Lisch nodule

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Synonyms and keywords: Sakurai-lisch nodule

Overview

Lisch nodules are well defined melanocytic hamartomas of the iris. Lisch nodules generally appear as dome-shaped gelatinous masses. Lisch nodules masses are more commonly develop on the surface of the iris, also known as iris hamartomas. Lisch nodules are gold-tan to brown in color, they may grow up to 2 mm in diameter and can be of different sizes on the same iris. Lisch nodules arise from mast cells, pigmented cells and fibroblast-like cells. The presence of Lisch nodules is the most common clinical sign of Neurofibromatosis 1; ninety-three percent of cases are bilaterally affected and an average of 25 nodules can be counted on each iris. Once iris hamartomas have developed, they remain stable throughout life. In 80% of eyes, Lisch nodules may be found in the inferior quadrants of the iris and this may be related to greater sun exposure, one of the postulated factors in the development of these benign tumefactions.

Historical Perspective

• 

  Multiple small, oval, yellow-brown papules (Lisch nodules) in the right iris(Red arrows). case courtesy by E. G. Adams et al.

  In 1882, Neurofibromatosis (NF), described by Friedrich Daniel Von Recklinghausen.
• NF is a neuroectodermal abnormality constituted by a set of clinical symptoms that compromise the skin, nervous system, bones, eyes and other sites.
• Lisch Nodules were named after the infamous Austrian ophthalmologist Karl Lisch(1907-1999) who was also called as "Ophthalmological Pope".
• Besides general ophthalmology, Lisch was interested in scientific research. He published more than 120 scientific papers in German science journals.
• In 1937, Karl Lisch published an article on the iris hamartomas and their association with neurofibromatosis 1, now known as "Lisch nodules", while at the University Eye Clinic in Munich.
• Lisch'a article described his observations in 3 patients with neurofibromatosis:
  • Patient 1: A 39 year old male who had been affected with several nodules and pigmented lesions on the skin, typical of neurofibromatosis, since the age of 15 years. His mother and his sisters had a similar disorder. Lisch observed several brown nodules on the surface of the iris. The nodules could be seen even without the slit lamp due to the greyish-blue color of the iris.
  • Patient 2: 27 year old patient with similar cutaneous and iris lesions could be detected along with a family history of neurofibromatosis. In comparison to the first patient the iris nodules were much more pigmented.
  • Patient 3: A 44 year old male suffered form bilateral optic nerve gliomas with chiasmal involvement. The slit lamp examination revealed tiny iris nodules in both eyes.

Classification

• There is no established system for the classification of Lisch nodules.

Pathophysiology

• A hamartoma is defined as a benign tumor or nodular growth that is composed of proliferating mature histologically normal cells that normally reside at the affected tissue.
• NF1 is due to mutations in the NF1 gene, located at chromosome 17q11.2.
• Lisch nodules are generally not present in central NF(neurofibromatosis)/NF(neurofibromatosis)-2.
• Neurofibromin, the protein product encoded by the gene, is expressed in many tissues, including brain, kidney, spleen, and thymus.
• Mutations in the NF1 gene result in loss of production or reduced function of protein; this causes a wide spectrum of clinical findings, including NF1-associated tumors.
• Histopathologically, Lisch nodules are composed of melanocytes and spindle cells, usually concentrated on the superficial layers of the iris stroma.
• The spindle cells are larger than the normal iris melanocytes.
• Immunohistochemical studies show positive reaction against the following
  • Vimentin
  • Smooth muscle actin
  • Neuron specific enolase.

Causes

• Lisch Nodules commonly associated with neurofibromatosis and is caused by genetic defects or mutations that either are passed on by a parent or occur spontaneously at conception.

Differential diagnosis

• Lisch nodules must be differentiated from Iris mammillations, Iridocorneal endothelial syndrome, Rieger's anomaly or syndrome, Iris nevi, Melanoma, Inflammatory conditions such as Sarcoidosis, Leprosy, Tuberculosis and Syphilis.

Epidemiology and Demographics

Incidence

• The incidence of Lisch nodules is approximately 1 in 2600 to 3000 individuals worldwide.
• Approximately one-half of the cases are familial (inherited).
• The remainder are the result of de novo (sporadic) mutations.

Prevalence

• The prevalence of Lisch nodules is approximately 1 in 3500 individuals worldwide.

Age

• Lisch nodules are predominantly visible in children usually after the age of six years.

• Lisch Nodule incidence in NF1 increases with age and their prevalence raises by about 10% per year of life, up to age 9.
• Lisch nodules are found in 93% of adults with NF-1 but have not been described in NF-2.
• Lisch Nodules may be found in a very limited number of individuals without NF.
• The de novo mutations occur primarily in paternally derived chromosomes, and the likelihood of de novo NF1 increases with advanced paternal age.

Risk Factors

• The biggest risk factor for Lisch nodules associated with neurofibromatosis is a family history of the disorder.

Screening

• Lisch Nodules are not regularly screened, they’re usually detected when other signs and symptoms of neurofibromatosis appear.

• However, Lisch nodules are seen in 95% of children with NF1 by age 20.

Natural History, Complications and Prognosis

Natural History

• The symptoms of Lisch Nodules usually develop in the first decade of life, and mostly asymptomatic.

Complications

• Common complications of Lisch Nodules include:
  • Optic gliomas
  • Pseudarthrosis
  • Progressive vision loss
  • Choroid hamartomas
  • Retinal tumors
  • Prominent corneal nerves

Prognosis

• Prognosis is generally good of patients with Lisch Nodules.

Diagnosis

Diagnostic Criteria for neurofibromatosis 1

• (National Institute of Health Consensus Development Conference 1988)
  • 6 or more café au lait macules
    • Cafe au lait macules should be >0.5 cm in length in children
    • Cafe au lait macules should be >1.5 cm in length in adults
  • 2 or more cutaneous neurofibromas or one plexiform neurofibroma
  • Axillary or groin freckling
  • Optic gliomas
  • 2 or more Lisch nodules especially iris hamartomas which can be seen on slit lamp examination
  • Bony dysplasia with or without pseudarthrosis
  • First degree relative with NF1

• The diagnosis is primarily based on clinical assessment and two or more of the features are required to confirm the diagnosis.

Physical Examination

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  Lisch nodules and near-infrared reflectance image (case 4). At least five Lisch nodules were detected and were classified as scale III (A). Note that 14 bright, patchy lesions were detected by near-infrared reflectance (B). The hyper-reflective point at the center of the image is an optical artifact. Case courtesy by Shinji Makino et al

  Lisch nodules occur in 90% of adults with neurofibromatosis 1.
• Eye-findings include orange-brown colored specks.
• Lisch nodules are usually elevated and tan in appearance.
• Lisch nodules are benign hamartomas that can be seen without magnification.
• Also known as melanocytic hamartomas of the iris, often associated with neurofibromatosis (NF) I.
• Other associated ophthalmologic findings are optic gliomas.
• Optic gliomas can alter color vision and can produce progressive vision loss.

Diagnostic Studies

• On slit-lamp examination, they have a smooth, dome-shaped appearance and are usually light brown, although some can be very pale.
• Slit lamp examination can differentiate them from nevi on the iris by demonstrating elevated lesion instead of flat ones.
• Lisch nodules develop during childhood, after the appearance of café-au-lait spots but before peripheral neurofibromas.

• 

  (a) Microsection showing bundles of wavy spindle cells with serpentine nuclei in fascicles (H&E, ×10x), (b) Strong S-100 positivity of tumor cells (×40x), (c) café au lait macule (arrow) in the back, (d) axillary freckle, (e) Lisch nodule (arrow) in slit-lamp examination, and (f) father of patient with multiple cutaneous neurofibromas. Case courtesy by Rachna Rath et al.

  This is useful in confirming the diagnosis of NF1 in children with no family history and only multiple café-au-lait spots.

Treatment

Medical Therapy

• There is no treatment for the underlying disease nor any necessity to treat these small benign lesions which do not interfere with visual function.
• Lifelong monitoring is necessary because of the widespread manifestations and serious threat of complications such as:
  • Visual impairment
  • Renal hypertension
  • Ischemia of major organs.

Primary Prevention

• There are no established measures for the primary prevention of Lisch nodules.

Secondary Prevention

• There are no established measures for the secondary prevention of Lisch nodules.