Acroosteolysis dominant type (AOD) is a rare genetic osteolysis syndrome characterized by acro-osteolysis of distal phalanges and generalized osteoporosis associated with additional ossification anomalies, craniofacial dysmorphism, dental anomalies and a wide range of other characteristics.
Prevalence is unknown; approximately over 80 cases have been described to date
AOD has a variable and broad clinical evolving spectrum. AOD manifests clinically from infancy or early childhood onwards with a mild cranio-facial dysmorphism with features becoming gradually coarser over time. Facial dysmorphic features include bathrocephaly with prominent occiput, mild hypertelorism with telecanthus, downslanted eyes with bushy eyebrows (synophrys), low-set ears, long philtrum, micrognathia with highly arched palate or cleft palate, and short neck. The cardinal signs (habitually in late childhood or adolescence) comprise progressive acroosteolysis of distal phalanges and short and broad digits (with or without associated pain). Associated ossification anomalies are multiple wormian bones, thickened cranial vault, absent frontal sinus, elongated sella turcica, basilar impression/platybasia leading to various neurologic symptoms (mostly in adolescents and adults) secondary to stretching of the cranial nerves, and generalized osteoporosis resulting in biconcave vertebrae, vertebral collapse, and scoliosis. Hydrocephalus and syringomyelia may be seen even prior to development of basilar impression/platybasia. Other abnormalities include recurrent respiratory tract infections, abnormal deep voice, hearing loss and joint laxity. A short stature, an early loss of permanent teeth and hirsutism are observed in adults. Cystic kidney disease is rare but an essential syndromic component in a subset of patients. Affected individuals may present with congenital heart disease, respiratory, renal and digestive tract malformations, and umbilical hernia in the first months of life.
AOD is caused by truncating mutations in the NOTCH2 gene (1p12). All mutations lie within the last coding exon of NOTCH2 resulting in a gain of function due to the loss of the protein-destabilizing PEST domain. NOTCH2 mutations have been reported in a variant Alagille syndrome (see this term).
Diagnosis is often delayed due to relative late onset of acroosteolysis of distal phalanges. Diagnosis is based on clinical and radiological examinations. DEXA (dual energy radiodensitometry) is beneficial to ascertain presence of osteoporosis. Acroosteolysis shows two different patterns of bone resorption: from the distal end of the terminal phalanx and a transverse band of osteolysis. Genetic testing confirms the diagnosis.
Differential diagnosis may include pycnodysostosis and Hutchinson-Gilford Progeria Syndrome (see these terms) based on clinical and x-ray findings, however, patients lack premature aging seen in progeria nor increased bone density and decreased mandible angle observed in pycnodysostosis.
In case of family history prenatal diagnosis is feasible ((i)NOTCH2(/i)).
AOD is transmitted as an autosomal dominant trait with a high penetrance. In addition, numerous novel sporadic cases are reported.
No treatment exists for AOD, but early osteoporosis might be treated by bisphosphonates, alone or in combination with teriparatide.
Patients have a normal life expectancy. However, osteoporosis and respiratory dysfunction are severe morbidity factors.
Last update: March 2014