Lisch nodules are melanocytic hamartomas composed of melanocytes, elongated fibroblasts and mast cells. While they do not cause morbidity or disability, they represent a diagnostically significant finding that can guide further work-up and management. Despite a broad differential (iris mammillations, iris nevi, iris melanoma, Kogan-Reese syndrome, granulomatous iritis, iris cysts, retinoblastoma and Brushfield spots), the characteristic appearance of Lisch nodules makes them readily recognizable in most cases. They appear as pale to dark brown, dome-shaped nodules with smooth or feathery margins, varying in size. They are irregularly distributed across the anterior iris surface and may occasionally be visible in the iridocorneal angle on gonioscopy. ^{Reference Cruciani, Carmen Piraino, Albanese, Rahimi and Abdolrahimzadeh1}

Lisch nodules are traditionally regarded as a principal hallmark of neurofibromatosis type 1 (NF1), and the presence of two or more Lisch nodules is part of the diagnostic criteria. ^{Reference Legius, Messiaen and Wolkenstein2,Reference Hom, Moodley, Rothner and Moodley3} Most patients with NF1 show bilateral involvement. Unilateral Lisch nodules are less common and are thought to represent mosaicism in segmental NF (SNF). ^{Reference Cruciani, Carmen Piraino, Albanese, Rahimi and Abdolrahimzadeh1,Reference Adams, Stewart, Borges and Multiple4} Lisch nodules without other signs of NF1 are exceedingly rare, with only few cases reported to the best of our knowledge. ^{Reference Adams, Stewart, Borges and Multiple4–Reference Eltantawy and Ho6} We describe a patient with unilateral Lisch nodules and no other NF1 manifestations, underscoring the importance of recognizing this rare finding.

A 45-year-old woman, known since childhood to have variation in iris color, was noted by her optometrist to have iris nodules during a routine eye examination.

Her past medical history included hypothyroidism and anxiety. Best-corrected visual acuity was 20/20 in both eyes. Pupils measured 4 mm, were equal and reacted normally to light without a relative afferent pupillary defect. Slit-lamp examination revealed multiple iris lesions consistent with Lisch nodules in the right eye, predominantly distributed between 2 and 10 o’clock, with a few additional ones superiorly. No Lisch nodules were present in the left eye (Figures 1 and 2). Palpebral fissure height measured 11 mm bilaterally, and extraocular movements were full.

Figure 1.

Slit-lamp photograph demonstrating multiple Lisch nodules in the right eye.

Figure 2.

Slit-lamp photograph demonstrating the absence of Lisch nodules in the left eye.

Humphrey 24-2 visual field testing showed subtle nonspecific changes in the right eye and normal findings in the left (mean deviation −1.0 dB Oculus Dexter (right eye), −0.76 dB Oculus Sinister (left eye)). Optic disks were normal.

On physical examination, there were no stigmata of NF1 including cutaneous nodules, café au lait macules, axillary or inguinal freckling or plexiform neurofibroma. MRI of the brain and spine was unremarkable, with no findings suggestive of NF1. Exon-based NF1 molecular genetics analysis was completed, and no pathogenic variant was found. Given the low suspicion of NF1 disease based on personal and family history, no further genetic analysis such as RNA sequencing was conducted.

When iris nodules present in isolation, particularly when unilateral, the key diagnostic challenge is determining their clinical significance and underlying etiology. A careful and systematic approach to the differential diagnosis of solitary or unilateral iris lesions is therefore warranted. In this case, the characteristic appearance and distribution of the nodules strongly supported the diagnosis of Lisch nodules and prompted consideration of NF1.

Neurofibromatosis represents a group of neurocutaneous syndromes with a predisposition to develop nerve sheath tumors. NF1, or von Recklinghausen disease, is a multisystem condition of neural crest origin caused by pathogenic variants in the NF1 gene on chromosome 17q. It is inherited in an autosomal dominant fashion, with complete ^{Reference Cruciani, Carmen Piraino, Albanese, Rahimi and Abdolrahimzadeh1} or possibly reduced ^{Reference Safonov, Nomakuchi and Chao7} penetrance, and exhibits highly variable expressivity ranging from minimal to severe disease.

Two forms of NF1 exist: full NF1 where all the cell in the body contain a likely pathogenic NF1 variant and mosaic NF1 where NF1 likely pathogenic variant is present only in a subset of cells. Segmental is a form of mosaicism where NF1 features are restricted to one body region, usually following a dermatomal distribution. It arises from a postzygotic somatic variant of the NF1 gene, occurring later in embryogenesis, resulting in mosaicism. Clinical variation depends on which tissues are affected. Since the mutation involves somatic cells, SNF is typically non-heritable, though transmission is possible in cases of gonadal mosaicism. Cases have been described in which offspring of adults with Lisch nodules developed NF1. ^{Reference Cruciani, Carmen Piraino, Albanese, Rahimi and Abdolrahimzadeh1,Reference Nicita, Iannetti and Spalice5} Although most cases are reported in adults, segmental NF1 can appear at any age. The sequence of clinical findings in affected areas often mirrors that seen in generalized NF1. ^{Reference Nicita, Iannetti and Spalice5}

Ocular findings in NF1 may include Lisch nodules, optic pathway gliomas, eyelid or conjunctival neurofibromas, choroidal hamartomas, orbital plexiform neurofibromas, prominent corneal nerves, posterior embryotoxon, congenital ectropion uveae, heterochromia iridis, glaucoma, angle anomalies, congenital hypertrophy of the retinal pigment epithelium, myelinated nerve fibers and astrocytic hamartomas. ^{Reference Nicita, Iannetti and Spalice5} In the largest ophthalmic series of segmental NF1 (72 patients), no Lisch nodules or other ocular stigmata were detected, and NF1 pathogenic variants were not found in blood DNA. ^{Reference Nicita, Iannetti and Spalice5} This was attributed to sparing of ocular tissue by the somatic mutation.

The literature suggests that unilateral Lisch nodules without other NF1 features may represent a localized mosaic form of the disease. Negative genetic testing does not rule this out, as it may be explained by a confined somatic NF1 mutation limited to the iris. Confirmation would require an iris biopsy, but this is unwarranted considering the invasive nature of the procedure for this benign, non-vision-threatening condition. ^{Reference Adams, Stewart, Borges and Multiple4–Reference Eltantawy and Ho6,Reference Toonstra, Dandrieu, Ippel, Delleman, Rupert and Huitema8} The presence of isolated Lisch nodules does not allow prediction of NF1 transmission risk, as gonadal involvement in mosaic NF1 cannot be excluded. ^{Reference Nicita, Iannetti and Spalice5}

Unilateral Lisch nodules require vigilance from both physicians and patients, with careful attention to features that may suggest mosaic NF1. Evaluation should include dermatologic examination for café-au-lait macules, axillary or inguinal freckling, and subcutaneous neurofibromas with attention to dermatomal or segmental distribution; comprehensive ophthalmologic examination to exclude neoplastic iris lesions and assess for additional findings characteristic of NF1, including optic pathway glioma; screening for skeletal or developmental manifestations and malignancy; review of family history for NF1 features; and referral for genetic testing when appropriate. Patients need to be informed about the potential risk of transmission to offspring, the limitations of tissue sampling and the need for long-term follow-up given the poorly understood natural history of unilateral Lisch nodules. Recognition of this rare presentation is essential to ensure appropriate counseling, monitoring and surveillance.