Section 13. Neurocutaneous Disorders

The neurocutaneous disorders are a group of inherited conditions associated with skin, CNS, and other systemic abnormalities. Embryologically, the skin and nervous system are derived from the same neural crest origin, and thus it is not surprising that many neurologic disorders have associated skin abnormalities.

Neurofibromatosis (NF) is an autosomal dominant disorder characterized by café au lait spots and tumors of the nervous system.

NF has seven recognized subtypes:

1. NF-1: von Recklinghausen disease, mutation in NF1 gene, abnormal neurofibromin.

2. NF-2: Acoustic neuroma, mutation in NF2 gene abnormal merlin/neurofibromin2.

3. NF-3: Mixed NF.

4. NF-4: Variant NF.

5. NF-5: Segmental NF.

6. NF-6: Café au lait macules (CALMs) only.

7. NF-7: Late-onset NF.

Synonym von Recklinghausen disease.

Epidemiology

Age Birth: plexiform neurofibromas. Aging from 2 to 3 years: CALM, freckling. Puberty: other neurofibromas.

Gender M > F.

Race All races.

Incidence NF-1, 1:3000 people; NF-2, 1:50000 people.

Heredity AD, with variable expressivity.

Pathophysiology

NF-1 is an autosomal dominantly inherited disorder caused by a mutation in chromosome 17q11.2. The gene product, “neurofibromin,” negatively regulates the ras-family of signal molecules through GTP activating protein (GAP) function. NF-2 is an autosomal dominantly inherited disorder caused by a mutation in chromosome 22q12.2. The gene product, “merlin,” is thought to be involved in actin cytoskeletal signaling.

History

CALMs are not usually present at birth but appear during the first 3 years; neurofibromas appear during late adolescence and may be tender to palpation. Clinical manifestations can vary depending on which organ is affected: hypertensive headache (pheochromocytomas), pathologic fractures (bone cysts), mental retardation, brain tumor (astrocytoma), short stature, precocious puberty (early menses, clitoral hypertrophy).

Physical Examination

Skin Findings

CALMs 2-mm to > 20-cm-brown macules (90%) (Fig. 13-1).

Crowe’s Sign Frecklelike macules in the axillary or inguinal folds (80%) (Fig. 13-2).

Neurofibromas Tan nodules with “button hole sign”—invagination with the tip of finger (60%–90%) (Fig. 13-3).

Plexiform Neuromas Soft tan loose lesions, described as a “bag of worms” (25%).

Distribution of Lesions Randomly distributed but may be localized to one region (segmental NF).

General Findings

Eye Lisch nodules (>90%), hypertelorism (25%), glaucoma.

Musculoskeletal Macrocephaly (20%–50%), sphenoid wing dysplasia (<5%), scoliosis (10%), spina bifida, pseudoarthrosis (2%), thinning of long bone cortex, local bony overgrowth, absent patellae.

Tumors Optic glioma (15%), peripheral nerve tumors (15%), pheochromocytoma (1%), juvenile myelomonocytic leukemia (especially in patients with JXGs), rhabdomyosarcoma, duodenal carcinoid, somatostatinoma, parathyroid adenoma.

CNS Learning disorder (50%), seizures (5%), mental retardation (5%), hydrocephalus (2%).

Cardiovascular Hypertension (30%), pulmonary stenosis (1%), renal artery stenosis (2%).

Laboratory Examinations

Dermatopathology

CALM Increased melanin within the epidermis, increased melanocytes, giant melanosomes.

Neurofibromas Dermal small nerve fibers with surrounding fibroblasts, Schwann cells, and perineural cells.

Plexiform Neurofibromas Large hypertrophied nerves with spindle-shaped fibroblasts and Schwann cells in a myxoid matrix.

Wood’s Lamp CALMs are more easily visualized with Wood’s lamp examination.

Differential Diagnosis

CALMs can also be present in Albright’s syndrome (polyostotic fibrous dysplasia). The CALMs in Albright’s syndrome frequently have a jagged “coast of Maine” border as compared to the CALMs in NF-1, which have smooth “coast of California” borders. Other criteria listed above are required to establish a diagnosis of NF.

Course and Prognosis

There is a variable involvement of the organs affected over time, with NF-1 patients being most severely involved. Skin problems can range from just a few pigmented macules to marked disfigurement with thousands of nodules, segmental hypertrophy, and plexiform neurofibromas. The mortality rate is higher than in the normal population, principally because of the development of systemic tumors and complications during adult life.

Management

It is important to establish the diagnosis to follow patients with a multidisciplinary approach.

NF-1 The diagnosis of NF-1 can be made if two of the following NIH criteria are met:

1. 1. Six or more CALMs (<5 years CALM >5 mm each, >5 years : CALM >1.5 cm each).

   2. Multiple freckles in the axillary and/or inguinal regions (Crowe’s sign).

   3. Two or more neurofibromas of any type, or one plexiform neurofibroma.

   4. Bony lesion (sphenoid wing dysplasia, thinning of long bone cortex, with or without pseudoarthrosis).

   5. Optic nerve glioma(s).

   6. Two or more Lisch nodules (iris hamartomas) on slit lamp examination.

   7. First-degree relative (parent, sibling, or child) with NF-1 by the above criteria.

Ninety-seven percent of NF-1 patients meet these criteria by 8 years, hundred percent by 20 years. In NF-1, support groups help with social adjustment in severely affected persons. An orthopedic physician should manage the two major bone problems: kyphoscoliosis and tibial bowing. The plastic surgeon can do reconstructive surgery on the facial asymmetry. The language disorders and learning disabilities should be evaluated by psychological assessment. Close follow-up annually should be mandatory to detect sarcomas and leukemias.

NF-2 The diagnosis of NF-2 can be made by:

1. 1. CT scan or MRI demonstrating bilateral acoustic neuromas or

   2. A first-degree relative (parent, sibling, child) with NF-2 and either:

   • a. Unilateral nerve VIII mass or
   • b. Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

NF-5 In NF-5, the diseaselike has a segmental distribution because of postzygotic mutation and mosaicism. Involvement of the gonads in these individuals can result in offspring with full-blown NF-1, thus genetic counseling is recommended.

Tuberous sclerosis is an autosomal dominant disease characterized by the triad of seizures, mental retardation, and skin findings (congenital white spots, facial angiofibromata).

Synonyms Epiloia (epilepsy, low intelligence, angiofibroma), Bourneville disease.

Epidemiology

Age Infancy.

Gender M = F.

Race All races.

Incidence 1:10000.

Genetics AD, more than 75% of cases are new mutations.

Pathophysiology

Gene defects in chromosome 9p34 (termed TSC1, 33%–50% of patients) and chromosome 16p13 (termed TSC2, 50%–64% of patients) and have been identified. Chromosome 9q34 affects the gene product “hamartin,” a protein that interacts with tuberin in some fashion. Chromosome 16p13 affects the gene product “tuberin”—a protein that may regulate ras proteins through GAP domain. Both chromosome mutations lead to genetic alterations of ectodermal and mesodermal cells with hyperplasia and a disturbance in embryonic cellular differentiation.

History

White macules appear at birth or in infancy (90% occur by 1 year of age, 100% appear by the age of 2 years) followed by a shagreen patch (seen in 40% of patients between 2 and 5 years of age) and facial angiofibromas at puberty). The skin changes often precede the systemic symptoms. Seizures (95%) and infantile spasms (70%) follow skin signs, and earlier-onset seizures lead to more marked mental retardation.

Physical Examination

Skin Findings (96%)

1. 1. Hypomelanotic macules (ash leaf spot, confetti macules, and thumbprint macules), 90% by 1 year (Fig. 13-4A and B).

   2. Facial red papules/nodules (adenoma sebaceum, angiofibromas), <20% at 1 year, 80% by adulthood (Fig. 13-5).

   3. Truncal yellow-brown plaques (Shagreen “leather” patch, connective tissue nevus) in 40%—favors buttock area (Fig. 13-6).

   4. Peri-/subungual papules (fibromas, Koenen tumors) in 30% to 60% (Fig. 13-7).

   5. Forehead fibrous plaque (hamartomas) in 20% (Fig. 13-8).

   6. CALMs in 30%.

General Findings

Eye Retinal hamartomas (40%), achromic retinal patches (40%), retinal astrocytoma.

Musculoskeletal Cystic bone refraction.

Dental Pitted enamel (90%), gingival fibromas.

Pulmonary Lymphangioleiomyomatosis (30% females).

Renal Bilateral angiolipomas (90%), cysts, carcinoma.

Endocrine Precocious puberty hypothyroidism.

CNS Seizures (95%), subependymal nodules (80%), cortical tubers (90%), infantile spasms (70%), mental retardation, intracranial calcification, giant cell astrocytoma.

Cardiac Myocardial rhabdomyoma (80%), Wolff-Parkinson-White syndrome.

Laboratory Examinations

Dermatopathology White macules: decreased number of melanocytes, decreased melanosome size, decreased melanin in melanocytes, and keratinocytes. Angiofibromata: dermal fibrosis, capillary dilation, absence of elastic tissue. CALM: Increased melanin within the epidermis, increased melanocytes, giant melanosomes.

Wood’s Lamp Accentuates depigmented and hyperpigmented lesions.

Skull X-ray Multiple calcific densities are seen in 50% to 75% of individuals.

MRI or CT Scan In smaller children, when skull radiographs are not diagnostic, small calcifications and ventricular dilation are helpful in diagnosis.

Differential Diagnosis

The diagnosis may be difficult or impossible in an infant or child when white macules are the only cutaneous finding. Initially, TS may be confused with nevus depigmentosus, vitiligo, or piebaldism. The angiofibromata (adenoma sebaceum) of the face are almost pathognomonic but do not appear until late infancy or older.

Even when typical white ash leaf or thumbprint macules are present, it is necessary to confirm the diagnosis. A pediatric neurologist can then evaluate the patient with a study of the family members, and by obtaining various types of imaging. It should be noted that mental retardation and seizures may be absent.

Course and Prognosis

Diagnostic criteria for tuberous sclerosis complex have either two major features as listed below or one major feature plus two minor features:

1. 1. Major features include facial angiofibromas or forehead plaque, ungual or periungual fibromas, three or more hypomelanotic macules, shagreen patch (connective tissue nevus), retinal nodular hamartomas, cortical tubers, subependymal nodules, subependymal giant cell astrocytoma, renal angiomyolipoma, cardiac rhabdomyoma, lymphangioleiomyomatosis.

   2. Minor features include confetti skin lesions, dental pits, gingival fibromas, retinal achromic patch, cerebral white matter radial migration lines, renal cysts, rectal polyps, bone cysts, or nonrenal hamartomas.

Management

Treatment is targeted at affected organs. In severe cases of TS, 30% of patients die before the fifth year of life and 50% to 75% before reaching adult age. Most die from CNS tumors of status epilepticus.

Every newly diagnosis TS patient should have either a CT scan or MRI to look for confirmatory subependymal nodules or cortical tubers in the brain. Seizures can be controlled with anticonvulsant therapy. Renal ultrasounds should be obtained to monitor for polycystic kidney disease. ECGs can be abnormal before arrhythmias appear clinically. In women, a lung CT scan will detect lymphangioleiomyomatosis. Additionally, ophthalmologic examination, neurodevelopmental testing, genetic counseling, and support groups are recommended.

Incontinentia pigmenti (IP) is an X-linked dominant (male lethal) disease affecting the skin, CNS, eyes, and skeletal system. The skin of affected females has “marble cake” lines of Blaschkoid pigmentation with four distinct stages: Inflammatory/vesicular, verrucous, hyperpigmented, and hypopigmented/ atrophic. Eighty percent of IP patients have eye, CNS, or skeletal manifestations.

Synonym Bloch-Sulzberger syndrome, Bloch-Siemens syndrome.

Epidemiology

Age Vesiculobullous stage: first days to weeks.

Gender Females, 97%. Disease is prenatally lethal to males.

Prevalence Rare.

Genetics XLD, some sporadic.

Pathophysiology

The linear skin lesions in IP reflect mosaicism from lionization (X inactivation).

Two gene loci for IP have been identified:

1. 1. IP1 with Xp11/autosome translocations causing pigmentary abnormalities without a preceding inflammatory phase.

   2. IP2 with XLD mutations in the NEMO gene (xq28). These mutations are suspected to produce a failure of immune tolerance in ectodermal tissues resulting in an autoimmunelike reaction in heterozygote girls and a fatal graft-versus-host-like disease in homozygous boys.

Physical Examination

Skin Findings

Inflammatory Stage (newborn to few months) Linear vesicles/bullae on trunk. extremities at birth or (Fig. 13-9).

Verrucous Stage (few months to 1 year) Linear verrucous lesions, resolves after several months (Fig. 13-10).

Hyperpigmented Stage (1 year to adolescence) Reticulate hyperpigmented streaks (seen in 100% of patients, Fig. 13-11).

Hypopigmented Stage (adulthood) Hypopigmented atrophic linear streaks, devoid of hair, and sweat pores.

General Findings

Eye Microphthalmia, retinal vascular abnormalities, pseudoglioma, cataracts, optic atrophy.

Musculoskeletal Skull abnormalities, scoliosis.

CNS Mental retardation (16%), seizures (3%), spastic abnormalities (13%).

Other Pulmonary hypertension, asymmetric breast development, supernumerary nipples, conical/missing teeth (64%), nail dystrophy (7%), nail tumors, and peripheral eosinophilia during inflammatory phase (74%).

Differential Diagnosis

The differential can vary from stage to stage.

Inflammatory Stage Can be confused with herpes, epidermolysis bullosa, linear IgA, childhood bullous pemphigus.

Verrucous Stage Can be confused with an epidermal nevus.

Hyperpigmented Stage Can be confused with linear and whorled nevoid hypermelanosis, lichen planus, lichen nitidus.

Hypopigmented Stage Can be confused with hypomelanosis of Ito.

Laboratory Examinations

Dermatopathology

Inflammatory Stage Intraepidermal vesicles with eosinophils, focal dyskeratosis.

Verrucous Stage Acanthosis, irregular papillomatosis, hyperkeratosis, basal cell vacuolization.

Hyperpigmented Stage Extensive deposits of melanin in melanophages in the upper dermis.

Hypopigmented Stage Decreased melanin as well as appendages in affected skin.

Hematology Peripheral eosinophilia in inflammatory stage.

Radiography Lytic effects on distal phalanges.

Course and Prognosis

Up to 80% of patients have systemic disease. There is a poor prognosis and developmental delay in patients who develop seizures during the first week of life. Absence of seizures and normal developmental milestones appears to predict a good prognosis. The pigmentary changes may persist for many years and gradually fade, completely disappearing in adolescence or early adulthood.

Management

No treatment is effective or required for the cutaneous lesions of IP, other than symptomatic relief. Neurologic, dental, ophthalmic evaluations, and genetic counseling/support groups for carrier females is advisable because up to 80% of affected children have associated congenital defects.

A heterogenous group of disorders that have in common: hypopigmented streaks in a Blaschko distribution associated with CNS, ocular or musculoskeletal abnormalities.

Synonyms IP achromians, pigmentary mosaicism, linear nevoid hypopigmentation.

Epidemiology

Age Birth, early infancy or childhood.

Gender M = F

Prevalence 1:8000.

Race Equal, but more noticeable in darker skin types.

Genetics Usually sporadic, AD cases reported.

Pathophysiology

Chromosomal mosaicism has been detected in 30% of patients. The mosaic karyotype can be in autosomes or X chromosomes, and can be a wide variety of chromosomal defects including aneuploidies. The pigmentary streaks may be caused by two cellular clones with different pigment potential or reflect a number of pigmentary gene mutations.

History

Skin hypopigmentation is in a whorled, Blaschkoid pattern; present at birth or early childhood. It is asymptomatic but persists for life. Associated systemic disease may include seizures, mental retardation, skeletal abnormalities, and strabismus.

Physical Examination

Skin Findings

Type Macular.

Color Tan to off-white.

Shape Linear, streaked, whorled. “Marble cake” following lines of Blaschko (Fig. 13-12).

Distribution Ventral trunk, flexor surfaces of limbs. Scalp, palms, soles spared.

General Findings

Internal manifestations occur in 75% to 94% of patients.

CNS Seizures, mental retardation, macrocephaly.

Eye Strabismus, heterochromia iridis, microphthalmia, nystagmus.

Musculoskeletal Scoliosis, asymmetry of limbs, dwarfism, small stature, polydactyly, syndactyly, spina bifida occulta.

Hair Alopecia, hirsutism, facial hypertrichosis.

Dental Anodontia, dental dysplasia.

Other Hepatomegaly, diaphragmatic hernia.

Differential Diagnosis

Diagnosis is made on history and physical examination. The differential diagnosis includes IP, Goltz syndrome, nevus depigmentosus, depigmented lichen striatus, or vitiligo.

Laboratory Examinations

Dermatopathology Skin may appear normal of have decreased areas of melanin. There is no pigment incontinence in contrast to IP.

Management

No treatment for the skin lesions is needed. The skin lesions may slowly repigment in late childhood. Therapeutics are directed toward controlling neurologic symptoms and correcting skeletal malformations.