INTRODUCTION Van der Hoeve (1920) applied the term phakomatoses (from the Greek phakos, meaning “mother spot,” “mole,” or ―freckle‖). These diseases have many features in common— hereditary transmission Involvement of organs of ectodermal origin (nervous system, eyeball, retina, and skin) slow evolution of lesions in childhood and adolescence Tendency to form hamartomas (benign tumor-like formations due to maldevelopment), and a disposition to fatal malignant transformation.
Major syndromes 1. Tuberous sclerosis complex 2. Neurofibromatosis 3. Sturge-Weber syndrome 4. Ataxia-telangiectasia 5. Von Hippel-Lindau
Other - AD Hemorrhagic telangiectasia (Osler-Rendu-Weber) Incontinentia Pigmenti Achromians (Hypomelanosis of Ito) AR Chediak-Higashi Divry-Van Boegart Meckel-Gruber Xeroderma pigmentosa X-linked Albright syndrome (polyostotic fibrous dysplasia) Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) Fabry disease Incontinentia Pigmenti (Bloch-Sulzberger) No inheritance Cobb syndrome (cutaneous meningeal angiomatosis) Linear Sebaceous Naevus of Jadassohn
TUBEROUS SCLEROSIS(BOURNEVILLE DISEASE) Tuberous sclerosis is a congenital disease of hereditary type in which a variety of lesions, due to a limited hyperplasia of ectodermal and mesodermal cells, appear in the skin, nervous system, heart, kidney, and other organs. It is characterized clinically by the triad of adenoma sebaceum, epilepsy, and mental retardation.
HISTORY Virchow recognized scleromas of the cerebrum (1860 ) Von Recklinghausen reported a similar lesion combined with multiple myomata of the heart (1862) Bourneville’s articles, appearing between 1880 and 1900, presented the first systematic accounts of the disease, and it was he who related the cerebral lesions to those of the skin of the face. Vogt (1890) -significance of the neurocutaneous relationship and formally delineated the triad of facial adenoma sebaceum, epilepsy, and mental retardation. ―Epiloia,‖ a term for the disease introduced by Sherlock in (1911)
EPIDEMIOLOGY This disease has been described in all parts of the world and is equally frequent in all races and both sexes. The disease is determined by two autosomal dominant genes. The estimated prevalence is 1 in 20,000 to 300,000. Tuberous sclerosis accounts for about 0.66 percent of the mentally retarded in institutions and 0.32 percent of epileptics.
ETIOLOGY The disease is inherited in an autosomal dominant fashion. The abnormal gene is localized to one of two sites—the long arm of chromosome 9, designated as TSC 1 (hamartin), and the short arm of chromosome 16, TSC 2 (tuberin). Hamartin and tuberin interact to suppress cell growth and function as tumor suppressor proteins. This may, in part, explain the proclivity to develop various growths and hamartomas. The tumor-like growths in different organs may include cells of more than one type (e.g., fibroblasts, cardiac myoblasts, angioblasts, glioblasts, and neuroblasts), and their number is locally excessive.
CLINICAL FEATURES The disease may be evident at the time of birth but more often the infant is judged at first to be normal. In approximately 75 percent of cases, attention is drawn to the disease initially by the occurrence of focal or generalized seizures or by retarded psychomotor development. The facial cutaneous abnormality, adenoma sebaceum, appears later in childhood, usually between the fourth and tenth years.
Seizures -In the first year or two they take the form of massive flexion spasms with hypsarrhythmia. As many as 25 percent of patients with these types of seizures have been found to have tuberous sclerosis. Later, the seizures change to more typical generalized motor and psychomotor attacks or atypical petit mal.
Mental function continues to deteriorate slowly. Exceptionally there is a spastic weakness or mild choreoathetosis of the limbs and in a few cases an obstructive hydrocephalus. In nearly half of the cases, affective and behavioral derangements, often of hyperkinetic and aggressive type are present.
CUTANEOUSMANIFESTATIONS In approximately 90 percent of patients with tuberous sclerosis, congenital hypomelanotic macules—―ash-leaf‖ lesions appear before any of the other skin lesions. The hypomelanotic areas are arranged in linear fashion over the trunk or limbs and range in size from a few millimeters to several centimeters. Their configuration is oval, in the shape of an ash leaf. Electron microscopic examination of the hypomelanotic lesions shows a normal or reduced number of melanocytes, but their dopa reaction is reduced and melanosomes are small.
The well-developed facial lesions (adenomas of Pringle), pathognomonic of tuberous sclerosis, are present in 90 percent of patients over 4 years of age. Typically they are red to pink nodules with a smooth, glistening surface, and they tend to be limited to the nasolabial folds, cheeks, and chin.
The ―shagreen patch‖ (a plaque of subepidermal fibrosis) found most often in the lumbosacral region. It appears as a flat, slightly elevated, flesh colored area of skin 1 to 10 cm in diameter, with a ―pigskin,‖ ―elephant hide,‖ or ―orange peel‖ appearance). Subungual fibromas usually appear at puberty and continue to develop with age.
PATHOLOGY Tubers: Broadening, unnatural whiteness, and firmness of parts of some of the cerebral convolutions. On the surface of the brain, they range in width from 5 mm to 2 or 3 cm. Their cut surface reveals a lack of demarcation from cortex and white matter and the presence of white flecks of calcium. Under the microscope ,the tubers are seen to be composed of interlacing rows of plump, fibrous astrocytes. In the cerebral cortex and ganglionic structures, derangements of architecture result from the presence of abnormal-appearing cells: greatly enlarged―balloon‖ neurons and glial cells Neoplastic transformation of abnormal glial cells usually takes the form of a large-cell astrocytoma, less often of a glioblastoma or meningioma
Lab -The calcific lesions tend to be periventricular and are particularly well shown on the CT scan. MRI is more sensitive in detecting hamartomatous subcortical lesions.
TREATMENT Genetic counseling AEDs ACTH-used to suppress infantile spasms Dermabrasion of facial lesions Surgery –single epileptogenic cortical tuber
NEUROFIBROMATOSIS Epidemiology -Neurofibromatosis (NF) is a common hereditary disease in which the skin, nervous system, bones, endocrine glands, and sometimes other organs are the sites of a variety of congenital abnormalities. Prevalence of the disease -30 to 40 per 100,000 Incidence - one case in every 2500 to 3300 births
CAUSE AND PATHOGENESIS NF comprises two distinct disorders, the genes for which are located on different chromosomes. Both are inherited in an autosomal dominant pattern with a high degree of penetrance 50% of the cases are due to new mutations. NF1 is caused by a mutation located near the centromere on chromosome 17 in a gene called neurofibromin. The second type, in which the main feature is bilateral acoustic nerve neuromas, is caused by a gene termed merlin Cellular elements derived from the neural crest (i.e., Schwann cells, melanocytes, and endoneurial fibroblasts, the natural components of skin and nerves) proliferate excessively in multiple foci, and the
Neurofibromatosis Type 1(Classical or Peripheral NF) Spots of hyperpigmentation and cutaneous and subcutaneous neurofibromatous tumors are the basis of clinical diagnosis. Pigmentary changes in the skin are nearly always present at birth, but neurofibromas are infrequent at that age. Approximately one-third were found to have only the cutaneous manifestations
The cardinal features of neurofibromatosis are café au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules).Café-au-lait spot This is a flat, oval eruption of the color of coffee with cream or darker brown. It varies in size and appears on the trunk and extremities. A café-au-lait spot on the axillary fossae, called axillary freckling, is thought to be a specific symptom of NF1. Café-au-lait spots are present in 70% of all newborns. After infancy, the number of spots does not increase.
Neurofibroma- A neurofibroma is a soft tumor of normal skin color or light brownish-pink of various sizes. It may be produced on any site of skin. It may be elevated and dome-shaped or papillary, or flat and palpable. neurofibroma first appears between childhood and puberty, after which it gradually enlarges and increases in number. It may increase rapidly during pregnancy and after delivery. Nodular plexiform neurofibroma, neurofibroma in the peripheral nerves, is a slightly palpable, spindle-shaped tumor that appears on the skin over the subcutaneous nerves
Lisch nodule- This is a small whitish spot (actually a hamartoma) in the iris that was present in 94 percent of Riccardi’s type 1 cases.
Other features- Complex partial and generalized tonic-clonic seizures are a frequent complication Hydrocephalus secondary to aqueductal stenosis – rare Macrocephaly with normal-sized ventricles is a common finding Cerebral vessels may develop aneurysms, or stenosis resulting in moyamoya disease Precocious puberty may become evident in the presence or absence of lesions of the optic chiasm and hypothalamus Hypertension, which may result from renal vascular stenosis or a pheochromocytoma The incidence of pheochromocytoma, rhabdomyosarcoma, leukemia, and Wilms tumor is higher than in the general population Tumors that occur in NF1 are optic nerve gliomas, astrocytomas of brain and spinal cord, and malignant peripheral nerve tumors
Neurofibromatosis Type 2 (Acoustic or Central NF)- Bilateral acoustic neuromas - most distinctive feature (In contrast with NF-1 – optic gliomas). Symptoms of hearing loss, facial weakness, headache, or unsteadiness may appear during childhood, although signs of a cerebellopontine angle mass are more commonly present in the 2nd and 3rd decades of life. Café au-lait spots and skin neurofibromas - less common in NF-2 Posterior subcapsular lens opacities -50% of patients with NF-2. CNS tumors - including Schwann cell and glial tumors, and meningiomas are common in patients with NF-2. Gene for NF-2 is located near the center of the long arm of chromosome 22q1.11
PATHOLOGY Neurofibroma is formed by Schwann cells and intraneural fibroblasts, with thin undulating collagen fibers in the middle. Verocay bodies, which are characteristic to neurilemmoma, are found in NF2. The pigmented (cafe au lait) lesions contain only the normal numbers of melanocytes. The dark color of the skin is due to an excess of melanosomes in the melanocytes.
DIAGNOSTIC CRITERIA OFNEUROFIBROMATOSISTYPE 1 AND TYPE 2 NF 1: > 2 criteria 1. > 6 café-au-lait macules >5 mm prepubertal > 15 mm postpubertal 2. > 2 neurofibromas or 1 plexiform neurofibroma 3. Freckling axillary/inguinal 4. > 2 Lisch nodules (iris hamartomas) 5. Optic pathway glioma 6. Bone lesion (sphenoid dysplasia, thinning long bone cortex + pseudarthrosis) 7. First degree relative
Treatment – The skin tumors should excised if they are cosmetically objectionable or show an increase in size, suggesting malignant change. Plexiform neuromas about the face pose especially difficult problems. Cranial and spinal neurofibromas are amenable to excision, and the gliomas and meningiomas usually demand surgical measures as well. Bilateral optic nerve gliomas are usually treated with radiation,unilateral ones are excised. Genetic counseling.
STURGE WEBERSYNDROME Sporadic in occurrence Frequency : 1/50,000 live births Consists of a constellation of symptoms and signs Facial nevus (port-wine stain) Seizures Hemiparesis Stroke like episodes Intracranial calcifications In many cases, mental retardation
Etiology – Result from anomalous development of the primordial vascular bed in the early stages of cerebral vascularization. The blood supply to the brain, meninges, and face is undergoing reorganization, while the primitive ectoderm in the region differentiates into the skin of the upper face and the occipital lobe of the cerebrum. In patients with Sturge-Weber syndrome, the overlying leptomeninges are richly vascularized and the brain beneath becomes atrophic and calcified, particularly in the molecular layer of the cortex
Clinical manifestations- Facial nevus is present at birth, tends to be unilateral, and always involves the upper face and eyelid. The nevus may also be evident over the lower face, trunk, and in the mucosa of the mouth and pharynx. Buphthalmos and glaucoma of the ipsilateral eye are common complications. Seizures develop in most patients in the 1st year of life. Typically focal tonic-clonic and contralateral to the side of the facial nevus .
Seizures may become refractory to anticonvulsants and are associated with a slowly progressive hemiparesis in many cases. Transient stroke-like episodes or visual defects persisting for several days and unrelated to seizure activity is due to thrombosis of cortical veins in the affected region. Neurodevelopment appears to be normal in the 1st year of life Mental retardation or severe learning disabilities are present in at least 50% in later childhood Probably the result of prolonged generalized seizures and increasing cerebral atrophy secondary to local hypoxia and use of numerous anticonvulsants
Diagnosis : Skull radiograph -Intracranial calcification (white lesions) in the occipitoparietal region. Characteristically assumes a serpentine or railroad-track appearance. CT scan highlights the extent of the calcification that is usually associated with unilateral cortical atrophy and ipsilateral dilatation of the lateral ventricle. MRI is a useful adjunct to CT for delineation of the size and location of the vascular malformation and the presence of white matter lesions
Treatment Seizure control. Identification and management of behavioral or learning problems. Because of the risk of glaucoma - regular measurements of intraocular pressure with a tenonometer is indicated . Facial nevus - Flashlamp-pulsed laser therapy often provides excellent clearing of the port-wine stain, particularly if it is located on the forehead
ATAXIA TELENGIECTASIA Ataxia-telangiectasia has been attributed to defective repair of DNA. The inheritance pattern is autosomal recessive. The onset of the disease coincides more or less with the acquisition of walking, which is awkward and unsteady. By the age of 4 to 5 years, the limbs become ataxic, and choreoathetosis,grimacing, and dysarthric speech are added.
The eye movements become jerky, with slow and long- latency saccades, and there is also apraxia for voluntary gaze. The characteristic telangiectatic lesions, appear at 3 to 5 years of age or later and are most apparent in the outer parts of the bulbar conjunctivae, over the ears, on exposed parts of the neck, on the bridge of the nose and cheeks in a butterfly pattern, and in the flexor creases of the forearms.
The disease is progressive, and death usually occurs in the second decade from intercurrent bronchopulmonary infection or neoplasia—usually lymphoma, less often glioma. There is an absence or decrease in several immunoglobulins - IgA, IgE and isotypes, IgG2, IgG4. This immunodeficient state accounts for the striking susceptibility of these patients to recurrent pulmonary infections and bronchiectasis. The defective gene (designated ATM) is a kinase that mediates DNA repair by halting the cell cycle after DNA damage.
THE von HIPPEL – LINDAU SYNDROME An autosomal dominant trait with variable penetrance and delayed expression Incidence of 1/36,000 people Caused by germ line mutations in the VHL tumor suppressor gene located on 3p25–26 Affects many organs, including the cerebellum, spinal cord, medulla, retina, kidney, pancreas, and epididymis 25% of patients with cerebellar hemangioblastoma have retinal angiomas
Major neurologic features: cerebellar hemangioblastomas and retinal angiomata. Patients with cerebellar hemangioblastoma present with symptoms and signs of increased intracranial pressure. Spinal cord - abnormalities of proprioception and disturbances of gait and bladder dysfunction. CT scan and MRI typically show a cystic cerebellar lesion with a vascular mural nodule .
Retinal angiomas are characterized by small masses of thin- walled capillaries that are fed by large and tortuous arterioles and venules. Cystic lesions of the kidneys, pancreas, liver, and epididymis as well as pheochromocytoma are frequently associated with von Hippel-Lindau disease. Renal carcinoma is the most common cause of death. Regular follow-up and appropriate imaging studies are necessary to identify lesions that may be treated at an early stage.
LINEAR NEVUS SYNDROME Sporadic condition characterized by a facial nevus and neurodevelopmental abnormalites . The nevus is located on the forehead and nose and tends to be midline in its distribution. May be quite faint during infancy but later becomes hyperkeratotic, with a yellow brown appearance. More than half of patients have a seizure disorder and are mentally retarded. The seizure may be generalized, myoclonic, or focal motor. A wide variety of cerebral lesions—unilateral cerebral atrophy, porencephalic cyst, leptomeningeal hemangioma, arteriovenous malformation, and atresia of cerebral arteries and veins.
RENDU –OSLER-WEBER SYNDROME(HERIDITARY HEMMORHAGICTELENGIECTASIA) This vascular anomaly is transmitted as an autosomal dominant trait. It affects the skin, mucous membranes, gastrointestinal and genitourinary tracts, lungs, and occasionally the nervous system. Absence of elastic fibers and smooth muscles leads to telangiectasia in the arteriovenous anastomotic region. The significance of the lesions lies in their hemorrhagic tendency.
They may give rise to severe and repeated epistaxis or gastric, intestinal, or urinary tract bleeding. Pulmonary fistulas constitute another important feature of the generalized vascular dysplasia. An unexplained gastrointestinal, genitourinary, intracranial, or intraspinal hemorrhage warrants a search for small cutaneous lesions, which are easily overlooked
NEUROCUTANEOUSMELANOSISClinical features: Neurocutaneous melanosis is nonfamilial and occurs in both men and women. Large congenital melanocytic nevus, in most cases a giant hairy pigmented nevus, is present on nearly half the trunk or multiple congenital small melanocytic nevi disperse over the whole body. CNS symptoms such as increased intracranial pressure and secondary hydrocephalus occur. These are accompanied by headache, vomiting, epileptic seizure and intelligence impairment. Malignant melanoma often develops on the site of the body with giant hairy nevus and leptomeninx.
Neurocutaneous melanosis is caused by proliferation of melanoblasts that originate from neural crests in the skin and central nervous system (e.g., leptomeninx). In the brain, perivascular proliferation of melanocytes impairs reabsorption of cerebrospinal fluid, leading to hydrocephalus MRI Brain, lumbar puncture and ventriculography are necessary for diagnosis. Increased levels of proteins and reduced sugar levels are often found in the cerebral fluid. Melanin-containing cells may be present. Symptomatic therapy such as shunting for hydrocephalus and anti-epilepsy drugs are useful for central nervous symptoms. Patients rarely live beyond the age of 20 years.
Incontinentia pigmenti(Bloch-Sulzberger syndrome) It is X-chromosome dominantly inherited; female patients greatly outnumber male patients. Characteristic pigmentation occurs on the skin. The symptoms are clinically classified into 4 stages.1. Inflammatory stage2. Verrucous stage3. Pigmented stage4. Regression stage
Ocular symptoms: Ocular symptoms develop in about one third of incontinentia pigmenti cases. Strabismus is most common followed in frequency by cataract, glioma and microphthalmos. Central symptoms: Epilepsy and intelligence impairment may be caused in half of the cases. Abnormality may occur in teeth (e.g.deficiency, developmental retardation) and bones (e.g., dwarfism, hyperdactylia).
INCONTINENTIA PIGMENTIACHROMIANS (HYPOMELANOSISOF ITO) It is inherited as autosomal dominant trait. Typical skin changes occur as hypopigmented lesions on head, trunk or limbs. Females are affected more Approximately 75% of patients have anamolies affecting the CNS, eyes, hair, teeth, skin and nails. CNS abnormalities include mental retardation, seizures and motor system dysfunction. Electron microscopy reveals few melanosomes, sparely dendritic melanocytes and a reduction in the number of melanosomes in keratinocytes.
PARRY-ROMBERGSYNDROME It is usually apparent in early childhood and rarely shortly after birth. It is charecterised by progressive loss of facial soft tissue, cartilage and bone. This atrophic process ceases by the end of second decade of life. Neurological deficits include - recurrent headaches, ipsilateral horner’s syndrome, contralateral partial seizures and hemiparesis. Cranial CT can be normal or documents cerebral atrophy.
Klippel-Trenaunay-Weber syndromeClinical features and Pathogenesis There is fragility of mesodermal tissue in the vascular walls. Cutaneous hemangioma simplex is present at birth in many cases. Lymphangioma, congenital venectasia, angiokeratoma and congenital arteriovenous fistula may also occur and become distinct with age Klippel-Trenaunay- Weber syndrome is also characterized by enlargement and overgrowth of the bone and soft tissue
The bone abnormality usually occurs in the leg on the same side of the body as the skin lesion, or rarely, on the opposing side. Angioma in internal organs, syndactylism or other dysplasia of fingers and toes, and heart failure (if the arteriovenous fistula is severe) may occur. The different length of the legs results in claudication and compensatory scoliosis.
Diagnosis and treatment Diagnosis can be confirmed by bone radiography and systemic CT scan. Laser therapy is conducted when the hemangioma simplex raises cosmetic concerns. Ligation or excision is performed on arteriovenous fistulae, because they may cause heart failure.
MAFFUCCI SYNDROME Rare disease of unknown etiology characterised by multiple enchondromas with secondary hemangiomas and malformations of bone. Enchondromas affect the small bones of hands and feet or any bone preformed in cartilage. During childhood they increase in size. Neurological complications are secondary to either cerebral encroachment by cranial enchondromas or a primary brain tumor.
WYBURN-MASONSYNDROME Cutaneous vascular nevi Retinal and optic nerve vascular malfomations Ipsilateral cerebral avm involving visual pathways and mid-brain Typically unilateral