Leukemia Overview: Symptoms, Signs, Treatment and Causes
Diagnosis Of Neurofibromatosis Type 1 (NF1)
Diagnostic CriteriaIt's important to know that an accurate diagnosis of NF1 can only be made by a physician with expertise in the diagnosis and treatment of neurofibromatosis. Because people with NF1 often have multiple café-au-lait spots, the disorder should be suspected in someone with six or more spots, at least five millimeters in size before puberty and 15 millimeters in size after puberty. There is no relationship between the number of café-au-lait spots and the severity or prognosis of the disorder.
While the presence of café-au-lait spots is one criterion for the diagnosis, at least two features of the disorder need to be present to confirm the condition. A diagnosis of NF1 is made through an extensive physical examination and, in some cases, biopsies, imaging studies, or additional medical tests to confirm the presence of any of the following diagnostic criteria of NF1 established by the National Institutes of Health (NIH) in 1987 based on a consensus of experts in the field.
Because many features of NF1 are age-related, they are not often present in very young children with the disorder. Many features often appear over time – frequently not until late childhood (age 7-10) or adolescence and the onset of puberty.
As a result, it is often impossible to make a definitive diagnosis of NF1 in a young child with only multiple café-au-lait spots. Also, there are other conditions, for example a rare disorder called Legius syndrome, that can be associated with multiple cafe-au-lait spots. Legius syndrome is not associated with the tumors that occur in NF1; it is often necessary to do genetic testing to distinguish Legius syndrome from NF1 in a young child who presents only with cafe-au-lait spots.
Even if the child is affected, it could take years before another feature of the disorder appears to confirm the diagnosis. For this reason, doctors often annually reexamine these children to look for the appearance of new features. If any are found, the diagnosis is clear; if not, the question remains unsettled.
In cases where a diagnosis cannot be made based on the presence of physical symptoms, genetic testing for the NF1 gene mutation is currently available and may be appropriate for some families in order to confirm a diagnosis of NF1. A genetic counselor can provide guidance and information regarding the suitability of genetic testing in these cases.
Possible Explanations For The Presence Of NF Clinical Features And A Negative Genetic Test
This month, I'd like to discuss the options that are available when an individual has clinical features of any of the three types of NF but genetic testing is negative.Genetic Testing for NF1 Next-generation sequencing (NGS), using blood or saliva samples, is the most frequently used genetic test to detect variants that cause the condition (referred to as "pathogenic variants") in the NF1 gene. NGS involves sequencing of the entire genome, or, in some cases, the entire component of the genome that is encoded for protein (referred to as the "exome"). A gene is encoded in segments, called exons, which code for the amino acids of a protein, separated by introns, which are intervening sequences. Most NGS technology is capable of detecting variants in the exons and around the borders of introns and exons. However, occasionally a variant exists deep in the intron that is more difficult to detect.RNA-Based Testing RNA-based testing might be used when a pathogenic variant cannot be identified using NGS. RNA is the molecule that copies the genetic information for a particular protein from DNA and moves it to the part of the cell where protein is made. The UAB Medical Genomics Laboratory can perform NF1 RNA testing, which can be done in cases of a negative or inconclusive NF1 result using NGS. RNA-based testing is a highly specialized, intensive process that requires well-trained technicians with distinct expertise. It detects an abnormality in the RNA copy (mRNA) of the NF1 gene and can be used to identify a genetic variant deep within the intron. Some individuals who have received an inconclusive result with NGS can receive an NF1 diagnosis with RNA-based testing.Mosaicism Mosaicism is also a possibility in individuals with clinical features of NF1 who receive a negative genetic test result. In these cases, the NF1 pathogenic variant affects some cells in the body but not all due to acquisition of a mutation during development. NGS can sometimes detect a minor cell population in the blood that can confirm mosaicism, but if cells with the variant are not present in blood in sufficient numbers, they will not be detected. The next best approach is testing of cells in neurofibromas or café-au-lait spots. The UAB Medical Genomics Laboratory is one of few labs anywhere equipped to perform testing of these tissues; this technique requires obtaining biopsies of tumors or café-au-lait spots (preferably two or more) and transporting tissue that contains Schwann cells (neurofibromas) or melanocytes (café-au-lait spots) to be grown in a cell culture system.While the UAB laboratory stopped tumor testing during the COVID-19 pandemic, they are currently performing final validation to resume tumor testing and have already resumed offering melanocyte cultures for café-au-lait spots. Because of the "two-hit" genetic mechanism that causes the development of tumors and café-au-lait spots in individuals with NF1, one would expect two NF1 pathogenic variants to be present in the tumor Schwann cells or café-au-lait spot melanocytes; one is an acquired mutation, and one is the mosaic variant. All people have two copies of the NF1 gene, one inherited from each parent. In individuals with NF1, one copy of the NF1 gene is altered (the variant) due to either inheriting the variant-containing gene from a parent, or a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the "first-hit" genetic variant. For a neurofibroma or café-au-lait spot to develop in someone with NF1, a random genetic mutation must occur to the other copy of the NF1 gene in the tissue that will become the neurofibroma or café-au-lait spot; this is referred to as the "second-hit" variant.
Genetic Testing for NF2 and Schwannomatosis Blood samples are often used to perform NGS to identify a pathogenic variant in the NF2 gene that confirms a diagnosis of NF2. However, many individuals with NF2 have mosaicism, which can only be detected by testing tumor tissue. For this testing, fixed tissue, even tissue that may have been archived for years, can be used. Mosaicism is also common in people who have schwannomatosis. Here, too, tumor testing, including testing of archived fixed tissue, can be done if blood testing is negative.When these approaches do not produce a definitive answer, it is important to note that, regarding NF2, both vestibular schwannomas and meningiomas can occur in individuals in the general population who do not have NF2. In the case of schwannomatosis, it is possible that other genes yet to be discovered may also be associated with the condition.
Individuals with Multiple Neurofibromas It is known that the gene product of NF1, neurofibromin, functions as a regulator of a protein called RAS. RAS is a key component of the RAS/MAPK cell signaling pathway that controls cell growth and development. This pathway involves multiple proteins that are involved in transmission of signals received at the cell surface to regulate genes in the cell nucleus. It has been learned that variants in genes that encode these other proteins in the pathway also can lead to medical disorders, which are collectively called "RASopathies."One of these disorders, Noonan syndrome, is a distinct disorder from NF1, but in rare instances can cause individuals to develop neurofibromas around the spine, similar to NF1. Noonan syndrome is characterized by short stature, cardiac defects, characteristic facial appearance, and learning and developmental problems. Genes associated with Noonan syndrome (there are several, all encoding proteins that act in the RAS signaling pathway) can be tested in individuals with multiple spinal neurofibromas who have negative NF1 testing. It should be noted that some people with NF1 have some features that overlap with Noonan syndrome, which is not surprising given that both conditions involve changes in genes that encode proteins acting in the RAS signaling pathway. Some of these individuals are given the label "NF-Noonan syndrome." It should be noted, though, that this is distinct from Noonan syndrome itself, due to changes in genes other than NF1; these individuals do not have two separate disorders, but rather have NF1 with some features reminiscent of Noonan syndrome.Also, some individuals who have NF-like symptoms such as café-au-lait spots and skin fold freckles may have a pathogenic variant in the SPRED1 gene that is associated with a condition called Legius syndrome, another disorder associated with disruptions in the RAS/MAPK pathway. This condition, which is also associated with learning disabilities, can be impossible to distinguish from NF1 in young children who have only café-au-lait spots and skin fold freckles and no family history of NF1. Diagnosis of Legius syndrome is confirmed by NGS of the SPRED1 gene, which is usually tested in a panel alongside the NF1 gene.
Explanations for Negative Genetic Tests If all genetic testing options are exhausted, there are additional possibilities. First, the clinical diagnosis of NF may be inaccurate and should be reevaluated. For example, the individual could have symptoms of another disorder, such as a RASopathy, that overlaps with NF features. Another explanation is that there are other genetic mechanisms yet to be identified that are associated with the clinical features. Newer genomic testing technologies may be able to identify these genes in the future. Still, patients with clinical features for whom genetic testing is negative should be followed clinically by an NF specialist.I Was Kicked Off Plane Over My Rare Condition…I Was Humiliated, Says Nurse
A NURSE claiming she was left "humiliated" after being kicked off a flight because of her skin condition is threatening to sue the airline.
Brianna Solari said she flew for a procedure to remove non-cancerous tumours on her skin before she was allegedly booted off the flight.
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Brianna Solari is the nurse claiming she got kicked off a flight because of her skin conditionCredit: KCRA3
The nurse said airline staff accused her of having chickenpox and prying into her healthCredit: KCRAThe nurse flew to LA from Sacramento on Wednesday with Southwest Airlines and was due to return a day after the surgery.
But she claims she was interrogated by a flight attendant on Thursday over the condition of her skin, which appeared inflamed as a result of her Neurofibromatosis.
She told local television station KCRA-TV that staff on Flight 3471, asked her to leave the plane after "concerns" were raised.
Brianna said they suspected she had chickenpox and were worried she'd pass the highly infectious disease onto other passengers.
They allegedly asked if she had any medical conditions or diseases and she explained she'd just had surgery.
Brianna claims airline staff said she needed her to be checked by doctors before they'd let her fly.
She then said the flight attendant called a Southwest Airlines doctor.
Brianna said she requested to speak to the doctor directly about her condition, but the employee allegedly refused to let her.
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Watch transformation of man whose 'tiny spot' grew to melon-sized tumourShe said: "This is absolutely discrimination! Violating my medical privacy.
"They don't have to know I just said I had surgery, and that should be it.
Neurofibromatosis leaves mum from Huddersfield covered in lumps"They shouldn't be prying into my private medical information.
She added: "I said [to them] 'let me speak to the doctor'. I wasn't examined by this physician."
Brianna has Neurofibromatosis, a genetic disorder that causes non-cancerous tumour growths all over the skin.
Sufferers are often left with visibly red and bumpy skin.
Brianna explained: "I lack an enzyme, which is neurofibromin, which is a tumour suppressor.
"So tumours grow along nerves and can be tiny, little pinpoint tumours, or they can be enormous. Some of them can be very disfiguring."
She said she was left "humiliated, embarrassed and ashamed" by the ordeal and had to get a letter from her surgeon clearing her to fly.
Airport staff accepted her documents and put her on the next flight to Sacramento, but she was enraged at her delay getting back home.
Brianna added: "It's already difficult enough with this condition because I did have some visible tumours on my face and my arms, and people would comment."
She said they handed her a $500 flight voucher and a $45 meal voucher as compensation but wants to pursue legal action in spite of this.
Brianna said she'll never fly with Southwest Airlines again and that the situation "could have been handled much more professionally".
The nurse told the TV network: "They should have waited until they had all of the information before making a decision that ultimately impacted my day, my flight, my travelling."
A representative from Southwest Airlines told The New York Post: "We are disheartened to learn of the Customer's experience flying flying out of Hollywood Burbank Airport with us and extend our deepest apologies for the inconvenience.
"Even though our team ultimately received clearance for the customer to travel, we weren't able to do so in time for the flight's departure.
"We rebooked her on a later flight, offered a travel voucher for a future flight along with a meal voucher, and we're following up with her directly to discuss the situation."
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Brianna claimed Southwest Airlines kicked her off a plane from Hollywood Burbank Airport (stock image)Credit: GettyWhat is Neurofibromatosis?
THE rare genetic condition has forms type 1 and type 2 but both cause tumours to grow along the sufferer's nerves, according to the NHS.
Growths are usually non-cancerous but symptoms differ across type 1 and type 2.
If you have type 1, which is much more common, you may have brown birthmarks known as café au lait spots.
Sufferers also have neurofibromas - soft, non-cancerous tumours on or under the skin and are more likely to have learning difficulties.
They may also get clusters of freckles in odd places like the underarms or groin and issues with bones, eyesight, and nervous system.
But if you have the rarer type 2, you're more likely to have hearing loss, tinnitus and balance problems.
Sufferers are also prone to getting tumours inside the brain, spinal cord or along the nerves to the arms and legs.
This can lead to weakness in the arms and legs, and persistent headaches.
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