Neurocutaneous syndromes …

Laura Flores-Sarnat MD

Developmental Malformations

Updated 07.07.2023
Released 07.29.2004
Expires For CME 07.07.2026

Neurocutaneous syndromes

Author: Laura Flores-Sarnat MD

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Editor: Harvey B Sarnat MS MD FRCPC

Neurocutaneous syndromes

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Introduction

Overview

Neurocutaneous syndromes are a diverse group of distinctive developmental diseases that affect the nervous system and the skin and have systemic lesions in multiple organs, including bone, endocrine glands, eye, kidney, heart, and lung. Neoplasms, both benign and malignant, are frequent in some of the diseases. In several neurocutaneous syndromes overgrowth is a primary feature. Neurocutaneous syndromes share a common embryological basis as all are disorders of neural crest and, therefore, can be included in the group of neurocristopathies. Autosomal dominant transmission is present in neurofibromatosis 1 and tuberous sclerosis complex, the two most frequent neurocutaneous syndromes. Different Mendelian traits are expressed in other neurocutaneous syndromes. The majority of neurocutaneous syndromes, however, are probably single gene mutations; hence, patients lack a family history of the disorder, and they are “sporadic” diseases. In all the neurocutaneous syndromes included in this review, the defective genes have been identified. Epidermal nevus syndromes and neurocutaneous melanocytosis are characterized by nevi; other neurocutaneous syndromes are characterized by vascular lesions, such as Sturge-Weber syndrome, Klippel-Trenaunay syndrome, PHACES syndrome, and megalencephaly-capillary malformation syndrome. Waardenburg syndrome, a well-known neurocristopathy, also fulfills the criteria to be considered a primary neurocutaneous syndrome.

Key points

	• Neurocutaneous syndromes are a group of congenital disorders that have in common the involvement of the ectodermal derivatives, nervous system, and skin, but also include many mesodermal and endodermal derivatives.
	• Many lesions are hamartomatous.
	• Neoplasia can arise from many of the lesions.
	• Overgrowth of many tissues including brain (hemimegalencephaly) occurs in several neurocutaneous syndromes.
	• Genetic mutations are identified in most neurocutaneous syndromes.
	• Neurocutaneous syndromes are neurocristopathies

Historical note and terminology

The association of neurologic disease with cutaneous and retinal lesions was recognized in the 19th century by Van der Hoeve, a Dutch ophthalmologist who coined the term “phakomatosis” (Greek phakos meaning spot or lens “lentil”) (145; 146). Initially he included tuberous sclerosis, neurofibromatosis, and von Hippel-Lindau disease. The concept of “phakomatosis” lost its original meaning when Van der Hoeve included Sturge-Weber syndrome, which is not characterized by phakomas or hamartomas (56). Etymologically, this term also is inadequate to encompass this entire group because it does not include the nervous system. It is still used by some authors but in a more restricted context (74). In any case, its use should be reserved to those conditions that manifest retinal hamartomas (“phakomas”), as in the original description, including those with inconstant retinal lesions, such as hereditary hemorrhagic telangiectasia, also known as Rendu-Osler-Weber disease (described by Rendu in 1896, Osler in 1901, and Weber in 1907). On the other hand, von Hippel-Lindau disease is a phakomatosis because of the presence of retinal and CNS hemangioblastomas with multisystemic involvement, but it does not correspond to a neurocutaneous disorder because these patients do not have developmental cutaneous lesions.

The term “neurocutaneous syndromes” was introduced by Yakovlev and Guthrie in 1931 to describe this group of disorders as “congenital malformations affecting more or less selectively the ectodermal structures, ie, the nervous system, the skin, the retina, the eyeball and its contents; sometimes visceral organs are also involved” (150). It has the merit of linking the two most obvious manifestations of this group of disorders. However, this term also is not technically correct because cutaneous denotes only the epidermis and dermis, and subcutaneous lesions such as lipomas and subcutaneous neurofibromas also frequently appear in neurocutaneous syndromes. Besides, it is now known that these syndromes involve not only ectodermal derivatives but many other structures than brain and skin. The term “neurocutaneous” should not be applied to infectious diseases that affect the skin and nervous system, such as leprosy. Nevertheless, “neurocutaneous syndromes” remains the best terminology, but should be restricted to primary developmental disorders.

Clinical manifestations

Presentation and course

The neurocutaneous syndromes are a broad group of congenital disorders with diverse genetic, clinical, and pathological features that have developmental lesions of the skin and of the central and peripheral nervous systems in common. Subcutaneous and systemic involvement is frequent. In many of these conditions, a tendency to develop tumors in multiple sites in the body or progressive asymmetric overgrowth can occur. Many of these disorders are hamartomatous in nature, and produce benign tumors, but patients also may develop malignancies. The genetic etiology has been identified in several conditions, which facilitates molecular confirmation.

Evolution of the neurocutaneous syndromes. At present, over 100 neurocutaneous syndromes are described in the literature. Neurologists tend to recognize a more limited number of neurocutaneous syndromes than do some other specialists because of stricter criteria of nervous system involvement.

The various neurocutaneous syndromes are a heterogenous group of multisystemic diseases, some hereditary and others sporadic, that involve the nervous system, the skin, and often other organs. They include neurofibromatosis 1 and 2, tuberous sclerosis complex, Sturge-Weber syndrome, ataxia-telangiectasia, neurologic phenotypes of epidermal nevus syndromes that include linear sebaceous nevus syndrome, Proteus syndrome, CLOVES syndrome (congenital lipomatous asymmetric overgrowth, vascular malformations, epidermal nevi, and skeletal and spinal anomalies), and Heide syndrome (45), Klippel-Trenaunay syndrome, Parkes Weber syndrome, incontinentia pigmenti, hypomelanosis of Ito, and many more. Numerous congenital anomalies, functional abnormalities and tumor formation in other organ systems outside the brain and skin were gradually identified as associated features in many neurocutaneous syndromes, particularly in the most common, tuberous sclerosis complex and neurofibromatosis 1 (56; 31; 114; 119). In the past, it was believed that there were two types of neurofibromatosis (type 1 and type 2), but now it is recognized that they are clinically and genetically distinct diseases and should be considered separate entities. They should, therefore, no longer be named neurofibromatosis type 1 and neurofibromatosis type 2, but rather neurofibromatosis 1 and neurofibromatosis 2 (43).

It is important to make a distinction between primary and secondary neurocutaneous syndromes because they have different pathogeneses and prognoses, and the approach to investigation and management also is different. Primary neurocutaneous syndromes are developmental, dysgenetic conditions. Secondary neurocutaneous syndromes are not developmental disorders; they are the result of, or complications of, previous conditions, usually metabolic or infectious diseases. Examples include: Fabry disease, a lysosomal storage disease caused by deficiency of alpha-galactosidase; Lesch-Nyhan disease, due to a disorder in purine metabolism, which exhibits cutaneous lesions secondary to accidental or self-inflicted injuries; Menkes disease is secondary to abnormal copper transport and metabolism. In this case, the cutaneous and central nervous system lesions are secondary to the metabolic defect; etc.

Key symptoms and characteristics of the neurocutaneous syndromes. In addition to the characteristic cutaneous hypo- or hyperpigmented lesions, vascular lesions and nevi in each of the neurocutaneous syndromes, pathognomonic in some cases and overlapping in others, multiple common features are known. Cutaneous and/or internal vascular dysplasias are frequent and they are the main feature in Sturge-Weber syndrome, Klippel-Trenaunay syndrome, Parkes Weber syndrome (20), Rendu-Osler-Weber syndrome (hereditary hemorrhagic telangiectasia) (132; 54; 131; 147), and megalencephaly-capillary malformation (91), formerly known as macrocephaly-cutis marmorata telangiectatica congenital (25; 99; 115; 78), and PHACES (posterior fossa malformations, facial hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal anomalies) syndrome (53; 76; 36; 63; 106; 137). Subcutaneous and intracranial/intraspinal lipomas are found in several neurocutaneous disorders: epidermal nevus syndrome (particularly Proteus syndrome), Klippel-Trenaunay syndrome, encephalocraniocutaneous lipomatosis, and others. Progressive overgrowth is present in several of the above. Lipomas cause a variety of symptoms depending on the localization (47), including scoliosis with paraparesis (148). In encephalocraniocutaneous lipomatosis, common locations of lipomas are the cerebellopontine angle and/or spinal region (57; 97; 98); vascular hyperplasia and angiogenesis in three distinct involved sites (hairless patch, eyelid papules, hypertrophic conjunctiva) have been reported by Alakad and colleagues (02). The presence of lipomas, together with the cutaneous and vascular lesions, as mentioned above, can be linked with abnormal development in the neural crest (47). With few exceptions (Sturge-Weber syndrome), most of the well-known neurocutaneous syndromes have multisystemic involvement. Congenital alopecia, bitemporal or as a band involving also occipital or parietal scalp, is one of the main characteristics in Gómez-López-Hernández syndrome (55; 85; 138). The other basic features are rhombencephalosynapsis and defective development of the trigeminal nerve. This syndrome is often underdiagnosed and infrequently detected in infants (109; 151). Ocular anomalies are frequent in many neurocutaneous syndromes; they are also prominent in oculocerebrocutaneous or Delleman-Oorthuys syndrome (32; 33; 95; 96); the cutaneous hyperpigmentation may have a striking resemblance to incontinentia pigment (113). In several patients, hydrocephalus and agenesis of corpus callosum have been reported (14).

The tendency to develop malignancies is observed in several neurocutaneous syndromes. For example, in neurofibromatosis 1, in addition to benign neurofibromas and Schwannomas, a high incidence is seen of pheochromocytoma of the adrenal medulla and of optic nerve glioma (pilocytic astrocytoma). Neurofibromatosis 1 patients have a high risk of developing soft-tissue sarcomas and particularly malignant peripheral nerve sheath tumors, often with an aggressive clinical presentation and poor outcome (44). Hamartomatous cells in the brain in tuberous sclerosis frequently become neoplastic as subependymal giant cell astrocytoma (SEGA). Patients with neurocutaneous melanocytosis are at high risk to develop melanoma of the skin and leptomeninges (52; 13). The association of ataxia-telangiectasia with several types of malignancies has been recognized for a long time. Studies on ataxia-telangiectasia families have shown that obligate female carriers have increased risk of developing breast cancer (110). The subependymal nodules of tuberous sclerosis can obstruct the foramen of Monro at any age, causing unilateral hydrocephalus, but benign neoplastic transformation of subependymal lesions into giant cell astrocytomas usually does not occur until after infancy. The genes causing neurofibromatosis 1 and 2 (NF1 and NF2) and those responsible for tuberous sclerosis (TS1 hamartin and TS2 tuberin) are tumor-suppressor genes, amongst their other functions, and mutations in these genes undoubtedly contribute to the development of malignancies. Cerebellar lesions observed in tuberous sclerosis complex are associated with TSC2 mutations (16). Pancreatic neuroendocrine tumors are not included in the diagnostic criteria for tuberous sclerosis complex; however, they are relatively common in children and young adults (72). In ataxia-telangiectasia, exposure to the ultraviolet rays of the sun or artificial ultraviolet light greatly accelerates not only the tendency of cancer of the skin, but also lymphomas. Neurocutaneous melanocytosis is characterized by giant or multiple congenital melanocytic nevi, sometimes associated with malignant melanocytic tumors of the brain, particularly of the leptomeninges, and also the nevi (129). In the brain, these lesions may result in either ischemic or hemorrhagic infarcts, though they only rarely undergo malignant cellular changes as sarcomas. There are several reports of neurocutaneous melanocytosis associated with Dandy-Walker malformation (125; 50).

Overgrowth is a frequent and obvious clinical manifestation in many neurocutaneous syndromes (26; 83; 91) and can be localized or markedly asymmetrical. Mosaicism explains involvement of various organs with asymmetrical expression and localized features. Unlike germline mutations that occur at conception and involve all cells, somatic mosaicism has a mixture of clones of normal and abnormal progenitor cells, with the abnormal cellular clones often showing dysregulation of growth and differentiation as well as proliferation. In hemicorporal hypertrophy, the cellular defect is trophic and anaplastic rather than neoplastic. Hemimegalencephaly, also due to mosaicism, is associated with several neurocutaneous syndromes; it is most frequent in neurologic phenotypes of epidermal nevus syndrome, in particular linear sebaceous nevus syndrome, Proteus syndrome, CLOVES syndrome, and Heide syndrome (45). It is less common in Klippel-Trenaunay-Weber syndrome and in hypomelanosis of Ito, and rare in incontinentia pigmenti, tuberous sclerosis, and encephalocraniocutaneous lipomatosis (46; 48). Neurologic expression frequently includes epilepsy, global developmental delay, and intellectual deficit, but the expected neurologic presentation depends on the specific disease. Some features are already evident at birth, but others are not expressed until later in childhood or even early adult life. In neurofibromatosis 1, polyneuropathies are progressive over years and café-au-lait spots and cutaneous neurofibromas continue to appear over many years; pheochromocytoma may not be clinically expressed until later childhood or adolescence. In neurofibromatosis 2, acoustic neuromas (ie, Schwannomas) usually do not cause hearing loss until adult life. These tumors involve the vestibular branch of the acoustic nerve only rarely in neurofibromatosis 1, but are common in neurofibromatosis 2; the auditory branch of the acoustic nerve may become involved in both diseases.

On rare occasions, two or more neurocutaneous disorders coexist, which may complicate the clinical picture and prognosis (03; 59; 100). It is thought that when Klippel-Trénaunay syndrome and Sturge-Weber syndrome coexist, the presence of persistent, extensive, and aberrant Mongolian spots carries a worse prognosis. This may be particularly true in children of Asian, Hispanic, or African ethnicity (59). Phakomatosis pigmentovascularis, named by Ota in 1947, is a rare syndrome characterized by the association of a widespread vascular nevus with an extensive melanocytic nevus (61; 140; 102). In some cases it can be associated with better known neurocutaneous syndromes (42). An infant with a complex combination of neurocutaneous melanocytosis, encephalocraniocutaneous lipomatosis, and epidermal nevus syndrome presented a severe neurologic picture associated with hemimegalencephaly (01). Another example of coexistence of multiple neurocutaneous syndromes is phakomatosis pigmentovascularis type IIb associated with Klippel-Trenaunay syndrome and congenital triangular alopecia (142). There are also reports of Sturge-Weber syndrome with Klippel-Trenaunay syndrome (108). The coexistence of MRI signs of Sturge-Weber syndrome with tuberous sclerosis in a child might suggest common anomalous angiogenesis (30).

Systemic involvement due to mosaicism is characteristic of neurocutaneous syndromes that also causes hemimegalencephaly (80) explains the association with several neurocutaneous syndromes, in particular neurologic phenotypes of epidermal nevus syndrome (45). Defects in enamel and other dental anomalies are seen in tuberous sclerosis complex, incontinentia pigmenti, and Proteus syndromes. Cardiovascular anomalies such as coarctation of the aorta, septal defects, and also anomalous conduction system manifested as congenital arrhythmias observed in linear sebaceous nevus syndrome are secondary to defects in the cardiac neural crest (49). The cardiovascular malformations in PHACE syndrome also are produced by the same mechanism.

Endocrinopathies, including diabetes mellitus, thymoma, and hypophosphatemia, may appear clinically at any age (06; 81). Bony dysplasias usually are evident early in life. Striated muscle is affected in some neurocutaneous syndromes, such as Proteus syndrome, and cardiac muscle is affected in others, such as tuberous sclerosis complex. The immune system is affected in ataxia-telangiectasia (Louis-Barr disease). The expression may be incomplete at times, resulting in forme fruste. The extent and severity of manifestations is usually the clinical expression of genetic polymorphism, with ratios of normal and abnormal DNA found in different organs as an expression of mosaicism, and these differences vary almost randomly in different individuals, even in the same families. Funduscopic examination is an important component of the physical examination because ocular, retinal, and conjunctival anomalies are frequent in many neurocutaneous syndromes, such as tuberous sclerosis, linear sebaceous nevus syndrome, the most frequent neurologic phenotype of epidermal nevus syndrome (45), Sturge-Weber syndrome, and ataxia telangiectasia; optic nerve atrophy may be detected in children with optic gliomas associated with neurofibromatosis 1. The two most frequent neurocutaneous syndromes are neurofibromatosis 1, with an incidence of 1 in 3000 (119), and tuberous sclerosis, with an incidence of 1 in 6000 to 10,000 (31). Sturge-Weber syndrome, epidermal nevus syndromes, and ataxia-telangiectasia are less frequent. Neurofibromatosis 2 is much less frequent than neurofibromatosis 1, with an estimated incidence of 1 in 50,000 (119). Most other neurocutaneous syndromes are rare.

Prognosis and complications

In general, the prognosis of neurocutaneous syndromes is guarded because of the frequent systemic involvement and the progressive course of several manifestations such as epilepsy, focal or regional overgrowth, vascular lesions, etc. Another important factor is the tendency to develop malignant tumors, including skin cancers or leukemia in particular cases. The impact on prognosis, complications, and outcome should consider aspects of quality of life (04; 118).

Biological basis

At present, genetic mutations are identified in the majority of neurocutaneous syndromes.

The embryological basis of neurocutaneous syndromes has fascinated physicians but had evaded understanding for almost two centuries. The traditional explanation was that skin and the nervous system both derive from the ectodermal germ layer at gastrulation, hence, a disturbance should involve both derivatives. This concept was reinforced in the early 20th century by the discovery of the principle of induction. For example, if the primordial retina of the embryonic optic cup is defective, it cannot induce the differentiation of a crystalline lens and cornea, and so the overlying ectoderm simply forms more epidermis. From this principle, an idea was extrapolated that a defective neuroepithelium somehow induces a defective epidermis at a time when the ectodermal germ cell layer is only beginning to differentiate. However, induction more frequently occurs between, rather than within, germ layers, as in the induction by the mesodermally-derived notochord of the neural placode to form a floor plate in the ventral midline at the initiation of neurulation, an induction mediated by the gene Sonic hedgehog (SSH). Furthermore, many of the cutaneous anomalies in the neurocutaneous syndromes are from mesodermal, not ectodermal, derivatives, such as the vascular malformations and an excess or a paucity of pigment-forming melanocytes in the dermis.

Another factor that plays an important role in linking dysplasias of both skin, brain, and systemic is the formation and migration of neural crest cells from the dorsal midline of the closing neural tube. Neural crest arises segmentally in all three primitive cerebral vesicles: rhombencephalon, mesencephalon, and prosencephalon. In the face, mesencephalic neural crest forms not only structures of the peripheral nervous system, such as the ciliary ganglion and Schwann cells, but also many nonneural tissues of mesodermal origin: melanocytes of the skin, stria vascularis of the cochlea and other sites, membranous bones of the orbits and face, most of the globe of the eye, connective tissues and vascular structures (58; 79; 133; 19). The midline linear hyperpigmented nevus nevi of the forehead in sebaceous nevus syndrome, for example, denotes a disturbance of prosencephalic neural crest, and neurofibromatosis almost certainly involves a disturbance of rhombencephalic neural crest (47).

The explosion of molecular genetic data diminishes the importance of embryonic germ layers, long believed to be fundamental in cellular lineage, because it is now recognized that the same organizer and regulator genes program development and cytological differentiation in various tissues, and that genes do not respect embryonic germ layers. Examples are the HOX and PAX families, both primordial in the embryonic segmentation of the neural tube but also in the ontogenesis of bone, kidney, gut, and many other tissues. This genetic programming is not single gene deletions or mutations but involves downregulation of downstream genes in a cascade, overexpression of antagonistic genes, and complex multigenetic interactions. Trophic factors important in neural crest migration and maturation also might be defective in some of these syndromes. Though most malformations involve tissues of at least two germ layers, a few seem specific to a single germ-cell layer, in particular some cerebral malformations. However, even such dysgeneses as lissencephaly type I (Miller-Dieker syndrome) that are largely confined to the brain also can be suspected clinically by characteristic dysmorphic facies that denote other germ layers, again due to mesencephalic neural crest involvement. Many families of genes are primordial not only in neural tube development and segmentation but also are essential to craniofacial development (10).

With the recognition of congenital malformations of the brain due to defective genetic programming, all neurocutaneous syndromes may be examples, though only some are transmitted as Mendelian traits. Many overlapping features of various neurocutaneous syndromes can be attributed to a common cause that affects parts of the neural tube from which neural crest tissue is derived; hence, the entire category of “neurocristopathies” now includes the group of “primary” neurocutaneous syndromes (47). Waardenburg syndrome, a well-known neurocristopathy, was first described by Van der Hoeve (144). Four types of Waardenburg syndrome exist, all characterized by a hypopigmentary disorder due to an absence of melanocytes (112; 47) The neurosensorial congenital deafness and other neurologic manifestations justify the inclusion of this entity in the group of neurocutaneous syndromes (47). The etiology of the four forms of Waardenburg syndrome is known already, however, it is a constellation of signs and symptoms and therefore it is still justified to continue calling it a syndrome (47).

Neuropathological findings can be almost as diverse as the clinical manifestations. Nevertheless, the microscopic findings can be nearly identical in several different diseases. For example, the findings in hemimegalencephaly tissue are indistinguishable when they occur in the isolated form or associated with neurocutaneous syndromes (51). In general, the cerebral lesions of the neurocutaneous syndromes may be summarized as (1) malformations of cerebral architecture or dysplasia, ie, the laminar or nuclear relations of neurons within a region, orientation of neurons, and defective neuroblast migrations; (2) hamartomas in which cellular growth and differentiation, including cellular lineage, are defective, as well as architecture (eg, tuberous sclerosis; hemimegalencephaly); megalocytic, dysplastic neurons and glial cells and multinuclear neurons may be demonstrated; (3) abnormal vasculature and microcirculation, sometimes leading to cerebral microinfarcts, hemorrhages, and dystrophic calcifications; (4) maturational delay or arrest, including myelination; (5) abnormal synaptogenesis and cerebral circuitry that probably contribute to epilepsy; (6) neoplastic transformation or anaplasia; (7) distinct histological patterns within tubers based on semiautomated histological quantification and to find clinically significant correlations.

In a neuropathological study of cortical tubers and perituberal cortex from patients who had epilepsy surgery, the mTORC1 activation was assessed and also giant cells, dysmorphic and normal neurons, oligodendrocytes, calcification, gliosis, angiogenesis, inflammation, and myelin content. The correlation with presurgical MRI provides criteria to define clinico-pathological features of cortical tubers identified by MRI (101).

The category of “neurocutaneous syndromes” includes molecular genetic bases that are integrated with the classical clinical and pathological findings. Proteus syndrome is due to a mutation in the AKT1 gene (83) and hemimegalencephaly, a related anomaly, is associated with a closely related defective gene, AKT3 (80). Several neurocutaneous syndromes, in particular neurologic phenotypes of epidermal nevus syndrome, can be associated with hemimegalencephaly or focal cortical dysplasia (45). Hemimegalencephaly, cortical tubers, and cortical dysplasia type 2 exhibit enhanced levels of abnormally phosphorylated tau protein and evidence of mTOR hyperactivation (122). In PIK3CA-related overgrowth spectrum there is an abnormal PI3K-AKT-mTOR pathway activation (71; 70; 84; 89). Lipidosis of neurons and glia in hemimegalencephaly suggest metabolic impairment of mTOR hyperactivation related to tauopathy (124). Inhibition of mTOR pathway signaling during embryogenesis could prevent abnormal brain development in tuberous sclerosis complex (141).

In sum, the embryological bases of the neurocutaneous syndromes include (1) the defective expression of genes that program both skin and nervous system; (2) defective neural crest can explain zones of cutaneous hyper- or hypopigmentation, anomalous vascular malformations of the skin, meninges, and other tissues, focal dysplasias and neoplasias of the central and peripheral nervous systems, including benign neurofibromas and schwannomas (Sarnat and 45). Trophic disturbances in cellular differentiation occur in tuberous sclerosis complex and in hemimegalencephaly associated with several neurocutaneous syndromes, in particular the neurologic phenotypes of epidermal nevus syndrome, such as linear sebaceous nevus syndrome, Proteus syndrome, CLOVES syndrome, and Heide syndrome (45); (3) the common derivation of skin and CNS from the ectodermal germ layer, once believed of great importance, probably plays a minimal role in pathogenesis (48). Epidermal, sebaceous, and melanocytic nevoid proliferations are spectra of mosaic RASopathies (09; 86).

The majority of neurocutaneous syndromes are “sporadic” single gene somatic postzygotic mutations. Hence, patients lack a family history of the disorder. In some, a clear Mendelian inheritance exists, exemplified in the autosomal dominant trait strongly expressed in neurofibromatosis 1 and 2 and in tuberous sclerosis. In others, such as incontinentia pigmenti (Bloch-Sulzberger syndrome), X-linked inheritance is demonstrated with linkage at the Xq28 locus; mutations in the NEMO gene cause this disease (136). The specific genetic mutations are known in tuberous sclerosis (two genes), neurofibromatosis 1 and 2, and ataxia-telangiectasia. In most of the syndromes, neither autosomal nor X-linked transmission is evident, and the disorders appear sporadic. Sturge-Weber disease is an example. It was demonstrated that Sturge-Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ (130).

This confirmation of the pathogenesis of port wine stains and Sturge Weber syndrome due to mutations in GNAQ also includes activation of MAPK, or PI3K, or both to these malformations. Current data support that: (1) port wine stains are a multifactorial malformation involving the entire physiological structure of human skin; (2) port wine stains should be pathoanatomically redefined as "a malformation resulting from differentiation-impaired endothelial cells with a progressive dilatation of immature venule-like vasculature"; (3) dysregulation of vascular MAPK and/or PI3K signaling during human embryonic development contributes to the pathogenesis and progression of port wine stains and Sturge Weber Syndrome; and, (4) sporadic low-frequency somatic mutations, such as GNAQ and PI3K, work together, not in isolation, defining the development of the vascular phenotypes (104). Many other sporadic syndromes are almost certainly genetic in origin as well, but are single gene or multiple gene mutations or deletions. Studies on human tuberous sclerosis complex and animal models contribute to elucidate the critical roles of hamartin and tuberin in regulating the growth and differentiation of neural cells (92). Several investigators have demonstrated that the TSC1- and TSC2-encoded proteins bind as cytoplasmic heterodimers and act to inhibit the activity of the serine kinase mammalian target of rapamycin (mTOR) (65; 37). The mTOR hyperactivation has been associated with abnormal phosphorylated tau overexpressed in dysplastic neurons in tuberous sclerosis, as also occurs in hemimegalencephaly (124). There are approximately 700 allelic mutant TSC1 and TSC2 gene variants that exhibit variable penetrance and pleiotropy. A clear genotype-phenotype correlation has not been established, although in general patients with TSC2-associated disease may be more severely affected (28). Tuberous sclerosis complex is characterized by increased mammalian target of rapamycin (mTOR) activation and growth of benign tumors in several organs throughout the body. In the rare case of patients who present tubers but absence of subependymal nodules no mutation was identified in TSC1-TSC2, suggesting mosaicism with a first postzygotic mutation in the neuroectoderm (15).

No measures to prevent any of the neurocutaneous syndromes are known, though prenatal detection is available for some, such as neurofibromatosis 1, tuberous sclerosis, Sturge-Weber syndrome (18), and neurologic phenotypes of epidermal nevus syndrome that include linear sebaceous nevus syndrome, Proteus syndrome, CLOVES syndrome, and Heide syndrome (45).

Genetic counseling may be provided as with any hereditary disease with Mendelian transmission, and risk factors for rare nonmendelian genetic mutations can be estimated for parents who want this information for their family planning. Consanguinity is rare (22).

Diagnostic workup

Skin lesions at times are diagnostic, such as the multiple types of lesions of tuberous sclerosis. Neuroimaging studies are essential for the confirmation of the neurocutaneous disorders (82). They provide information for determining the site and extent of cerebral lesions. Magnetic resonance (MR) imaging is of particular importance. In Sturge-Weber syndrome, MR perfusion imaging with dynamic gadolinium bolus is a sensitive indicator of perfusion abnormalities that can be performed easily at the same time as the diagnostic scan, permitting correlation with perfusion abnormalities and high-resolution imaging (39).

Though MRI is more precise and has higher resolution, CT often is more helpful in determining the presence of periventricular calcifications in tuberous sclerosis and also may be used to study the parents of affected children for subclinical evidence of the autosomal dominant trait. The risk of radiation, however, precludes its routine use and use for sequential follow-up. Specific genetic markers in blood or in cultured fibroblasts from skin biopsy are useful in some disorders in which the diagnosis is not obvious because of a paucity of cutaneous lesions but with neurologic symptoms and signs or a family history. Biopsy of questionable lesions of skin or peripheral nerve (eg, cutaneous neurofibromas) may confirm the nature of the lesions. The indications for procedures such as neuroimaging, biopsies, and genetic testing depends on the suspected diagnosis, the family history (or lack thereof), and the inconclusiveness of pathognomonic physical findings. At times, serial MRI may be needed over years, for example, to follow the progress of subependymal and cortical lesions in tuberous sclerosis and to ensure that obstructive hydrocephalus at the foramen of Monro is not developing. It is important to detect every neurocutaneous disorder as early as possible. Most of these conditions can and should be diagnosed during pregnancy by fetal ultrasound or MRI. A large neonatal subependymal giant cell astrocytoma was identified in utero at 19 weeks of gestation in a high-risk pregnancy with no family history of tuberous sclerosis complex (111). Molecular genetic testing confirmation is now available for multiple neurocutaneous syndromes (69). Sturge-Weber syndrome is caused by somatic mutation in GNAQ (130). Demonstration of PIK3CA mutations in patients with distinctive presentation known as PIK3CA-related overgrowth spectrum includes several neurocutaneous syndromes, CLOVES syndrome (77), MCAP syndrome (90; 84), and Klippel-Trenaunay syndrome (71; 143; 89). Given the complexity of neurocutaneous syndromes, a multidisciplinary approach has been advocated in order to provide optimum care (73).

In all patients with neurocutaneous syndromes, it is particularly important to establish an early multidisciplinary approach due to the complex presentation that involves multisystemic anomalies.

Early diagnosis of tuberous sclerosis complex, and other neurocutaneous syndromes, before seizure onset, is feasible and is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early tuberous sclerosis complex diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination, and genetic testing should be performed early in every patient suspected of having tuberous sclerosis complex (135). Prenatal diagnosis of most neurocutaneous syndromes with ultrasound or MRI is important due to their multiple symptoms and complications. In a report of four cases of Klippel-Trenaunay syndrome prenatally diagnosed, one had a rare ectrodactyly of the hand (68).

Management

Management depends largely on the individual diseases and their clinical expression. Cutaneous and subcutaneous lesions often may be treated medically, and not only for cosmetic purposes, for example, the facial angiomas or “port wine stain” in Sturge-Weber syndrome. The evidence that the activation of MAPK, PI3K, or both, contributes to the malformations in the pathogenesis and progression of port wine stains and Sturge Weber syndrome represents a potential treatment approach targeting these aberrant dysregulated signaling pathways (104). Several options are available for the treatment of hemangiomas including surgical resection with the varioscope, an operating microscope, and laser therapy. (21). Dermabrasion may be used to minimize facial angiofibromas (ie, the “adenoma sebaceum” of tuberous sclerosis, an obsolete term because these cutaneous lesions are neither adenomatous nor sebaceous). Topical everolimus has been used for facial angiofibromas (34). Lipomas in the face can be selectively resected. In the case of congenital facial infiltrative lipomatosis, a high risk of recurrence after surgery exists. Individual tubers or subependymal hamartomas in tuberous sclerosis at times may be approached surgically if obstructive hydrocephalus or rapid growth suggesting neoplasia are evident. Pheochromocytomas should be treated both by resection of the lesion and medical control of blood pressure. Cutaneous neurofibromas may be selectively excised for diagnostic confirmation and for cosmetic reasons, but multiple subcutaneous or cutaneous lesions are not practical to remove. In certain cases, complex surgery is required, for example in severe sphenoid wing dysgenesis (88). Radiotherapy should be used cautiously in children with neurofibromatosis 1 due to a significantly increased risk of second nervous system tumors after radiation (40; 127). The finding that the mTOR pathway may participate in the development of tumors in neurofibromatosis type 1 and tuberous sclerosis complex has encouraged investigation of a possible therapeutic role for mTOR inhibitors such as everolimus (Rapamycin) (41; 27).

Patients with neurofibromatosis 2 receiving bevacizumab reported a decrease of tumor volume in 47%, hearing improvement in 56%, and better outcomes. However, toxicity included hypertension, proteinuria, dysgeusia, and amenorrhea (139).

Everolimus is effective and safe in infants and young children with epilepsy and subependymal giant cell astrocytoma secondary to tuberous sclerosis complex (75; 29). Pancreatic neuroendocrine tumors in tuberous sclerosis complex are relatively common and can also be treated with everolimus (72). Cardiac rhabdomyomas detected in the perinatal period sometimes show spontaneous regression; however, in severe cases, everolimus has been beneficial (94; 35; 07). An infant with multiple cortical tubers who developed refractory epileptic spasms and acute encephalopathy was controlled after total corpus callosotomy (105). Subependymal giant cell astrocytomas are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex. Early neurosurgical resection has been the only standard treatment until recently, when it was found that patients experienced clinically significant response to everolimus and early shrinkage of the subependymal giant cell astrocytomas with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals (93). Recommendations suggest early introduction of vigabatrin if ictal discharges occur on EEG recordings, even without clinical expression (135).

Often the diagnosis of tuberous sclerosis complex is made after the appearance of seizures. However, presymptomatic or early treatment with vigabatrin is recommended to improve neurodevelopmental outcome. Early diagnosis, before the onset of seizures, is important (23).

Surgical treatment in neurocutaneous syndromes is often necessary. A report describes a rare case of massive bilateral angiomyolipomas in a tuberous sclerosis patient who presented with spontaneous symptomatic bleeding, anorexia, and failure to thrive. Selective renal embolization was performed to decrease the bleeding and volume of the renal tumor and correct the anorexia and failure to thrive (12). Surgical resection of subependymal giant cell astrocytomas is still considered as the first-line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. Sirolimus, an inhibitor of mTOR, is now used in the treatment of vascular anomalies in children (60).

Removal of large and giant melanocytic nevi to reduce the risk of melanoma has been recommended by dermatologists and plastic surgeons, using a variety of procedures (05). Bittencourt and colleagues do not support multiple skin surgeries in these patients because the risk of fatal neurocutaneous melanocytosis is higher than the risk of cutaneous melanoma (13). In infants, neurocutaneous melanocytosis can present with increased intracranial pressure and hydrocephalus that requires ventriculoperitoneal shunt. Symptomatic neurocutaneous melanocytosis refractory to radiotherapy and chemotherapy has a poor prognosis (128). Capillary malformations can be treated with pulsed dye laser and venous malformations with sclerotherapy or embolism of the ectatic veins (89). Perinatal treatment of hemimegalencephaly with everolimus is plausible (149). Cannabidiol has been recommended for drug-resistant epilepsy in tuberous sclerosis (62).

Social and psychosocial support has been recommended for patients with tuberous sclerosis complex (04), but it is important for all patients with neurocutaneous syndromes.

A meta-analysis suggests that the neurofibromatoses are broad-spectrum diseases affecting physical function, bodily pain, mental health, social function, and general health (118).

Special considerations

Evaluation of quality of life. A systematic review and meta-analysis of quality of life in neurofibromatosis patients suggests that the broad-spectrum of neurofibromatosis manifestations affect physical function, bodily pain, mental health, social function, and general health (118).

A study found that the quality of life of children with tuberous sclerosis complex was lower than those of children who suffer from asthma, diabetes, cancer, and inflammatory bowel disease due to the need to acquire coordinated medical care across disciplines, including psychosocial and social support (04).

Impaired quality of life is found in all patients with tuberous sclerosis complex regardless of the presence of epilepsy and learning disabilities. The psychosocial domain is most affected.

The evaluation of quality of life is important in all patients with neurocutaneous syndromes.

Pregnancy

Pregnancy usually is uncomplicated. Tuberous sclerosis complex, Sturge-Weber syndrome (18), and neurologic phenotypes of epidermal nevus syndrome may be diagnosed in the last trimester by fetal ultrasound or MRI. Rarely, fetal subependymal giant cell astrocytoma may be diagnosed by MRI (66). A patient with undiagnosed Sturge-Weber syndrome complained of headache during pregnancy that disappeared after she gave birth to a child without a port wine birthmark through caesarean section. This case supports the premise that pregnant women with Sturge-Weber syndrome can deliver safely (87; 134). A report of four prenatally diagnosed cases of Klippel-Trenaunay syndrome showed a rare case with ectrodactyly of the hand in one fetus (68). Hemimegalencephaly associated with neurocutaneous syndromes may be diagnosed by prenatal ultrasound or MRI. Children with hemimegalencephaly and macrocephaly may require caesarean section because of cephalopelvic disproportion. No known environmental risk factors in pregnancy (eg, drugs or radiation) exist for developing neurocutaneous syndromes. An unusual case of severe pain due to a tuberous renal lesion and the obstetric management of the patient with intrathecal opioids was reported (17). Most neurocutaneous syndromes can be detected prenatally by ultrasound or fetal MRI for their cerebral and systemic involvement and even by detection of the cutaneous lesion as in the case of linear nevus sebaceous in the forehead (103). Genetic prenatal diagnosis of neurocutaneous syndromes due to PIK3CA mutations is important and can be performed in cultured amniocytes (38). Prenatal diagnosis of tuberous sclerosis complex is important because it has a positive impact on the treatment of systemic complications, including epilepsy (23).

Anesthesia

Patients with neurocutaneous syndromes often require surgery and, in general, no contraindications or complications related to the anesthetic procedure are seen. In a patient with Delleman-Oorthuys syndrome (oculocerebrocutaneous syndrome) the perioperative course was uneventful; however, he had significant preoperative complications such as seizures and an episode of aspiration pneumonia (117). These complications may arise in any patient with severe neurologic deficit, which occurs in many patients with neurocutaneous syndromes. In particular cases, patients with epidermal nevus syndrome require specific anesthetic anticipation. In neurofibromatosis 1, anesthetic complications may occur with neurofibromas in the oropharynx, larynx, and tongue (64) or gastric outlet obstruction (126). Anesthetic care of patients with Osler-Weber-Rendu syndrome should include several interventions such as control of bleeding, maintaining adequate oxygenation, and balance of hemodynamic values that optimize perfusion without compromising anesthetic depth (107). In these patients, transesophageal echocardiogram may be indicated to rule out intracardiac thrombus and significant structural cardiac anomalies (116). A child with PHACES syndrome presented left facial hemangiomas, coarctation of the aorta, aplasia of the left vertebral artery, and stenosis of the left internal carotid artery. During the surgical repair of the aorta under general anesthesia she developed cerebral hypoperfusion that was corrected after increasing the inhalational oxygen concentration (67).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Laura Flores-Sarnat MD

Dr. Flores-Sarnat of the University of Calgary has no relevant financial relationships to disclose.
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Editor

Harvey B Sarnat MS MD FRCPC

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.
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ICD & OMIM codes

ICD-9: Neurofibromatosis unspecified: 237.70

Tuberous sclerosis: 759.5

Other congenital hamartoses not elsewhere classified: 759.6
ICD-10: Neurofibromatosis: Q85.0

Tuberous sclerosis: Q85.1

Other phakomatoses, not elsewhere classified: Q85.8

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Neurocutaneous syndromes

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Epidermal nevus syndrome
Epilepsy
Hemimegalencephaly
Hypomelanosis of Ito
Incontinentia pigmenti
- Intellectual disability
- Malformations of the brain
- Megalencephaly
- Neurofibromatosis type 1
- Sturge-Weber syndrome
- Tuberous sclerosis complex
- Waardenburg syndrome

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Neurocutaneous syndromes

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X-linked hydrocephalus (L1 syndrome)

Carnitine palmitoyltransferase II deficiency

Cerebro-oculo-facio-skeletal syndrome

Pyruvate carboxylase deficiency

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Vanishing white matter disease

Wilson disease

Schizencephaly

Neurocutaneous syndromes

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

ICD & OMIM codes

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Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Carnitine palmitoyltransferase II deficiency

Cerebro-oculo-facio-skeletal syndrome

Pyruvate carboxylase deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Wilson disease

Schizencephaly

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