Rothmund-Thomson Syndrome Workup
- Author: Sylvia Hsu, MD; Chief Editor: Dirk M Elston, MD more...
By sequence analysis of RECQL4, a disease-causing mutation can be identified in approximately 66% of individuals diagnosed with Rothmund-Thomson syndrome. Although the sensitivity of the genetic test is 66%, the clinical specificity approaches 100%; thus a negative test does not rule out the diagnosis of Rothmund-Thomson syndrome but a positive test is confirmatory.
A Clinical Utility Gene Card for Rothmund-Thomson syndrome, published in 2012, summarizes guidelines for the use of genetic testing for the syndrome using mutational analysis of the RECQL4 gene. In classic cases, a correct diagnosis may be made on clinical findings (such as early-onset facial poikiloderma accompanied by radial-ray defects, growth defects, and sparse hair). Genetic testing of the RECQL4 gene is of particular value in evaluating borderline or atypical cases in which other genodermatoses presenting with poikiloderma or other overlapping features such as poikiloderma with neutropenia, dyskeratosis congenita, Werner syndrome, and Fanconi anemia must also be considered. Additionally, the test should be offered to all juvenile osteosarcoma cases with poikilodermalike lesions. In these cases, genetic testing of the RECQL4 gene would allow for establishment of the correct diagnosis and thus accurate syndrome-specific surveillance.
In Rothmund-Thomson syndrome (poikiloderma congenitale), baseline skeletal radiographs of the long bones by age 5 years are recommended due to the high frequency of skeletal dysplasias, many of which may be clinically asymptomatic.
Histologic examination of poikilodermatous skin in children reveals a flattened, atrophic epidermis with derma-epidermal junction edema and dermal vasodilatation, possibly with a perivascular lymphocytic infiltrate. Adult skin in exposed areas reveals patchy Bowenoid dyskeratosis in the epidermis and fragmented dermal elastic tissue.
Kitao S, Shimamoto A, Goto M, et al. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet. 1999 May. 22(1):82-4. [Medline].
Kitao S, Lindor NM, Shiratori M, Furuichi Y, Shimamoto A. Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products. Genomics. 1999 Nov 1. 61(3):268-76. [Medline].
Larizza L, Magnani I, Roversi G. Rothmund-Thomson syndrome and RECQL4 defect: splitting and lumping. Cancer Lett. 2006 Jan 28. 232(1):107-20. [Medline].
Leonard A, Craft AW, Moss C, Malcolm AJ. Osteogenic sarcoma in the Rothmund-Thomson syndrome. Med Pediatr Oncol. 1996 Apr. 26(4):249-53. [Medline].
Wang LL, Gannavarapu A, Kozinetz CA, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst. 2003 May 7. 95(9):669-74. [Medline].
Popadic S, Nikolic M, Gajic-Veljic M, Bonaci-Nikolic B. Rothmund-Thomson syndrome. The first case with plantar keratoderma and the second with coeliac disease. Acta Dermatovenerol Alp Panonica Adriat. 2006 Jun. 15(2):90-3. [Medline].
Otsu U, Moriwaki S, Iki M, Nozaki K, Horiguchi Y, Kiyokane K. Early blistering, poikiloderma, hypohidrosis, alopecia and exocrine pancreatic hypofunction: a peculiar variant of Rothmund-Thomson syndrome?. Eur J Dermatol. 2008 Nov-Dec. 18(6):632-4. [Medline].
Macris MA, Krejci L, Bussen W, Shimamoto A, Sung P. Biochemical characterization of the RECQ4 protein, mutated in Rothmund-Thomson syndrome. DNA Repair (Amst). 2006 Feb 3. 5(2):172-80. [Medline].
Werner SR, Prahalad AK, Yang J, Hock JM. RECQL4-deficient cells are hypersensitive to oxidative stress/damage: Insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome. Biochem Biophys Res Commun. 2006 Jun 23. 345(1):403-9. [Medline].
Woo LL, Futami K, Shimamoto A, Furuichi Y, Frank KM. The Rothmund-Thomson gene product RECQL4 localizes to the nucleolus in response to oxidative stress. Exp Cell Res. 2006 Oct 15. 312(17):3443-57. [Medline].
Dietschy T, Shevelev I, Pena-Diaz J, et al. p300-mediated acetylation of the Rothmund-Thomson-syndrome gene product RECQL4 regulates its subcellular localization. J Cell Sci. 2009 Apr 15. 122:1258-67. [Medline].
Maire G, Yoshimoto M, Chilton-MacNeill S, Thorner PS, Zielenska M, Squire JA. Recurrent RECQL4 imbalance and increased gene expression levels are associated with structural chromosomal instability in sporadic osteosarcoma. Neoplasia. 2009 Mar. 11(3):260-8, 3p following 268. [Medline]. [Full Text].
Wu J, Capp C, Feng L, Hsieh TS. Drosophila homologue of the Rothmund-Thomson syndrome gene: essential function in DNA replication during development. Dev Biol. 2008 Nov 1. 323(1):130-42. [Medline]. [Full Text].
Ferrarelli LK, Popuri V, Ghosh AK, Tadokoro T, Canugovi C, Hsu JK, et al. The RECQL4 protein, deficient in Rothmund-Thomson syndrome is active on telomeric D-loops containing DNA metabolism blocking lesions. DNA Repair (Amst). 2013 Jul. 12(7):518-28. [Medline]. [Full Text].
Gupta S, De S, Srivastava V, Hussain M, Kumari J, Muniyappa K, et al. RECQL4 and p53 potentiate the activity of polymerase ? and maintain the integrity of the human mitochondrial genome. Carcinogenesis. 2014 Jan. 35(1):34-45. [Medline].
Prendiville JS, Fine JD, Esterly NB. Kindler syndrome and epidermolysis bullosa simplex. J Am Acad Dermatol. 1990 Aug. 23(2 Pt 1):327-8. [Medline].
Mehollin-Ray AR, Kozinetz CA, Schlesinger AE, Guillerman RP, Wang LL. Radiographic abnormalities in Rothmund-Thomson syndrome and genotype-phenotype correlation with RECQL4 mutation status. AJR Am J Roentgenol. 2008 Aug. 191(2):W62-6. [Medline].
Larizza L, Roversi G, Verloes A. Clinical utility gene card for: Rothmund-Thomson syndrome. Eur J Hum Genet. 2012 Nov 28. [Medline].
Geronemus RG. Treatment of the cutaneous vascular component of the Rothmund-Thomson syndrome. Pediatr Dermatol. 1996 Mar-Apr. 13(2):175. [Medline].
Zils K, Klingebiel T, Behnisch W, Mueller HL, Schlegel PG, Fruehwald M, et al. Osteosarcoma in patients with Rothmund-Thomson syndrome. Pediatr Hematol Oncol. 2015 Feb. 32 (1):32-40. [Medline].
Piquero-Casals J, Okubo AY, Nico MM. Rothmund-thomson syndrome in three siblings and development of cutaneous squamous cell carcinoma. Pediatr Dermatol. 2002 Jul-Aug. 19(4):312-6. [Medline].
Howell SM, Bray DW. Amelanotic melanoma in a patient with Rothmund-Thomson syndrome. Arch Dermatol. 2008 Mar. 144(3):416-7. [Medline].