LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies

BMC Medical Genetics

Silverio Perrotta⁵  Giuseppe Mirone³  Mario Cirillo⁴  Fulvio Della Ragione¹  Giulio Piluso¹  Teresa Giugliano¹  Saverio Scianguetta⁵  Giuseppe Limongelli²  Giuseppe Pacileo²  Claudia Santoro¹ 

[1] Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy;Division of Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy;Department of Pediatric Neurosurgery, Santobono Children’s Hospital, Naples, Italy;Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell’ Invecchiamento, Second University of Naples, Naples, Italy;Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, Via Luigi De Crecchio, 4, Naples 80138, Italy

关键词: PTPN11;    RASopathy;    Neurofibromatosis type 1;    LEOPARD syndrome;   

Others  :  1092099
DOI  :  10.1186/1471-2350-15-44

 received in 2014-01-16, accepted in 2014-04-22,  发布年份 2014

【 摘 要 】

Background

Diagnosis within RASopathies still represents a challenge. Nevertheless, many efforts have been made by clinicians to identify specific clinical features which might help in differentiating one disorder from another. Here, we describe a child initially diagnosed with Neurofibromatosis-Noonan syndrome. The follow-up of the proband, the clinical evaluation of his father together with a gene-by-gene testing approach led us to the proper diagnosis.

Case presentation

We report a 8-year-old male with multiple café-au-lait macules, several lentigines and dysmorphic features that suggest Noonan syndrome initially diagnosed with Neurofibromatosis-Noonan syndrome. However, after a few years of clinical and ophthalmological follow-up, the absence of typical features of Neurofibromatosis type 1 and the lack of NF1 mutation led us to reconsider the original diagnosis. A new examination of the patient and his similarly affected father, who was initially referred as healthy, led us to suspect LEOPARD syndrome, The diagnosis was then confirmed by the occurrence in both patients of a heterozygous mutation c.1403 C > T, p.(Thr468Met), of PTPN11. Subsequently, the proband was also found to have type-1 Arnold-Chiari malformation in association with syringomyelia.

Conclusion

Our experience suggests that differential clinical diagnosis among RASopathies remains ambiguous and raises doubts on the current diagnostic clinical criteria. In some cases, genetic tests represent the only conclusive proof for a correct diagnosis and, consequently, for establishing individual prognosis and providing adequate follow-up. Thus, molecular testing represents an essential tool in differential diagnosis of RASophaties. This view is further strengthened by the increasing accessibility of new sequencing techniques.

Finally, to our knowledge, the described case represents the third report of the occurrence of Arnold Chiari malformation and the second description of syringomyelia with LEOPARD syndrome.

【 授权许可】

   
2014 Santoro et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Stevenson DA, Swensen J, Viskochil DH: Neurofibromatosis Type 1 and Other Syndromes of the Ras Pathway. In Neurofibromatosis. Edited by Kaufmann D. Basel: Karger; 2008:32-45.
• [2]van der Burgt I: Noonan syndrome. Orphanet J Rare Dis 2007, 14:2-4.
• [3]Roberts AE, Allanson JE, Tartaglia M, Gelb BD: Noonan syndrome. Lancet 2013, 381:333-342.
• [4]Tartaglia M, Zampino G, Gelb BD: Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol 2010, 1:2-26.
• [5]van der Burgt I, Berends E, Lommen E, van Beersum S, Hamel B, Mariman E: Clinical and molecular studies in a large Dutch family with Noonan syndrome. Am J Med Genet 1994, 1:187-191.
• [6]Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002, 70:1555-1563.
• [7]National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Arch Neurol (Chicago) 1988, 45:575-578.
• [8]Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer ML, Eldridge R: NIH conference: neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med 1990, 113:39-52.
• [9]De Luca A1, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B: NF1 gene mutations represent the major molecular event underlying neurofibromatosis–Noonan syndrome. Am J Hum Genet 2005, 77:1092-1101.
• [10]Gorlin RJ, Anderson RC, Blaw M: Multiple lentigines syndrome. Am J Dis Child 1969, 17:652-662.
• [11]Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Wilson M, Calabrò R, Pizzuti A, Dallapiccola B: Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet 2004, 41(5):e68.
• [12]Brems H1, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E: Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature Genet 2007, 39:1120-1126.
• [13]Tidyman WE, Rauen KA: The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 2009, 19:230-236.
• [14]Messiaen LM1, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD: Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 2000, 15:541-545.
• [15]Aoki Y1, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, Watanabe Y, Ogura T, Matsubara Y: Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet 2013, 93:173-180.
• [16]Martínez-Quintana E, Rodríguez-González F: LEOPARD Syndrome Caused by Tyr279Cys Mutation in the PTPN11 Gene. Mol Syndromol 2012, 2:251-253.
• [17]Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G: Neurofibromatosis Type 1 in Genetic Counseling Practice: recommendations of the National Society of Genetic Counselors. J Genet Counsel 2007, 16:387-407.
• [18]Ferner RE1, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A: Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007, 44:81-88.
• [19]Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman JJ, Fryns JP: Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat 1996, 8:51-56.
• [20]Carcavilla A, Pinto I, Muñoz-Pacheco R, Barrio R, Martin-Frías M, Ezquieta B: LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria. Eur J Pediatr 2011, 170:1069-1074.
• [21]Nyström AM, Ekvall S, Berglund E, Björkqvist M, Braathen G, Duchen K, Enell H, Holmberg E, Holmlund U, Olsson-Engman M, Annerén G, Bondeson ML: Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet 2008, 45:500-506.
• [22]Muram TM1, Stevenson DA, Watts-Justice S, Viskochil DH, Carey JC, Mao R, Jackson B: A cost savings approach to SPRED1 mutational analysis in individuals at risk for neurofibromatosis type 1. Am J Med Genet A 2013, 161A:467-472.
• [23]Lepri FR1, Scavelli R, Digilio MC, Gnazzo M, Grotta S, Dentici ML, Pisaneschi E, Sirleto P, Capolino R, Baban A, Russo S, Franchin T, Angioni A, Dallapiccola B: Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Medical Genetics 2014, 15:14.
• [24]Beier AD, Barrett RJ, Burke K, Kole B, Soo TM: Leopard syndrome and Chiari type I malformation: a case report and review of the literature. Neurologist 2009, 15:37-39.
• [25]Agha A, Hashimoto K: Multiple lentigines (Leopard) syndrome with Chiara I malformation. J Dermatol 1995, 22:520-523.
• [26]Reinker KA, Stevenson DA, Tsung A: Orthopaedic conditions in Ras/MAPK related disorders. J Pediatr Orthop 2011, 31:599-605.
• [27]Tubbs RS, Rutledge SL, Kosentka A, Bartolucci AA, Oakes WJ: Chiari I malformation and neurofibromatosis type 1. Pediatr Neurol 2004, 30:278-280.
• [28]Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberge C, Gewillig M, Fryns JP: PTPN11 mutations in LEOPARD syndrome. J Med Genet 2002, 39:571-574.