- Neurofibromatosis type 1 (NF1) is the most common type of neurofibromatosis.
- Incidence: approximately 1 in 2,600–3,000 individuals, regardless of ethnicity and gender
- Inherited in about half of the cases
- Life expectancy:
- The mean age at death is 54.4 years.
- The median age at death is 59 years.
- Autosomal dominant inheritance
- Less commonly, de novo mutations (primarily in paternally derived chromosomes)
- Mutations in the NF1 gene located on chromosome 17
- NF1 encodes neurofibromin, a cytoplasmic protein.
- Predominantly expressed in neurons, Schwann cells, oligodendrocytes, leukocytes
- Multidomain molecule regulating several important intracellular processes:
- RAS RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis-cyclic AMP pathway
- Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade
- Adenylyl cyclase
- Cytoskeletal assembly
- Also functions as a tumor suppressor
- Involvement of neurofibromin in various pathways explains the wide range of clinical manifestations.
- Café au lait macules (CALMs):
- Flat, uniformly hyperpigmented macules
- Appear in the 1st year after birth
- Increase during early childhood
- Appears in the axillary or inguinal regions
- Apparent by 3–5 years of age
- Lisch nodules:
- Raised tan-colored hamartomas of the iris
- More common in adults than in children
- Peripheral neurofibromas:
- Optic pathway gliomas:
- Low-grade pilocytic astrocytomas
- Occur in children < 6 years of age
- Rare in older children and adults
- Most children have normal vision.
- Some gliomas may be symptomatic with progressive visual loss.
- Other CNS neoplasms:
- Low-grade astrocytomas
- Brainstem gliomas
- Soft tissue sarcomas:
- Malignant peripheral nerve sheath tumors
- GI stromal tumors
- Glomus tumors
- Other tumors:
- Juvenile myelomonocytic leukemia
- Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
- Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
- Peripheral neurofibromas:
- Bone abnormalities:
- Long bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones dysplasia and pseudoarthrosis
Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy.
Structure of Bones lesions:
- Vertebral defects
- Nonossifying fibromas within long bones
- Sphenoid wing dysplasia
- Short stature
- Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis
- Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
- Neurologic abnormalities:
- Cognitive deficits and learning disabilities
- Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
- Peripheral neuropathy
- Congenital heart disease
- Other manifestations:
- Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
- Irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome
- Pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension
- Pulmonary artery stenosis
- Interstitial lung disease
- Bullous lung disease
- Arterial dissection (rare)
The diagnosis of NF1 is usually made clinically based on the typical clinical presentation and confirmed by genetic testing.
- Diagnostic criteria: At least 2 features must be present:
- ≥ 6 CALMs:
- > 5 mm in diameter in prepubertal individuals
- > 15 mm in diameter in postpubertal individuals
- The longest diameter is measured.
- Ordinary room light is used.
- ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma
- Freckling in the axillary or inguinal regions
- Optic glioma
- ≥ 2 Lisch nodules
- A distinctive bony lesion (e.g., sphenoid dysplasia, thickening of the cortex of long bones with or without pseudoarthrosis)
- A 1st-degree relative (parent, sibling, or offspring) with NF1 defined by the above criteria
- ≥ 6 CALMs:
- Genetic testing
- Screening of family members
- Prenatal testing
- Neuroimaging (MRI or CT), potential findings:
- Focal bright spots on T2-weighted images (disappear with age)
- Increased brain volume
- Abnormal cerebral vasculature
- Cutaneous and subcutaneous neurofibromas
- Removal by surgery, laser, or electrodesiccation
- Indications for removal include:
- Interference with function
- Gabapentin (for pruritus)
- Plexiform neurofibromas:
- Selumetinib (for tumor regression)
- Surgical resection (debulking)
- Imatinib or pegylated interferon (shrinkage)
- Optic pathway gliomas and other low-grade gliomas:
- Radiation (avoided in pediatric individuals)
- High-grade gliomas:
- Surgical resection
- Conventional radiation + temozolomide
- Malignant peripheral nerve sheath tumors:
- Surgical resection
- Adjunctive radiation therapy
- Surgery, if feasible
- GI stromal tumors: poorly responsive to imatinib
- Cognitive and learning deficits:
- Learning disabilities: academic support
- Speech deficits: speech therapy
- Motor impairment: occupational therapy and PT
- Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures: antiseizure drugs
- Peripheral neuropathy: Treat the underlying cause and alleviate symptoms.
- Psychosocial issues: counseling
- Hypertension: antihypertensives
- Genetic counseling for affected individuals and their families
- Neurofibromatosis type 2 Neurofibromatosis type 2 Neurofibromatosis type 2 is a neurocutaneous disorder that can arise from mutations in the NF2 gene located in chromosome 22 and may be inherited in an autosomal dominant fashion or occur from de novo mutations. The main clinical features are bilateral vestibular schwannomas, intracranial/spinal meningioma, and intramedullary and extramedullary spinal tumors. Neurofibromatosis Type 2: a neurocutaneous disorder that can arise from mutations in the NF2 NF2 Neurofibromatosis type 2 is a neurocutaneous disorder that can arise from mutations in the NF2 gene located in chromosome 22 and may be inherited in an autosomal dominant fashion or occur from de novo mutations. The main clinical features are bilateral vestibular schwannomas, intracranial/spinal meningioma, and intramedullary and extramedullary spinal tumors. Neurofibromatosis Type 2 gene. The main clinical features are bilateral vestibular schwannomas and intracranial/spinal meningiomas. Diagnosis is made clinically and confirmed based on genetic testing, MRI, and histopathology. Tumor surveillance, follow-up, and screening of at-risk family members are recommended. Management includes surgical intervention, radiation therapy, and/or monoclonal antibody therapy with bevacizumab.
- Noonan syndrome: a genetic disorder that occurs following a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in one of several genes involved in the RAS RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis signaling pathway, especially protein-tyrosine phosphatase, nonreceptor type. Clinical features include short stature, webbed neck, hypertelorism, downward eye slant, low-set ears, pulmonic stenosis, and CALMs. Management involves the identification and timely monitoring of various clinical presentations.
- Tuberous sclerosis Tuberous sclerosis Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the TSC genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). Tuberous Sclerosis: an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder that mainly presents with neurocutaneous symptoms. Mutation in the TSC gene causes excessive tumor-like growth in the brain, eyes, heart, kidney, and lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs. Cutaneous manifestations include hypopigmentation (i.e., ash-leaf spots) or excessive growth (i.e., angiofibroma). The diagnosis is made clinically and confirmed by genetic testing. Management entails a multidisciplinary approach that targets the monitoring and treatment of various manifestations of the disorder.
- Constitutional mismatch repair-deficiency syndrome: a rare autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder resulting from the inheritance of deleterious mutations in both copies of 1 of the 4 mismatch-repair genes. Constitutional mismatch repair-deficiency syndrome results in early-onset (< 18 years of age) hematologic, brain, or colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix cancers and may present with skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin pigmentations similar to those in NF1. Diagnosis is made clinically. Management is centered around early screening for tumors and genetic counseling for families of affected individuals.
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