What is Lisch Nodules?
In 1918, Waardenburg first discovered pigmented spots in the colored part of the eye, also known as the iris. Later, in 1937, an Austrian eye doctor named Karl Lisch found out these spots were connected to a condition named neurofibromatosis type 1 (NF1). These spots, known as Lisch nodules, are harmless growths that are colored and can be found in almost all adults with NF1, making it the most common sign of NF1.
In 1981, a researcher named Riccardi was the first to use the term ‘Lisch nodule’ in a scientific document. Friedrich Daniel Von Recklinghausen, a German disease researcher, recognized NF1 as a disease that can be inherited from your parents.
NF1 is known as a neurocristopathy, which means it’s a disease affecting nerves that come from specific cells called neural crest cells. It’s an inherited condition that can change from parent to child, and it has a high chance of having new mutations or changes in genetic material. It’s characterized by unusual growth of tissues that come from the neural crest cells.
Lisch nodules themselves don’t cause any problems with vision. However, the conditions related to NF1, some of which can be severe or life-threatening, and can affect vision, are important to discuss.
What Causes Lisch Nodules?
Lisch nodules are a typical sign of a condition known as NF1, or Neurofibromatosis type 1. They’re abnormal growths, often seen on the iris, the colored part of the eye. Usually, they are mainly found in people with NF1, though very rarely they can be seen in other conditions like segmental neurofibromatosis and Watson syndrome. Lisch nodules can also occasionally occur in Neurofibromatosis type 2.
The exact cause of Lisch nodules is not well understood. Some studies suggest they originate from melanocytes, which are cells that produce pigment in the body, and that they could be similar to a benign (non-harmful) tumor called a neurofibroma, which might contain pigmented cells, cells similar to fibroblasts (cells that make up connective tissue), and mast cells (a type of immune cell).
NF1 is a common disorder caused by a mutation or change in a gene that suppresses tumors, specifically the neurofibromin gene. This disorder primarily affects the nervous system and skin. People with NF1 have a higher chance of developing both benign (non-cancerous) and malignant (cancerous) tumors. It is important to note that the severity of NF1 can vary greatly, even within the same family, and these variations are thought to be due to genetic modifiers or variations in other genes.
Risk Factors and Frequency for Lisch Nodules
Neurofibromatosis Type 1 (NF1) is a condition that occurs in about one in every 2500 to 3500 newborns around the world. Lisch nodules (LNs), a feature of this condition, are found in roughly 78% of NF1 patients based on a 2005 study with 132 participants. Although these nodules are not visible when a child is born, they tend to appear as the person ages. For example:
- At 5 years old, about 50% of NF1 patients have LNs.
- By 15 years old, this increases to 75%.
- When these patients reach 30, 90% to 95% of them will have LNs.
Signs and Symptoms of Lisch Nodules
Lisch nodules are small, yellowish-brown bumps found all over the iris, the colored part of your eye. They’re usually found in pairs and can be seen on all areas of the iris. Their color can vary, appearing darker in blue eyes and lighter in brown eyes. As you age, you might have more of them, and they might get bigger. But generally, they don’t cause any symptoms or vision problems and don’t need to be treated.
Neurofibromatosis type 1 (NF1) is a condition that affects both the nervous system and the skin. To diagnose NF1, doctors use criteria from the National Institutes of Health. If a patient has two or more of the following features, they might have NF1:
- More than 6 café-au-lait macules (light brown skin spots) larger than 0.5 cm in prepubertal individuals and over 1.5 cm in postpubertal individuals
- Two or more neurofibromas (tumors on nerve tissue) or one large neurofibroma
- Freckles in the underarm or groin area
- A type of brain tumor called an optic glioma
- Two or more Lisch nodules
- A bone lesion, such as sphenoid dysplasia or tibial pseudoarthrosis
- A first-degree relative with NF1
Not everyone with NF1 has the same symptoms. Café-au-lait spots are common and appear due to pathogenic melanocytes. These skin cells carry a specific mutation that leads to the light brown spots. Freckling in certain areas like the underarm or groin is seen in 90% of people, and neurofibromas can affect any organ and vary in number. It’s also possible to experience several eye symptoms related to NF1, and the number of Lisch nodules and neurofibromas usually increase as the person ages.
Optic nerve gliomas occur in 15% of people with NF1 and are found along the optic nerve. ‘Sphenoid wing dysplasia’ is a slow, progressive thinning of the bone at the base of the skull and affects the eye socket. This can result in the brain’s temporal lobe pushing into the eye socket, causing a visible pulsation and facial deformity. If this happens, surgery might be necessary. Other rare eye symptoms include abnormalities in the eyelid, cornea, and iris, glaucoma, and tumors that affect the nerve fibers, among other things.
Testing for Lisch Nodules
If a doctor suspects that a patient might have Neurofibromatosis Type 1 (NF1), a condition characterized by changes in skin coloring (café-au-lait spots) and benign (noncancerous) tumors of nerves (neurofibromas), they will mainly look for certain physical signs. They typically don’t order genetic tests for NF1. This is because it’s difficult to draw a clear connection between specific gene changes (mutations) found in a person with NF1, and the exact symptoms they will have (this is called the genotype-phenotype correlation).
The NF1 gene is quite large and complex, and scientists have found more than a thousand different mutations in it. But fewer than 20% of these mutations occur repeatedly. Therefore, careful physical examination of the patient is very important. This is because people with NF1 can develop complications that affect the nervous system, heart, digestive system, hormonal glands, eyes, and bones.
There have been reports of patients with segmental neurofibromatosis, a form of NF1 that only affects one part of the body, who have developed certain eye changes called Lisch nodules (LNs). An example is a 47-year-old man who had NF2, a different type of neurofibromatosis, with symptoms like hearing loss and unsteady gait. An MRI scan showed he had benign tumors called acoustic neuromas, and he had multiple Lisch nodules in his right eye.
There are also two examples of people with these eye changes who didn’t show any other signs of NF1. One was a 43-year-old man whose sister and niece both had Lisch nodules but no other signs of NF1. Another example was a 21-year-old woman with many Lisch nodules in one eye, but otherwise healthy. However, when her skin was examined under special light (Wood’s light), she was found to have a faintly colored spot (a ‘hypopigmented macule’) on her back.
Hence, physical examination and accurate diagnosis is vital to identify any potential complications in NF1 patients.
Treatment Options for Lisch Nodules
If you experience complications with your eyes, heart, brain, nervous system, hormones, spine, or long bones due to a condition called neurofibromatosis, it is critical that you are referred to specialists for proper treatment. Sometimes, you might have growths called neurofibromas, which can be uncomfortable or cause changes to your appearance. Surgery to remove these growths is rarely necessary.
However, if you develop a type of cancer called a malignant peripheral nerve sheath tumor because of neurofibromatosis, surgery to remove the tumor is usually needed. If you develop a type of spine curvature, known as nondystrophic scoliosis, you can be treated without surgery. But if you develop another type of spine curvature, known as dystrophic scoliosis, you might need surgery.
Guidelines for treating another complication of neurofibromatosis, a type of brain tumor called an optic nerve glioma, are not clear. Sometimes, surgery can even lead to complications that can threaten your vision. Therefore, it’s important that a team of different healthcare professionals work together to decide the best treatment for you. If a child with neurofibromatosis develops attention-deficit hyperactivity disorder (ADHD), a common treatment option is a medication called methylphenidate.
What else can Lisch Nodules be?
When trying to diagnose a condition known as Lisch nodules (LN), doctors look at differentiating it from several other eye conditions. These conditions can show similar symptoms but are fundamentally different diseases. So, the conditions to be ruled out include:
- Iris mammillations, which show up as regularly spaced brown hill-shaped bumps in the eye
- Multiple iris nevi, that appear as black flat or slightly raised spots often with blurry edges
- Cogan-Reese syndrome, a type of disease that creates irregularly shaped growths on the iris
- Specific changes in the eye associated with inflammation called granulomatous iritis (Busacca, Koeppe, and Berlin nodules)
- Iris cysts, wherein brownish bags filled with fluid form either on the front or back of the eye’s iris
- Brushfield spots, small grey-white spots generally visible on the outskirts of the iris- commonly associated with Down Syndrome
- Iris melanoma, a type of eye cancer that is seen as black spots on the iris and may cause other eye complications
- Leiomyoma, a type of non-cancerous tumor
- Xanthogranuloma, a condition that creates yellowish vascular masses on the iris and can lead to complications such as internal eye bleeding and glaucoma
- Secondary metastatic nodules which are unusual tumors from other parts of body like lungs, breasts, etc landing up in the iris, seen often as lumpy growth or thickness in the iris
Each of these conditions have specific characteristics, which doctors identify and distinguish to make an accurate diagnosis.
What to expect with Lisch Nodules
People with a condition called NF1 have a high chance of developing both harmless (benign) and dangerous (malignant) tumors. A specific type of dangerous tumor, known as Malignant peripheral nerve sheath tumors (MPNSTs) can occur in about 2% to 5% of people with NF1. MPNSTs are a severe type of tumor that originates from certain body tissues.
If a person with NF1 notices a quick change in the size of a preexisting tumor known as a neurofibroma, constant pain, internal bleeding in the tumor, or the tumor spreading to nearby parts of the body, this may indicate that the neurofibroma is becoming malignant and turning into an MPNST. This transition from a neurofibroma to a malignant condition is very serious and often leads to relapses and the tumor spreading to distant parts of the body. Studies show that the average survival rate 5 years after diagnosis ranges from 16% to 52% for these patients.
Therefore, people with NF1 should be regularly checked by their doctor for signs of malignancy, as this change in a neurofibroma is very serious and can have severe consequences.
Possible Complications When Diagnosed with Lisch Nodules
About a quarter of people with a condition called Neurofibromatosis (NF) might experience problems like certain types of skin and spinal tumors, cancers like neurofibrosarcoma, scoliosis or curvature of the spine, blockage in the channel that allows fluid to move within the brain, pheochromocytoma or tumors in the adrenal gland, unusual development of the blood vessels, bone issues present at birth, brain tumors, learning disabilities, attention problems, and behavioral issues.
High blood pressure is noticed in 16% of people with this Neurofibromatosis Type 1, either due to primary hypertension or secondary hypertension caused by other conditions. The main causes of this secondary hypertension in people with NF-1 are generally due to narrowed renal arteries, then narrowing of the aorta and pheochromocytoma. Narrowing of one or both renal arteries is reported to occur 7 times more often than pheochromocytoma. Therefore, it’s important that these patients monitor their blood pressure and check their heart health every year.
Additionally, issues with the eye can occur in these patients, including optic tumors, specific types of skin tumors, and congenital glaucoma. Patients with NF1 have a 5% to 15% higher risk of developing cancer compared to the general population. A frequent complication of NF1 called Plexiform neurofibromas can lead to the development of malignant nerve sheath tumors, mostly located near the spine, the sacral plexus, around the hip region, and near the rectum. Tumors of the optic nerve may result in vision problems and can even be life-threatening, especially in young children. Symptoms of these tumors sometimes appear before the age of 6 with loss of visual acuity or bulging eyes. As it can be challenging to diagnose this in children who cannot yet express themselves verbally, screening during early childhood is critical to detect it early and to start treatments as soon as possible.
Common Issues:
- Certain types of skin and spinal tumors
- Cancers like neurofibrosarcoma
- Scoliosis or curvature of the spine
- Blockage in the channel that allows fluid to move within the brain
- Pheochromocytoma or tumors in the adrenal gland
- Unusual development of the blood vessels
- Bone issues present at birth
- Brain tumors
- Learning disabilities
- Attention problems
- Behavioral issues
- Primary or secondary hypertension
- Eye problems including optic tumors, specific types of skin tumors, and congenital glaucoma
- Risk of developing cancer
- Malignant nerve sheath tumors
- Vision problems due to optic nerve tumors
Preventing Lisch Nodules
Discussing genetics can get very complex with NF1 — a genetic disorder — because of considerable differences in how it shows up within and between families. Children of a parent having NF1 have a 50% chance of receiving the NF1 gene, however, the way it appears might be very diverse. It’s important to have in-depth eye and full-body check-ups, along with an analysis of family health history, for patients and their close family members.