Alternative titles; symbols
ORPHA: 950; DO: 14669;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q24.2 | Acrodysostosis 1, with or without hormone resistance | 101800 | Autosomal dominant | 3 | PRKAR1A | 188830 |
A number sign (#) is used with this entry because acrodysostosis-1 with or without hormone resistance (ACRDYS1) is caused by heterozygous mutation in the PRKAR1A gene (188830) on chromosome 17q24.
Acrodysostosis-1 (ACRDYS1) is a form of skeletal dysplasia characterized by short stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia. Affected individuals often have advanced bone age and obesity. Laboratory studies show resistance to multiple hormones, including parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin (summary by Linglart et al., 2011). However, not all patients show endocrine abnormalities (Lee et al., 2012).
Genetic Heterogeneity of Acrodysostosis
See also ACRDYS2 (614613), caused by mutation in the PDE4D gene (600129) on chromosome 5q12.
Maroteaux and Malamut (1968) described acrodysostosis as a condition in which small hands and feet were associated with peculiar facies, including short nose, open mouth, and prognathism. Radiographs showed cone epiphyses. Mental deficiency was also frequent.
Robinow et al. (1971) reported 9 cases and reviewed 11 from the literature. No cases were familial.
Niikawa et al. (1978) described Japanese brother and sister, aged 7 months and 2 years, respectively, with severe nasal hypoplasia, peripheral dysostosis, blue eyes, and mental retardation. The mother showed nasal hypoplasia and irregular shortening of fingers and toes.
Butler et al. (1988) reported an affected 13-year-old boy and reviewed the literature. They emphasized the features of nasal and maxillary hypoplasia, peripheral dysostosis, decreased interpedicular distance, advanced skeletal maturation, and mental retardation. They suggested that the metacarpophalangeal pattern profile was characteristically abnormal and useful as a diagnostic tool. The first ray in the foot may be relatively hyperplastic. Their review suggested increased parental age.
Viljoen and Beighton (1991) reviewed the radiologic features in 12 affected children and found that epiphyseal stippling is a consistent and prominent characteristic during infancy.
Steiner and Pagon (1992) described an affected mother and daughter. The mother had been diagnosed at the age of 4 years and was pictured in the 1982 edition of Smith's Recognizable Patterns of Human Malformation. At the age of 20, she suffered from recurrent carpal tunnel syndrome. The daughter showed cone-shaped epiphyses as in the mother.
Linglart et al. (2011) reported 3 unrelated patients with short stature, peripheral dysostosis, nasal and maxillary hypoplasia, severe brachydactyly, epiphyseal stippling, and advanced bone age. Laboratory studies showed increased serum parathyroid hormone, low or normal calcium, and increased urinary cAMP excretion. All had evidence of multiple hormone resistance, including thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin.
Michot et al. (2012) reported 5 patients with ACRDYS1. All had short stature, severe brachydactyly, short metatarsals, metacarpals, and phalanges, and cone-shaped epiphyses in childhood. Only 2 had mild facial dysostosis and all had normal intellect. All had evidence of hormone resistance, with increased parathyroid hormone (PTH) and thyroid-stimulating hormone (TSH) and clinical hypothyroidism. Michot et al. (2012) also identified 4 patients with acrodysostosis-2 (614613) due to heterozygous mutations in the PDE4D gene (600129). Comparison of the 2 groups revealed interesting genotype-phenotype correlations. Those with PRKAR1A mutations had hormone resistance, short stature, normal intellect, and no facial dysostosis, whereas those with PDE4D mutations had characteristic facial features, namely midface hypoplasia with the nasal hypoplasia, moderate intellectual disability with speech delay, and lack of hormone resistance in 3 of the 4.
Lee et al. (2012) reported 2 unrelated patients with acrodysostosis-1. One had mild short stature, small hands, midface hypoplasia, lumbar stenosis, and mild developmental disability, but no evidence of endocrine dysfunction. The other patient, who had previously been reported by Graham et al. (2001) (case 1), had mild short stature, small hands with severe brachydactyly, cone-shaped epiphyses, midface hypoplasia, lumbar stenosis, and mild developmental disability. He had congenital and persistent hypothyroidism with hypoplastic thyroid gland, unilateral undescended testes, and moderate mixed hearing loss. He also had dextrocardia, Kartagener syndrome (244400), and multiple orthopedic problems. Lee et al. (2012) also reported 3 unrelated patients with ACRDYS2. In a comparison of the phenotypes, Lee et al. (2012) concluded that it was difficult to distinguish between the patients clinically. Both groups had mild short stature with brachydactyly, facial dysostosis, and spinal stenosis; both groups had variable endocrine abnormalities; and 4 of the 5 patients had some degree of developmental disability.
The heterozygous mutations in the PRKAR1A gene that were identified in patients with ACRDYS1 by Linglart et al. (2011) occurred de novo.
Jones et al. (1975) found elevated average paternal age in this disorder, thus supporting autosomal dominant inheritance.
Butler et al. (1988) found a pattern of autosomal dominant inheritance in 2 families (Niikawa et al., 1978; Frey et al., 1982).
Hernandez et al. (1991) described an affected mother and daughter, as did Steiner and Pagon (1992).
In 3 unrelated patients with acrodysostosis with hormone resistance, Linglart et al. (2011) identified a de novo truncating mutation in the PRKAR1A gene (R368X; 188830.0015). The mutation resulted in decreased protein kinase A sensitivity to cAMP, resulting in multiple hormone resistance and skeletal anomalies.
Michot et al. (2012) identified a heterozygous de novo R368X mutation in 4 unrelated patients with acrodysostosis and a de novo heterozygous Y373H mutation (188830.0016) in another patient with the disorder.
Lee et al. (2012) identified different de novo heterozygous missense mutations in the PRKAR1A gene (R335P, 188830.0017 and I327T, 188830.0018) in 2 unrelated patients with acrodysostosis-1. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Lee et al. (2012) suggested that the mutations would cause reduced cAMP binding, reduced PKA activation, and decreased downstream signaling.
Exclusion Studies
Because of the similarity between acrodysostosis and Albright hereditary osteodystrophy (AHO; 103580), both of which show shortening of the tubular bones of the hands and feet with cone-shaped epiphyses, Wilson et al. (1997) looked for abnormalities in the alpha subunit of the signal transducing protein, Gs, and in the GNAS1 gene (139320). In 2 unrelated patients with acrodysostosis, they found that Gs-alpha bioactivity in erythrocyte membranes was normal. Mutation analysis of the GNAS1 gene showed no sequence variation in 12 of the 13 exons examined. The results were interpreted as indicating that, at least in a proportion of patients with acrodysostosis, the condition is etiologically distinct from AHO.
Arkless, R., Graham, C. B. An unusual case of brachydactyly. Am. J. Roentgen. Radium Ther. Nucl. Med. 99: 724-735, 1967. [PubMed: 6020652]
Butler, M. G., Rames, L. J., Wadlington, W. B. Acrodysostosis: report of a 13-year-old boy with review of literature and metacarpophalangeal pattern profile analysis. Am. J. Med. Genet. 30: 971-980, 1988. [PubMed: 3055990] [Full Text: https://doi.org/10.1002/ajmg.1320300416]
Frey, V. G., Martin, J., Diefel, K. Die Akrodysostose--eine autosomal-dominant verebte periphere Dysplasie. Kinderarztl. Prax. 3: 149-153, 1982.
Graham, J. M., Jr., Krakow, D., Tolo, V. T., Smith, A. K., Lachman, R. S. Radiographic findings and Gs-alpha bioactivity studies and mutation screening in acrodysostosis indicate a different etiology from pseudohypoparathyroidism. Pediat. Radiol. 31: 2-9, 2001. [PubMed: 11200992] [Full Text: https://doi.org/10.1007/s002470000355]
Hernandez, R. M., Miranda, A., Kofman-Alfaro, S. Acrodysostosis in two generations: an autosomal dominant syndrome. Clin. Genet. 39: 376-382, 1991. [PubMed: 1860254] [Full Text: https://doi.org/10.1111/j.1399-0004.1991.tb03045.x]
Jones, K. L., Smith, D. W., Harvey, M. A. S., Hall, B. D., Quan, L. Older paternal age and fresh gene mutation: data on additional disorders. J. Pediat. 86: 84-88, 1975. [PubMed: 1110452] [Full Text: https://doi.org/10.1016/s0022-3476(75)80709-8]
Lee, H., Graham, J. M., Jr., Rimoin, D. L., Lachman, R. S., Krejci, P., Tompson, S. W., Nelson, S. F., Krakow, D., Cohn, D. H. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum. Genet. 90: 746-751, 2012. [PubMed: 22464252] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.004]
Linglart, A., Menguy, C., Couvineau, A., Auzan, C., Gunes, Y., Cancel, M., Motte, E., Pinto, G., Chanson, P., Bougneres, P., Clauser, E., Silve, C. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. New Eng. J. Med. 364: 2218-2226, 2011. [PubMed: 21651393] [Full Text: https://doi.org/10.1056/NEJMoa1012717]
Maroteaux, P., Malamut, G. L'acrodysostose. Presse Med. 76: 2189-2192, 1968. [PubMed: 5305130]
Michot, C., Le Goff, C., Goldenberg, A., Abhyankar, A., Klein, C., Kinning, E., Guerrot, A. M., Flahaut, P., Duncombe, A., Baujat, G., Lyonnet, S., Thalassinos, C., Nitschke, P., Casanova, J.-L., Le Merrer, M., Munnich, A., Cormier-Daire, V. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am. J. Hum. Genet. 90: 740-745, 2012. [PubMed: 22464250] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.003]
Niikawa, N., Matsuda, I., Ohsawa, T., Kajii, T. Familial occurrence of a syndrome with mental retardation, nasal hypoplasia, peripheral dysostosis, and blue eyes in Japanese siblings. Hum. Genet. 42: 227-232, 1978. [PubMed: 669707] [Full Text: https://doi.org/10.1007/BF00283643]
Robinow, M., Pfeiffer, R. A., Gorlin, R. J., McKusick, V. A., Renuart, A. W., Johnson, G. F., Summitt, R. L. Acrodysostosis: a syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am. J. Dis. Child. 121: 195-203, 1971. [PubMed: 5551869]
Smith, D. W. Recognizable Patterns of Human Malformation: Genetic, Embryologic and Clinical Aspects. (3rd ed.) Philadelphia: W. B. Saunders (pub.) 1982. Pp. 322-323.
Steiner, R. D., Pagon, R. A. Autosomal dominant transmission of acrodysostosis. Clin. Dysmorph. 1: 201-206, 1992. [PubMed: 1342871]
Viljoen, D., Beighton, P. Epiphyseal stippling in acrodysostosis. Am. J. Med. Genet. 38: 43-45, 1991. [PubMed: 2012131] [Full Text: https://doi.org/10.1002/ajmg.1320380111]
Wilson, L. C., Oude Luttikhuis, M. E. M., Baraitser, M., Kingston, H. M., Trembath, R. C. Normal erythrocyte membrane Gs-alpha bioactivity in two unrelated patients with acrodysostosis. J. Med. Genet. 34: 133-136, 1997. [PubMed: 9039990] [Full Text: https://doi.org/10.1136/jmg.34.2.133]