References:     . Since there are no curative treatment options available, treatment of neurocutaneous syndromes focuses on multidisciplinary symptom control. References:    . Clinical science Neurocutaneous syndromes phakomatoses are a group of inherited diseases that affect various organs, most notably the central nervous system and skin.
Neurofibromatosis type I and type II , tuberous sclerosis , and von Hippel-Lindau disease : autosomal dominant inherit ance or spontaneous mutation Ataxia telangiectasia : autosomal recessive in heritance Sturge-Weber syndrome : noninherited developmental anomaly. Bone involvement e. Ungual fibromas von Hippel-Lindau disease Characterized by development of numerous benign and malignant tumors Hemangioblastomas in the retina , cerebellum , brain stem, and spine Bilateral renal cell carcinoma Pheochromocytoma Renal and pancreatic cysts References:     .
Neurofibromatosis Excision or resection of neurofibromas , meningiomas , acoustic neuromas , and optic gliomas Surgery for kyphoscoliosis in neurofibromatosis type 1 Tuberous sclerosis Anticonvulsants and adrenocorticotropic agents e. Prepare and succeed on your medical exams. Flu Season is Here Talk to your healthcare provider about getting your child immunized today. Contact the Neuroblastoma Program Learn more about the Neuroblastoma Program. Causes How common are these syndromes? What causes neurocutaneous syndromes?
What causes a neurocutaneous syndrome in a child?
Both tuberous sclerosis and neurofibromatosis are caused by genetic mutations. Symptoms What are the symptoms of neurocutaneous syndromes? Here are some of the ways we can help: Patient education : From the first office visit, our nurses will be on hand to help answer any questions you may have — What kind of tests will my child need? Will my child get better? For years, families have come from around the corner and across the world, looking to Boston Children's for answers. This is the place where the most difficult challenges are faced head on, where the impossible becomes possible, and where families in search of answers find them.
Sandra L. Fenwick, CEO. Connect with Boston Children's Hospital. SUMMARY: Neurologists require a basic knowledge of and familiarity with a wide variety of neurocutaneous disorders because of the frequent involvement of the central and peripheral nervous systems. A simple routine skin examination can often open a broad differential diagnosis and lead to improved patient care. Dr Rosser has provided expert legal testimony on a variety of neurologic disorders in childhood.
The phakomatoses are a heterogeneous group of disorders that primarily affect the skin and central nervous system CNS. While phenotypically and genetically diverse, they are united by their origins in defects of the developing primitive embryonic ectodermal tissue, which gives rise to both the skin and nervous system. Most neurocutaneous syndromes are classified as single-gene disorders, but they have autosomal dominant, autosomal recessive, or X-linked inheritance patterns table Neurologists require a basic knowledge of and familiarity with a wide variety of neurocutaneous disorders because of the frequent involvement of the central and peripheral nervous systems in these conditions.
A simple routine skin examination can often open a broad differential diagnosis and lead to improved patient care in these cases. Recent advances in genetic technologies have furthered our understanding of the specific genetic defects and protein functions responsible for many neurocutaneous disorders, moving the field forward such that biologically based, targeted therapies are being developed for many associated complications.
Several neurocutaneous disorders have now been categorized as RASopathies , a group of related disorders caused by mutations in genes that regulate the RAS—mitogen-activated protein kinase MAPK pathway. This important biological pathway governs functions such as cell growth, proliferation, differentiation, and apoptosis.
Many of these disorders also carry a predisposition to both benign and malignant tumors. Almost all are associated with a range of mild to severe developmental disabilities. RASopathies with neurocutaneous features include neurofibromatosis type 1 NF1 , Legius syndrome, Noonan syndrome with multiple lentigines previously called LEOPARD syndrome , and capillary malformation-arteriovenous malformation syndrome.
As demonstrated in figure , many other well-known neurocutaneous disorders are linked through this web of biological connections. While a comprehensive list of neurocutaneous disorders is long, the most common neurocutaneous disorders encountered in neurologic clinical practice are reviewed in this article, including NF1, Legius syndrome, neurofibromatosis type 2 NF2 , Noonan syndrome with multiple lentigines, tuberous sclerosis complex, Sturge-Weber syndrome, and incontinentia pigmenti.
The genetic basis, diagnostic criteria, clinical features, and relevant management issues are discussed for each disorder. NF1 is the most common and well-known neurocutaneous disorder, occurring in approximately 1 in to 1 in individuals. In addition, the discovery of the clinically milder Legius syndrome described later in this article has increased the need to perform genetic testing to differentiate it from NF1.
NF1 primarily affects the skin, CNS, peripheral nervous system, eyes, and musculoskeletal system, but rarer complications can occur involving other organ systems. These are macular hyperpigmented lesions that are typically present at birth and grow in number and size over the first few months to years of life. Neurofibromas are benign nerve sheath tumors that occur along the length of peripheral nerves.
They typically develop in the preteen and adolescent years and are present in almost all affected individuals by adulthood figure Neurofibromas are often classified into cutaneous and subcutaneous groups. They have no malignant potential but can be cosmetically disfiguring and cause pruritus.
When visible externally, they may be covered with an irregular area of hyperpigmentation either with or without hypertrichosis. Internal plexiform neurofibromas may be only identifiable on imaging studies such as MRI. Plexiform neurofibromas are a significant cause of morbidity in NF1. As they progress over time, plexiform neurofibromas become intricately involved with the surrounding tissues. Thus, their presence often results in significant cosmetic disfigurement, organ compression, erosion of neighboring bone, vascular compromise, and neurologic deficits such as weakness, sensory change, and pain figure Unlike dermal neurofibromas, plexiform neurofibromas have a risk of malignant transformation, becoming malignant peripheral nerve sheath tumors.
Clinical warning signs of malignancy include rapid plexiform growth, severe pain, new neurologic deficits, and change in plexiform texture to a more solid hard mass. Malignant peripheral nerve sheath tumors are challenging to treat as they often cannot be fully resected and are resistant to chemotherapy. The population under 6 years of age is most at risk of developing optic pathway gliomas, with a median age of detection of approximately 3 years figure Several studies have demonstrated that chiasmatic and postchiasmatic lesions are the most likely to progress, while prechiasmatic lesions have a more benign course.
Additional involvement of the hypothalamus is not uncommon and can result in endocrinopathies such as precocious puberty. Treatment with chemotherapeutic agents is typically based on the development of visual symptoms but is sometimes undertaken when progressive growth is seen on serial neuroimaging. Brain MRIs in the pediatric NF1 population also often reveal T2-hyperintense lesions, which are now known to be benign and should not be confused with brain tumors.
Their presence waxes and wanes throughout childhood, with many resolving by adulthood. While general agreement exists that such a relationship is likely, the exact nature and pathogenesis are still unclear.
Neurocognitive and behavioral deficits are well-known neurologic complications of NF1. A wide range of cognitive domains are affected, including verbal learning, visuospatial skills, and executive functions such as attention and working memory. An ophthalmologic slit-lamp examination is often required to visualize them. They are markers of NF1 but do not cause vision or other ocular problems.
Specific musculoskeletal features of NF1 are part of the diagnostic criteria and are often easily identified at birth. Vasculopathy is a less common but important potential complication of NF1. Research has demonstrated that the expression of abnormal neurofibromin and dysregulation of the RAS-MAPK pathway in vascular epithelial cells promotes proliferative changes and altered vascular morphogenesis. Recent literature has shown that, compared to the general population, the odds of having any type of stroke are significantly elevated in both children and adults with NF1.
Adults and children have an increased risk for hemorrhagic stroke, while children are particularly at risk for ischemic strokes. Pheochromocytomas, gastrointestinal stromal tumors, leukemia, brain tumors, and breast cancer are all more common in patients with NF1 than in the general population. NF1 is best managed by experienced clinicians familiar with the disorder in a multidisciplinary setting with access to subspecialists with the expertise to care for NF1-related complications. Published guidelines exist for health supervision recommendations for children with NF1 and are in the process of being updated, but such recommendations are lacking for adult patients with NF1.
As the signs and symptoms of NF1 develop over time, longitudinal monitoring is necessary and specific management recommendations are age-related. Genetic counseling is an integral part of patient care and is most important at the time of diagnosis and with family planning.
Throughout childhood, annual skin examinations and monitoring of vision, skeletal growth, blood pressure, and neurocognitive development is important. Ophthalmologic examinations are recommended annually until 8 years of age and every 2 years thereafter until 18 years of age to assess for changes associated with optic pathway gliomas. While still a controversial issue, evidence-based medicine does not support the use of screening brain MRIs for optic pathway gliomas, but any child with vision deterioration, signs of endocrine abnormalities, significant headaches, seizures, marked increase in head size, or other concerning neurologic symptoms should undergo a brain MRI.
Management of adults with NF1 focuses on monitoring for benign tumors, malignancies, bone health, and vasculopathy as well as for progression of any complications identified earlier in life.
As our understanding of the functions of neurofibromin and the RAS-MAPK pathway have expanded, biologically targeted therapies have focused on treatment of the most severe NF1 complications. Numerous phase 1 and phase 2 clinical trials have been performed for the treatment of optic pathway gliomas, plexiform neurofibromas, malignant peripheral nerve sheath tumors, and NF1-related cognitive deficits.
Legius syndrome was first described in in a group of individuals who met the NIH diagnostic criteria for NF1 but who had no identifiable mutation in the NF1 gene. However, notably absent are other findings common to NF1, including Lisch nodules, optic pathway gliomas, neurofibromas, tibial dysplasia, and malignant peripheral nerve sheath tumors. Lipomas have been identified in several families with SPRED1 mutations and should not be confused clinically with neurofibromas. Dysmorphic facial features similar to those seen in Noonan syndrome, including hypertelorism, down-slanting palpebral fissures, and low-set posteriorly rotated ears, were noted in the first five families reported with Legius syndrome and have been found in other study populations.
For example, with few exceptions, there should be no need for the brain and spinal MRIs and ophthalmologic evaluations that are often part of routine NF1 care. NF2 is an autosomal dominant multisystem disorder that predisposes to the development of multiple benign nerve sheath tumors, CNS tumors, ophthalmic abnormalities, and neurocutaneous lesions. The NF2 gene maps to chromosome 22q12 and encodes the protein merlin also known as schwannomin , a tumor suppressor.
The diagnostic criteria for NF2 have evolved over the years to improve sensitivity as the genetic basis and defining clinical features have been elucidated. The Manchester criteria 34 are still frequently used, but in , Baser and colleagues built upon current knowledge to create criteria that can be used to reliably make an earlier diagnosis than prior criteria table NF2 most often presents in the second or third decade of life with hearing loss, tinnitus, or disequilibrium, which are attributable to vestibular schwannoma involvement.
Children with NF2 are more likely to come to medical attention because of nonvestibular etiologies, such as other brain tumors, spinal cord tumors, skin lesions, visual disturbances, and mononeuropathy case NF2 is now rarely confused with NF1, but schwannomatosis should be included in the differential diagnosis of any patient with suspected NF2. Schwannomatosis is a rare third form of neurofibromatosis, with clinical, genetic, and imaging overlap with NF2.
Ocular manifestations of phakomatoses (Neurocutaneous Syndromes)
Individuals with schwannomatosis often present in their twenties to thirties with chronic pain and symptoms relatable to nerve sheath tumors. While other cranial nerves can be involved, individuals with schwannomatosis can be distinguished from those with NF2 because they do not develop vestibular schwannomas. The cutaneous findings of NF2 are much less prominent than in other neurocutaneous disorders. Subcutaneous nodular palpable lesions can also often be identified. Vestibular schwannomas are benign tumors of the eighth cranial nerve and the hallmark of NF2.
They arise from within the internal auditory canal and expand into the cerebellopontine angle. They may initially develop and become symptomatic unilaterally but frequently become bilateral over time. Vestibular schwannomas are the primary cause of NF2-associated morbidity, causing sensorineural hearing loss, tinnitus, balance problems, and brainstem compression that progress over time figure Additional benign intracranial neoplasms also frequently develop in NF2. After vestibular schwannomas, oculomotor and trigeminal nerves are the next most commonly involved cranial nerves.
Like other tumors in NF2, they have variable growth rates and periods of relative quiescence. Meningiomas resulting in brain edema are more aggressive than those without edema and require more immediate intervention. Headaches, seizures, balance problems, and visual deterioration can result, depending on their location and the degree of compression of local tissues. One study found that the presence of NF2-associated meningiomas raised the relative risk of mortality by 2. Most NF2-associated spinal ependymomas have an indolent course, remain asymptomatic, and do not require intervention.
Interestingly, NF2 polyneuropathy occurs in the absence of associated nerve sheath lesions. Thus, a patient with NF2 with loss of deep tendon reflexes not explained by associated peripheral nerve schwannomas may need an evaluation for an underlying neuropathy.
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In addition, an underrecognized poliolike illness resulting in irreversible lower extremity monoplegia has been reported in pediatric NF2 and is rarer in adults. Unexplained amblyopia and strabismus are well-documented findings in early childhood NF2. Identification and ongoing monitoring of these abnormalities is important as they can potentially threaten vision.
Like many multisystem disorders, management of NF2 ideally involves specialists from numerous disciplines, including medical genetics, otolaryngology, neurosurgery, neurology, oncology, ophthalmology, and audiology. Depending on the lesions and symptoms identified, follow-up neuroimaging, audiology, and clinical evaluations are required on a regular basis in addition to monitoring by the appropriate subspecialists. Genetic testing and counseling are important components in the management of individuals with NF2.
A high rate of mosaicism exists in NF2, which can complicate confirmation of an NF2 diagnosis and assessment of the risk of family members developing NF2. Of note, while traditional treatment has focused on surgical interventions, over the past decade, attention has turned to the development and use of chemotherapeutic agents, such as bevacizumab, that target the biological pathways involved in tumor growth. These studies have thus far produced mixed results on outcome measures of tumor shrinkage and hearing restoration, but newer agents are in the pipeline.
Oncologic intervention with chemotherapy and radiation is reserved for the more aggressive lesions, which are less common in NF2.
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Noonan syndrome with multiple lentigines is an autosomal dominant RASopathy. The incidence of this rare condition is currently unknown. However, mutations in the RAF1 gene on chromosome 3p No specific diagnostic criteria have been identified for Noonan syndrome with multiple lentigines. Noonan syndrome with multiple lentigines was previously known as LEOPARD syndrome, with the mnemonic describing the clinical features: lentigines figure , electrocardiographic conduction defects, ocular hypotelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness.
When Noonan syndrome with multiple lentigines is suspected, prompt evaluation by a geneticist is recommended, including a thorough clinical assessment and appropriate genetic testing to confirm the diagnosis. A baseline clinical examination should evaluate for associated neurologic, cardiac, genitourinary, and hearing abnormalities. Noonan syndrome with multiple lentigines is inherited in an autosomal dominant fashion, so genetic counseling is necessary for patients and families as well.
A thorough cardiac evaluation, including a clinical examination, ECG, and echocardiogram, is warranted in all patients with Noonan syndrome with multiple lentigines beginning at a young age. It is also important for patients to have serial cardiac evaluations since hypertrophic cardiomyopathy and arrhythmias may develop over time. Hearing screening may need to be repeated annually as hearing loss has been reported to develop at older ages. Tuberous sclerosis complex is a multisystem autosomal dominant disorder that occurs in approximately 1 in individuals, causing hamartomatous lesions that primarily affect the brain, skin, heart, eyes, kidneys, and lungs.
Important genotype-phenotype correlations exist in tuberous sclerosis complex. Analysis of large familial populations of individuals with tuberous sclerosis complex have revealed that TSC1 cases tend to occur more often with a familial inheritance pattern and result in a milder clinical phenotype, while TSC2 cases occur most often sporadically and are characterized by more severe clinical complications. The diagnostic criteria for tuberous sclerosis complex were published in after the first International Tuberous Sclerosis Complex Consensus Conference and were updated in to incorporate the identification of a pathologic mutation in the TSC1 or TSC2 gene as confirmation of a tuberous sclerosis complex diagnosis table Identification of a pathologic mutation in the TSC1 or TSC2 gene is now sufficient to confirm the diagnosis, regardless of the clinical features present.
Tuberous sclerosis complex affects multiple organs of the body, including the skin, CNS, eyes, heart, and kidneys. The cutaneous features of tuberous sclerosis complex are numerous and represent hallmark findings of the disorder that often prompt a diagnostic workup. They are most often present at birth or develop during infancy and remain stable through the lifetime figure The clinical criteria require three or more of these lesions measuring at least 5 mm in diameter to be present to fulfill a major criterion.
Confetti lesions are small 1 mm to 3 mm collections of hypopigmented lesions that occur on the arms and legs and represent a minor feature. CNS involvement affects almost all individuals with tuberous sclerosis complex and clinically manifests with significant neurologic complications, including epilepsy, autism, developmental delays, and intellectual disability. The brain MRI in tuberous sclerosis complex reveals three primary findings: tubers, subependymal nodules, and subependymal giant cell astrocytomas SEGAs in a subset of patients. Tuberous sclerosis complex derives its name from tubers that represent areas of congenital cortical dysplasia and are caused by failure of neuronal migration during fetal development.
They can be detected in utero and are often present at birth, calcifying over time figure As hamartomatous brain lesions, tubers are responsible for the impairing clinical neurologic features of tuberous sclerosis complex, such as medically refractory epilepsy, while stable subependymal nodules remain asymptomatic. SEGAs are a pediatric phenomenon, presenting at the average age of 11 years and rarely developing de novo after 20 to 25 years of age. However, despite the controversies, SEGAs are typically defined by their location, size of 5 mm to 10 mm, contrast enhancement, and progressive growth, while subependymal nodules appear to be nonenhancing static lesions.
SEGA growth is usually slow, measured to be approximately 2 mm to 5 mm per year. When presenting acutely, patients may report headache, nausea, vomiting, ataxia, irritability, lethargy, increased seizures, or visual disturbance. These lesions can be life-threatening because of severe increased intracranial pressure or hemorrhage. SEGAs with an indolent course can be monitored on serial neuroimaging every 1 to 3 years, according to the published guidelines.
The majority of individuals with tuberous sclerosis complex experience intellectual, behavioral, and psychosocial impairments, which are now described with the comprehensive term tuberous sclerosis—associated neuropsychiatric disorders TAND. Depression and anxiety are also not uncommon. A TAND checklist has been validated, and placebo-controlled double-blind clinical trials are currently addressing the efficacy of everolimus in the treatment of TAND-related symptoms.
Tuberous sclerosis complex—associated lesions of the eye rarely affect vision. They are relatively common and are a minor diagnostic feature. The majority of cardiac rhabdomyomas remain asymptomatic, but they can be clinically significant depending on their size and location. Cardiac rhabdomyomas spontaneously regress in the first year of childhood and are less problematic in adolescence and adulthood. A variety of cardiac arrhythmias are also relatively common in children and adults with tuberous sclerosis complex. Irregular, slow, and fast heart rhythms have all been reported and can be clinically significant.
A cardiac rhabdomyoma underlying the conduction pathways is a frequent and well-known cause. An increased incidence of Wolff-Parkinson-White syndrome also exists in the tuberous sclerosis complex population. Renal manifestations are central to the diagnostic criteria and represent a major cause of morbidity and mortality in tuberous sclerosis complex. While often asymptomatic, angiomyolipomas may result in flank pain, hematuria, and spontaneous hemorrhage, which can be life-threatening.