Neurofibromatosis-1 (NF1, von Recklinghausen disease) is an autosomal dominant (AD) syndrome that results from a mutation in the NF1 gene on chromosome 17q11.2; with an incidence of ~ 1/3000 people, NF1 is the most common phakomatosis. The diagnosis requires at least two of the following: ≥ 6 of café au lait spots larger than 5 mm in diameter; axillary or inguinal freckles, two neurofibromas of any type or one or more plexiform neurofibromas; optic nerve or chiasmatic glioma; ≥ 2 Lisch nodules (pigmented hamartomas of the iris); first-degree relative with NF1; bony abnormalities, such as thinning of the cortical long bone or sphenoid dysplasia. Genetic confirmation is available. Spontaneous mutations account for ~ 50% of new cases, hence family history is often negative. Mosaicism is not uncommon. Neurofibromas are benign peripheral nerve tumors composed predominantly of Schwann cells and fibroblasts that can develop at any age. Plexiform neurofibromas have a 5% to 13% lifetime risk of malignant transformation into malignant peripheral nerve sheath tumors, which are associated with a poor 5-year survival. Optic nerve gliomas are the most common tumors in NF1. Given the complications associated with NF1, expert guidelines recommend annual evaluation to monitor blood pressure and developmental milestones (up to 18 years of age), as well as skin, musculoskeletal, and neurologic examinations.

Neurofibromatosis-2 (NF2) is an AD disease caused by a mutation on chromosome 22 of the NF2 gene, which produces a protein called merlin, a novel regulator of the tuberous sclerosis complex (TSC)/mTORC1 signaling pathway. It occurs in approximately 1 in 50,000 people. Onset occurs most often in the late teens or early adulthood and rarely in childhood. Patients with NF2 generally have fewer cutaneous findings and more central nervous system (CNS) tumors. The diagnostic criteria include: bilateral eighth nerve tumors (vestibular schwannomas); unilateral eighth nerve tumor and a first-degree relative with NF2; a first-degree relative with NF2 and two of the following: glioma, schwannoma, presenile posterior cataract, astrocytoma, neurofibroma of another type, plexiform neurofibroma, or retinal hamartoma. The MISME mnemonic is helpful: multiple inherited Schwannomas, meningiomas and ependymomas. Genetic confirmation is available and spontaneous mutations are common, so family history is often negative. As with NF1, mosaicism is not uncommon. Given the role of merlin in mTOR signaling, rapamycin is being investigated for the treatment of tumors related to NF2, but malignant degeneration is exceedingly rare.

Schwannomatosis is the third form of neurofibromatosis and is clinically and genetically distinct from NF1 and NF2. Most cases are likely related to inactivated mutations in the tumor suppressor genes SMARCB1 and LZTR1. Schwannomatosis typically presents in young adulthood with pain and multiple noncutaneous schwannomas, without vestibular schwannomas. The incidence is similar to NF2. Diagnostic categories include definite, possible, and segmental schwannomatosis.

Tuberous sclerosis complex is an AD disorder with variable penetrance related to defective cellular differentiation and proliferation, which affects the brain, skin, heart, kidneys, lungs, and other organs. Genetic diagnostic criteria were updated in 2012 and require only the identification of a pathogenic mutation in TSC1 or TSC2 located on chromosome 9 q34. Conventional genetic testing will fail to identify 10% to 25% of patients with TSC, and clinical expression is highly variable. Definite clinical diagnosis requires two major, or one major and two or more minor features. Major criteria include ≥ 3 hypomelanotic macules, at least 5 mm in diameter; ≥ 3 angiofibromas or fibrous cephalic plaques; ≥ 2 nail ungual fibromas; Shagreen skin raised patch; multiple retinal hamartomas; cortical dysplasias including tubers and cerebral white matter radial migration lines; subependymal nodules; subependymal giant cell astrocytoma; cardiac rhabdomyoma; lymphangioleiomyomatosis; ≥ 2 angiomyolipomas. Minor criteria include confetti skin lesions; ≥ 3 dental enamel pits; ≥ 2 intraoral fibromas; retinal achromic patch; multiple renal cysts; nonrenal hamartomas. Infants often present with seizures and cardiac involvement, while adults may present with more subtle findings. Common neurologic manifestations include seizures (in 80% to 90%), intellectual disability, and behavioral abnormalities. Cortical/subcortical tubers and calcified subependymal nodules can be seen on imaging, and 6% to 14% of patients will develop subependymal giant cell astrocytomas, which may lead to hydrocephalus. Roughly 60% will have a cardiac rhabdomyoma.

Von Hippel–Landau (VHL) disease is an AD syndrome with a prevalence of 1/40,000, caused by a mutation of the VHL gene on chromosome 3p25-26. VHL is characterized by hemangioblastomas of the retina and CNS, and visceral cysts and tumors of the kidney, pancreas, liver, islet cell, and epididymis, as well as pheochromocytoma. Diagnostic criteria include hemangioblastoma of the CNS (most commonly found in the cerebellum, medulla, spinal cord, or cerebral hemispheres) or retina, and one additional characteristic lesion or a direct relative with the disease. Careful screening of affected patients is the most important aspect of management and includes annual examination/urinalysis (including 24-hour collection for vanillylmandelic acid); direct ophthalmoscopy with vascular imaging (retinal hemangioblastoma); renal ultrasound; brain magnetic resonance imaging (MRI) or computed tomography (CT) every 3 years until age 50, then every 5 years thereafter, and abdominal CT every 3 years. There are also screening protocols for at-risk relatives.

Hereditary hemorrhagic telangiectasias (HHT; Osler-Weber-Rendu syndrome) is an AD disorder with high penetrance, which causes telangiectasias of the skin, mucous membranes, lungs, liver, and other organs as a result of mutations in either the HHT1 or the HHT2 gene on chromosome 12 ALK1. Neurologic manifestations are common and include headaches, vertigo, and seizures. Intraparenchymal hemorrhage is a feared complication, and screening with MRI and angiography generally occurs every 5 years. Treatment of cerebral arteriovenous malformations (AVMs) with embolization, resection, or radioablation may be necessary. Antibiotic prophylaxis is recommended for dental work given some risk of brain abscess related to occult pulmonary AVM.

Ataxia-telangiectasia is a progressive neurodegenerative autosomal recessive (AR) disease caused by mutation of the ATM gene located on chromosome 11q22.3, which normally produces a protein involved in regulating cell division and DNA damage repair. Affected individuals present in childhood with slowly progressive cerebellar ataxia and tremor, abnormal eye movements (e.g., oculomotor apraxia), impaired smooth pursuit, and eventually dystonia and chorea. Telangiectasias of the conjunctivae, ears, and flexor surfaces appear later. Systemic manifestations include immunodeficiency (decreased immunoglobulin [Ig]A, IgE, or IgG are seen in 80%), increased alpha-fetoprotein, recurrent pulmonary infections, sensitivity to ionizing radiation, and the development of lymphoid malignancies (10% to 15% by early adulthood). Early diagnosis helps to initiate screening for malignancies. Antioxidants such as vitamin E, alpha-lipoic acid, and folic acid are sometimes recommended, but it is unknown whether these are effective in slowing progression.

Xeroderma pigmentosa is a group of uncommon AR phakomatoses that result from a mutation in one of several genes involved in DNA repair (DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC). Cutaneous and ocular manifestations occur consequent to damage incurred by ultraviolet light exposure and generally develop in the first year or two of life. Blistering, persistent erythema with minimal sun exposure and marked freckling are common. Sunlight-induced keratitis and lid atrophy occur. Roughly half of all affected individuals will develop skin cancer. Approximately 25% of affected individuals develop neurologic manifestations including microcephaly, progressive dementia that begins in childhood, sensorineural hearing loss, ataxia, choreoathetosis, and absent deep tendon reflexes. Treatment of premalignant and malignant skin lesions, along with appropriate surveillance, is important; skin cancer, neurodegeneration, and visceral cancers are the most common causes of death.

Hypomelanosis of Ito is the third most common phakomatosis after NF1 and TSC, and is usually spontaneous. A variety of genetic aberrations occur, including aneuploidy, unbalanced translocations, ring chromosome 22, 18/X translocation, and mosaic trisomy 18 among others. Patients present with hypopigmented whorls, streaks, and patches that follow the lines of Blaschko in two-thirds of those affected. There are other skin manifestations, such as café au lait spots, focal hypertrichosis, trichorrhexis, and nail dystrophy. Of those with cutaneous findings, 50% to 80% have neurologic abnormalities, including seizures (50%) and intellectual disability. Structural pathology can include macrocephaly, cortical migration abnormalities, lissencephaly, and periventricular white matter lesions. From 50% to 70% will have other systemic signs that include ocular abnormalities, musculoskeletal anomalies, cardiac defects, and both renal and endocrine disorders.

Sturge-Weber syndrome (meningofacial angiomatosis with gyriform cerebral calcifications) is a sporadic syndrome characterized by facial cutaneous angioma (port-wine nevus) and ipsilateral leptomeningeal and brain angioma. Somatic mutations in GNAQ on chromosome 9 have been identified in some patients. Neurologic manifestations include seizures (72% to 80% with unilateral lesions; 93% when bilateral), intellectual disability, and focal neurologic deficits referable to the intracranial vascular lesion (often vision loss related to occipital lobe lesions). On neuroimaging, CT can demonstrate gyriform calcifications, and contrasted MRI reveals focal areas of calcification, atrophy, and vascular malformation. However, only 10% to 20% of children with port-wine nevus have a leptomeningeal angioma. Surgical resection of vascular lesions may help improve seizure control, but patient selection and timing of surgery is an area of debate. Functional imaging may help in lesion selection. Hemispherectomy or corpus callosotomy may be necessary in some cases.

Neurocutaneous melanosis is a rare congenital disorder of melanocyte development, which is characterized by large, pigmented, hairy nevi, intracranial melanoma, and intracranial hemorrhage. Leptomeningeal melanosis occurs in most patients and predominantly affects the base of the brain and the upper spinal cord, and can lead to obstructive hydrocephalus. Cerebrospinal fluid may demonstrate mild pleocytosis with cytopathology, consisting of round cells with small, ovoid nuclei, and abundant cytoplasm containing melanin granules. MRI demonstrates T1 hyperintense lesions in the cerebellum, anterior temporal lobes, and basilar meninges, as well as possible leptomeningeal contrast enhancement.

Incontinentia pigmenti is a rare X-linked disease (XLD) resulting from mutations in the NF-κB essential modulator (NEMO), which consists of skin (characteristic lesions that evolve from blisters to verrucous, then linear/pigmented, and eventually atrophic and hypopigmented), ocular, and CNS pathology. The skin lesions also tend to follow the lines of Blaschko, but should not be confused with hypomelanosis of Ito. Neurologic involvement has been historically overestimated, but a higher incidence of seizures has been noted, and while affected females are of normal intelligence, most males do not survive; however, those with mosaicism do survive, but usually have developmental delay and immunodeficiency.

Fabry disease (papular eruption, painful sensory neuropathy, and stroke)

Linear nevus syndrome (linear yellow papules, developmental disability, and seizures)

Klippel-Trenaunay-Weber syndrome (limb hypertrophy and hemangiomas)

Wyburn-Mason syndrome (facial angioma, retinal AVMs, cerebrovascular anomalies, and seizures)

NMS symptoms typically evolve over 24 to 72 hours. The first recognized symptom (often due to under recognition of subtle parkinsonism) is mental status change in the form of agitated delirium with confusion rather than psychosis; catatonic signs and mutism may be prominent. Concurrently, patients often begin to develop generalized muscular rigidity, increased tone or “lead pipe rigidity” with superimposed tremor; less commonly akinesia, bradykinesia, dystonia, opisthotonus, trismus, chorea, and other dyskinesias. Next, temperatures begin to rise above 38°C, and if untreated may rapidly escalate above 40°C. Autonomic instability typically follows in the form of tachycardia, tachypnea, and diaphoresis. The clinical course lasts around 7 to 10 days, with a longer time for depot neuroleptics due to slower clearance. In individuals with Parkinson disease who have been on dopamine agonists, NMS can occur in the setting of a sudden withdrawal of the agonist agent, dosage change, or medication change.

Characteristic laboratory findings include elevated CPK (200 to 10,000 IU/L) due to rhabdomyolysis, leukocytosis (10,000 to 40,000 cells/μL), metabolic acidosis, and iron deficiency. Cerebrospinal fluid and imaging studies are usually normal, but an electroencephalogram (EEG) may show non-generalized slowing. Toxicology screening is recommended.

The main risk factors for developing NMS are the initiation or increase in dose of a neuroleptic medication, or less likely, the abrupt cessation or reduction in dose of dopaminergic medications. Other risk factors include genetic factors, males under 40 years old, postpartum women, dementia with Lewy bodies, dehydration, physical exhaustion, exposure to heat, hyponatremia, iron deficiency, malnutrition, trauma, thyrotoxicosis, alcohol, psychoactive substances, and presence of a structural or functional brain disorder.

Many medical conditions can mimic the presentation of NMS, with some of the more common being heat stroke, central nervous system (CNS) infections, toxic encephalopathies, agitated delirium, status epilepticus, or drug-induced extrapyramidal symptoms. Other mimickers include infectious (brain abscess, encephalitis meningitis, rabies, septic shock, tetanus, delirium, lethal catatonia, nonconvulsive status epilepticus), pharmacological (anticholinergic delirium, drug-drug interaction, drug withdrawal, extrapyramidal side effects, malignant hyperthermia, serotonin syndrome), toxic exposure (heavy metals, lithium, salicylates, substances of abuse), or endocrine abnormalities (pheochromocytoma, thyrotoxicosis).

Both serotonin syndrome and malignant hypothermia share some core features of NMS and need to be distinguished from NMS, although symptom management may overlap as well. Intercurrent conditions such as burns, myxedema, or other causes of catatonia may complicate NMS.