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An acromelic dysplasia that is characterized by severe brachydactyly, peripheral dysostosis with facial dysostosis, nasal hypoplasia, and developmental delay.
ORPHA:950Classification level: Disorder
Less than 80 cases of Acrodysostosis (ACRDYS) have been reported in the literature to date.
Typical clinical features include severe peripheral dysostosis (short stature and brachydactyly affecting metacarpals, metatarsals and phalanges), facial dysostosis (broad face, widely spaced eyes and maxillonasal hypoplasia), and developmental delay. Advanced skeletal maturation, decreased vertebral interpedicular distance, and obesity are also frequently observed. Several features of acrodysostosis are similar to those present in patients with Albright's hereditary osteodystrophy (AHO) such as short stature, obesity and brachydactyly (in AHO, only 4th and 5th metacarpals and metatarsals). Prenatal onset, and multiple hormonal resistance, most frequently to parathyroid hormone (PTH) and thyroid stimulating hormone (TSH), are reported in approximately half of ACRDYS patients. While patients with PRKAR1A mutations (referred to as ACRDYS type 1) constantly present with significant hormonal resistance, hormonal resistance in patients with PDE4D mutations (referred to as ACRDYS type 2) is rare, and when present, is relatively mild. Various degrees of intellectual disability and/or behavioral disorders have also been reported in ACRDYS patients.
Acrodysostosis is caused by heterozygous mutations in either the PRKAR1A (17q24.2) or PDE4D (5q11.2-q12.1) genes. PRKAR1A mutations are gain-of-function leading to a constitutive loss of function in protein kinase A (by reducing the affinity of the protein subunits for cAMP, thereby hampering the dissociation from the catalytic subunit). A functional defect of PDE4D has not been characterized, but is expected to also be gain-of-function, leading to a constitutive loss of function in protein kinase A, at least in skeletal tissues.
Diagnosis is based on the clinical, biochemical and radiological (i.e. cone-shaped epiphyses) characteristics. It is confirmed by the genetic screening of PRKAR1A or PDE4D genes. Basal urinary cAMP levels normalized by creatininuria, a reflection of PTH biological activity in the renal proximal tubule, have been found significantly increased in patients with PRKAR1A mutations, but not in patients with PDE4D mutations.
Differential diagnosis includes brachydactyly type E, pseudohypoparathyroidism 1a or pseudopseudohypoparathyroidism.
In families with a known disease causing mutation, prenatal diagnosis is possible.
Most cases occur sporadically but autosomal dominant inheritance has been reported in some families, and in these cases genetic counseling is possible.
Management and treatment
There is no specific treatment for acrodysostosis. Patients should be screened for hormonal resistances, in particular to PTH and TSH, and treated appropriately following the same criteria, doses, and follow-up as in any other form of hypoparathyroidism and hypothyroidism, and eventually treated for any associated endocrinopathy. Dietary and lifestyle measures to prevent obesity and supportive care for cognitive functions are recommended. Attention must be given in children to height, growth velocity, and pubertal development.
Prognosis is unknown due to a lack of long-term patient data. Functional consequences, however, can decrease a patient's quality of life.