA activity.

• PRKAR1A Mutations for PKA Function: These mutations result in the production, stabilization, and preferential binding of mutant proteins to catalytic proteins and subsequent accelerated degradation of wild proteins. The cumulative amount of mutated proteins becomes more than the wild variant. This leads to impaired PKA activity.

• Loss-of-Function Mutations: This leads to unrestrained PKA activity, as seen in the Carney complex (skin pigmentations with benign mixed tumors of connective and endocrine origin). The mutation results in the degradation of mRNA resulting in haploinsufficiency (reduced level of wild genes that cannot handle normal load of protein requirement) of protein expression.

PDE4D Gene: PDE4D gene encodes the PDE4D enzyme that hydrolyses cAMP and plays an important role in controlling the location and correctness of cAMP-induced PKA signaling. All nine variants of the PDE4D enzyme are derived from the single PDE4D gene.

Twelve mutations are observed in PDE4D-related acrodysostosis, causing various defects in PKA signaling.

• Functional Defects: The mutations to the PDE4D gene cause a fault in the PKA activation, especially in the endochondral bone that is reflected in its phenotype.

• Gain-of-Function Defect: Heterozygous mutations of the PDE4D gene increase the catabolism of cAMP.

• Loss-of-Function Defect: The mutation leads to adrenal hyperplasia, as seen in Carney’s complex.

What Are the Phenotypic Similarities and Differences Between ADOHR and ADOP4?

Similarities:

• Facial and peripheral dysostosis (deformed face and digits).

• Enlarged big toe.

• Hypoplasia of the skull.

• Thickened calvaria.

• All tubular bones of the hand and feet are symmetrically affected.

• Cone-shaped epiphyses with early epiphyseal fusion.

• Widened lumbar interpeduncular distance (increased distance between lumbar vertebrae).

• Advanced bone age in children.

• Brachymetatarsia (small toes).

• Skin pigmentation or spots are present similar to McCune Albright syndrome and the Carney complex.

Differences:

1. Acrodysostosis:

• Maxillo-nasal hypoplasia with a flat nasal bridge is more severe in the ADOP4 type.

• ADOHR-affected children at birth are smaller than their gestational age.

• Some cases of the ADOP4 variant do not produce short stature.

2. Hormonal Resistance:

• All ADOHR cases are resistant to PTH (parathyroid hormone) with low serum calcium levels and high phosphate levels.

• ADOHR patients present with increased basilar urinary cAMP, low thyroxine, and increased TSH (thyroid-stimulating hormone).

• The response to LH (luteinizing hormone), FSH (follicle-stimulating hormone), Calcitonin, GHRH (growth hormone-releasing hormone), and epinephrine is altered in ADOHR patients.

• ADOP4 variant shows no PTH or TSH resistance.

3. Mental Retardation:

• Mental retardation is seen in ADOP4 patients rather than ADOHR patients.

• ADOHR patients show mind developmental disabilities and behavioral disorders.

How to Diagnose Acrodysostosis?

Diagnosis of Acrodysostosis is based on:

• Identification of characteristic symptoms.

• Detailed patient history.

• Clinical evaluation.

• Specialized tests.

Laboratory studies include:

• Prenatal fetal ultrasonography (sonography of the fetus in the womb).

• X-rays of the affected joints or bones.

• Molecular genetic testing to identify PRKAR1A and PDE4D gene mutations.

• Serum calcium, phosphate, TSH (thyroid-stimulating hormone), and PTH (parathyroid hormone) levels.

How to Treat/Manage Acrodysostosis?

• Early diagnosis and an interdepartmental approach can help to mitigate the shortcoming of the condition. Prenatal genetic screening and fetal ultrasonography go a long way in detecting the condition in the womb.

• The team of specialists should include pediatricians, orthopedists, pediatric endocrinologists, orthopedic surgeons, orthodontists, neurologists, ophthalmologists, physical therapists, and psychiatrists.

• All of the abnormalities can be dealt with by the corresponding specialists in the field. Growth hormones, vitamin D supplements, administration of TSH and PTH analog drugs, surgery to correct osseous defects, and orthodontic treatment for malocclusions can be done to manage acrodysostosis.

What Is the Prognosis of Acrodysostosis?

Countering the skeletal deformities, the prognosis is generally good for the patient. With interdisciplinary care and regular checkups, the patient can lead a fairly normal life.

What Is the Differential Diagnosis of Acrodysostosis?

• Albright hereditary osteodystrophy (disorder due to GNAS1 gene mutation).

• Progressive osseous heteroplasia (bone forms within skin and muscle tissue).

• Hypocalcemia (calcium deficiency).

• Hyperphosphatemia (high phosphate levels in the blood).

• Hypothyroidism or Cretinism (decreased thyroid hormone).

Conclusion:

Acrodysostosis is not a fatal condition. With early diagnosis and an interdisciplinary approach to treatment, all of the signs and symptoms can be managed. The patient can live a normal life, albeit under medication and care.