Neurocutaneous Syndrome

• This is characterized by multiple tumors within the central and peripheral nervous systems, cutaneous pigmentation, and lesions of the vascular system and viscera.
• Additionally, a tendency exists for a variety of tissues to undergo malignant transformation.
• The disease occurs in approximately 1 in 3,000 live births and is transmitted as a dominant trait with variable expression but virtually complete penetrance by the age of 5 years.
• No parental age effect occurs.
• It is the most common single-gene defect to affect the nervous system.
• Approximately one-half of the cases appear to be sporadic, and the mutation rate has been estimated at 1 in 10,000 gametes per generation, one of the highest mutation rates in humans.
• The gene for NF1 is located on the long arm of chromosome 17
• The gene encodes a cytoplasmic protein, named NEUROFIBROMIN.
• The NF1 gene is large and is intrinsically hypermutable; more than 100 mutations have been described.

Clinical Manifestations

• NF1 is a progressive disease process that can affect almost every organ.
• When many peripheral lesions are present, few lesions tend to be within the CNS and vice versa.
• Café-au-lait spots are the hallmark of neurofibromatosis and are present in almost 100% of patients.
• They are present at birth but increase in size, number, and pigmentation, especially during the first few years of life.
• The spots are scattered over the body surface, with predilection for the trunk and extremities, with sparing of the face.
• Various types of cutaneous tumors can be found.
• The most characteristic for NF1 is the pedunculated molluscum fibrosum and the subcutaneous neurofibromas.
• Generally, cutaneous tumors tend to enlarge slowly throughout life.
• Plexiform neuromas can occur in all affected tissues and lead to hypertrophy of one or more extremity, exophthalmos, or defects of the skull and orbit.
• Multiple nodules within the iris (iris hamartomas) were first described by Lisch.
• Lisch nodules are seen in almost all affected individuals aged 21 or more years, but only in one-half of children aged 5 to 6 years.
• Initially light colored, they become darker with time. Short stature is common
• A large proportion of these children experiences growth hormone deficiency.
• Skeletal abnormalities include low cervical or thoracic kyphoscoliosis, scalloping of the posterior portion of the vertebral bodies.
• Hypertension can develop owing to the presence of a pheochromocytoma, it also can be the result of renal artery stenosis, the most common of a variety of arterial abnormalities seen in neurofibromatosis.

• Genetically and clinically distinct from NF1.
• Less common and it is characterized by the development of CNS tumors, notably bilateral vestibular schwannomas.
• The gene for NF2 has been mapped to the long arm of chromosome 22 (22q11).
• Its gene product, merlin (schwannomin), shares significant homology with several actin-associated proteins.

Merlin

• A tumor suppressor which plays a role in the regulation of cell-cell adhesion, and in the reorganization of the actin cytoskeleton in response to growth factors, confluency, and changes in the shape of the cell.
• Merlin is absent from almost all schwannomas and from many meningiomas and ependymomas isolated from subjects with NF2.

• The most characteristic gross abnormality is the presence of tubers.
• These are numerous hard areas of gliotic tissue of varying size, after which this condition is named.
• On histologic examination they are sclerotic areas that consist of an overgrowth of atypical giant astrocytes, and groups of large, bizarre, and frequently vacuolated “monster cells.”
• Blood vessels in sclerotic regions show hyaline degeneration of their walls.
• In approximately half of subjects, calcium is deposited within the gliotic areas to an extent as to be visible on plain radiography of the skull or on computed tomographic (CT) scanning.
• Subependymal nodules found in the ventricular walls, particularly in the region of the foramen of Monro are multiple small, tumor-like nodules that project into the ventricles and, because of their appearance on pneumoencephalography were described as “candle drippings.”

Pathophysiology

• Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division.
• Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors.

• TSC affects tissues from different germ layers.
• Cutaneous and visceral lesions may occur, including adenoma sebaceum, cardiac rhabdomyomas, and renal angiomyolipomas.
• The central nervous system (CNS) lesions seen in this disorder include hamartomas of the cortex, ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of Monro.
• Manifestations of TS vary considerably with respect to age of onset, severity, and rate of progression.

The four main types of manifestations are

1. Mental retardation,
2. Seizures,
3. Cutaneous lesions,
4. Tumors in various organs including the brain.

• Mental retardation may often due to poor seizure control.
• Commonest seizures in them is infantile spasm.
• Cutaneous manifestation include adenoma sebaceum, shagreen patch, ash leaf macules
• Tumors
• Adenoma sebaceum (angiofibroma) consist of a red, papular rash over the nose, chin, cheeks, and malar region, appearing between ages 1 and 5 years.
• Depigmented nevi (ash leaf), are oval areas with irregular margins over the trunk and extremities are equally common.
• They are more readily visualized when the skin is illuminated with ultraviolet light (Wood lamp).
• Generally, they appear earlier than the adenoma sebaceum.
• They can be noted at birth and are seen before 2 years of age in more than one-half of the subject
• Ash leaf macules differ from vitiligo in that in vitiligo the melanocytes are absent, whereas in depigmented macules the melanocytes are normal, but the melanosomes are reduced and contain less melanin.
• Of the other cutaneous abnormalities, flattened fibromas are the most common.
• They appear in a variety of areas, including the trunk, gingivae, and periungual regions.
• In some infants, fibromas are found along the hairline or eyebrows.
• Shagreen patch. This is an uneven thickening of skin, grayish green or light brown, raised above the surrounding surface, usually in the posterior lumbosacral region.
• Café au lait spots are seen in 7% to 16% of subjects.

• Intracranial tumors are less frequent in TS than in neurofibromatosis.
• Although the numerous intraventricular nodules are technically tumors, they usually do not grow to the extent of producing increased intracranial pressure.
• Tumors are found in the neighborhood of the foramen of Monro, arising from either the walls of the lateral ventricles or the anterior portion of the third ventricle.
• On the basis of their histology, they have been classified as giant cell astrocytomas

• The diagnosis of TS is based on the characteristic skin lesions, seizures, and intellectual impairment or deterioration.
• In infants, the combination of depigmented areas of skin, infantile spasms, and delayed development is diagnostic.
• Diagnostic Criteria for Tuberous Sclerosis Complex has also been proposed.

Proposed diagnostic criteria

The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:

• Definite – Either two major features or one major feature plus two minor features.
• Probable – One major plus one minor feature.
• Suspect – Either one major feature or two or more minor features.

• DETAILED HISTORY— personal and family.
• DETAILED EXAMINATION
• The skin for Shagreen patch under a Wood's lamp (Ash leaf macules),
• The fingers and toes (ungual fibroma),
• The face (angiofibromas) and
• The mouth (dental pits and gingival fibromas).
• INVESTIGATIONS— Cranial imaging with non-enhanced CT or, preferably, MRI (cortical tubers and subependymal nodules).
• Renal ultrasound (angiomyolipoma or cysts).
• An echocardiogram in infants (rhabdomyoma).
• Fundoscopy (retinal nodular hamartomas or achromic patch).

• No specific treatment is available.
• Seizures are managed with anticonvulsant medications.
• In selected patients, resection of a single cortical epileptogenic tuber by stereotactic techniques or open craniotomy can result in a marked reduction of seizure frequency.
• Role of RAPAMYCIN: Various investigators have also proved that topically applied rapamycin causes regression of facial angiofibromas, giving better cosmetic results.
• Resection of intraventricular tumors is reserved for children who develop ventricular obstruction.
• Regular neurologic examinations of the patient with TS should be carried out.

• Malformation of an embryonic vascular plexus.
• Basis of abnormalities of the skin, cortex, leptomeninges, and choroid.
• 5 to 8 weeks of gestation
• On pathologic examination of the brain, the essential feature is a leptomeningeal angiomatosis with a predilection for the occipital or occipitoparietal region of one cerebral hemisphere.
• On microscopic examination the walls of these vessels are encrusted with iron and calcium deposits.
• Cortical calcifications usually are found in the degenerated cortex underneath the vascular malformations.

• SWS is a progressive disease.
• The cutaneous port-wine nevus is present at birth and involves at least one eyelid or the supraorbital region of the face.
• An angioma of the choroid membrane of the eye is often associated with unilateral congenital glaucoma and buphthalmos.
• Up to 90% of may develop focal or generalized seizures.
• These are usually the initial neurologic manifestation and frequently begin in the first year of life.
• Seizures can progressively become more refractory to medication and can be followed by transient or permanent hemiparesis.
• Hemiparesis, often with homonymous hemianopia,
• Glaucoma can be present at birth or develop over the years in up to 60% of patients.
• Less commonly, symptoms owing to hemangiomas involve the viscera e.g hematuria and gastrointestinal hemorrhages.
• Intracranial hemorrhages are rare.

• Often, the coexistence of a facial vascular nevus and seizures should suggest SWS.
• MRI is presently the diagnostic modality of choice.
• Characteristically, calcifications are arranged in parallel lines (“railroad tracks”) or serpentine convolutions that are most striking in the occipital and parieto-occipital areas.
• Double contoured curvilinear sign.

Multi specialists

• Ophthalmologic consultation should be obtained, management of glaucoma.
• Some children have rare complex partial seizures, but in the context of SWS, carbamazepine should be initiated after the first seizure.
• Neurosurgeon – lobectomy/hemispherectomy

• Cerebellar signs appear in infancy or early childhood.
• The telangiectases, which are characteristically located over the exposed areas, bulbar conjunctivae, bridge of the nose, ears, neck, and antecubital fossae, first seen at between 3 and 10 years of age and become more marked with exposure to sunlight.
• Thinning and premature graying of the hair and loss of skin elasticity and subcutaneous fat also are prominent.
• Approximately 85% of patients develop choreoathetosis, and nystagmus.
• Hypotonia, diminished reflexes, and generalized muscular weakness also have been observed and occur later.
• Intelligence usually becomes impaired as the illness progresses.
• Most patients experience recurrent sinopulmonary infections.
• Neoplastic disease is common.
• In particular, children with AT are 40 to 100 times more likely to develop lymphoma, leukemia, lymphosarcoma, and Hodgkin's disease than their peers.
• Oculocutaneous lesions and the neurologic picture particularly the oculomotor apraxia fully developed are almost diagnostic.
• Progressive cerebellar ataxia.

• Elevated serum a-fetoprotein (up to 95% of patients).
• Elevated carcinoembryonic antigen nearly all patients.
• IgE concentrations are usually low, and the IgM may be of the low molecular weight variety.
• IgG2 or total IgG levels may be decreased
• The most frequent humoral immunologic abnormality is the selective absence of IgA, which is present in 50–80% of these patients.
• Hypercatabolism of IgA also occurs.

Diagnosis

• The characteristic defect in serum immunoglobulins, impaired delayed hypersensitivity responses, and the demonstration of spontaneous chromosome breaks also can assist in the diagnosis.
• Prenatal diagnosis of the disease by genotype analysis is also possible.

• No specific treatment prevents the neurologic progress of AT.
• Intercurrent sinopulmonary infections can be prevented by gamma globulin therapy or treated with antibiotics and postural drainage.

First phase

• First few weeks of life:
• Consists of erythematous linear streaks and plaques of vesicles that are most pronounced on the limbs and circumferentially on the trunk.
• Linear configuration is unique.
• Histopathologically, epidermal edema and eosinophil-filled intraepidermal vesicles are present.
• Eosinophils also infiltrate the adjacent epidermis and dermis.
• Blood eosinophilia up to 65% also is common.
• The first stage generally resolves by 4 month of age.

Second phase

• As blisters on the distal limbs resolve, they become dry and hyperkeratotic, forming verrucous plaques.
• The verrucous plaques rarely affect the trunk or face and generally involute within 6 mo.
• Epidermal hyperplasia, hyperkeratosis, and papillomatosis are characteristic.

The third or pigmentary phase

• It is the hallmark of incontinentia pigmenti.
• It generally develops over weeks to months and may overlap the earlier phases, be evident at birth, or, more commonly, begin to appear within the first few weeks of life.
• Hyperpigmentation more often is apparent on the trunk than the limbs and is distributed in macular whorls, reticulated patches, flecks, and linear streaks that follow Blaschko lines.
• The axillae and groin are invariably affected.
• The sites of involvement are not necessarily those of the preceding vesicular and warty lesions.
• The pigmented lesions, once present, persist throughout childhood.
• They generally begin to fade by early adolescence, however, and often have disappeared by age 16 yr.

Fourth phase

• Hypopigmented, hairless, anhidrotic patches or streaks occur as a late manifestation, they may develop, however, before the hyperpigmentation of stage three has resolved.
• The lesions develop mainly on the flexor aspect of the lower legs and less often on the arms and trunk.

Diagnosis is made on clinical grounds, although major and minor criteria have been established to aid in diagnosis.

• Consists of bizarre, patterned, hypopigmented macules arranged over the body surface in sharply demarcated whorls, streaks, and patches that follow the lines of Blaschko.
• The palms, soles, and mucous membranes are spared.
• The hypopigmentation remains unchanged throughout childhood but fades during adulthood.

• The most commonly associated abnormalities involve the nervous system, including
• Mental retardation (70%),
• Seizures (40%),
• Microcephaly (25%),
• Muscular hypotonia (15%).
• Macrocephaly (23%)
• The musculoskeletal system is the second most frequently involved system, affected by scoliosis and thoracic and limb deformities.
• Hemihypertrophy
• Minor ophthalmologic defects (strabismus, nystagmus) are present in 25% of patients, and 10% have cardiac defects.