July 15, 2024

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Who is prone to get type 1 neurofibromas?

Who is prone to get type 1 neurofibromas? What are the clinical manifestations of NF1 patients?


Who is prone to get type 1 neurofibromas?  Although NF1 patients have an increased risk of glaucoma, this is a rare finding that occurs in 1%-2% of NF1 patients.

Clinical manifestations of patients with NF1: Among children with NF1, the three most common clinical manifestations are brown spots, intertrigeminal spots, and Lisch nodules, which are found in 95%, 100%, 81%, and 50%-90% of patients, respectively. Neurofibromas (15%), bone lesions (up to 60%), optic nerve pathway gliomas (OPGs, 15%), and affected first-degree family members constitute this criterion.

About 95% of NF1 patients reached the diagnostic criteria at the age of 8 years, and all patients reached the diagnostic criteria at the age of 20. However, NF1 patients are also prone to other neurological, ophthalmological, dermatological, cardiovascular, gastrointestinal and endocrine manifestations that are not included in the diagnostic criteria.


Epidemiology and pathogenesis of NF1

Who is prone to get type 1 neurofibromas? Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by a single gene defect. The inheritance of NF1 follows the typical Mendelian pattern of autosomal dominant disease, with full penetrance and variable expression affecting 50% of the offspring of affected individuals. In fact, every person who inherits this gene will show symptoms or signs by the age of 5. The new mutation rate of type 1 neurofibroma gene (NF1) is 1:10000, the highest among all genes; therefore, about half of the type 1 neurofibroma cases are sporadic mutations.

Type 1 neurofibromatosis genes have the characteristics of large size, pseudogenes, lack of clustering of mutations in a specific region of the gene, and a wide variety of possible lesions, making mutation detection laborious and complicated; however, there is now direct genetic testing. A typical NF1 patient can have a high mutation rate (over 95%). At present, the diagnosis of type 1 neurofibromas is still a clinical diagnosis, and genetic testing is mostly used for reproductive decision-making or when abnormalities in the diagnosis are suspected, and the clinical diagnosis is not confirmed.

The NF1 gene encodes neurofibrillin, a cytoplasmic protein that is negatively regulated by the Ras proto-oncogene. The Ras proto-oncogene is a key signal molecule that controls cell growth. Most mutations in the NF1 gene produce a truncated form of neurofibrin and disrupt normal cell cycle regulation. This may explain why NF1 patients have a higher risk of benign and malignant tumors.

A single cell can function with only 1 normally replicated gene, but when a second somatic mutation occurs in the selected cell, a complete loss of gene function (loss of heterozygosity) is the clinical feature of NF1 loss of normal regulation of the cell cycle. During development, mutations in NF1 also occur, leading to somatic mosaicism. This resulted in a segmental NF1 phenotype, whose characteristics were found to be limited to one part of the body. Segmental NF1 is not as common as NF1, affecting 1 in 36,000-40,000 people. Patients with segmental NF1 usually do not pass the disease to their offspring unless the reproductive system is also affected.



What eye problems can type 1 neurofibromas cause?

Optic glioma is the most common intraorbital and intracranial manifestation of NF1, with an incidence of 5% to 25%.

The most famous and common feature of anterior segment NF1 is Lisch nodules, which is one of the typical manifestations of NF1. Lisch first described 119 cases of iris melanocyte hamartoma in 1937, which histologically contained an irregular collection of spindle cells.

Compared with sporadic cases (54%), they are more common in familial cases (93%) and more common in the lower half of the iris. The appearance of Lisch nodules is related to age, not to the severity of the disease, the number of neurofibromas or brown spots.

Lubs and colleagues reported that the prevalence of Lisch nodules in NF1 children under 3 years old was only 5%, 42% in 3e4 years old, 55% in 5-6 years old, and Lisch nodules in adults over 21 years old. 100%. Beauchamp reports that the prevalence of patients under 10 years of age is 53%, and the prevalence of patients over 29 years of age is 100%. Therefore, the absence of Lisch nodules in children does not exclude NF1.


Although NF1 patients have an increased risk of glaucoma, this is a rare finding that occurs in 1%-2% of NF1 patients. Elevated intraocular pressure may be a combination of multiple potential mechanisms, such as angle abnormalities, angular pigmentation, secondary angle closure caused by anterior adhesions, and neurofibromatous infiltration of aqueous humor outflow.

Gonioscopy in patients with NF1 may show normal angles or subtle changes, such as mild forward insertion of the iris, protrusion of the iris, or thinness of the ciliary body; however, even with these symptoms, glaucoma is still rare. Grant and Walton estimate that 1 in 300 children with glaucoma have nf1-related glaucoma.

NF1 rarely affects the retina, but it has several manifestations. Astrocytic hamartoma is a mulberry-like mass in the superficial layer of the retina or optic disc. Although it is usually seen in tuberous sclerosis, it is also described in NF1. Other pathologies include capillary hemangioma and combined hamartoma of the retina and retinal pigment epithelium. Vision-threatening complications such as retinal detachment, neovascular glaucoma, and vitreous hemorrhage are associated with these pathologies.

The prevalence of mild to moderate myopia (0.5 to 6.0 diopters) in NF1 patients is higher than that of the general population (23.8% vs 16.5% age-matched control group). The incidence of high myopia, astigmatism, and hyperopia is not high; however, except for Lisch nodules, patients with any other eye or orbital diseases are excluded from this study. Another study found that a 17-year-old Israeli with NF1 The myopia rate of recruits was 24%, compared with 19% in the control group. These refractive changes may be due to congenital glaucoma, which leads to enlargement of the eyeballs, but there is no record of NF1 glaucoma.


(source:internet, reference only)

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