Phacomatoses

phacomatoses

1. Phakomatoses Presented by Dr Rohit Rao

2. Phakomatoses derived from Greek word phakomata or birth mark Syndromes characterized by hamartomas of the skin, eye, central nervous system (CNS), and other viscera are collectively called Phacomatosis

3. Neurofibromatosis

4. Neurofibromatosis type 1 (NF1), the most common type,von Recklinghausen's neurofibromatosis or peripheral neurofibromatosis. Neurofibromatosis type 2 (NF2) or central or bilateral acoustic neurofibromatosis.

5. Neurofibromatosis Type 1 Most common phacomatosis autosomal -dominant disorders . The gene involved in NF1 is on chromosome 17 (17q11.2). It encodes for neurofibromin , a tumour suppressor

6. Clinical Features Cutaneous Findings Cafà ©-au- lait spots and other hyperpigmented skin lesions seen in 99% of adults with NF1. Cafà ©-au- lait spots are pigmented, flat (macular) skin lesions typically with smooth edges. Present at birth, they increase in size and number.

7. Other pigmented lesions include freckles ( lentigines ) These areas of hyperpigmentation are present in axilla or groin.

8. Neurofibromas are benign nerve sheath tumors consisting of Schwann cells, fibroblastic elements, and embedded axons. Solitary neurofibromas Located on skin, especially on trunk, & face. Arise in deep peripheral nerves, spinal nerve roots, and autonomic nerves of blood vessels. Multiple neurofibromas are pathognomonic of NF1. Plexiform neurofibroma , diffuse mass with extensive interdigitations with surrounding tissue.

9. Multiple neurofibromas Plexiform neurofibroma

10. Ocular Findings Lisch Nodules most common eye lesions Melanocytic hamartomas of the iris, Highly characteristic of NF1. Multiple, tan-colored nodules, seen with slit lamp on iris . Eyelids may be affected by either isolated neurofibromas or plexiform neurofibromas . Plexiform neurofibromas :bag of worms. May be associated with bony defects in the temporal, frontal, or sphenoid bones.

11. Plexiform neurofibromas Isolated neurofibromas

12. Congenital glaucoma associated with upper eyelid neurofibroma . Gonioscopy shows iris insertion anterior to scleral spur. Angle appears to be covered by a membrane. Optic nerve gliomas are pilocytic hamartomas of anterior visual pathways. Bilateral optic nerve gliomas are pathognomonic of NF1. Pulsatile exophthalmos due to sphenoid dysplasia . Prominent corneal nerves. Conjunctival and scleral neurofibroma are rare.

13. Prominent corneal nerves Optic nerve gliomas

14. MANAGEMENT Patients need detailed counseling regarding the prognosis, genetic, and psychological aspects of disease. First-degree relatives should be evaluated. Malignant tumors : excision, chemotherapy, and/or radiotherapy may be indicated.

15. Management of optic nerve glioma remains controversial. Therapeutic indication and outcomes with various forms of treatment include observation, chemotherapy, excision, and radiotherapy. Long-term follow- up shows a good prognosis. Chemotherapy may stabilize vision or induce tumor regression in more than 50% of cases.

16. NEUROFIBROMATOSIS TYPE 2

17. Central NF Unlike NF1, cutaneous findings are not predominant . Schwannomas are the characteristic tumors of NF2.

18. Autosomal dominant About 50% of cases represent new mutations. Chromosome 22q12. It encodes a protein known as schwannomin

19. SYSTEMIC FINDINGS Bilateral vestibular schwannomas (VS) are diagnostic of NF 2. The mean age at onset of VS is less than 25 years Symptoms of NF2 are due to VS rather than to ocular involvement. Deafness with or without tinnitus is most common. Seizures, vertigo, and numbness are less common. Blindness occurs as presenting symptom in only 1% of cases.

20. Spinal schwannomas are present in more than 75% of the cases with NF2. Additionally, intracranial or optic nerve meningiomas and spinal ependymomas are also observed.

21. OPHTHALMIC FINDINGS Posterior subcapsular cataract or wedge cortical cataracts. Retinal hamartoma and combined hamartomas of the retina and retinal pigment epithelium (RPE). Rarely Lisch nodules

22. Wedge cortical cataracts

23. Combined hamartomas of RPE and retina

24. MANAGEMENT Patients should be screened by neurologic, ophthalmic, and neuro-otologic testing. MRI (contrast-enhanced, multi planar T1- weighted) is a cost-effective first-line investigation in detection of VS. Majority (90%) of patientspresent with bilateral VS. Management of VS include observation, stereotactic radiotherapy, and surgical resection.

25. VON HIPPEL–LINDAU DISEASE

26. Eugen von Hippel , a German ophthalmologist, coined the term angiomatosis retinae in 1904. Arvid Lindau , a Swedish pathologist, established a relationship between cerebellar and retinal hemangioblastomas

27. Autosomal dominant VHL gene on chromosome 3p25-26

28. SYSTEMIC FINDINGS VHL disease is a multisystem disorder with a predilection for the retina and CNS. Retinal capillary hemangiomas (RCH) occur in ‹ 75% of cases, CNS hemangiomas in more than 50%, renal carcinomas in ‹ 50% , and pheochromocytomas in ‹ 25%. Probability of developing any components of disease increases with age.

29. Central nervous system hemangioma commonly involve cerebellum (75%) and spinal cord (15%). Tend to be multiple and occur at a younger age as compared to sporadic cases. Headache is initial symptom of cerebellar hemangiomas and pain is common symptom of spinal cord hemangiomas .

30. Renal cell carcinoma is leading cause of mortality. Bilateral in 93% of cases; multiple, renal cysts, and occur at younger age compared to sporadic cases. Pheochromocytomas , rare benign tumors of adrenal medulla, tend to be multiple and bilateral. Elevated serum levels of catecholamines ( norepinephrine and epinephrine) that lead to symptoms such as palpitations, headaches, and sweating.

31. OPHTHALMOLOGIC FINDINGS Retinal capillary hemangioma (RCH) is one of the most common manifestations Circumscribed, round retinal lesion with an orange-red color with prominent feeder vessels. Presence of multiple RCH (two or more), other manifestations of VHL disease, or a positive family history are diagnostic of underlying VHL disease.

32. MANAGEMENT Treatment of RCH determined by size, location, and associated subretinal fluid, retinal traction, and visual potential of eye. Retinal angiomas can be effectively treated with cryotherapy or laser photocoagulation

33. Early diagnosis increases the likelihood of successful treatment yet the ocular lesions are asymptomatic prior to RD. Should undergo periodic ophthalmologic evaluation beginning at about age 5 years. Life expectancy may be improved by early detection and treatment of various tumors.

34. TUBEROUS SCLEROSIS

35. Coined by Desire Magloire Bourneville (1840–1909), a French physician. He described a patient with seizures, hemiplegia , mental subnormality , and renal tumors. He based the terminology tuberous sclerosis, on multiple potato-like (tubers) lesions in the brain

36. GENETICS Tuberous sclerosis complex (TSC) includes two genetic diseases (TSC1 and TSC2) with autosomal dominant inheritance or sporadic. The genes responsible for TSC, TSC1 (chromosome 9q34)71 and TSC2,72 have now been identified. TSC1 and TSC2 genes, encode the proteins hamartin and tuberin , respectively.

37. SYSTEMIC FINDINGS Characterized by hamartomas of various organs. Hamartomas in the brain ( astrocytoma and ependymoma ) lead to childhood seizures and mental retardation.

38. Clinical manifestations of TSC1 and TSC2 are similar except that the TSC1 is milder with a reduced risk of mental retardation as compared to TSC2. Other findings of TSC1 such as seizures, renal involvement, facial angiofibroma , and retinal hamartomas are also less frequent or less severe compared to TSC2.

39. Cutaneous manifestations of TSC are mainly of diagnostic significance. Hypomelanotic macules are the most frequent and the earliest finding, best visualized with Wood’s lamp (UV light). Fibrous plaques appear as reddish-orange patches on the forehead. Facial angiofibromas are not present at birth and appear usually by age 5 years.

40. Shagreen patches Subungual fibromas Hypomelanotic macules

41. Facial angiofibromas

42. Visceral manifestations include pulmonary lymphangiomyomatosis , renal angiomyolipoma , and cardiac rhabdomyoma Imaging studies such as MRI of brain and CT - abdomen are important to detect CNS and visceral involvement.

43. OPHTHALMOLOGIC FINDINGS Retinal or Optic nerve hamartomas Three morphologic types of retinal astrocytic hamartomas are opthlamoscopically recognized: More common subtle, flat, round, semitranslucent lesion; Large, elevated, nodular, and calcified mulberry lesion; Mixed type of lesion, being calcified in the central portion and semitranslucent in the periphery.

44. Semitranslucent lesion Mulberry lesion Mixed type

45. MANAGEMENT Depends upon location & extent of organ involvement. Retinal astrocytic hamartomas usually need only periodic evaluation by ophthalmoscopy and fundus photography. Patients with TSC-related mental retardation require supervision for daily living.

46. Common causes of mortality are renal disease, brain tumors and status epilepticus . Patients need lifelong follow-up for early detection of potentially life threatening complications.

47. STURGE–WEBER SYNDROME

48. Sturge (1879) reported the case of a child with facial “port-wine stain,” epilepsy, buphthalmos , and a dark choroid. Schirmer had noted the association with glaucoma in 1860. Weber (1922) reported brain X-ray findings of “ railtrack ” sign

49. SYSTEMIC FINDINGS Predominant manifestation is a diffuse hemangioma in leptomeninges , choroid, and facial skin. Sturge –Weber syndrome with its neural involvement leads to intractable seizures, developmental delay, and behavioral problems.

50. Cutaneous manifestations of nevus flammeus , although most evident, are mainly of diagnostic significance, Glaucoma and diffuse choroidal hemangioma may be associated with some visual loss.

51. Leptomeningeal hemangiomatosis is ipsilateral to cutaneous involvement. This can lead to a seizure disorder due to effects on underlying cerebral cortex. Contrast-enhanced MRI for detecting cerebral atrophy and leptomeningeal angiomatous malformations. If MRI is normal, CT scan to detect intracranial calcifications.

52. Leptomeningeal angiomatous Intracranial calcifications Rail-track sign

53. Cutaneous hemangioma is also called nevus flammeus or port wine stain . Only 10 % are associated with SWS. SWS only occurs in patients with, involvement of V1 or V2 distribution of trigeminal nerve. Bilateral port wine stains have higher associatpon . Leptomeningeal and ocular involvement in SWS are always associated with port wine stain involving eyelids.

54. Port wine stain

55. OPHTHALMOLOGIC FINDINGS Glaucoma is the most frequent manifestation of SWS and occurs in 70% of all cases. Angle maldevelopment or raised episcleral venous pressure can lead to glaucoma.

56. Incidence of glaucoma is higher if the eyelids are involved with nevus flammeus . Choroidal hemangioma is usually unilateral and ipsilateral to the nevus flammeus . Appears as an orange-colored, diffuse choroidal thickening associated with exudative RD.

57. Exudative RD Choroidal hemangioma Choroidal thickening

58. MANAGEMENT Medical therapy of glaucoma is effective in some cases, but eventually require multiple trabeculectomies combined trabeculotomy with trabeculectomy, or even drainage implants. Choroidal hemangioma can be treated with low-dose standard radiotherapy or with proton beam radiotherapy. Seizures are generally controlled with medications but intractable cases require surgical resection of leptomeningeal angiomatosis with underlying cerebral cortex.

59. ATAXIA TELANGIECTASIA

60. Madame Louis-Bar in 1941 described a young boy with progressive cerebellar ataxia and oculocutaneous telangiectasia . Term ‘ ataxia telangiectasia ’ was proposed by Boder and Sedgwick in 1958 Autosomal recessive . Causative gene in AT is called ATM (ataxia - telangiectasia mutated gene) and is found on chromosome llq22.3.

61. SYSTEMIC FINDINGS Childhood neurodegenerative disorder with neural, ocular, and cutaneous manifestations associated with immune dysfunction. Progressive cerebellar ataxia in early childhood is hallmark of AT Show increased sensitivity to the tissue-damaging side effects of therapeutic radiation and chemotherapeutic agents.

62. Defective T-cell function associated with hypoplasia of the thymus and decreased levels of circulating immunoglobulin. Recurrent respiratory tract infections are a serious problem, Increased susceptibility to various malignancies, particularly lymphomas and leukemias , contributes to early mortality.

63. Ocular findings Telangiectasia of conjunctiva has later onset than ataxia and appears at age 3-7 years. First noted in the interpalpebral bulbar conjunctiva away from limbus . Later ocular telangiectasia becomes generalized and simulates a conjunctivitis.

64.  Ocular abnormalities include oculomotor apraxia , deficient accommodation, impaired smooth pursuit, hypometric saccades,nystagmus , absence of optokinetic nystagmus , frequent blinking. Combination of oculomotor apraxia and failure to suppress the vestibulo -ocular reflex is characteristic.

65. Patients will develop impairment of pursuits by school age. Increased saccadic latency, saccadic hypometria , and saccadic intrusions are also seen. Visual acuity, pupillary response, and funduscopic examination are usually normal.

66. MANAGEMENT AT patients suffer from recurrent sino -pulmonary infections because of immune dysfunction. AT-associated malignancies such as lymphoma and leukemia require modified chemotherapy and radiotherapy dosages because of hypersensitivity to radiation and chemotherapy-induced DNA damage.