Unilateral Lisch Nodules in a 47-year-old Woman Without Other Stigmata of Neurofibromatosis Type I:...
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2013 Ophthalmic Genetics, 2013; 34(3): 178–179 Copyright ! Informa Healthcare USA, Inc. ISSN: 1381-6810 print / 1744-5094 online DOI: 10.3109/13816810.2012.739258 LETTER TO THE JOURNAL Unilateral Lisch Nodules in a 47-year-old Woman Without Other Stigmata of Neurofibromatosis Type I: An Example of Segmental Neurofibromatosis? Francesco Nicita 1 , Ludovico Iannetti 2 , Alberto Spalice 1 , Laura Papetti 1 , Fabiana Ursitti 1 , Enrico Properzi 1 and Martino Ruggieri 3 1 Department of Pediatrics, Child Neurology Division, Policlinico Umberto I, Sapienza University, Rome, Italy, 2 Department of Ophthalmology, Policlinico Umberto I, Sapienza University, Rome, Italy, and 3 Chair of Pediatrics, Department of Formative Processes, University of Catania, Catania, Italy Keywords: eye; Lisch nodules; mosaicism; Neurofibromatosis; NF1 gene A 47-year-old woman, with no personal or familial history of Neurofibromatosis type 1 (NF1) or 2, was referred for evaluation of left unilateral Lisch nodules (LN) discovered through a routine eye care performed one month before (Figure 1a and b). Fundus oculi evaluation was normal in both eyes. The patient had occasionally attended routine eye examinations since her childhood, without discovering anomalies. Her past medical history was remarkable for migraine with aura, essential hypertension, and mild hyper- cholesterolemia. No other NF1 stigmata were noticed with the exception of one very pale 1.0 1.0 cm cafe `- au-lait spot below the left leg. Magnetic resonance imaging of brain and spine, cardiac and abdominal ultrasound findings were unremarkable. The term segmental NF1 is used when the NF1 stigmata are confined to one or more body segments because of somatic mosaicism for the NF1 gene. Segmental NF1 is estimated to be rarer than the full- blown phenotype, with a prevalence of 1 in 36–40,000 subjects. 1 In patients with segmental form, the involved parts of the body may develop all the manifestations with the same chronological order as they appear in the generalized phenotype. 2 Ocular NF1 manifestations include LN, optic pathway glioma, eyelid and/or conjunctival neurofibromas, choroidal hamartomas, and orbital plexiform neuro- fibromas. Lisch nodules, asymptomatic melanocytic hamartomas of the iris, are the most common ocular NF1 findings and are included among diagnostic criteria. 1 They usually develop during childhood with their prevalence increasing with age (90–100% of adult patients with generalized NF1). 3 LN have been reported only occasionally in seg- mental NF1 4,5 or in partial unilateral lentiginosis. 6 In all these cases the patients had NF1 manifestations in body areas close to the eye (ie, head, chest and face). 4–6 A genetic study revealed a somatic mosaicism of the NF1 gene in one case. 5 In the largest study on the ophthalmological manifestations in segmental NF1, no LN or other eye NF1 stigmata were observed in a cohort of 72 subjects, and no NF1 gene mutations in blood DNA were discovered. The postulated explanation for the absence of ocular involvement in these patients was that the eye was too far from tissues with NF1 mutation or that genetic anomalies involved tissues different from the eye. 2 Conversely, it is known that the eye and the optic pathway may be altered in segmental NF1 phenotypes primarily involving the ocular system. In fact, plexiform Correspondence: Alberto Spalice, MD, PhD, Department of Pediatrics, Child Neurology Division, Policlinico Umberto I, Sapienza University of Rome, Viale Regina Margherita 324, 00161 Rome, Italy. Tel: þ39 06 49979311. Fax: þ39 06 49979312. E-mail: [email protected] Received 6 July 2012; accepted 6 October 2012 178 Ophthalmic Genet Downloaded from informahealthcare.com by Monash University on 09/12/13 For personal use only.
Transcript of Unilateral Lisch Nodules in a 47-year-old Woman Without Other Stigmata of Neurofibromatosis Type I:...
2013
Ophthalmic Genetics, 2013; 34(3): 178–179
Copyright ! Informa Healthcare USA, Inc.
ISSN: 1381-6810 print / 1744-5094 online
DOI: 10.3109/13816810.2012.739258
LETTER TO THE JOURNAL
Unilateral Lisch Nodules in a 47-year-old WomanWithout Other Stigmata of Neurofibromatosis Type I:
An Example of Segmental Neurofibromatosis?
Francesco Nicita1, Ludovico Iannetti2, Alberto Spalice1, Laura Papetti1,Fabiana Ursitti1, Enrico Properzi1 and Martino Ruggieri3
1Department of Pediatrics, Child Neurology Division, Policlinico Umberto I, Sapienza University, Rome, Italy,2Department of Ophthalmology, Policlinico Umberto I, Sapienza University, Rome, Italy, and 3Chair of
Pediatrics, Department of Formative Processes, University of Catania, Catania, Italy
Keywords: eye; Lisch nodules; mosaicism; Neurofibromatosis; NF1 gene
A 47-year-old woman, with no personal or familialhistory of Neurofibromatosis type 1 (NF1) or 2, wasreferred for evaluation of left unilateral Lisch nodules(LN) discovered through a routine eye care performedone month before (Figure 1a and b). Fundus oculievaluation was normal in both eyes. The patienthad occasionally attended routine eye examinationssince her childhood, without discovering anomalies.Her past medical history was remarkable for migrainewith aura, essential hypertension, and mild hyper-cholesterolemia. No other NF1 stigmata were noticedwith the exception of one very pale 1.0� 1.0 cm cafe-au-lait spot below the left leg. Magnetic resonanceimaging of brain and spine, cardiac and abdominalultrasound findings were unremarkable.
The term segmental NF1 is used when the NF1stigmata are confined to one or more body segmentsbecause of somatic mosaicism for the NF1 gene.Segmental NF1 is estimated to be rarer than the full-blown phenotype, with a prevalence of 1 in 36–40,000subjects.1 In patients with segmental form, theinvolved parts of the body may develop all themanifestations with the same chronological orderas they appear in the generalized phenotype.2
Ocular NF1 manifestations include LN, optic pathway
glioma, eyelid and/or conjunctival neurofibromas,choroidal hamartomas, and orbital plexiform neuro-fibromas. Lisch nodules, asymptomatic melanocytichamartomas of the iris, are the most common ocularNF1 findings and are included among diagnosticcriteria.1 They usually develop during childhoodwith their prevalence increasing with age (90–100%of adult patients with generalized NF1).3
LN have been reported only occasionally in seg-mental NF14,5 or in partial unilateral lentiginosis.6
In all these cases the patients had NF1 manifestationsin body areas close to the eye (ie, head, chest andface).4–6 A genetic study revealed a somatic mosaicismof the NF1 gene in one case.5 In the largest study onthe ophthalmological manifestations in segmentalNF1, no LN or other eye NF1 stigmata were observedin a cohort of 72 subjects, and no NF1 gene mutationsin blood DNA were discovered. The postulatedexplanation for the absence of ocular involvementin these patients was that the eye was too far fromtissues with NF1 mutation or that genetic anomaliesinvolved tissues different from the eye.2 Conversely,it is known that the eye and the optic pathway may bealtered in segmental NF1 phenotypes primarilyinvolving the ocular system. In fact, plexiform
Correspondence: Alberto Spalice, MD, PhD, Department of Pediatrics, Child Neurology Division, Policlinico Umberto I, SapienzaUniversity of Rome, Viale Regina Margherita 324, 00161 Rome, Italy. Tel: þ39 06 49979311. Fax: þ39 06 49979312.E-mail: [email protected]
Received 6 July 2012; accepted 6 October 2012
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neurofibromas of the orbit or the eyelid can be theonly manifestation of segmental NF1; furthermore,isolated optic pathway glioma, which behaved bothbiologically and radiographically as a typical NF1-associated tumor, has been hypothesized to representa form of segmental NF1.2,7
Few reports have described unilateral LN withoutany other NF1 manifestations.5,8 There are also threefamilies with parents having unilateral or bilateral LNand sons with full blown NF1 (Tenconi R personalcommunication).2,9,10 The hypothesized genetic mech-anisms existing in these families is a somatic ocular(eg, of the iris) and germinal mosaicism of themutated NF1 gene in the parents, that results in avery limited ‘‘segmental’’ manifestation of NF1 (eg,LN) in the parents and in the full blown phenotype inthe offspring. In contrast to the previously reportedcases, our patient was older (eg, 47-years-old versus14- and 19-year-olds), and the absence of other NF1manifestations at this age indicates that a mosaicismfor NF1 gene is limited to a very restricted area, that isthe left iris, and not involving other tissues. We cannotexclude a concomitant germinal mosaicism since ourpatient does not have children. Isolated LN of the irismay represent a further rare form of segmental NF1 ofthe eye.
At present there are no means to exclude involve-ment of both somatic and gonadic tissue in a subjectwith segmental phenotype, and therefore the exactlevel of risk is not definable with current knowledge.Gonadic tissue may harbor the mutated NF1 gene alsoif the body segment affected is distant from thegonads. From this point of view, the presence – orlack – of LN in the setting of segmental NF1 shouldnot be interpreted as a predictor for transmission ofNF1 to offspring, although the effective risk cannot beprecisely estimated.
Declaration of interest: The authors report no con-flicts of interest. The authors alone are responsiblefor the content and writing the paper.
REFERENCES
1. Ruggieri M, Upadhyaya M, Di Rocco C, et al.Neurofibromatosis type 1 and related disorders.In: Ruggieri M, Pascual-Castroviejo I, Di Rocco C, editors.Neurocutaneous disorders: phakomatosis and hamarto-neoplastic syndromes. Wien/New York: Springer-Verlag,2008; 51–151.
2. Ruggieri M, Pavone P, Polizzi A, et al. Ophthalmologicalmanifestations in segmental neurofibromatosis type 1.Br J Ophthalmol 2004;88:1429–1433.
3. Lubs MLE, Bauer MS, Formas ME, et al. Lisch nodulesin Neurofibromatosis type 1. New Engl J Med1991;324:1264–1266.
4. Weleber RG, Zonana J. Iris hamartomas (Lisch nodules)in a case of segmental neurofibromatosis. Am JOphthalmol 1983;96:740–743.
5. Ceuterick SD, Van den Ende JJ, Smets RME. Clinical andgenetic significance of unilateral Lisch nodules. Bull SocBelge Ophtalmol 2005;295:49–53.
6. Rao GS. Partial unilateral lentiginosis with Lisch nodules:a forme frusta of segmental neurofibromatosis? Indian JDermatol Venereol Leprol 2004;70:114–115.
7. Listernick R, Mancici AJ, Charrow J. Segmentalneurofibromatosis in childhood. Am J Med Genet2003;121A:132–135.
8. Lal G, Leavitt JA, Lindor NM, et al. UnilateralLisch nodules in the absence of other features ofNeurofibromatosis 1. Am J Ophthalmol 2003;135:567–578.
9. Toonstra J, Dandrieu MR, Ippel PF, et al. Are Lischnodules an ocular marker of neurofibromatosis genein otherwise unaffected family members? Dermatologica1987;174:232–235.
10. Riccardi VM, Riccardi AL. Penetrance of vonRecklinghausen neurofibromatosis: a distinction betweenpredecessors and descendant. Am J Hum Genet1988;42:284–289.
FIGURE 1. (a) Lisch nodules in the left eye, mainly located at the temporal portion; (b) no Lisch nodules are observed in the right iris.
Ocular segmental Neurofibromatosis type I 179
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