Abstract
Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype–phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
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References
Maroteaux P, Malamut G. Acrodysostosis. Presse Med. 1968;76:2189–92.
Robinow M, Pfeiffer RA, Gorlin RJ, et al. Acrodysostosis. A syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am J Dis Child. 1971;121:195–203.
Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Horm Res. 2005;63:65–74.
Linglart A, Menguy C, Couvineau A, et al. Recurrent PRKAR1A variant in acrodysostosis with hormone resistance. N Engl J Med. 2011;364:2218–26.
Michot C, Le Goff C, Goldenberg A, et al. Exome sequencing identifies PDE4D variants as another cause of acrodysostosis. Am J Hum Genet. 2012;90:740–5.
Lynch DC, Dyment DA, Huang L, et al. Identification of novel variants confirms PDE4D as a major gene causing acrodysostosis. Hum Mutat. 2013;34:97–102.
Linglart A, Fryssira H, Hiort O, et al. PRKAR1A and PDE4D variants cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. J Clin Endocrinol Metab. 2012;97:E2328–2338.
Mitsui T, Kim OH, Hall CM, et al. Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2. Am J Med Genet A. 2014;164A:2529–34.
Verloes A, Le Merrer M, Farriaux JP, Maroteaux P. Metaphyseal acroscyphodysplasia. Clin Genet. 1991;39:362–9.
Kaname T, Ki CS, Niikawa N, et al. Heterozygous variants in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cell Signal. 2014;26:2446–59.
Lee H, Graham JM Jr., Rimoin DL, et al. Exome sequencing identifies PDE4D variants in acrodysostosis. Am J Hum Genet. 2012;90:746–51.
Li N, Nie M, Li M, et al. The first variant identified in a Chinese acrodysostosis patient confirms a p.G289E variation of PRKAR1A causes acrodysostosis. Int J Mol Sci. 2014;15:13267–74.
Lindstrand A, Grigelioniene G, Nilsson D, et al. Different variants in PDE4D associated with developmental disorders with mirror phenotypes. J Med Genet. 2014;51:45–54.
Muhn F, Klopocki E, Graul-Neumann L, et al. Novel variants of the PRKAR1A gene in patients with acrodysostosis. Clin Genet. 2013;84:531–8.
Nagasaki K, Iida T, Sato H, et al. PRKAR1A variant affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance. J Clin Endocrinol Metab. 2012;97:E1808–1813.
Rhayem Y, Le Stunff C, Abdel Khalek W, et al. Functional characterization of PRKAR1A variants reveals a unique molecular mechanism causing acrodysostosis but multiple mechanisms causing carney complex. J Biol Chem. 2015;290:27816–28.
McKnight GS, Cummings DE, Amieux PS, et al. Cyclic AMP, PKA, and the physiological regulation of adiposity. Recent Prog Horm Res. 1998;53:139–59.
Cummings DE, Brandon EP, Planas JV, Motamed K, Idzerda RL, McKnight GS. Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature. 1996;382:622–6.
London E, Rothenbuhler A, Lodish M, et al. Differences in adiposity in Cushing syndrome caused by PRKAR1A variants: clues for the role of cyclic AMP signaling in obesity and diagnostic implications. J Clin Endocrinol Metab. 2014;99:E303–10.
Wang H, Edens NK. mRNA expression and antilipolytic role of phosphodiesterase 4 in rat adipocytes in vitro. J Lipid Res. 2007;48:1099–107.
Kim MJ, Park SK, Lee JH, et al. Salt-inducible kinase 1 terminates cAMP signaling by an evolutionarily conserved negative-feedback loop in beta-cells. Diabetes. 2015;64:3189–202.
Atabek ME, Pirgon O, Sert A. Metabolic syndrome manifestations in an adolescent with acrodysostosis. J Pediatr Endocrinol Metab. 2007;20:739–41.
Sezer N, Sutbeyaz ST, Koseoglu F, Aras M, Akin C. Adult case of acrodysostosis with severe neurologic involvement. J Back Musculoskelet Rehabil. 2009;22:125–9.
Das S, Roy S, Munshi A. Association between PDE4D gene and ischemic stroke: recent advancements. Int J Neurosci. 2016;126:577–83.
Jorgensen C, Yasmeen S, Iversen HK, Kruuse C. Phosphodiesterase-4D (PDE4D)—a risk factor for atrial fibrillation and stroke? J Neurol Sci. 2015;359:266–74.
Dieux-Coeslier A, Moerman A, Holder M, et al. Metaphyseal chondrodysplasia with cone-shaped epiphyses: a specific form involving the lower limbs. Am J Med Genet A. 2004;124A:60–6.
Cantú JM, Hernández A, Panduro-Cerda A, et al. Autosomal dominant acrodysostosis. Hum Genet. 1979;47:345–6.
Hernández RM, Miranda A, Kofman-Alfaro S. Acrodysostosis in two generations: an autosomal dominant syndrome. Clin Genet. 1991;39:376–82.
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. 1978;42:227–32.
Sheela SR, Perti A, Thomas G. Acrodysostosis: autosomal dominant transmission. Indian Pediatr. 2005;42:822–6.
Steiner RD, Pagon RA. Autosomal dominant transmission of acrodysostosis. Clin Dysmorphol. 1992;1:201–6.
Davies SJ, Hughes HE. Familial acrodysostosis: can it be distinguished from Albright's hereditary osteodystrophy? Clin Dysmorphol. 1992;1:207–15.
Taillet-Bellemère C, Maroteaux P. Acrodysostosis in a sister and brother born to normal parents. Ann Pediatr. 1991;38:31–6.
Babak T, Deveale B, Armour C, Raymond C, Cleary MA, van der Kooy D, Johnson JM, Lim LP. Global survey of genomic imprinting by transcriptome sequencing. Curr Biol. 2008;18:1735–41.
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Michot, C., Le Goff, C., Blair, E. et al. Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia. Eur J Hum Genet 26, 1611–1622 (2018). https://doi.org/10.1038/s41431-018-0135-1
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DOI: https://doi.org/10.1038/s41431-018-0135-1
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