Interpretation of the national guidelines for neurofibromatosis type I in France in 2020

Interpretation of the national guidelines for neurofibromatosis type I in France in 2020

Interpretation of Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966

【Abstract】Neurofibromatosis type I (NF1) is a common autosomal dominant genetic disease, with a global incidence of 1/3000-1/6000, which seriously endangers the physical and mental health
of patients.
In order to improve the early recognition of NF1 for better early monitoring and follow-up and symptomatic treatment, the French NF-France Network developed the French National Guidelines for Neurofibromatosis Type I on the basis of a large literature review and multidisciplinary expert consensus, which in addition to the 1988 National Institutes of Health (NIH).
In addition to the NF1 standard of care, new evidence is included that may have the potential to diagnose and treat or have a significant impact
on the future management of NFI disease.

【Keywords】type I neurofibromatosis; Milk coffee stains; Guide interpretation

Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases, with a prevalence of 1 in 3000 to 1 in 6000, NF1 is a multisystem genetic disease
involving the skin, nerves and bone systems.
Patients with NF1 have a high incidence of malignancy and a life expectancy 10-15 years
shorter than the general population.
In February 2020, a total of 70 expert members including the French Neurofibromatology Network (NF-France Network) formulated the French National Guidelines for Neurofibromatosis Type I (1) (hereinafter referred to as the Guidelines) on the basis of a large number of literature and multidisciplinary expert consensus Published in the Orphanet Journal of Rare Diseases in February 2020, the latest highlight of the guidelines is the inclusion of a new diagnostic reference protocol in addition to the traditional NF1 standard of care to allow early intervention in the diagnosis of NF1
。 In addition, the "Expert Consensus on Clinical Diagnosis and Treatment of Type I Neurofibromatosis (2021 Edition)" formulated by the China Multicenter Neurofibromatosis Multicenter Treatment Collaborative Group in November 2021 has been published online in the Chinese Journal of Reparative and Reconstructive Surgery (illustrated with the consensus part at the end of the article) (2).

The formulation of these guidelines and consensus provides a theoretical basis
for the diagnosis and treatment of type I neurofibromatosis.
In this regard, the author will briefly introduce and interpret
the important parts of the relatively unfamiliar French neurofibromatosis type I guidelines.

1.
Diagnosis

1.
1 NF1 clinical diagnosis

NF-1 diagnosis is mainly based on the diagnostic criteria of the National Institute of Health Consensus Development Conference (NIH), and NF1 :(1) and 6 can be diagnosed if the following two or more of the following are met One or more milk coffee spots, with a maximum diameter of 5 mm or more before puberty and more than 15 mm after puberty; (2), 2 or more neurofibromas of any type or 1 plexiform fibroma; (3) freckles in the armpit or inguinal area; (4) optic pathway glioma; (5), 2 or 2 Lisch nodules-iris hamartomas; (6) Characteristic bony changes, such as sphenoid dysplasia, thinning of pseudoarticular or long bone cortex; (7) First-degree immediate family members have a history of
NF-1.
97% of NF-1 patients meet NIH criteria by age 8 years and all meet NIH criteria by age 20 (3).

NF-1 signs generally appear in a certain order, with coffee-stained spots in milk, axillary freckles, Lisch nodules, and neurofibromas
.
Typical bone lesions usually appear within the first year of life, and the average age of onset of optic glioma is 3 to 6 years
.

New evidence

Only 50% of children under 2 years of age with sporadic NF1 are diagnosed according to NIH diagnostic criteria, which often leads to a delay in diagnosis (3, 4).

Some scholars suggest that in addition to the NIH diagnostic criteria for NF1, the diagnosis of NF1 should include other clinical signs and symptoms such as juvenile yellow granulomas of the skin (Juvenile xanthogranulomas, JXG) in addition to the NIH criteria for skin diagnosis and anemia nevus can also help diagnose NF1, and extracutaneous symptoms such as macrocephaly and unidentified bright objects also play an important role
in diagnosing NF1.
JXG and anemia nevi are seen in most children with NF1 under 2 years of age and are found
in 80% of NF1patients with an underdiagnosis of NIH.
Therefore, JXG and anemia nevus can be used as a reference
for early diagnosis of NF1.
In addition, multiple café au lae spots may also be seen in other syndromes and should be identified, such as Legius syndrome, an autosomal dominant disorder
caused by SPRED1 mutations.
It is characterized by multiple coffee spots, which may be accompanied by freckles, and there are no NF 1 typicalsymptoms such as neurofibromas, Lisch nodules, optic pathway gliomas, and bone abnormalities (5, 6).

In a study of 71 patients younger than 20 years with 6 or more café milk spots, only 66.
2 percent were diagnosed with NF1 and 8.
5 percent were diagnosed with Legius syndrome, 25.
3% without causative variants (7).

Therefore, genetic testing can help confirm the diagnosis
of NF1 in children with multiple café freckles and/or axillary freckles but do not meet other diagnostic criteria.

1.
2 Genetic diagnosis

The diagnosis of NF1 disease is clinically dependent, and genetic testing
is not required when the diagnosis is established.
Genetic testing is particularly helpful in patients with atypical clinical presentation or inadequate NIH diagnosis (8).

For children with multiple café au laconia as the only clinical feature and no family history of NF1, genetic testing can differentiate NF1 disease from other syndromes, such as Legius syndrome and Noonan syndrome (7), Genetic testing can also help inform parents about getting pregnant again
.
Although NF1 can be definitively diagnosed by genetic testing, specific NF1 mutations do not predict disease severity or complications, and no direct gene-phenotype correlation
has been found in patients with NF1 mutations, except for a few case reports.

New evidence

Many experts believe that the diagnosis of NF1 should include molecular testing, which can identify and diagnose NF1
in childhood early.
Traditional analytical methods (cDNA and/or DNA-Sanger sequencing and copy number alterations) have been able to identify approximately 95% of NF1 gene mutations, and more recently multiplex PCR has been used for NF1 and SPRED1 Next-generation targeted sequencing is carried out, and the sensitivity can be as high as 98.
5%.

1.
3 Genetic counseling

NF1 is a completely autosomal dominant disorder in which 50% of children born to parents with this disorder have NF1
.
Therefore, once a child is diagnosed with NF1, the family history
should be asked in detail.
Genetic counseling should be provided to NF1 patients and all of their first-degree relatives
.
Once the disease-causing NF1 mutation is found in a parent, prenatal and preimplantation genetic testing
can be performed.
In addition, because NF1 has different clinical manifestations, it is not yet possible to predict the severity of
the disease.

2.
The main manifestations of NF1 and its management

2.
1 Skin manifestations

2.
1.
1 Benign manifestations

2.
1.
1.
1 Coffee stains and freckles on milk

Café au lax stains usually appear at birth and are visible in more than 90% of patients (7).

More than 80% of NF1 patients have freckles in the skinfolds (9).

They can occur in any area of the skin folds, including the women's armpits, inguinal area, interchondral area, neck, upper eyelids, and under the breasts, among others (10).

Coffee stains and freckles in milk have no malignant potential and do not require special treatment
.

2.
1.
1.
2 Neurofibromas

Neurofibromas are benign peripheral schwannomas and are the main characteristic manifestation
of NF1.

There are four main types of neurofibromas:

(1) Cutaneous fibromas: usually occur in late puberty, in the form of soft flesh-colored or purple nodules, as fibroids grow, there may be peduncles
.
This type of fibroma occurs in the vast majority (>95%) of patients with NF1 (11), ranging in numbers from a few to several thousand, and although there is no risk of malignant transformation, it can cause significant discomfort and cosmetic defects
.
Treatment
is recommended only for patients with severe clinical manifestations and/or aesthetic discomfort with secondary psychological reactions.
Treatment depends on the number and location
of lesions.
First-line treatments include surgical excision and/or CO2 laser ablation
.
The latter is especially helpful
for small lesions on the face and neck.
Second-line treatments include radiofrequency ablation and electrocautery
.
Electrocautery is a useful tool because it is able to treat hundreds of neurofibromas at once under general anesthesia, with high clinical efficacy and low morbidity rates
.

(2) Subcutaneous neurofibroma: often develops in adolescence, occurring in at least 20% of NF1 patients (11).

A soft, subcutaneous mass that can be soft to the touch and may cause tingling or even nerve dysfunction in the affected nerve
.

(3) Internal (nodular) neurofibroma: this type of fibroma cannot be detected by physical examination, which is associated with a "high-risk phenotype" because malignant schwannomas can develop from internal neurofibromas, so closer clinical monitoring and MRI examination of the appearance or growth changes of internal tumors are required, This allows for earlier diagnosis and more effective treatment
of malignant schwannomas in these high-risk patients.

(4) Plexiform neurofibromas: plexiform neurofibromas are congenital, present in 20%-26% of NF1 patients, when using whole-body imaging, up to 50% of NF1 patients can find internal plexiform neurofibromas (12, 13).

These lesions present as subtle enlargements of soft tissues with "folded" textures or pigmented plaques, with or without hirsutism
.
These tumors can invade surrounding structures, including muscles and bones, and can cause severe pain and bone destruction (14).

Facial plexiform neurofibromas can be potentially devastating and are associated with underlying hemidystrophy and sphenoid dysplasia (15).

plexiform neurofibromas may remain asymptomatic; It can also cause serious complications such as neurological deficits, disfigurement, and pain
.
These tumors carry a lifelong risk of
transformation into malignant schwannomas.
The management of these injuries is complex and is particularly recommended in cases of onset and/or aesthetic discomfort with psychological effects
.
Radiation therapy is contraindicated for benign tumors because of the risk of
secondary malignant degeneration.
Surgical resection is the first-line treatment
.

New evidence

Over the past few years, advances have been made
in the medical treatment of plexiform neurofibromas.
Thanks to advances in volumetric magnetic resonance imaging and whole-body magnetic resonance imaging, several treatments have been studied in clinical trials, which has made it possible to accurately assess how tumors respond
to new treatments.

Drugs such as the farnesyltransferase inhibitor tipifarnib, the rapamycin inhibitor sirolimus, and the fibroblast inhibitor pirfenidone had no significant effectiveness
.
Imatinib (Imatinib) and pegylated interferon have been shown to reduce the size of plexiform neurofibromas in a limited number of patients (16).

Oral selective mitogen-activating protein kinase inhibitor semetinib may be effective
in children with NF1 in inoperable plexiform neurofibromas.

2.
1.
1.
3 JXG

JXG is benign yellow to brown papules
.
They usually appear in children under 2 years of age with NF1 disease and usually disappear automatically before the age of 5 years (17).

2.
1.
1.
4 Anemia nevus

Anemia nevi are congenital hypopigmentation, fusion, and variegated macules that occur more commonly on the anterior chest wall and occur in up to 50% of patients with
NF1.

2.
1.
1.
5 Hemangioma

Hemangiomas are also associated with NF1, and they are usually multiple and recurrent and can be distinguished from symptomatic subcutaneous neurofibromas
.
They cause local tenderness, severe paroxysmal pain, and sensitivity
to cold.
If the lesion is painful, surgical removal
should be considered.

2.
1.
2 Malignant manifestations

Malignant peripheral nerve sheath tumors (MPNSTs)

MPNSTs are a rare and aggressive neurogenic soft tissue sarcoma, accounting for about 5%~10% of all soft tissue sarcomas, of which about 50% occur in NF1 (18).

Patients with NF1 have a lifetime risk of developing MPNST in 8-16% and are likely to occur at age 20-35 years
.
Most MPNST develop from plexiform neurofibromas or nondermal neurofibromas
.
MPNST may be highly vigilant when neurofibromas present with persistent, substantial, or difficult-to-control pain, new-onset neurologic deficits, rapidly enlarged plexiform neurofibromas, or their hardness changes from soft to hard (19).

Risk factors for MPNST include giant internal neurofibromas, massive subcutaneous neurofibromas, atypical neurofibromas, and neurofibromatous neuropathy
.
MPNSTs have a high degree of malignancy, about 70% are high-grade, can metastasize extensively, have a poor prognosis, have a median survival of 18 months, and a 5-year survival rate of 21% (19, 20).

Persistent, substantial, or difficult-to-control pain, new neurologic deficits, rapid enlargement of existing plexiform neurofibromas, or their hardening from soft to hard
.
MRI helps determine the size and location of lesions, but it is not easy to distinguish between benign and malignant
.
18F-Deoxyglucose-positron emission tomography/electron computed tomography (18F-FDG PET/CT) is the most sensitive and specific indicator for differentiating benign from malignant (21).

The biopsy should be performed
under the guidance of MRI or FDG18F-FDG PET/CT.

Once the diagnosis of MPNST is suspected, a multidisciplinary approach involving surgeons, radiologists, pathologists, oncologists, neurologists, and radiation oncologists should be adopted to develop the best strategy for diagnosis and treatment
.
Complete surgical resection of MPNST is the best treatment option and should be tumor-free and spared margins (up to 3 cm if possible) (22).

Palliative radiation therapy can be used for patients with incomplete or unresectable tumors, which can delay tumor recurrence with local control, but has no significant effect
on prolonging survival.
Chemotherapy is an important treatment for MPNST, including drugs commonly used to treat sarcoma can also be used in MPNST, such as doxorubicin, trebectidine, ifosfamide, dacarbazine, and pazopanib.

Follow-up is generally recommended every 3 months for 3 years, then every 6 months for 2 years, and then annually
.

2.
2 Ophthalmic manifestations

Lisch nodule is an asymptomatic 1-2 mm yellow-brown dome-shaped iris papule, the parenchyma of which is essentially iris melanin hamartoma, which begins to develop around the age of 3 years and is found
in all patients at the age of 30 years.
Lisch nodules
can be best observed by examining the undilated iris with a slit lamp.
The choroid, another of the most commonly affected structures of NF1, is considered a distinct sign of NF1, appearing as bright patchy nodules
in near-infrared reflections.
In addition, spiral retinal vessels can be found in about one third of patients with NF1, and spiral retinal vessels are generally single isolated with unilateral secondary or tertiary retinal venulous abnormalities and spiral curvature (23).

Others such as congenital and acquired glaucoma, idiopathic congenital ptosis, and neurofibromas that invade the eyelids are other recognized ocular-related complications
of NF1.

2.
3 Optic pathway glioma

Optic pathway gliomas (OPGs) are low-grade gliomas
that originate in the visual pathway or hypothalamus.
Patients have a young age of onset (more common <in children aged <b13>6 years, mean age 4.
2 years), and most have visual impairment and endocrine dysfunction
.
Among them, 15-20% of children with NF1 can be accompanied by optic OPG, which is generally inert in biological behavior and is more common
in low-grade hair cell astrocytoma.

Treatment of gliomas of optic nerve pathways

The natural history of OPG in children with NF1 is variable and unpredictable, and most patients do not have tumor progression
.
If a child with NF1 is found to have visual symptoms or signs (proptosis, decreased vision, or precocious puberty) or ophthalmic abnormalities, brain and orbital MRI should be performed to determine whether OPGs are present, and OPGs should be followed
up for a long time, even if there is little progression after puberty.
Treatment
is necessary only in a very small number of patients with symptomatic neoplasms accompanied by clinically significant growth and progressive vision loss.
For most symptomatic patients with OPG, chemotherapy is OPG first, and chemotherapy drugs including carboplatin+/vincristine, vinblastine, irinotecan, and avastin can degenerate tumors, but very few children can restore normal vision
after treatment.
Surgery is of very limited use in OPG because it causes permanent nerve damage, but surgical procedures for orbital tumors with large vision loss are desirable
.
Tumor decompression is also feasible if necessary, particularly if
the third ventricle is compressed with secondary hydrocephalus.
Radiation therapy with OPG is not recommended for children with NF1 because radiation increases the likelihood of OPG transitioning to malignancy, whether glioma or MPNST.

Because infantile complaints are rarely subjectively informed, all children diagnosed with NF1 should be followed up annually, generally until at least 13 years of age
.
Examination should include visual acuity, visual field, color vision, and assessment
of the pupil, eyelids, eye movements, iris, and fundus.
In addition to routine eye care, adult patients with NF1 do not need to see a specialist ophthalmologist
.
Routine detection of OPG by MRI in asymptomatic children with NF1 is currently controversial and should only be requested
if OPG disease is suspected.
In children under 6 years of age with NF1, systematic MRI screening did not have a clear convincing benefit as it had no effect
on the therapeutic management of OPGs.
Treatment of OPGs begins only when visual acuity decreases (clinically detectable); Although MRI screening helps with early OPGs, chemotherapy does not improve the final visual outcome
.
The primary indications for neuroimaging should be determined
by annual clinical and ophthalmologic evaluation.

New evidence

Clinical trials evaluating mTOR and MEK inhibitors for the treatment of optic nerve pathway gliomas are currently underway (NCT01158651 and NCT02285439).

Preliminary results from the NCT01089101 trial showed that 10 (40%) of 25 (40%) patients with NF-associated OPG disease were receiving sermetinib (Selumetinib Partial response was achieved after treatment (MEK1/2 inhibitor) with a progression-free survival rate of 96+/4%.

Only one patient progressed
during treatment.
Bevacizumab (anti-vascular endothelial growth factor antibody) alone or in combination with chemotherapy drugs has been shown to be a well-tolerated and effective treatment that rapidly controls tumors to protect vision and increase morbidity
.

2.
4 Orthopedic manifestations

2.
4.
1 Congenital dysplasia of long bones

Congenital dysplasia of long bones (mainly tibia, but also fibula, radius, and ulna) is typical of NF1 disease (7.
2%)
.
Long bone curvature can lead to obvious deformities and fragile bones
that are prone to fracture.
Recurrent fractures that fail to heal can lead to pseudoarticular formation (2–3.
6%)
.
Infants with arching require prompt imaging evaluation and referral to an orthopedic surgeon
familiar with the management of NFl-related orthopedic problems in children.

2.
4.
2 Dysplasia of the butterfly wings

The sphenoid bone includes multiple ossifying centers that fuse to form an important part of
the orbit.
Sphenoid wing dysplasia is a prominent feature of NF1 and occurs in a small number of patients (1 to 7%)
.
And often unilateral
.
Sometimes the absence or thinning of the sphenoid wing is secondary to the presence of
a chorusoid neurofibroma.
In most cases, it is found early in life and may develop
over time.
Patients with pterodysplasia may also have pulsatile exophthalmos without vision loss; The absence of butterfly wings can cause the temporal lobe to protrude into the orbit.

2.
4.
3 Scoliosis

Scoliosis is a common orthopedic manifestation in patients with NF1 disease (10-28%) and is often associated with spinal dysplasia, which is found in more than 70% of NF1 patients
.
Therefore, patients with NF1 require an annual evaluation
of the spine in childhood and early adolescence.

2.
4.
4 Congenital chest deformities, such as pectus excavatum or carina

Patients with NF1 have been reported to have congenital chest deformities such as pectus excavatum or carina.

Patients with NF1 are at higher risk of bone mineralization disorders (48% of NF1 patients have osteopenia and 25% osteoporosis).

This is secondary to disorders of phosphorus and calcium metabolism, including vitamin D deficiency
in children and adults.
Patients are at high
risk of fracture due to congenital dysplasia and bone mineralization disorders.

2.
5 Endocrine manifestations

2.
5.
1 Disorders of puberty and developmental delay

One third of NF1 patients are short in stature and are not related
to disease severity.
20-30% of NF1 adolescents experience delayed
puberty.
On the other hand, precocious puberty
occurs in 3% of patients.
Older children should be evaluated for early development of secondary sex characteristics or abnormal growth acceleration, as they may be associated with
optic gliomas involving the optic chiasm.

Effects of hormones on neurofibromas

Various steroid hormone receptors (receptors for estrogen, progesterone, growth hormone, and androgens) are found in neurofibroma tumor cells, possibly explaining their growth and development
during puberty or pregnancy.
Steroid hormones have been shown to trigger the growth
of neurofibromas and multiple sclerosis in vitro.
However, to date, there are insufficient clinical or epidemiological data to prohibit the use of these hormones, including hormonal contraception
, in patients with NF1.

2.
6 Cardiovascular manifestations

High blood pressure is common in children with NF1 (16-19%) and increases
with age.
Essential hypertension is the most common form of NF1 in adults; However, due to the lack of large-scale studies, it is uncertain whether essential hypertension is a feature associated with NF1 or a mere coincidental condition
.

Although essential hypertension is the most common cause of hypertension for NF1, it can also be caused
by renal vascular disease (such as renal artery stenosis), paraganglioma, pheochromocytoma, and coarctation of the aorta.
Therefore, blood pressure in patients with NF1 disease should be assessed at least annually
.
Physicians should investigate all NF1 patients for paraganglioma and pheochromocytoma with symptoms of catecholamine overdose (sweating, palpitations, headache) and typical unstable and/or unstable hypertension that does not respond to standard therapy, which typically presents in adults with an average age of 40 years with NF1 patients
.

New evidence

A recent prospective study of 234 NF1 patients found a pheochromocytoma prevalence of 7.
7%, well above the prevalence reported in previous studies
.
Vascular lesions are a common phenomenon in patients with NF1 disease and a common cause of
death in patients under 30 years of age.
It can affect any arterial vessel, leading to cerebrovascular events, renal artery stenosis, or peripheral vascular insufficiency
.
One of the potentially serious manifestations of NF1 disease is cerebrovascular disease, manifested by narrowing or occlusion of the internal carotid artery, middle cerebral artery, and anterior cerebral artery, moyamoya disease, and aneurysm formation
.

Patients with NF1 disease have a tendency to bleed, especially during
neurofibroma surgery.
Bleeding is attributed to NF1-related arterial dysplasia and primary hemostatic disorders
.

3.
Neurological evaluation

NF1 has an important impact
on the central nervous system (CNS).

3.
1 Epilepsy

Seizures are more common
in patients with NF1 disease than in the general population.
It occurs in 8% of patients with NF1 disease, and seizures range from infancy to late
middle age.
All types of seizures occur, but focal seizures predominate
.
Focal seizures can be caused
by intracranial tumors.
Therefore, seizures should result in systematic neuroimaging of
central nervous system lesions (tumors, aqueduct stenosis, vascular lesions).
In almost 30% of cases, epilepsy is resistant to treatment, which is associated with
severe mental retardation.

3.
2 Cognitive impairment

The most common neurological complication is mild cognitive impairment, and children with NF1 disease should be evaluated early in life by neurological and psychological screening to closely monitor their developmental progression
.
Neurocognitive impairment is a common manifestation of NF1 and includes low IQ, behavioral problems, and learning difficulties
.
Learning difficulties include visuospatial and visual-motor disorders, language disorders, fine and gross motor disorders, executive function problems, and attention deficit hyperactivity disorder, behavioral abnormalities, autism spectrum disorder, and psychosocial problems may also occur
in patients with NF1.
Delays in psychomotor and/or language development must prompt physicians to refer the child to appropriate professionals for early intervention and management
.
Methylphenidate can control attention deficit disorder very well; Cognitive behavioral therapy may be helpful
.

New evidence

A preclinical trial, using an NF1 mouse model of learning disabilities, determined that increased RAS/ERK signaling led to neuronal plasticity disorders as well as spatial and attention impairments
.
Subsequently, these defects were reversed with treatment with HMG-COA reductase inhibitors [217].

Two randomized controlled trials have shown no improvement in cognitive function with simvastatin [218,219].

Although phase I studies of lovastatin showed improvements in cognitive function [220], phase II trials did not show any benefit
.
So far, there is not enough evidence to justify
the use of statins to treat cognitive impairment in individuals with NF1.
An ongoing clinical trial is currently investigating the effects
of lamotrigine on cognition in NF1.

3.
3 Unidentified Bright Objects

Multiple high-intensity lesions were seen on brain T2WI in NF1 patients, with no mass effect and no enhancement
.
UBO tends to occur in the basal ganglia (internal capsule), cerebellum, brainstem, thalamus and other parts
.
Studies have shown high sensitivity (70-97%) and specificity (79-100%) for UBO in children with NFI, and some scholars have suggested that BU be included in the diagnostic criteria
for NF1 in children.

New evidence

Over the past decade, new technologies based on MRI have been introduced and further improved in the detection of colorectal cancer
.

4.
Tumor manifestations

NF1 is associated
with an increased risk of malignancy and a life expectancy 10-15 years shorter than the general population.
Malignancy is the leading cause of
death from NF1.
People with NF1 are four times
more likely to develop malignancy than the general population.

Compared with the general population, NF1 patients are 2-3 times more likely to develop esophageal, gastric, colon and lung cancers; 3-7 times more likely to develop liver, thyroid, ovarian, breast, malignant melanoma, non-Hodgkin lymphoma and chronic myeloid leukemia; The likelihood of developing small bowel tumors is 15 times higher and the likelihood of developing bone cancer is 20 times
higher.

Patients with NF1 disease should follow the same screening guidelines
as the general population.

Over the past few years, the field of breast cancer in NF1 patients has received increasing attention
.
In fact, multiple studies have shown that breast cancer in NF1 patients primarily affects women under the age of 50; The mortality rate is higher than that of women with breast cancer in the
general population.
Based on the increased risk of early-stage breast cancer in women with NF1, experts recommend annual mammogram screening
starting at age 40.
Treatment of NF1-related breast cancer is similar
to that of breast cancer in the general population.

The most common brain tumor affecting NF1 patients with central nervous system tumors is OPG disease, which affects 15% to 20% of children with NF1
.

Brainstem gliomas (BSG).

The second most common brain tumor in NF1 patients is BSG
.
These are indolent tumors that occur in slightly older children and are often found
incidentally in neuroimaging studies.
Similar to OPGs, these tumors are usually hairy astrocytomas
.

Gastrointestinal neuroendocrine tumors Gastrointestinal stromal tumors are soft tissue sarcomas that can be located anywhere in
the digestive system.
In patients with NF1 disease, gastrointestinal stromal tumors tend to occur at an earlier age, are usually multiple, and often occur in the small intestine
.
The most common reported symptoms are abdominal pain, bowel obstruction, bleeding, and bowel perforation
.

Rare neuroendocrine tumors derived from endocrine cells of the gastrointestinal tract (duodenal somatostatinoma, pancreatic somatostatin and insulinoma, small intestinal carcinoid) have also been reported
in patients with NF1 disease.
Their diagnosis should prompt a search for multiple endocrine tumors type
1.

5.
Follow-up and management of specific cases

Medical follow-up of patients with NF1 disease relies on active collaboration
between multiple healthcare providers with a multidisciplinary approach.
Once the diagnosis of NF1 is suspected, immediate lifelong monitoring
is recommended.
NF1 specialists should conduct annual clinical evaluations
of children and adults with high-risk phenotypes.
Otherwise, NF1 patients without a high-risk phenotype or complications should see an NF1 specialist every 2 to 3 years, and the rest annually to a primary care physician, dermatologist, or pediatrician.

Annual clinical examinations can detect complications early, reduce morbidity and improve quality of life
.

pregnancy

Female patients with NF1 disease are not contraindicated to become pregnant; However, careful evaluation and close follow-up of their pregnancies are necessary
.
Hormonal changes associated with pregnancy may lead to the emergence of new neurofibromas and an increase in
the size of existing neurofibromas.
While maternal mortality does not appear to be increasing, there may be an increase in maternal morbidity in pregnant women with NF1 disease, particularly hypertension, pre-eclampsia, placental abruption, and vascular complications
.
Caesarean section is even more
so in NF1 patients.
Fetal complications include preterm birth and intrauterine growth restriction
.

conclusion

In short, the (protocole national de diagnostic et de soins; PNDS) PNDS can be used by healthcare providers as a guideline for the management of NF1 patients because it provides an in-depth follow-up strategy
for NF1 patients.
Once a diagnosis of NF1 is suspected, lifelong monitoring begins
.
Given the complexity of the disease, the management of children and adults with NF1 requires the involvement of a full range of healthcare providers and communication
between specialties.
Further research is emerging in the hope of further elaborating on the best strategies for
disease management.
Finally, the evolving understanding of the molecular pathogenesis of NF1 and the elaboration of specific preclinical mouse models of NF1-related malignant diseases provide a promising basis for
the concept of innovative rational molecularly targeted drugs.