Phakomatoses

Question 1

• Phakomatoses

Answer 1

neurocutaneous syndromes that were initially defined as a group of diseases that would affect the embryonal ectoderm, thus they typically affect the skin, CNS and eyes. In general this is what binds them together. Phakomatosis= birthmark or “mother spot” because people tend to get marks on the skin related to these. Ectodermal involvement is not a strict requirement to be considered a phacomatosis, there is a broad range of things.

Question 2

Inheritance pattern of phakomatoses and similar conditions

Answer 2

Almost all are autosomal dominant, except Sturge Weber and Wyburn Mason (sporadically inherited, or Wild they both have a W in the name); ataxia-telangiectasia which is autosomal recessive (may or may not be phakomatosis) and incontinentia pigmenti which is x linked dominant (may or may not be considered phakomatosis).

Question 3

Naming the phakomatoses

Answer 3

According to the AAO technically include neurofibromatosis, tuberous sclerosis (Bourneville syndrome), cerebrofacial angiomatosis (Sturge-Weber syndrome), retinal angiomatosis (Von Hippel disease), Von Hippel Landau, ataxia telangiectasia (Louis-Bar Syndrome) and Wyburn-Mason syndrome. Klippel-Trenaunay-Weber syndrome have been included by some authors.

Question 4

• Neurofibromatosis Type 1

Answer 4

Also known as Von Recklinghausen. Gene is on chromosome 17 and there are 17 letters in Von Recklinghausen. Gene is NF1. Autosomal dominant.

Question 5

o Findings in NF1

Answer 5

Skin findings include café au lait spots, neurofibroma (for eyes relevant one is plexiform neurofibroma; S-shaped). If someone has a plexiform neurofibroma of the upper eyelid, they will tend to have a higher incidence of open angle glaucoma in that eye as well as ptosis. Brain/CNS findings include optic pathway gliomas, buzzword is fusiform enlargement can go from optic nerve to chiasm. Therapies for this include chemo and radiation. Ocular manifestations of NF1: lisch nodules (like café au lait spots of the eyes); sphenoid bone dysplasia (manifests as pulsatile exophthalmos), and capillary hemangiomas.

Question 6

o Diagnostic criteria for NF1

Answer 6

2 or more of 7 characteristics. Mnemonic is CALBORN—Café au lait spots, Axillary freckling, Lisch nodules, (sphenoid) Bone dysplasia, Optic gliomas, Relative matching these criteria, Neurofibromas

Question 7

• Neurofibromatosis Type 2:

Answer 7

Gene is NF2 and it is on chromosome 22. Autosomal dominant.

Question 8

o Eye findings for NF2

Answer 8

Mnemonic is PEW=posterior subcapsular cataract; epiretinal membranes, wedge shaped cortical cataracts “NF2 plays at the pew”

Question 9

o Skin and brain findings for NF2

Answer 9

neurofibromas (skin); acoustic neuromas, schwannomas and meningiomas

Question 10

o Diagnostic criteria for NF2

Answer 10

: Bilateral acoustic neuromas, first degree relative with NF2 and any of the findings discussed from eye, skin and CNS findings

Question 11

• Tuberous Sclerosis

Answer 11

Also called Bourneville syndrome. Triad (Vogt’s triad) is cognitive impairment, seizures and facial angiofibromas (look a lot like acne). Basically they are angiofibromas or astrocytomas affecting the CNS, skin and eyes. Cognitive impairment and seizures related to astrocytomas in the brain. Usually periventricular or in basal ganglia and look like calcifications.

Question 12

o Skin findings in Tuberous sclerosis

Answer 12

TS have ash leaf spots on the skin, facial angiofibroma (look like acne), and lumbrosacral shagreen patch

Question 13

o Eye findings in tuberous sclerosis

Answer 13

astrocytic hamartomas and angiofibromas (may also be called phakomas) white flat dome like lesion or mulberry looking lesion.

Question 14

o Other non-CNS, skin or eye findings in tuberous sclerosis

Answer 14

cardiac rhabdomyomas, important to know because it can be lethal if not found.

Question 15

• Von Hippel Lindau disease

Answer 15

autosomal dominant, on VHL gene on chromosome 3 (it is supposed to be a tumor suppressor gene). Characterized by findings of hemangioblastomas throughout. Skin findings are rare. Ocular findings are retinal hemangioblastomas which can lead to transudate and serous retinal detachment and can require laser or cryo and some may try to use anti-VEGF. CNS findings also hemangioblastomas (usually cerebellum). Also associated with renal cell carcinoma and pheochromocytoma

Question 16

• Sturge Weber Syndrome

Answer 16

also called encephalofacial angiomatosis. Sporadic inheritance (W in the name because it is Wild). Leptomeningeal vascular malformations can cause calcifications in the brain, seizures, neurologic and cognitive impairment/deficits. Eye findings include choroidal hemagiomas (tomato catsup fundus) with diffuse generalized reddish color to the choroid. Other eye findings include anterior segment dysgenesis which can lead to glaucoma (usually occurs early in life). If you develop glaucoma after the age of 10 it’s less likely due to anterior segment dysgenesis and more likely due to increased episcleral venous pressure

Question 17

• Ataxia-Telangiectasia

Answer 17

: Also called Louis Bar Syndrome. It is the only one that is autosomal recessive. Some consider it a phakomatosis, some do not. CNS manifestation include ataxia, variable intellectual disability. Skin and eye findings include telangiectasias, including conjunctival telangiectasias. Also difficulty initiating of saccades, similar to oculomotor apraxia. The involved gene is the ATM gene which is a tumor suppressor gene so higher rates of things like lymphoma, leukemia and breast cancer. They need early screening. They can also get thymic hypoplasia which can decrease the level of circulating T cells and they are particularly susceptible to radiation because of the defective ATM gene

Question 18

• Causes of conjunctival telangiectasias

Answer 18

mnemonic is SOFA—Sickle cell, Ossler-Weber-Rendu, Fabry’s disease, and Ataxia-Telangiectasia. There are other things that can cause it but these are the big four.

Question 19

• Incontinentia Pigmenti

Answer 19

: X-linked dominant. The CNS manifestations include microcephaly, hydrocephalus and seizures, can be variable. Uniquely people get macules on the trunk and shins and they are from erythematous bullae that then collapse down into pigmented macules. These patterns follow the lines of blaschko which are wavy/whirled/mosaic lines across the body that represent the growth of the different embryologic cell lines of the skin. Ocular manifestations look just like bilateral ROP, tractional membranes, poorly developed retinal vasculature. Should be on differential for ROP when not premature.

Question 20

o DDx for ROP

Answer 20

FEVR familial exudative vitreoretinopathy, incontinentia pigmenti. To differentiate you can look for extraocular manifestations of incontinentia pigmenti such as the CNS findings and the macules on the trunk.

Question 21

• Wyburn-Mason Syndrome

Answer 21

Also called retinal racemose angioma, inheritance is sporadic, “W” for Wild. CNS manifestations are AV malformations which can bleed and cause seizures, neurologic deficits, etc. They can also get angiomas on the face and look like angiomas or nevi on the skin. They can occur in other locations like the mandible. For example, can have excessive bleeding after a dental procedure due to angioma in the mandible.

Question 22

• Klippel-Trenaunay-Weber Syndrome

Answer 22

vascular nevi which tend to be on the extremities, compared to Wyburn mason syndrome which tend to be on the head, but can also have vascular anomalies anywhere on the eye. Essentially causes vascular anomalies of the eyes and extremities. (phakomatosis-like syndrome).