FEATURE Common Neurocutaneous Syndromes - Healio · in Patients with Neurofibromatosis Type 1 • Development (learning disabilities and cognitive impairment) • Visual acuity and

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FEATURE

Common Neurocutaneous SyndromesHeather Little, DO; Deepak Kamat, MD, PhD; and Lalitha Sivaswamy, MD

Abstract

Neurocutaneous syndromes are a di-

verse group of neurologic disorders with

concurrent skin manifestations. Most neu-

rocutaneous syndromes have a genetic ba-

sis and are believed to arise from a defect

in the differentiation of the primitive ecto-

derm. In this regard, the skin can be a win-

dow into the central nervous system and

can aid in the diagnosis of neurologic dis-

ease in children. The cutaneous signs may

be subtle, which places great importance

on the physical examination skills of clini-

cians providing primary care to children.

Early recognition can help with proper

diagnosis, formulating a treatment plan,

anticipating potential complications, mak-

ing appropriate referrals, and offering ge-

netic counseling to families. [Pediatr Ann.

2015;44(11):496-498,500-504.] The skin and the central nervous system (CNS) are derived from a common embryologic origin dur-

ing fetal development. Mutations affecting the formation, migration, and differen-tiation of these cells are responsible for a group of diseases termed neurocutaneous syndromes, with considerable overlap of neurologic and dermatologic manifesta-tions. This review discusses the clinical spectrum, diagnostic criteria, and manage-ment of some of the most common neu-rocutaneous syndromes in children. It also emphasizes the role of the primary care provider in caring for these children and summarizes important areas of the annual physical examination.

NEUROFIBROMATOSISNeurofibromatosis (NF) was previous-

ly considered a single disorder, but is now divided into two genetically distinct forms: NF type 1 (NF1) and NF type 2 (NF2).1

Both types are transmitted by autosomal dominant inheritance with considerable variation in expression, but approximately 50% of patients represent new, spontane-ous mutations.1

NF1 NF1 is the most common neurocuta-

neous syndrome with a prevalence of ap-proximately 1 in 3,000 people.2 The NF1 gene is located on chromosome 17 and is responsible for encoding the protein neurofibromin, which aids in the down-regulation of cellular proto-oncogenes. Mutations in the NF1 gene result in re-duced amounts of functional neurofibro-min, causing the wide variety of clinical features and associated tumors.3

Clinical FeaturesSkin. The most common skin manifes-

tations are café au lait spots, as all patients will have them by age 2 years. Café au

Heather Little, DO, is a Pediatric Neurology

Resident, Children’s Hospital of Michigan. Deepak

Kamat, MD, PhD, is a Professor of Pediatrics, and

Vice Chair of Education, Department of Pediatrics,

Wayne State University; and a Designated Institu-

tional Official, Children’s Hospital of Michigan.

Lalitha Sivaswamy, MD, is an Associate Professor

of Pediatrics and Neurology, Wayne State Univer-

sity School of Medicine; and the Program Direc-

tor for the Child Neurology Residency Program,

and Pediatric Neurologist, Children’s Hospital of

Michigan.

Address correspondence to Lalitha

Sivaswamy, MD, Departments of Pediatrics and

Neurology, Children’s Hospital of Michigan, 3901

Beaubien Boulevard, Detroit, MI 48201; email:

[email protected].

Disclosure: The authors have no relevant fi-

nancial relationships to disclose.

doi: 10.3928/00904481-20151112-11

Figure 1. Axillary freckling in a toddler with neurofibromatosis type 1. Figure courtesy of Tor Shwayder, MD, Director, Pediatric Dermatology, Henry Ford Hospital.

PEDIATRIC ANNALS • Vol. 44, No. 11, 2015 497

FEATURE

lait spots are flat, pigmented lesions that increase in number and size until puber-ty.2 Freckling in the axillary and inguinal area is another common cutaneous find-ing that tends to begin in early childhood (Figure 1). Cutaneous neurofibromas occur in 99% of patients and manifest as single or multiple firm, rubbery bumps of varying sizes on the skin.

Eye. Lisch nodules are small hamarto-mas on the iris that don’t impair vision and are seen in nearly all patients by age 21 years.2 Optic gliomas are benign tumors that occur in 15% to 20% of patients.4 Pa-tients with optic gliomas may also have precocious puberty if there is invasion of the hypothalamus.

Central nervous system: Learning dif-ficulties occur in the majority of patients with NF1, although severe cognitive im-pairment is rare.2,4,5 Gliomas may occur in all parts of the nervous system but have a preference for the optic nerves, brainstem, and cerebellum.6 Patients can also develop aqueductal stenosis, epilepsy, cerebral gli-omas, and central nervous system (CNS) vasculopathy.6,7 NF1 vasculopathy can re-sult in cerebrovascular disease, including carotid artery stenosis, moyamoya syn-drome, hemorrhage, and aneurysm.7

Peripheral nervous system. Plexiform neurofibromas are benign tumors that grow along the length of a nerve and can cause significant morbidity because of the propensity for diffuse nerve and plexus involvement.8 Malignant peripheral nerve sheath tumors can occasionally arise from preexisting plexiform neurofibromas and are predominately found in adults.

Renal. Pheochromocytoma and renal artery stenosis are rare, but must be con-sidered in patients with hypertension.4

Orthopedics. Sphenoid dysplasia caus-ing orbital proptosis, scoliosis of the spine, and bowing of long bones may occur in patients with NF1.

DiagnosisThe diagnostic criteria for NF1

(Table 1) are reliable and based on clini-

cal assessment. An important caveat to note is that skin findings develop over time and only half of children with NF1 will meet diagnostic criteria in infancy; thus, a thorough annual examination is crucial. Magnetic resonance imaging (MRI) may provide additional diagnostic information as areas of increased T2 signal intensity (formerly called unidentified bright ob-jects [UBOs]) are often present and are pathognomonic of NF1.9 DNA testing is available but rarely needed.

ManagementOnce the diagnosis is considered,

referral should be made to a clinician skilled in the diagnosis of NF1. A multi-disciniplinary team is ideal for the care of

children with NF1 (Table 2). Management is primarily supportive, such as controlling seizures with antiepileptic drugs, provid-ing educational help for children with aca-demic challenges, orthopedic intervention when necessary, and performing surgery for symptomatic and accessible brain and nerve tumors. Baseline brain and spine MRI and routine screening investigations in asymptomatic patients are not recom-mended as they do not influence manage-ment.4 All children with NF1 younger than age 10 years should undergo yearly eye examinations. All children with uncom-plicated disease should be assessed once a year, at minimum, by a physician knowl-edgeable in the manifestations of NF1, preferably in a multidisciplinary clinic.

TABLE 1.

Diagnostic Criteria for Neurofibromatosis Type 1Presence of two or more of the following features is considered diagnostic • Six café au lait spots >5 mm in diameter in prepubertal children or >15 mm in postpubertal

children

• Two or more neurofibromas or one plexiform neurofibroma

• Freckling in the axillary or inguinal region

• Optic glioma

• Two or more iris hamartomas (Lisch nodules)

• A distinctive osseous lesion (sphenoid dysplasia or thinning of long bones)

• A first-degree relative with neurofibromatosis type 1

Adapted from the National Institutes of Health.29

TABLE 2.

Important Areas of Annual Physical Examination in Patients with Neurofibromatosis Type 1

• Development (learning disabilities and cognitive impairment)

• Visual acuity and fundoscopy until age 7 years (optic pathway glioma, glaucoma)

• Head circumference (rapid increase might indicate tumor or hydrocephalus)

• Height and weight (abnormal pubertal development)

• Pubertal development (precocious puberty due to pituitary/hypothalamic lesion)

• Blood pressure (consider renal artery stenosis/pheochromocytoma)

• Cardiovascular examination (congenital heart disease)

• Evaluation of spine (scoliosis ± underlying plexiform neurofibromas)

• Skin examination (cutaneous, subcutaneous, and plexiform neurofibromas)

• Focal neurologic symptoms or examination findings (plexiform or cerebral neurofibroma,

aqueductal stenosis)


FEATURE

NF2The defining feature of NF2 is the de-

velopment of bilateral vestibular schwan-nomas (VS). NF2 is caused by mutations in the NF2 gene, which is located on chromosome 22 and is responsible for encoding the protein merlin.2 The esti-mated prevalence is 1 in 60,000.1,10

Clinical FeaturesSkin. Skin manifestations in NF2 are

more subtle and less common than in NF1. About 70% of patients with NF2 have skin tumors, which are usually schwannomas, but occasionally neurofi-bromas can occur.10

Eye. Patients often suffer from re-duced visual acuity due to cataracts, op-tic nerve meningiomas, or extensive reti-nal hamartomas.

CNS. VS typically appear in early adulthood and present with hearing loss, tinnitus, and dizziness. Other CNS tu-mors, such as meningiomas and epen-

dymomas, can also occur. In childhood, patients often present with symptoms from an intracranial meningioma, spinal tumor, or cutaneous tumor.10

DiagnosisDiagnosis is made by taking a thor-

ough clinical and family history, conduct-ing a physical examination (including ophthalmic examination), and obtaining MRI of the brain and spinal cord. Genetic testing can be performed in the setting of a positive family history or to confirm di-agnosis of NF2, although it is not a part of the diagnostic criteria (Table 3).

ManagementManagement of NF2 involves surgical

removal of symptomatic cranial and spi-nal tumors as well as supportive care.10 In the setting of a positive family history, screening for VS should begin at age 10 years. In asymptomatic patients without tumors, MRI of the brain should be con-ducted annually for those younger than age 20 years and every 3 to 5 years for those older than age 20 years. Once tu-mors are present, MRI screening should be performed annually. MRI of the spine should be performed every 3 years or if new symptoms arise.10

TUBEROUS SCLEROSIS COMPLEX Tuberous sclerosis complex (TSC) is

a neurocutaneous disorder that results in the growth of benign tumors and can affect virtually every organ system. The two most common systems affected are the skin and the brain, and there is a wide range of phenotypic variability. TSC has an estimated prevalence of 1 in 6,000 newborns, making it the second most-common neurocutaneous disorder.2,11,12

TSC is caused by mutations in the TSC1 and TSC2 genes, which act as tu-mor suppressor genes. The TSC1 gene is located on chromosome 9 and produces the protein hamartin. The TSC2 gene is located on chromosome 16 and produces the protein tuberin. Hamartin and tuberin

bind to form a complex that inhibits the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Loss of regulation of the mTOR path-way leads to abnormal differentiation and development of cells, causing benign tumors to form.13 Although TSC is inher-ited in an autosomal dominant fashion, two-thirds of TSC cases are due to new, spontaneous mutations.14

Clinical FeaturesSkin. Hypomelanotic macules (ash

leaf spots) are seen in 90% of patients11 (Figure 2). Facial angiofibromas (ad-enoma sebaceum) (Figure 3) are another common finding and are characterized by reddish spots or bumps on the face in a butterfly distribution. A Shagreen patch is an isolated raised plaque in the skin over the lower back or buttocks that is seen in 50% of affected children by adolescence.2 Ungual fibromas, small tumors under the toenails or fingernails, may also be present (Figure 4). Other cu-taneous findings include skin tags, café au lait spots, and poliosis (depigmenta-tion of the hair), although these are not unique to TSC.

Eye. Phakomas (retinal astrocytic hamartomas) are benign tumors of the eye appearing as white patches on the retina. Generally they do not cause vision loss or other vision problems, but they can be used to help diagnose the disease.

CNS. Seizures are most often the first presenting symptom of TSC, especially infantile spasms.2 Most children will also experience some degree of developmen-tal delay. Behavioral problems can be a significant issue, including aggression, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and/or self-harming behavior. About one-third of children with TSC meet criteria for autism spectrum disorder. Glial tumors, such as subependymal giant cell astrocy-tomas, are common and form in the walls of the ventricles. The growth of these tu-mors near the foramen of Monro can im-

continued on page 500

TABLE 3.

Manchester Criteria for Diagnosis of

Neurofibromatosis 2I. Bilateral vestibular schwannomas

OR

II. A first-degree relative with NF2 AND

either

• Unilateral vestibular schwannoma OR

• Any two of: meningioma, schwannoma,

glioma, neurofibroma, posterior

subcapsular lenticular opacities

OR

III. Unilateral vestibular schwannoma AND

• Any two of: meningioma, schwannoma,

glioma, neurofibroma, posterior

subcapsular lenticular opacities

OR

IV. Multiple meningiomas AND

• Unilateral vestibular schwannoma OR

• Any two of: schwannoma, glioma,

neurofibroma, cataract

Abbreviation: NIH, National Institutes of Health.

Adapted from Evans.30

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pede the flow of cerebrospinal fluid, lead-ing to obstructive hydrocephalus. Cortical tubers generally form on the surface of the brain and can lead to various neurologic symptoms depending on location.

Renal. Angiomyolipomas are the most common kidney lesion found in TSC. These benign lesions are usually bilateral and asymptomatic. However, they can bleed, and cause pain or kidney failure.

Renal cysts are also common. Cysts are usually small, few in number, and cause no serious problems. In rare instances, patients may develop a pattern similar to polycystic kidney disease during child-hood causing impaired kidney function.

Cardiac. Rhabdomyomas are found in 50% of people with TSC and are often detected on prenatal ultrasound. The ma-jority of these lesions are asymptomatic and will spontaneously regress over time. In rare circumstances, they can cause ar-rhythmias or block left ventricular out-flow.

Lung. Lymphangioleiomyomatosis (LAM) exclusively affects women and is found in one-third of women with TSC in the third to fourth decade of life.15 LAM is a tumor-like disorder in which cells proliferate in the lungs, and there is lung destruction with cyst formation.14 Multi-nodular multifocal pneumocyte hyperpla-sia is a more benign tumor that occurs in men and women equally.

DiagnosisThe diagnosis of TSC has classically

been based on a clinical examination in combination with imaging of the brain, heart, liver, and kidneys. Identification of a pathogenic mutation in TSC1 or TSC2 is now considered sufficient for the di-agnosis of TSC regardless of the clini-cal findings.16 However, 10% to 25% of TSC patients do not have an identifiable mutation, and thus a normal result does not exclude TSC.16 The diagnostic crite-ria for TSC are listed in Table 4.

ManagementSimilar to NF, a multidisciplinary

team approach is often helpful in the management of TSC, as outlined in Table 5. All patients suspected of having TSC should undergo MRI of the brain with and without contrast.17 MRI should be repeated every 1 to 3 years in asymp-tomatic patients and sooner if the patient is having symptoms. At the time of diag-nosis, abdominal MRI should be obtained

and repeated every 1 to 3 years to assess for the presence of renal lesions.17 Women age 18 years and older should have base-line pulmonary function testing and high-resolution chest computed tomography to evaluate for LAM.17 All patients should have a detailed dermatologic examination at the time of diagnosis and a dental exam-ination performed every 6 months.17 In pe-diatric patients, an echocardiogram should be obtained at the time of diagnosis to evaluate for rhabdomyoma, and if present, the echocardiogram should be repeated every 1 to 3 years until its regression.17 An electrocardiogram should also be obtained to evaluate for cardiac arrhythmia and con-duction defects. An initial ophthalmologic evaluation is recommended for all patients to evaluate for retinal hamartomas. An annual ophthalmologic evaluation is war-ranted in patients with confirmed ophthal-mologic lesions or visual symptoms.

STURGE-WEBER SYNDROMESturge-Weber syndrome (SWS) is a

rare neurocutaneous disorder that has clas-sically been defined as a triad of vascular malformations involving the face, eye, and brain. The prevalence of SWS is estimated to range from 1 in 20,000 to 50,000 live births.14 SWS occurs due to sporadic mu-tations and appears to be due to failure of the embryonal cephalic venous plexus to regress and mature, leading to tortuous and abnormal vasculature in the face and brain.18

Clinical FeaturesSkin. Facial angiomas (ie, port-wine

stains) (Figure 5) are usually present at birth and found in the ophthalmic (V1) and maxillary (V2) distributions of the tri-geminal nerve.14 The size of the cutaneous angioma does not correlate with the size of the intracranial angioma. Facial angiomas are unilateral in 70% of children and when the facial nevus is bilateral, the intracranial angioma is usually unilateral.

Eye. Glaucoma occurs in 50% to 70% of children with SWS, usually developing

continued from page 498

Figure 2. Hypomelanotic macule in a 5-month-old infant with tuberous sclerosis.

Figure 3. Facial angiofibromas on an adolescent boy with tuberous sclerosis.

Figure 4. Ungual fibroma on the fifth digit of a teenager with tuberous sclerosis


FEATURE

in the first decade of life.2 Glaucoma de-velops due to vascular anomalies involv-ing the eye, leading to increased episcleral venous pressure. Glaucoma can be unilat-eral or bilateral, regardless of the location of the facial angioma.

CNS. The majority of leptomenin-geal angiomas involve the parietal and occipital regions ipsilateral to the facial angioma. Bilateral brain lesions are rare but can occur.2 Seizures occur in 80% to 90% of children with SWS.2,14 Onset of epilepsy is generally within the first year of life, and the seizures are usually focal in nature. The majority of children with SWS who have seizures in the first year will have some degree of cognitive im-pairment. Hemiplegia occurs in as many as 33% to 50% of children.2,14 Hemiplegia often appears after a focal onset seizure and progresses in severity after subsequent seizures. Transitory episodes of hemiple-gia lasting days or weeks can follow a pro-longed seizure. It is controversial whether the seizures cause the injury to the brain or vice versa.18 Hemianopia may also be present contralateral to the occipital lobe involvement.

DiagnosisWhen a newborn has a facial port-wine

stain, ophthalmologic examination and neuroimaging must be performed. The ideal imaging modality is an MRI of the brain with contrast to best visualize the leptomeningeal angioma. The presence of facial and leptomeningeal angioma sug-gests type I SWS. Type II SWS has facial angioma and glaucoma without evidence of intracranial lesions, and type III pres-ents with only leptomeningeal angioma.19

ManagementThe seizures are often intractable

and difficult to control with anticonvul-sant medications. Hemispherectomy can sometimes improve seizure control as well as development, and should be consid-ered if seizure activity proves medically intractable.14 Aspirin therapy may reduce

the incidence of stroke-like episodes, and is typically used in individuals with either recurrent vascular events or progressive

neurologic deficits.14,19 An ophthalmolo-gist can aid in the treatment of glaucoma, if present. Treatment of the port-wine stain by pulsed dye laser may also be consid-ered for cosmetic reasons.

INCONTINENTIA PIGMENTIIncontinentia pigmenti (IP) is a relative-

ly uncommon multisystem disorder with a prevalence of 0.7 per 100,000 people.20 Over 70% of children with IP have muta-tions in the NEMO gene, located on chro-mosome Xq28 (officially known as the IKBKG [inhibitor of kB kinase gamma] gene). Because the condition is inherited in an X-linked dominant manner, most af-fected children are girls.21 The condition is usually fatal in boys.

Clinical FeaturesSkin. Unlike other neurocutaneous dis-

orders, the skin lesions of IP tend to change over the course of the child’s life. Stage I consists of an erythematous vesicular or bullous rash that is present in the neona-tal period (Figure 6). The lesions follow a linear pattern on the arms and legs with a whorled appearance on the trunk (Figure 7). Stage II lesions that follow within a few weeks are wart-like or verrucous. The le-sions of stage III are hyperpigmented and may persist into adolescence. Stage IV lesions are hypopigmented and hairless and persist for the rest of the person’s life. Dermatologic stages may overlap, and not every child goes through all suc-

Figure 5. Bilateral port-wine stain on a 13-year-old boy with Sturge-Weber syndrome.

TABLE 4.

Diagnostic Criteria for Tuberous Sclerosis

ComplexTSC genetic diagnostic criteriaThe identification of either a TSC1 or TSC2

pathogenic mutation in DNA from normal

tissue is sufficient to make a definite

diagnosis of TSC

TSC clinical diagnostic criteriaDefinite diagnosis: two major features or

one major plus two minor features

Probable diagnosis: one major and one

minor feature

Possible diagnosis: one major feature

Major features

Facial angiofibromas or forehead

plaque

Ungual fibroma, nontraumatic

Hypomelanotic macules (three or

more)

Shagreen patch

Multiple retinal nodular hamartomas

Cortical tuber

Subependymal nodule

Subependymal giant cell astrocytoma

Cardiac rhabdomyoma (single or

multiple)

Renal angiomyolipoma or pulmonary

lymphangiomyomatosis

Minor features

Multiple randomly distributed pits in

dental enamel

Hamartomatous rectal polyps

Bone cysts

Cerebral white matter radial migra-

tion lines

Gingival fibromas

Nonrenal hamartoma

Retinal achromic patch

“Confetti” skin lesions

Multiple renal cysts

Abbreviation: TSC, tuberous sclerosis complex.

Modified with permission from Krueger and Northrup.16


FEATURE

cessive stages. Stage I lesions occur in over 90% of children, usually appear in the first week of life, and often clear by 4 months. The lesions of IP follow the lines of Blaschko (embryologic lines of development) along the skin, and this constitutes a salient feature of this dis-ease. Other dermatologic manifestations include wooly hair and alopecia. Nail in-volvement may range from nail pitting to onychogryphosis.22

Eye. Ophthalmologic features occur in about 20% to 30% of children and include retinal detachment, retinal artery occlusion, congenital cataract, and microphthalmia.23

CNS. Neurologic features are present in approximately 30% of children with IP and range from epilepsy to stroke and de-velopmental delay.21 Seizures and strokes may occur in the first week of life, and in the vast majority of cases neurologic symptoms are most prominent in infancy and early childhood. Ischemic strokes caused by microvascular infarcts or in-flammatory mechanisms are believed

to account, at least partly, for the abnor-malities on brain imaging, which include diffuse lesions in the white matter of the brain, cerebral hemorrhage, and general-ized atrophy of the brain parenchyma.24,25

DiagnosisHistologic examination of affected tis-

sue reveals infiltration of the epidermis with eosinophils during stage I of the disease, which is a highly characteristic feature. Other changes such as dyskerato-sis, apoptosis, and increased free melanin may also be helpful toward making a de-finitive diagnosis.25 An MRI of the brain should be obtained if there are neurologic manifestations.

Diagnosis can usually be established by using clinical criteria of Landy and Donnai21 (Table 6). Confirmatory diag-nosis can be made by demonstrating mu-tations in the IKBKG gene in situations in which there is ambiguity.

ManagementTreatment is supportive, as in the case

of other neurocutaneous syndromes dis-cussed above. Patients should have regu-lar ophthalmologic evaluations in the first year of life for retinal detachment. Refer-ral to a neurologist should occur if sei-zures commence. The pediatrician should closely monitor head circumference and developmental milestones.

HYPOMELANOSIS OF ITO Hypomelanosis of Ito (HI) is a disor-

der involving the cutaneous, central ner-vous, and musculoskeletal systems, akin to IP criteria already discussed. The con-dition was first described by Ito in 1952.27 No consensus exists regarding the identi-ty of the gene causing HI. The prevalence has not been clearly ascertained.

Clinical FeaturesSkin: The skin manifestations of HI

include streaks or whorls of hypomela-nosis on the trunk, limbs, or head, in-terspersed with areas of normal skin

Figure 6. Erythematous vesicular rash following a linear pattern on the leg of a neonate with incon-tinentia pigmenti. Figure courtesy of Tor Shway-der, MD, Director, Pediatric Dermatology, Henry Ford Hospital.

Figure 7. Hyperpigmented lesions in a linear and whorled pattern on a 13-month-old girl with incontinentia pigmenti. Figure courtesy of Tor Shwayder, MD, Director, Pediatric Dermatology, Henry Ford Hospital.

TABLE 5.

Important Areas of Annual Physical Examination in Patients with TSC

• Development (learning disabilities and cognitive impairment)

• Psychiatric assessment (aggression, ADHD, OCD, ASD)

• Head circumference (rapid increase might indicate SEGA or hydrocephalus)

• Visual acuity (screening for visual symptoms to suggest optic hamartoma)

• Renal function (blood pressure: increased risk of secondary hypertension, creatinine, BUN, GFR)

• Cardiovascular examination (arrhythmia)

• Pulmonary examination in adolescent girls (screen for exertional dyspnea and shortness of

breath suggesting LAM)

• Dental examination (every 6 months) (defects in tooth enamel and intraoral fibroma)

• Skin examination (hypomelanotic macules, shagreen patch, facial angiofibromas)

• Focal neurologic symptoms or examination findings (cortical tubers)

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorders; BUN, blood urea nitrogen; GFR, glomerular filtration rate; LAM, lymphangioleiomyomatosis; OCD, obsessive-compulsive disorder; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex.


FEATURE

(Figure 8). The skin lesions are caused by lack of melanocytes or hypomelanosis in the affected cells.28 The swirls of hy-popigmentation follow the embryologic lines of Blaschko. The skin lesions are usually present at birth, invariably mani-fest within the first few years of life, and darken over time, blending into normal skin as the child reaches adulthood. Alo-pecia and anomalous hair pigmentation have also been observed.

Eye. Strabismus, cataracts, and retinal degeneration may constitute the ocular manifestations.

CNS. Psychomotor retardation, au-tism, epilepsy, language disorders, hypo-tonia, and macro- and microcephaly are common neurologic manifestations in children with HI. Approximately 50% to 75% of affected children have features re-lated to the nervous system.28,29 One-third of children with HI and epilepsy are re-fractory to seizure medications.28 A wide variety of brain malformations, such as migrational disorders, hemimegalen-cephaly, microcephaly, and dysgenesis of the corpus callosum, have been described that can account for the clinical features.

Skeletal. The skeletal features may consist of short stature, limb asymmetry, scoliosis, chest deformities, coarse facial features, and finger anomalies.

DiagnosisThe diagnosis requires only a thor-

ough physical examination with atten-tion to the neurologic and dermatologic features. Multidisciplinary care with in-volvement of an ophthalmologist, neurol-ogist, pediatrician, and dermatologist is optimal. No clear-cut diagnostic criteria have been set forth.

CONCLUSIONNeurocutaneous syndromes are a fas-

cinating group of diseases that can affect several organ systems and be diagnosed at the bedside by an observant clinician. Knowledge of the common clinical fea-tures of these disorders can be helpful in

providing guidance to families of affect-ed children. Primary care health provid-ers play a significant role in coordinating the care of these complex multisystem disorders.

REFERENCES 1. Menkes J, Sarnat H, Maria B. Child Neurology.

7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.

2. Fenichel DGM. Clinical Pediatric Neurology: A Signs and Symptoms Approach. 7th ed. Phil-adelphia, PA: Saunders Elsevier; 2013.

3. Cichowski K, Shih TS, Schmitt E, et al. Mouse models of tumor development in neurofibro-

matosis type 1. Science. 1999;286(5447):2172-2176.

4. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis. J Med Genet. 2007;44(2):81-88.

5. Hyman SL, Shores A, North KN. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology. 2005;65(7):1037-1044.

6. Créange A, Zeller J, Rostaing-Rigattieri S, et al. Neurological complications of neurofibroma-tosis type 1 in adulthood. Brain. 1999;122(Pt 3):473-481.

7. Friedman JM, Arbiser J, Epstein JA, et al. Cardiovascular disease in neurofibromatosis 1: a report of the NF1 Cardiovascular Task Force. Genet Med. 2002;4(3):105-111.

Figure 8. Multiple streaky, hypopigmented skin lesions on a 15-year-old boy with profound cognitive impairment. Figure courtesy of Tor Shwayder, MD, Director, Pediatric Dermatology, Henry Ford Hospital.

TABLE 6.

Proposed Diagnostic Criteria for Incontinentia Pigmenti

No Evidence of IP in a First-Degree Female Relative

Evidence of IP in a First-Degree Female Relative

Major criteriaa

Typical neonatal rash

Typical hyperpigmentation

Linear atrophic lesions

Minor criteria

Dental involvement

Alopecia

Abnormal nails/hair

Retinal disease

Presence of one or more of the following is

suggestive of IP in a girl

History or evidence of typical rash (eg,

vesicles), hyperpigmentation, hairless

streaks

Anomalous dentition

Wooly hair

Retinal disease

aAt least one major criterion is necessary to make a firm diagnosis. The presence of minor criteria provided supportive evidence.Abbreviation: IP, incontinentia pigmenti.

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FEATURE Common Neurocutaneous Syndromes - Healio · in Patients with Neurofibromatosis Type 1 • Development (learning disabilities and cognitive impairment) • Visual acuity and