Phakomatoses is the coined by van der Hoeve in 1920, to describe a group of hereditary neurological disorders that have cutaneous and ocular stigmata. It is derived fro Greek root 'Phako' meaning birth mark/mother spot. They are a group of disorders characterized as dysplasias or neoplasms of organs derived from the embryonic ectoderm. They have common features of neuroepidermal maldevelopment and undifferentiated cells with disturbed patterns of cell migration.

They are commonly divided into:

1) Neurofibromatosis, 2) Tuberous sclerosis, 3)von Hippel-Lindau disease, and 4) Neurocutaneous angiomatosis.

All phakomatoses do not manifest ocular and cutaneous findings;

VHL shows no skin markers and the neurocutaneous angiomatoses no ocular lesions.

Many similarities exist between these groups, and several families have been reported with overlapping manifestations of two phakomatoses. The genetic abnormality in many of these disorders has not yet been identified and the fact that stigmata of more than one of these syndromes have been seen in the same patient could indicate that they are all due to an abnormality in a small group of genes.

The recognition of one of these  syndromes in a patient mandates genetic screening of other family members to provide genetic counseling. Finally, the CNS abnormalities can exist with out these disorders.

 NEUROFIBROMATOSIS:

This is the commonest of the phakomatoses, with a reported incidence of one in 3000 births. It is an autosomal dominant disease with high penetrance, but variable expression. This syndrome has been variously classified in literature, but recently consensus is for two types which account for over 95% of all cases. Other cases of neurofibromatosis represent either poorly expressed or variant types.

Neurofibromatosis-2 (NF-2):

This was previously called central neurofibromatosis or bilateral acoustic neurofibromatosis. It is an autosomal dominant disease, with the genetic abnormality on chromosome 22. Though the method of gene expression is not clear. It is much less common than NF-1.

 TUBEROSE SCLEROSIS (Bourneville’s disease or Epiloia):

Von Recklinghausen, in 1862, described association between cardiac myomas and brain sclerosis.

Bournville, in 1880,  correlated cortical tubers, seizure and mental retardation, and called it ' tuberous sclerosis'.

Vogt Henrich, in 1908, described the clinical triad- adenoma sebaceum, seizures, and mental retardation.

Lesions are also seen in other organs such as the retina, heart, kidney and lungs.

In the eye, retinal hamartomas occur. They rarely lead to visual problems.

Cardiac rhabdomyomas occur in about 30% of patients; they may remain asymptomatic or may produce heart failure in infancy. Renal angiomyolipomas are commonly found in these patients.

Clinical features:

The clinical diagnosis of TS can be made by Vogt's triad of seizures, mental deficit and adenoma sebaceum.

The disorder can, however, present variably.

In fetal stage, ultrasound or fetal echocardiogram may reveal hydrocephalus, and cardiac myoma.

At birth, ash leaf spots and infantile spasms are characteristic.

In children, seizures predominate. The seizures are mostly tonic-clonic or infantile myoclonic, though partial motor and complex partial seizures are also seen. Petit mal attacks are lot common. The degree of mental retardation in these patients varies and regression has been noticed in older patients. 45% of them may have normal intelligence.

Severely affected children exhibit bizarre purposeless hand movements and posture, but no true athetosis or chorea.

In later life, there may be spastic hemiplegia or diplegia. They may be due to either uncontrolled seizures or to the development of a brain tumor. Motor deficits are rare, though they may be seen as a manifestation of a brain tumor. There may be features of obstructive hydrocephalus, due to intraventricular SEGA.

Roach et al  has listed the following criteria for the diagnosis of TS.

Definite: one primary and two sec or one sec and two tertiary;

Probable: one sec and one tertiary or three tertiary;

Suspected: one sec or two tertiary.

Imaging:

On CT, cortical tubers, unless calcified, are difficult to identify. The calcifications are mostly just lateral to the foramen of Munro and in the body of the lateral ventricle, though rarely, they may occur in the wall of the third and fourth ventricles.The tendency for these lesions to protrude into the lateral ventricle, distinguishes them from other calcified lesions seen in cytomegalovirus infection, cysticercosis and toxoplasmosis. Other lesions which may encroach into the ventricles, e.g. heterotopic grey matter or ependymomas are not multiply and do not calcify. Venticulomegaly, perhaps due to high CSF protein may be seen in children.

MRI scan of the brain is the most sensitive study. Cortical tubers appear as focally expanded gyri, which do not enhance. They are iso/hypodense intracerebral lesions are seen especially in the frontal, parietal and occipital lobes, represent areas of defective myelination and heterotopic hamartomatous tissue which occur particularly at the junction of grey and white matter. These are seen in 12-69% of cases, but are not diagnostic of TS when they occur in isolation.

Bands of abnormal signal intensity radiating from the ventricles to the cortical mantle and / or wedge shaped lesions with their apex at the ventricle and their base at a cortical tuber. White matter mass lesions appear less often; they are hyperdense on T2 and hypo/isodense on T1.

Subependymal (SEGA) tumors are seen as isodense lesions enhancing uniformly with contrast. They are located mainly at the foramen of Munro and produce obstructive hydrocephalus. They may, occasionally, have a cystic component. Asymmetrical ventricular dilatation may be seen in the absence of tumor.

Management:

Treatment involves controlling seizures with antiepileptic drugs and special education for the mentally handicapped.

ACTH , and lesionectomy is highly selected patients may help. The life expectancy of these patients is decreased, the causes of death being cardiac failure, brain tumors, status epilepticus and renal failure.

No need for surgical intervention in asymptomatic patients. Asymptromatic children must be followed up periodically.

The brain tumors can be excised in adults with a good prognosis; subtotal excision to relieve hydrocephalus,may suffice.

In children, the associated hydrocephalus may be shunted, and the child is reviewed periodically.

Role of radiotherapy is controversial.

 VON HIPPEL-LINDAU DISEASE (retino cerebellar angiomatosis):

The von Hippel-Lindau (VHL) disease or complex is an autosomal dominant disorder with variable expression, characterized by either more than one hemangioblastoma within the neuraxis associated with at least one visceral manifestation. No cutaneous stigmata arc seen in patients with VHL complex. It has an incidence of about one in 40,000 live births. It is probably caused by a gene complex that maps to the short arm of chromosome 3.

The association of retinal, cerebellar and visceral lesions was made, in 1926. by Arvid Lindau, who started his work by investigating cerebellar cysts. The retinal angiomas had been described earlier, by Collins, in 1894 and by von Hippel, in 1904. Brandt published the autopsy results of von Hippel's patient and described tumors in the viscera in addition to those in the brain and the spinal cord.

Retinal angiomas arc seen in over 50 per cent of patients with the VHL complex and may be the only finding in children under 10 years of age. The lesions are seen mostly in the peripheral parts of the retina, though they have also been recorded at the macula and the optic disc. They are usually seen in both the eyes.. Photocoagulation is the treatment of choice. As new lesions may appear in course of time, the patients must be kept under regular ophthalmological follow up.  

 NEUROCUTANEOUS ANGIOMATOSES:

These are a group of genetic disorders which have an abnormality of blood vessels of the skin and nervous system as their only common feature, and arc grouped together for convenience. Each syndrome has other systemic angiomata as well as hematopoietic and immunological deficiencies.

Ataxia telangiectasia (Louis-Bar or Border-Sedgwick syndrome) is an autosomal recessive disorder with progressive ataxia, cutaneous telangiectasias. Prognosis is poor, with death usually occurring in the second decade due to infection or neoplasia as a

dermatomes, with a hemangioma of the spinal cord at the same level.

The lesion is seen as a spinal variant of Sturge weber syndrome.

Fabry's disease (Angiokeratoma Corporis Diffusum) results from the accumulation of ceramide trihexoside in the media and endothelium of small blood vessels, due to a deficiency of alpha galactosidase. It is an X linked recessive disorder, characterized by telangiectasias of the lower half of the body. Skin lesions apart, renal function may be impaired with resultant hypertension and myocardial infarction. More severe forms have diffuse involvement of vessels of the peripheral nerves and of the CNS, leading to CVAs in young adults. Painful polyneuropathy is another neurological problem.

Other rarer syndromes include

Fibrous dysplasia (Albright's syndrome)-dysplasia of bones, irregular cafe-au-lait pigmentation, sexual precocity in females, endocrine disturbances, mental retardation, seizures and 'ground glass' radilogic appearance of bones.

Osler-weber-Rendu syndrome (Hereditary hemorrhagic telengiectasia)-autosomal dominant disease with angiomas of the skin, mucosal surfaces, and nervous system, and usually presents with hemorrhage and should be excluded in all patients with multiple AVMs, or family history of SAH, or repeated epistaxis.

Wyburn-Mason syndrome -AVM in the midbrain with unilateral retinal and facial malformations.

Neurocutaneous melanosis (Rokitansky-van Bogaert syndrome)-cutaneous  by pigmented nevi, intracerebral melanotic pigmentations, and  hydrocephalus.

Incontinentia pigmenti (Bloch-Sulzberger syndrome)-cutaneous bullae, verrucation, crustation and pigmentations, and cerebral palsy and seizures. Ocular, skeletal, and cerebral malformations may be there.

Multiple nevoid basal cell carcinoma (Ward-Gorin-Goltz syndrome)-multiple basal cell carcinomas. skeletal anomalies, congenital  hydrocephalus, medulloblastoma, visceral cysts and malformations.

Cutaneomeningospinal angiomatosis (Berenbruch-Cushing-Cobb syndrome)-cutaneous vascular nevus, angiomas in spinal cord, vertebrae and viscera.

Systemic angiomatosis (Ullmann's syndrome)-cavernous and telangiectatic angiomatosis of CNS and viscera, cutaneous angioma.

Oculocerebral angiomatosis (Bregeats's syndrome)-oculo-orbital angiomatosis, thalamoencephalic angioma, cutaneous angioma.

Neurocutaneous lipomatosis-intracranial and intraspinal lipomata, leptomeningeal lipomatosis, facial; and axial cutaneous lipomata, visceral lipomatosis, skull lipomatosis, cranial, cerebral, and spinal cord anomalies.