Acrodysostosis-2 is a rare skeletal dysplasia characterized by brachydactyly, facial dysostosis, and spinal stenosis. Many patients have intellectual disability and some have hormone resistance (summary by Michot et al., 2012 and Lee et al., 2012).
For ... Acrodysostosis-2 is a rare skeletal dysplasia characterized by brachydactyly, facial dysostosis, and spinal stenosis. Many patients have intellectual disability and some have hormone resistance (summary by Michot et al., 2012 and Lee et al., 2012). For a discussion of genetic heterogeneity of acrodysostosis, see ACRDYS1 (101800).
Michot et al. (2012) reported 4 unrelated patients, ranging in age from 3 to 7 years, with acrodysostosis-2. All had advanced bone age, facial dysostosis with nasal hypoplasia and depressed nasal bridge, severe brachydactyly with short metacarpals, metatarsals, ... Michot et al. (2012) reported 4 unrelated patients, ranging in age from 3 to 7 years, with acrodysostosis-2. All had advanced bone age, facial dysostosis with nasal hypoplasia and depressed nasal bridge, severe brachydactyly with short metacarpals, metatarsals, and phalanges, and cone-shaped epiphyses. All also had intellectual disability with speech and psychomotor retardation. One had intrauterine growth retardation, but none had short stature. None had evidence of hormone resistance, except 1 who had increased parathyroid hormone (PTH). Two patients developed intracranial hypertension due to sinus thrombosis. Michot et al. (2012) also reported 5 patients with ACRDYS1. 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 3 unrelated patients with ACRDYS2. All had small hands and midface hypoplasia, 2 had mild short stature, and 2 had lumbar stenosis. One had normal psychomotor development, 1 had significantly impaired development, and the third had mild developmental disability. One had congenital hypothyroidism, 1 had cryptorchidism, and 1 had no endocrine abnormalities. Two of the patients had previously been reported by Graham et al. (2001) (as case R1 and case 2, respectively). Additional features noted by Graham et al. (2001) included maxillonasal hypoplasia, brachydactyly, cone-shaped epiphyses, and intrauterine growth retardation. Lee et al. (2012) also identified 2 patients with ACRDYS1 due to mutations in the PRKAR1A gene. In a comparison of the phenotypes, Lee et al. (2012) concluded that it was difficult to distinguish 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. Lynch et al. (2013) reported 4 unrelated patients with sporadic ACRDYS2 and 1 family in which 3 sibs had the disorder. All patients had typical features, including round face, hypoplastic nares with upturned nose, and maxillary hypoplasia. In addition, several individuals had a flattened nasal bridge, hypertelorism, and epicanthal folds. Skeletal abnormalities included brachydactyly and shortening of the metacarpals and metatarsals with relative sparing of the first toe. None had evidence of decreased interpedicular distance. All had some degree of learning disability, developmental delay, and/or intellectual disability. Five patients had obesity, and 5 had eczema, chronic rhinitis, or asthma. Males tended to have cryptorchidism or hypospadias. Only 1 patient had short stature and only 1 had congenital hypothyroidism, suggesting that endocrine abnormalities are not common in this disorder. The father of the affected sibs showed subtle abnormalities, including brachydactyly and mild learning disability.
In 4 unrelated patients with acrodysostosis-2, Michot et al. (2012) identified 4 different de novo heterozygous missense mutations in the PDE4D gene (600129.0001-600129.0004). The first 2 mutations were identified by exome sequencing and confirmed by Sanger sequencing. Although ... In 4 unrelated patients with acrodysostosis-2, Michot et al. (2012) identified 4 different de novo heterozygous missense mutations in the PDE4D gene (600129.0001-600129.0004). The first 2 mutations were identified by exome sequencing and confirmed by Sanger sequencing. Although all 4 missense mutations were predicted to be pathogenic by PolyPhen and were absent from 200 controls, functional studies were not performed. Michot et al. (2012) concluded that the mutations resulted in decreased phosphodiesterase activity, a dysregulation in cAMP levels, and alterations in the cAMP signaling pathway, resulting in the growth and intellectual deficits in these patients. Independently and simultaneously, Lee et al. (2012) identified de novo heterozygous missense mutations in the PDE4D gene (600129.0005-600129.0007) in 3 unrelated patients with ACRDYS2. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. The mutations were predicted to be pathogenic and were absent from almost 6,000 exomes, but no functional studies were performed. However, because PDE4D is a dimer, the missense alleles may cause the phenotype via a dominant-negative effect on the protein. In 3 sibs with ACRDYS2, Lynch et al. (2013) identified a heterozygous mutation in the PDE4D gene (A243V; 600129.0008). Their father, who also carried the mutation, was found to have subtle clinical abnormalities consistent with the disorder. Four additional unrelated patients with a similar phenotype were each found to carry a de novo heterozygous missense mutation in the PDE4D gene. The data confirmed that PDE4D is a major locus for acrodysostosis, as different mutations were identified in all 5 probands in the series.