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Year : 1992  |  Volume : 58  |  Issue : 3  |  Page : 147-154

Lisch Nodules

Correspondence Address:
Sanjay Singh

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More than anything else Lisch Nodules have influenced the way we think about neurofibromatoses. This review concentrates on these tiny iris lesions.

How to cite this article:
Singh S, Singh G, Pandey S S. Lisch Nodules. Indian J Dermatol Venereol Leprol 1992;58:147-54

How to cite this URL:
Singh S, Singh G, Pandey S S. Lisch Nodules. Indian J Dermatol Venereol Leprol [serial online] 1992 [cited 2021 Jan 20];58:147-54. Available from:

  Introduction Top

In 1882 von Recklinghausen described a disease characterized by the presence of multiple neurofibromas.[1] This disease, now known as neurofibromatosis type 1, [2] is of great importance not only to the thousands of affected patients and their physicians but also to researchers concerned with genetics, melanin synthesis, neural-crest embryology, cell-cell interactions, cancer, and other disciplines. [3] Lisch Nodules are the most consistent features of neurofibromatosis type 1, [4] and are a critical part of how we look at all the neurofibromatoses. [3]

  History Top

Pigmented iris hamartomas were first described by Waardenberg in 1918. [5] Lisch reported these iris spots in 3 adult patients with generalized neurofibromatosis in 1937, [6] Thus pointing out an association between these spots and generalized neurofibromatosis. The term Lisch Nodule was used for the first time in a formal publication by Riccardi in 1981, [3] and since then this term has become very popular.

Recently the National Institute of Health concensus Development Conference on Neurofibromatosis held in Bethesda, Maryland in July 1987 kept the presence of 2 or more Lisch Nodules as one of the criteria for the diagnosis of neurofibromatosis type 1. [2]

  Classification of Neurofibrornatosis Top

In the past decade it has emerged that there are at least 2 genetically distinct forms of neurofibromatoses. [2],[7] These are neurofibromatosis type 1 (previously described as `classic' or `generalized' or `peripheral' or Von Recklinghausen neurofibromatosis) and neurofibromatosis type 2 (previously described as `central' or `bilateral acoustic' neurofibromatosis). Both types of neurofibromatoses are autosomal dominant disorders [3],[8]. The prevalence of neurofibromatosis type 1 is very high, about 1 in 4,000 to 5,000 individuals, and that of neurofibromatosis type 2 is 1 in 50,000 individuals [3],[8],[9],[10] Variant forms also exist e.g., segmental neurofibromatosis [8], and familial cafe-au-lait macules, [9] is not established. [11] Neurofibromatosis type 1 accounts for more than 90 percent of all cases of neurofibromatosis. [12] The genetic and clinical implication of neurofibromatosis type 2 are quite different from those of neurofibromatosis type 1 [12],[13] The gene responsible for neurofibromatosis type 1 is located in the pericentromeric region of chromosome 17, [14] its precise localization to 17 q 11.2 has been shown. [15] Neurofibromatosis type 2 locus is probably on chromosome 22. [2],[16]

Clinically neurofibromatosis type 1 is defined by a triad of features : (1) cafe-au­lait macules, (2) neurofibromas, (3) Lisch Nodules. [3],[12],[17]

  Morphology Top

Lisch nodules are 1 to 2 mm yellow brown dome-shaped solid lesions in the iris. [12] Adults with neurofibromatosis type 1 usually have multiple, bilateral nodules. [18] They are found in all zones of the iris as smooth, gelatinous-appearing masses protruding from the iris surface. [19] Few of them may not be elevated, and they may be nonpigmented or highly pigmented. Their colour may be clear to yellow or brown. Lisch Nodules may be distinguished from naevi in the iris, which are flat or minimally elevated, densely pigmented lesions with blurred margins, by slit-lamp examination. [18] The size and number of Lisch Nodules increase with age. [18],[19],[20],[21],[22],[23]

Lisch Nodules are asymptomatic [3],[12] and do not result in any ophthalmologic complications.

  Visualization Top

Lisch Nodules are visualized only by an experienced ophthalmologist using binocular biomicroscopy and proximal rather than direct illumination. [24] They may be seen without magnification especially in adults. [24] They are best seen [12],[19] and distinguished from naevi in iris [18] by slit­lamp examination.

  Histogenesis Top

There are few reports documenting the characteristic clinical and pathologic features of Lisch Nodules ['25],[26] and considerable controversy exists regarding their histogenesis. Like neurofibromas, they were also considered to be hamartomas-abnormally organized collections of otherwise ostensibly normal differentiated cells, primarily neural crest­derived neurons and Schwann cells, plus fibroblasts, vascular endothelial cells, and mast cells. [3] Some believe they represent neurofibromas arising from peripheral schwannian elements. [27] Others suggest that Lisch Nodules may represent melanocytic hamartomas of neural crest origin and that they are identical to benign naevi of the iris. [25],[28],[29]

A recent report [30] provided electron microscopic confirmation of their melanocytic origin. This report described a 75-year-old man with neurofibromatosis type 1 who had a mature cataract with elevated intraocular pressure in his left eye. At the time of intraocular lens extraction, a sector iridectomy was performed. Electron microscopic studies of Lisch Nodules within the iridectomy specimen unequivocally established that the spindle-shaped cells within the nodules were of melanocytic origin. The authors concluded that Lisch Nodules in neurofibromatosis type 1 represent melanocytic hamartomas developing from differentiated melanocytes and that these are identical to iris naevi. They also demonstrated that Lisch Nodules that protrude into the anterior chamber of the eye are histologically identical to intrastromal nodules with ill-defined borders.

Some of the confusion regarding the histogenesis of Lisch Nodules stems from the misinterpretation of an earlier report. [27] This report described a 32-year-old man who had a 2.5x3x4 mm white nodule protruding from the iris inferiorly, the other iris had no spots or nodules. this nodule represented an isolated neurofibroma of the iris in a patient without any evidence of neurofibromatosis type 1. This article has subsequently been wrongly quoted as an evidence that cells within the Lisch Nodules in neurofibromatosis type 1 are schwanian in origin [30]. Recently a report on the structure of Lisch Nodules has been published [31]

  Age of Appearance Top

Lisch Nodules begin to appear in early childhood and are found in almost all adult patients of neurofibromatosis type 1. [23] They were found in 5 percent of children with neurofibromatosis type 1 less than 3 years of age. [18] This and several other reports [20],[21],[22],[23] suggest that they appear in childhood and that the belief [24] that they do no appear until age 16 years is incorrect. Contrary to the belief that eye examination will not help in settling the significance of a few cafe-au-lait macules in a child [24] the detection of Lisch Nodules in some such children will certainly be very helpful.

  Incidence in Neurofibromatosis type 1 Top

Lisch Nodules are present in 94 to 97 percent of patients over 6 years and about 30 percent of younger patient [20],[21],[22],[23] A study of 77 patients [20] showed that the presence of Lisch Nodules is related to age. Lisch Nodules were found in 92 percent (56 of 61) patients aged 6 years or older, whereas the incidents was only 19 percent (3 of 16 patients) in those aged 0 to 5 years. The majority of these nodules were bilateral (55 of 59 patients). In one smalll series [19] they were found in 73 percent of the patients, but the criteria for diagnosing neurofibromatosis type 1 [2],were not available by then. Another drawback of earlier studies [19],[20],[22],[32] was the small size of samples which didn't permit the subdivision of those under 11 years of age into smaller groups.

A recent study [18] has utilized the current criteria for diagnosing neurofibromatosis type 1 [2] and has found Lisch Nodules in 100 percent of the patients over the age of 20 years. This study was conducted on a large sample of 162 patients from 120 families and 5 children with probable neurofibromatosis type 1. The overall prevalence of Lisch Nodules was 73.7 percent, similar to the prevalence of neurofibromas which teas 68.3 percent. Only 5 percent of children less than 3 years of age had Lisch Nodules. The prevalence was 42 percent among children 3 to 4 years of age and it rose to 55 percent among the children 5 to 6 years old. All 65 adults 21 years of age or older had Lisch Nodules. The prevalence of Lisch Nodules was greater than that of neurofibromas in all but the youngest age group. Lisch Nodules were never the only. sign of neurofibromatosis type 1. This study suggests. that Lisch Nodules make their appearance in childhood and their incidence increases with age.

  Relationship with other features of Neurofibromatosis type 1 Top

In one study, [19] the number and size of Lisch Nodules correlated closely with the severity of sxin involvement in neurofibromatosts type 1, although other studies [3],[18] do not support this view. The proportion of Lisch Nodules was found to be similar in the patients who had central nervous tumours (19 of 27 patients; 70 percent) and those who did not (87 of 118 patients; 74 percent). [18] As there is no association between Lisch Nodules and the overall clinical severity of neurofibromatosis type 1, they can not be used to predict the clinical course of the disease. [18]

  Absence of Lisch Nodules and risk of Neurofibromatosis type 1 Top

In the study quoted, [18] the risk of having the gene for neurofibromatosis type 1 in children with no Lisch Nodules was estimated. The risk of having the gene reduced from 50 percent at birth to 31 percent at 5 to 6 years of age, 15 percent at 9 to 14 years of age, 8 percent at 15 to 20 years of age, and 0 percent in those over the age of 20 years.

  Diagnosis of Neurofibromatosis type 1 Top

The major defining features of neurofibromatosis type 1 are multiple cafe­au-lait macules, periphera-I neurofibromas, and Lisch Nodules, [12] The importance of Lisch Nodules in the diagnosis of this disease has been appreciated only in the past decade. [18] Currently accepted diagostic criteria, [2] which are more stringent than those used previously, [16] are being reproduced below in order to emphasize the presence of Lisch Nodules as a diagnostic feature of neurofibromatosis type 1. According to these guidelines [2] the diagnosis of neurofibromatosis type 1 is made in an individual if 2 or more of the following are found:

1. Six or more cafe-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals

2. Two or more neurofibromas of any type or one plexiform neurofibroma

3. Freckling in the axillary or inguinal region

4. Optic glioma

5. Two or more Lisch Nodules (iris hamartomas)

6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis

7. A first-degree relative (parent, sibling, or offspring) with neurofibromatosis type 1 by the above criteria.

  Future Diagnosis of Neurofibromatosis type 1 Top

A brief discussion on this aspect here will help us later in assessing the relative merits of the advanced procedures versus examination of eyes for Lisch Nodules in the diagnosis of neurofibromatosis type 1. Genetic linkage studies with DNA markers have become available lately for prenata1 [33] and presymptomatic diagnosis of familial neurofibromatosis type 1 in suspected cases. But this technique can not be used for suspected sporadic cases, which constitute about 50 percent of all cases. [18],[20],[24] It is likely that the means for routine detection of neurofibromatosis type 1 gene abnormalities will be available in a year or tWo [35] The size of this gene has been variously estimated to be 200 to 300 Kilobases, so the gene is very large. [14],[36],[37],[38],[39] Many different types of mutational events (chromosomal translocation, insertion, deletion, and point mutations) can lead to the expression of neurofibromatosis type 1 phenotype [17],[18] Further, progression of neurofibroma to neurofibrosarcoma may depend on alteration at p53 locus on the short arm of chromosome 17. [40] Therefore, in sporcadic cases, the practical value of DNA diagnosis will be limited. [18]

  Lisch Nodules in otherwise unaffected relatives of patients with Neurofibromatosis type 1 Top

A recent report from Netherlands [41] described a 43-year-old man with neurofibromatosis type 1 whose one of the sisters had multiple Lisch Nodules, while her eldest daughter had one Lisch Nodule. Neither of these 2 subjects had any signs of cutaneous or systemic neurofibromatosis. This was the first time when Lisch Nodules were shown in the absence of other features of neurofibromatosis in relatives of patients of this disease. We have seen multiple bilateral Lisch Nodules in otherwise unaffected 48-year-old elder brother and 8-year-old daughter of a male patient with neurofibromatosis type 1 (unpublished observations). Eight-year-old daughter of the patient may develop neurofibromas in future, as these may, unlike Lisch Nodules, appear and increase in size and number during puberty [42] and pregnancy .[ 43].[44] This possibility does not exist in the case of our patient's elder brother. Therefore, it appears that Lisch Nodules are the ocular marker of neurofibromatosis type 1' gene in otherwise normal family members of patients with neurofibromatosis type 1. These unexpected findings emphasize the necessity of examining all family members of the patients for Lisch Nodules in order to provide accurate genetic counselling.

  Lisch Nodules in Neurofibromatosis type 2 Top

Lisch Nodules have been reported only once [16] in a patient of neurofibromatosis type 2. This report described a 47-year-old male patient who had bilateral sensoryneural deafness and progressive ataxia. Magnetic resonance imaging showed the appearance of bilateral acoustic neuromas. Multiple Lisch Nodules were present in his right iris.

  Lisch Nodules in segmental Neurofibromatosis Top

Patients with segmental neurofibromatosis, which is due to a somatic mutation of neurofibromatosis type 1 gene, may rarely have Lisch Nodules. A patient, who had cafe-au-lait macules on right side of the body and Lisch Nodules only in the right eye, has been reported . [ 45]

  Lisch Nodules in Watson's Syndrome Top

Lisch Nodules are found in Watson's Syndrome (characterized by cafe-au-lait macules, pulmonary valvular stenosis, and mental retardation), a disease linked to the same markers that established the locus assignment for ordinary neurofibromatosis type 1. [46] Perhaps the gene for Watson's Syndrome is an alternative form of the gene for neurofibromatosis type 1. [17]

  Significance Top

Lisch Nodules are not found in normal individuals, [3],[24] and their presence seems to be pathognomonic for neurofibromatosis type [2],[18],[19],[20],[24] Multiple Lisch Nodules, unlike cafe'-au-lait macules and neurofibromas, are specific for neurofibromatosis type 1 [47],[48] As the practical value of DNA probes for diagnosing neurofibromatosis type 1 will be limited, evaluation with a slit lamp for the presence of Lisch Nodules will remain a simple, inexpensive, and noninvasive procedure in the early diagnosis and for providing accurate genetic counselling. [18] They should be looked for in the relations of a patient with. neurofibromatosis type 1, because they may be the only feature of this disease. [41] Repeated ophthalmologic examinations to look for Lisch Nodules are particularly useful in a child as Lisch Nodules often appear before neurofibromas. [18] Lisch Nodules allow us to discriminate between the types of neurofibromatoses'and distinguish between persons ' who bear a mutation at the neurofibromatosis type 1 locus on the long arm of chromosome 17 and those who do not. [17] In fact, the presence of the nodules probably contributed to the rapidity with which the gene assignment was made. [17] The absence of Lisch Nodules permits the virtual exclusion of the phenotype in persons, at risk above a certain age. [18] Conversely, serving as an ocular marker, [41] their presence allows the identification of at least one type of minimal expression of a neurofibromatosis type 1 mutation. [49]

  References Top

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