Review

RECENT ADVANCES IN THE PHAKOMATOSES JOHN R. PERSON, M.D. AND HAROLD 0. PERRY, M.D.

From the Department of Dermatology Mayo Clinic and Mayo Foundation, Rochester, Minnesota

The term phakomatosis was coined by the ophthalmologist Van der Hoeve' in 1920 to describe 4 conditions that share characteristic central nervous system and retinal tumors (phakomas). The conditions so grouped are neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, and von HippelLindau disease. The cutaneous involvement in all but von Hippel-Lindau disease is striking, and the cutaneous lesions are well known to most dermatologists. During the past few years, however, largely because of increasingly sensitive and sophisticated diagnostic techniques, systemic involvement in these conditions has been noted to be more common and diverse than previously realized. It isour purpose in this paper to briefly review the cutaneous involvement in these conditions and to consider in detail the recent nondermatologic advances.

though Crowe's data would indicate that the resultant mutation rate (1 x 1W4) is the highest known to exist in man, Sergeyev4believes that Crowe overestimated the incidence of neurofibromatosis and that the mutation rate is more likely about 4.4 to 4.9 x a rate similar to that of hemophilia and muscular dystrophy. The disorder shows no sexual, racial, or ethnic predilection. Neurofibromas are the hallmark of the disease. Cutaneous neurofibromas, also known as molluscum fibrosum, begin to appear in late childhood and adolescence and gradually increase i n size and number. Puberty and pregnancy often exacerbate the growth of the l e ~ i o n s Clinically, .~ the lesions are soft and fleshy, and when pressed, they can be invaginated into the skin ("buttonholing"). Histopathology6 of the neurofibromas shows a nonencapsulated but usually wellcircumscribed dermal tumor comprised of lightly eosinophilic, thin, wavy fibers, among which scattered oval-to-spindle-shapd nuclei are found. Metachromatic stains often reveal many mast cells. Electron m i c r o ~ c o p y ~ * ~ shows that the Schwann cell is the predominant cell type and that multiple axons are within its peripheral cytoplasm*The stroma consists largely of reticulum fibers

Neurofibromatosis Neurofibromatosis was first identified as a nosologic entity by von RecklinghausenZ in 1882. According to Crowe et a1.,3 its incidence is 1 per 2,500 to 3,000 live births. Although it is inherited as an autosomal dominant condition, in approximately half of Crowe's 203 patients the disease seemed to have arisen by spontaneous mutation. All

Address for reprints: 1. R. Person, M.D., 76 Section of Publications, Mayo Clinic, 200 First Street SW, Rochester, MN 55901.

0011-9059-78-01 00-0001-01 20 @ International Society of Tropical Dermatology

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produced by scattered fibroblasts of the endoneural type. Subcutaneous neurofibromas occur either as discrete noduleson a peripheral nerveor as a diffuse neurofibromatosis of a nerve trunk, known as a plexiform neuroma. Clinically, the plexiform neuroma feels like a "bag of worms" and is pathognomonic of neurofibromatosis. Plexiform neuromas were present in 16% of Crowe's patients? Malignant degeneration of neurofibromas has been a subject of great controversy. D'Agostinoeta1.9 found that only 3.1 % of 678 patients developed neurofibrosarcomas, as did only 2% of Crowe's 203 patients? However, Brasfield and Das Gupta,lo in a series of 110 patients, found that 9 of 18 patients who were older than 50 years developed either a neurofibrosarcoma in a pre-existing neurofibroma or a malignant schwannomade novo. In the series of D'Agostino et al.,Y malignant degeneration was most common within a plexiform neuroma and was decidedly uncommon in cutaneous neurofibromas. Central nervous system involvement occurs in 3 to 8% of patients and most commonly consists of benign gliomas that can result in mass symptoms, obstructive hydrocephalus, and so forth? Malignant tumors, most commonly astrocytomas, may also occur. A large percentage of patients are retarded, but most show no discernible anatomic abnormalities? Rosman and Pearcell have ascribed the retardation to cortical dysgenesis. The most common cranial nerve lesion i s an acoustic neu rofibroma, which is often bi lateral.3 An optic nerve glioma i s the commonest intracranial tumor and may result in papilledema, retrobulbar neuritis, and finally, optic atrophy. Choroidal and retinal neurofibromas occur, as do lid lesions. Congenital glaucoma, however, is rare and occurs only when the disease is severe.l2Recently, a sine wave-like deformity of the lateral eyelid has been described as being diagnostic of orbital in~olvement.'~ Most patients have bone lesions, and these are usually the effect of pressure from intraos-

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seous or paraosseous neurofibromas? Osteomalacia14 or hypertr~phy'~ also may occur, and the resultant deformity may be severe. Vertebral scalloping is characteristically seen on roentgenograms.l6*'7 Congenital abnormalities, which are not related to the presence of neurofibromas, such as bowing of the tibia, also may be present and should be treated conservatively.'8 Oral neurofibromas occur in 1 to 5 % of patient^.'^ Laryngeal neurofibromatosis, although rare, has been occasionally reported.zO-zz Vaginalz3and bIadderz4-z6involvement are rare but are also the object of numerous case reports. Bladder neurofibromas are supposedly derived from the vesicoprostatic plexus in males and the uterovaginal plexus in femalesz4and it most commonly occurs as a submucosal mass in the area of the trigone and bladder neck.25 The main danger i s obstruction. Cystourethrograms show a characteristic irregular filling defect, but the diagnosis is unlikely to be made in the absence of cutaneous lesionsF6 Bladder lesions are very rare in children and are best preliminarily detected by rectal e~amination?~ Gastrointestinal tumors occur in about 10% of Seventy per cent of the tumors are neurofibromas, 2 0 % are leiomyomas, and 10% miscellaneous tumors. The jejunum and ileum are the most common sites of involvement, although neurogenic tumors generally occur in the st0mach.2~ Hochberg et a1.28found that 27 of 39 patients reported in the literature had gastrointestinal symptoms and that in 8 of the 39 patients the tumors were malignant. The most common complications are obstruction, usually from intussuception, and hemorrhage, caused by erosion or perhaps necrosis of a pedunculated tumor?O The neurofibromas most often arise subserosally from Auerbach's plexus and usually are pedunculated masses situated along the serosa of the antimesenteric border; hence, an extrinsic ratherthan an intraluminal defect is most common. This extrinsic location accounts for the low positivity of barium

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examinations; angiography is usually necessary for demonstration of the tumors.3l Rectal lesions detected at proctoscopy also have been r e p ~ r t e d ? ~ , ~ ~ Cardiovascular lesions in association with neurofibromatosis are more common than has been previously realized. Although not related to the presence of neurofibromas per se, Neiman et al.34found that 6 of 78 patients with neurofibromatosis had congenital heart disease, including pulmonic stenosis, aortic coarctation, atrial septal defect, ventricular septal defect,' and congenital heart block. Vascular neurofibromatosis was first well defined by FeyrterP5 who found 6 cases of vascular neurofibromatosis in 3,000 routine autopsies. Only 3 of the 6 cases were associated with other manifestations of neurofibromatosis. Feyrter classified the vascular lesions into 5 histologic types: pure intimal, mixed intimal, nodular aneurysmatic, nodular periarterial, and epithelioid. Vascular involvement of the renal arteries is becoming increasingly recognized as a leading cause of hypertension in the di~ease.3~*~' This is usually caused by a fibrous dysplasia of the vessel wall but occasionally by an adherent or intramural wurofibroma. Along with abdominal aortic coarctation, renal artery stenosis is the most common cause of hypertension in childhood neurofibromatosis?* Although the incidence of pheochromocytoma is disputed, it is extremely rare in Angiography of the stenotic renal arteries differs from atherosclerotic stenosis in that the vessels are smooth-bordered; it differs from fibromuscujar hyperplasia in that the poststenotic region is funnel-shaped rather than bulbous as in the usual poststenotic dilatati0n.3~A study of 600 patients with neurofibromatosis by Lynch et ai.4O revealed that only 15 had hypertension. of these, 3 had pheochromocytoma and 1 had possible renal artery stenosis. Swapp and Main,5 however, noted that the incidence of hypertension during pregnancy among women with neurofibromatosis was approximately 50%.

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Cafe-au-lait spots are extremely frequent in neurofibromatosis. Among Crowe's patients, 94% had at least 1 lesion and 78% had 6 or more lesions? Crowe noted that no normal adult has been found to have 6 or more cafeau-lait spots and suggested that the finding of 6 or more lesions larger than 1.5 cm in diameter is diagnostic of neurofibromatosis. The spots are present at birth and hence are the earliest and most visible clue to the diagnosis. Another pathognomonic sign, described by Crowe41 in 1964, is the presence of small freckle-like pigmented macules in the axillae and perineum. These were seen in approximately 20% of Crowe's patients. Benedict et al.42 noted that the melanotic macules of Albright's polyostotic fibrous dysplasia differ from those of neurofibromatosis in that they are usually larger, have more irregular borders ("coast of Maine"), tend not to cross the midline, and are rarely associated with giant melanosomes. Of their 19 patients with neurofibromatosis, all had giant melanosomes, whereas only 1 of their 10 patients with Albright's syndrome had them. These authors also found increased melanocytic activity, but not an increased number of melanocytes, within both types of cafe-au-lait spots. Johnson and Charnec0,4~however, found the concentration of DOPA-positive melanocytes to be increased in the cafe-au-lait spots of neurofibromatosis but decreased in the cafe-au-lait spots of normal persons, as is the case in ephelides. Two of their 8 patients also did not have giant melanosomes. Jimbow et alP4examined the giant melanosomes of neurofibromatosis ultrastructurally and found 3 types, which probably represented different stages of development. The giant melanosomes were comprised o f membrane-bound subunits containing electron-dense amorphous material, electron-lucent globular bodies, electrondense granular bodies, and finely granular substances. In addition, normal melanosomes and melanoma-type melanosomes were o b served. The authors also presented evidence

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that the giant melanosomes are different from other abnormal melanocytic inclusions, but they noted similarities with the granules in Aleutian mink. Konrad and W ~ l f also f ~ ~ have found similar granules in a nevus spilus. Pheochromocytoma, often bilateral and usually of adult onset, i s the most common endocrine manifestation of neurofibromat~sis,~ but its occurrence has probably been overemphasized. In Crowe’s3 series (203 patients) and in Lynch’s40 series (600 patients), the prevalence was only 0.5 % . Sexual precocity i s the most common endocrine abnormality in childhood, and in females, it must be differentiated from Albright’s syndrome. The cause i s considered to be hypothalamic g l i o m a t ~ s i sA . ~wide ~ variety of endocrine problems has been described in association with neurofibromatosis,46including acromegaly, hypogonadism, diabetes, hyperparathyroidism, hypopituitarism, and the carcinoid ~ y n d r o m e ; ~ however, ~ . ~ ~ none of these has been consistently associated with neurofibromatos is. Neurofibromatosis with endocrine involvement must be differentiated from multiple endocrine neoplasia-type Ilb, a syndrome of uncertain inheritance that consists of medullary carcinoma of the thyroid, pheochromocytoma, mucosal neuromas or hyperplastic corneal nerves, and a marfanoid h a b i t ~ s . @Recently, ,~~ this syndrome has been differentiated from the dominantly inherited Sipple ~ y n d r o m e ~or~ multiple -~~ endocrine neoplasia-type Ha, whose patients lack the nerve changes and marfanoid habitus but whose condition i s usually associated with hyperparathyroidism in addition to medullary carcinoma of the thyroid and pheoc h romoc ytom a. M u Iti p l e e ndoc r i ne neoplasia-type Ilb i s also genetically distinct from type Ila or Sipple’s syndrome. During the past 15 to 20 years, largely through the work of Pearse,52 a concept has developed that links seemingly dissimilar endocrine and neuroendocrine cells by similar properties of amine precursor uptake decarboxylation (APUD), argyrophilia, masked

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metachromasia, characteristic enzymes, and specific hormone production. These cells are considered to be derived from the neural crest and include the islets of Langerhans, the argentaffin cells of the gastrointestinal tract, the adrenal medulla, thyroidal parafollicular “C-cells,” the oat cells of the lung, pituitary corticotrophs and melanotrophs, and melanocytes. The syndromes of multiple endocrine neoplasia and neurofibromatosis are likely similar aberrations of this system. This concept also explains the various syndromes of “humors from tumors,” especially in regard to oat cell carcinoma of the lung. Because aberrattons within the APUD system may be multiple, it i s important to examine patients with insulinoma, Zollinger-Ellison syndrome, glucagonoma, pancreatic cholera, carcinoid, oat cell carcinoma of the lung, chemodectoma, Cushing’s disease, pheochromocytoma, medu llary carcinoma of the thyroid, and melanocytic hyperplasias or neoplasias for more widespread disorders of the APUD system. It should be of some philosophic comfort to endocrinologistsand dermatologiststhat most workers in evolutionary biology53believe that we vertebrates are descended from coelenterates. This implies that the neural crest derivatives constitute our most “basic” nervous system and that central nervous, musc u I0s kel et al , re na I, and card iovascu la r systems are evolutionary afterthoughts. Thetheoryofamultiplecelloriginof neurofibromatosis has been given credence by the work of Failkow et al.54 They studied 14 neurofibromas of a woman who was heterozygous for 2 X-linked G-6PD alleles. According to the Lyon hypothesis, each starting cell should contain only one active allele, but each of the 14 tumors showed activity of both alleles. Statistical analysis of these results indicated that the starting number of cells must be at least 150. Increased levels of nerve-growth stimulating factors, as measured by bioassay, were found in neurofibromatosisby Schenkein and colleague^.^^ The physiologic or pathologic

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significance of these factors, however, is unknown. Other workers,56 using a radioimmunoassay, have found that the levels of the specific beta-nerve growth factor are not elevated in neurofibromatosis. Interstitial pulmonary fibrosis has been associated with neurofibromatosis in at least 26 ~ases.5~ Thecause isunknown. The pulmonary fibrosis occurs predominantly in males, with a median age of 46 years. One patient studied in detail had no specific ultrastructural changes, and direct immunofluorescenceof lung tissue was negati~e.5~ Malignant melanoma may not be rare in neurofibromatosis. In the study by Brasfield and Das Gupta,lo melanoma developed in 6 of their 110 patients. Two of the 6 had bathing . trunk nevi. Malignant uveal melanoma also hasbeenreported in theophthalmologicliteraThere have been occasional case reports of nevoxanthoendotheliomas associated with neurofibromatosis, indicatingth at t he 2 cond itions may be related.60-63 Multiple neurilemmomas also have been described in neurofibromato~is.~~, 65 Many patients have also been described in whom neurofibromatosis seemed to coexist with tuberous sclerOsis66-68; the significance Qf this coexistence i s uncertain. Case reports of leukemia and neurofibromatosis are believed to represent a chance occurrence of the 2 conditi0ns.6~

Tuberous Sclerosis Tuberous sclerosis i s an autosomal dominantly inherited multisystem disorder which classically consists of the triad of epilepsy, mental retardation, and adenoma sebaceum. Of71 patients studied by Lagos and go me^,^^ 62% were retarded; 83% had adenoma Mbaceum which generally developed during Ihe first 5 years of life; and all of the retarded patients and 69% of the normal patients had kistories of seizures. The disease shows no racial, ethnic, or sexual predilection. Its incidence is estimated at 5 to 7 per 100,000. In his Series of 71 cases, Bundey71 found an au-

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tosomal dominant inheritance in 14% and no family history of the disorder in 8 6 8 . According to Fitzpatrick et aI.,’* 85% of patients have congenital hypopigmented “ash leaf” macules, but these were noted in only 15% of Lagos and Gomez’s patients.70These oval lesions are usually located on the trunk, and their number and size vary. Visualization is enhanced by Wood’s light. Histologically, normal numbers of melanocytes are present but the intensity of the dopa reaction is red ~ c e dBeing . ~ ~ present at birth, the lesions are the earliest clue to the disease. “Adenoma sebaceum” is actually an angiofibroma and i s seen in 80to 90% of patients. The lesions are reddish, waxy nodules that have a predilection for nasolabial folds and cheek and chin areas. Elastic tissue i s absent in the lesions.74 Subungual fibromas were noted in 17% of the patients in Lagos and Gomez’s series.70 These lesions usually have their onset at puberty, and they gradually increase in size.75 Histologically, they are similar to the angiofibromas, but capillary dilatation is absent.6 “Shagreen patches” are connective tissue nevi and clinically exhibit a “cobblestone” or “pigskin” appearance. They most commonly occur lumbosacrally.“ They were present in 21% in Lagos and Gomez’s patients.7O Cafeau-lait spots were found in 7% of Lagos and Gomez’s patients.7O Central nervous system lesions consist of hamartomatous “tubers,” which are largely limited to the cerebral cortex. Only rarely is the brain stem, cerebellum,76 or spinal cord involved.7° The tubers calcify in approximately 50% of cases (“brain In Lagos and Gomez’s series, 93% of patients had seizures, 87% had abnormal electroencephalograms, and 62% were retarded.7O Neoplastic transformation of the tubers, usually into astrocytomas, is not uncommon.” The earliest seizures, commonly called “infantile spasms,” consist of repetitive myoclonic contractions with tremors and opisthotonus; when these are associated with hypopigmented macules, the correct diag-

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cells rather than the expected muscle cells, nosis can be made in infancy.78Mental funcsupporting the supposedly disc redited theory tion gradually deteriorates with time.75 The of lnglissOthat the tuberous sclerosis complex benign gliotic tubers do not concentrate radionucleotide on brain scan unless an aswas due to the dissemination of immature trocytoma has developed.79Carotid angiogSchwann cells. Occasionally, cardiac involvement occurs; raphy shows berry-Iike aneurysms in the tubers during the late arterial phase.80Pneumoen- it consists of multiple discrete rhabdomyomas of the heart wall which can result in various cephalography shows characteristic "candle obstructive phenomena, myocardial dysfuncgutterings" in the lateral ventricles. Comtion, or conduction defects. The condition i s puterized axial tomography, which demonstratesthe hamartomaswelland isnoninvasive usually congenital. A number of symptomatic and without risk, is likely to become the diagpatients have been successfully treated surginostic method of choice to demonstrate cencally, and at least one has responded to medical treatment?' tral nervous system lesions.8' Pulmonary involvement i s rare, and fewer Two types of retinal gliomas occur: (1) than 40 patients have been described.92 peripheral lesions that are flat, white, and cirEighty-four per cent ofthe patients are women, cular and (2) nodular, mulberry-like lesions the average age at onset is 34 years and the that occur near the optic head.82 Phakomas major symptom is exertional dyspnea.g2Findoccurred in 53% of patients in Lagos and ings on chest roentgenogramsvary from a fine Gomez's series.'O Renal lesions occur in 50 to 80% of patients reticular pattern to multiple cysts?2 Fifty per cent of patients develop spontaneous and are usually bilateral.= Cystic lesions prepneumothorax, 27% have cough, and 27% dominate in children and the more common have hemoptysis.92Fifty-four per cent of paangiomyolipomas in adults.83The tumors usutients with pulmonary lesions have normal ally begin before the age of 25 yearsE3The intelligence, probably because patients with incidence of renal failure i s low, perhaps besevere involvement of the central nervous syscause the patients, especially the males, die of tem die before pulmonary symptoms can beother causes. When renal failure occurs, it i s come manifest.g2If the pulmonary lesions are secondary to a diffuse tumor that has replaced the cause o f death, it is usually from the p a r e n ~ h y m a .Glomerulonephritis ~~ and or cor p u l m ~ n a l e . The ~~*~~ hypernephromasalso have been r e p ~ r t e d . ~ ~pneumothorax ,~~ pathologic pattern of the pulmonary lesions There have been 20 reported casesof malignant transformation of angiomyolipomas, but varies with the stage of disease but usually in none of these has metastasis there i s diffuse leiomyomatosis; Valensig4beSymptoms are usually related to hemorrhage lieves that pulmonary lymphangioma andthe resultantflankpain.The hemorrhageis (leiomyoma with chylothorax) may representa forme fruste of tuberous sclerosis. probably due to absent elastic tissue in the Endocrine and metabolic abnormalities in angiomyolipomas (note similarity to angiofibromasJE7On excretory urogram, the antuberous sclerosis may not be uncommon but are varied and nonspecific. Goiter, giomyolipomas are indistinguishable from cysts; but on arteriography, they show charachypothyroidism, Cushing's syndrome, low pituitary-adrenal reserve, abnormal glucose teristic changes: increasedbut abnormallydistr ibuted vasc uIar ity, unusual tortuosity, and tolerance, precocious puberty, and adrenal characteristic aneurysmal dilatations of the hyperplasia have been de~cribed.9~ interlobular and interlobar arteries.88 (Note Bone lesions are uncommon, but cystic similarities to cerebral arteriography.) A recent rarefactions in the metacarpalsandphalanges, electron microscopic study of anwith cortical pitting and bowing, and sclerotic giomyolipomasg revealed blastic Schwann lesions of long bones have been described?6

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Oral nodules, fibromas, and papillomas are seen in 11% of patients, are usually the color of normal mucosa, and are most commonly located on the anterior gingiva of the maxilla The onset is usually in childhood or a d o l e ~ c e n c e . However, ~~ since the great majority of patients have a seizure disorder, one must rule out hydantoin-induced gingival h y p ~ p l a s i a Enamel .~~ defects are also common. Scanning electron microscopic examination of the involved enamel shows pitted defects, indentations and craters, which may be pathognomonicQg Splenic hamartomas, which may cause abdominal pain and splenomegaly, were noted in 44 cases.loO Rundleetal.lolfound increasedIgM levelsin 49 of 50 patients and decreased IgG levels in 29 of 54 patients. Davidlo2 found that the palmar dermatoglyphics were normal. Thecourseoftuberoussclerosis isgradually progressive, especially with regard to the lesions of the central nervous system. In the "full-blown" syndrome, 50 to 75% of the patients die before adulthood.75

Sturge-Weber Syndrome Sturge-Weber syndrome is generally considered to be a developmental anomaly consisting of encephalotrigeminal angiomatosis with underlying leptomeningeal angiomatosis and ocular involvement. The term encephalotrigeminal angiomatosis, however, is often used synonymously with SturgeWeber syndrome.'03 The syndrome was first described by Sturgelo4 in 1879 and the roentgenographicfindings were described by Weberlo5in 1922. Usually it is not a heritable disorder, but its occurrence in twins has been desc r ibed.Io6 The cutaneous lesion is present at birth and consists of nevus flammeus involving at least part of the distribution of the trigeminal nerve. The lesion may have a far wider distribution, however, and may coexist with the KlippelTrenaunay syndrome. The lesion is usually unilateral and ends sharply at the midline.

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There is no correlation between the extent of cutaneous involvement and the central nervous system involvement103; of 35 patients with "Sturge-Weber syndrome" studied by Petermanet aI.,Io75 had no cutaneous lesions. Lund108 found 7 of 144 patients without cutaneous lesions, and 2 of the 7 had leptomeningeal angiomatosis proved at surgery. The nevus flammeus generally darkens and may become nodular with age. The histopathologic features are generally normal until late childhood, at which time the capillary ectasias become manifest and gradually increase! Five patients with cutaneous melanosis, most commonly an atypical nevus of Ota, have been reported as having associated Sturge-Weber syndrome.lOg~llo Recently, adenoma sebaceum without other manifestations of tuberous sclerosis has been reported in association with typical Sturge-Weber syndr0me.l" Involvement of the central nervous system usually consists of unilateral leptomeningeal angiomatosis with progressivecalcification in the underlying cortex. Epilepsy occurs in 80% of patients and 50% have it before 1 year of age.lo8The seizures are usually Atrophy of the involved hemisphere with contralateral hemiparesis may occu r.lo8Many of these patients are retarded.l12 Roentgenographic evidence of laminated, concentric cortical calcifications has long been considered to be pathognomonic of Sturge-Weber syndrome, but similar calcifications recently have been seen in 2 children with acute lymphocytic leukemia in remission who had received both radiotherapy and intrathecally adm in istered meth~trexate.~'~ In these 2 cases, however, the gyriform calcifications were bilateral. Ultrastructural examination shows that the calcific deposits consist of built-up filaments and needle-like calcium apatite crystals that are found extracellularly and extrava~cularly.~~~ Bentson and his coll e a g u e ~ " ~found characteristic but not pathognomonic changes on cerebral arteriography. They found a lack of superficial corti-

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cal veins, nonfilling of the superior saggital sinus, and enlargement and tortuosity of the deep subependymal and medullary veins. They hypothesized that the pattern was due to the absence or nonfunction of cortical veins beneath the leptomeningeal angiomatosis, with collateral flow occurring centrally to the subependymal veins. Characteristic abnormalities also were noted on brain scan by Kuhl et a1.116 The abnormalities were not related to calcification or the presence of retardation. The affected hemisphere was smaller and showed diffusely increased uptake when compared with the normal hemisphere. Increased uptake was also frequently noted focally in the calcified areas. The authors emphasized that the hemispheral involvement and capillary alterations were deeper, more widespread, and more diffuse than was indicated by the leptomeningeal or calcified cortical lesions. Chang and his colleague^"^ performed isotope cisternography on an infant with Sturge-Weber syndrome before evidence of typical calcification was seen roentgenographically. The rapid disappearance of the isotope suggested increased circulation or absorption of cerebrospinal fluid by the involved hemisphere. Half of the patients with Sturge-Weber syndrome have ocular involvement, which may be in the form of angiomatosis of the conjunctiva, iris, or choroid, the latter possibly produc i ng retinal detachment; congenital (buphthalmos) or late-onset glaucoma that may cause blindness; or megalocornea.12The classic retinal lesion i s the choroidal angioma, which i s usually of adult onset; however, before this develops, ophthalmoscopy reveals that affected children have a bright red "tomato catsup" fundus without the usual blond areas.llS The choroidal angiomas are usually treated with photocoagulation if retinal detachment supervenes, but cryotherapy also shows promise as an effective treatment."g According to Weiss,'20 the glaucoma has 2 possible causes: an anterior segment anomaly causing increased resistance to outflow or a

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vascular anomaly causing increased venous pressure. He hypothesized that both factors are operative in congenital glaucoma. Sturge-Weber syndrome i s probably the only phakomatosis not associated with an increased risk of malignan~ies.'~7Kiely and PerrylZ1have reported Sturge-Weber syndrome in association with multiple myeloma, but the association i s probably a chance occurrence.

Von Hippel-Lindau Disease Von Hippel-Lindau disease is an autosomal dominant disorder consisting of retinal angiomas, first noted by von Hippe1lZ2in 1904, and cerebellar medullary angioblastic tumors, pancreatic cysts, and renal tumors and renal cysts, noted by Lindau in 1926.'= The skin is not usually involved in the disorder. Twenty per cent of patients have the central nervous system involved, usually as a cerebellar hemangioblastoma ("Lindau's tumor") although medullary tu mors, syr i ngomyel ia cavities, and ependymal cysts also can occur. Recently, a pituitary hemangioblastoma has been reported for the first time.124 Formes frustes of the disorder have been discovered by brain scan i n asymptomatic relatives of patients with known disease.lZ5Ten to 20% of cerebellar hemangioblastomas produceerythropoietin and are accompanied by a secondary polycythemia;lZ6 the polycythemia may disappear after excision of the tumor.lZ7 Ocular lesions are retinal angiomas that may eventually lead to retinal detachment. Angiomas that are less than 0.8 disk diameters are amenable to laser photocoagulation, but larger lesions usually cannot be effectively obl iterated:28 Renal lesions consist of benign cysts and hypernephromas, which are usually bilateral; but the interval between the onset of the first hypernephroma and the development of another in the contralateral kidney has varied from 3 to 14 years.'29 Ten per cent of hypernephromas and less than 8% of renal cysts also produce erythr~poietin.'~~ The histologic

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PHAKOMATOSES

features of the cerebellar and renal lesions may be similar and may be confused with metastatic lesion^.'^' Pheochromocytoma has now been reported in association with von Hippel-Lindau disease in 10 kind red^.'^^,'^ The lesions in von Hippel-Lindau disease are more commonly multiple, occur in younger patients, and are less malignant than are pheochromocytomas in general.'32,133SturgeWeber syndrome 'and tuberous sclerosis have not been associated with pheochromocytomas. Three patients with von Hippel-Lindau disease have been reported as also having neurofibromat~sis.'~~ A study of 3 kindreds by S h ~ k e i rshowed '~~ an autosomal recessive pattern of inheritance in 1 and an autosomal dominant pattern in 2.

References

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A suggested neuropathological basis for the associated mental defect. Brain 90:829, 1967. 12. Scheie H.G., and Albert, D. M.: Adler's Textbook of Ophthalmology. Eighth edition. Philadelphia, W. B. Saunders Co., 1969. 13. Smith, B., and English, F. P.: Classical eyelid border sign of neurofibromatosis. Br. J . Ophthalmol. 54:134, 1970. 14. Mittal, M. M., Gupta, N. C., and Sharma, M. L.: Osteomalacia in neurofibromatosis. J. Assn. Physicians India 19:823, 1971. 15. Kullmann, L., and Wouters, H. W.: Neurofibromatosis, gigantism and subperiosteal haematoma: Report of two children with extensive subperiosteal bone formation. J. Bone joint Surg. (Br.) 54:130, 1972. 16. Salerno, N. R., and Edeiken, J.: Vertebral scalloping in neurofibromatosis. Radiology 97:509, 1970. 17. Debaene, A., Acquaviva, P., Dufour, M, and Leg&, I: Lumbar vertebral scalloping during recklinghausen's disease. j. Radiol. Electrol. Med. Nucl. 54:149, 1973. 18. Rose, G. K.: Restraint in the treatment of a bowed tibia associated with neurofibromatosis. Acta Orthop. Scand. 46:704, 1975.

1. Van der Hoeve, J: Eye symptoms in tuberose sclerosis of the brain. Trans. Ophthalmol. SOC. UK 40:329, 1920.

19. Freedus, M. S., and Doyle, P. K.: Multiple neurofibromatosis with oral manifestations. J. Oral Surg. 33:360, 1975.

2. Von Recklinghausen, F. D.: Ueber die multiplen Fibrome der Haut und ihre Beziehungzu den multiplen Neuromen. Berlin, A. Hirschwald, 1882.

20. Morris, H. D., and Patterson, W. I.:Neurofibromatosis of the laryngopharynx. Can. J. Otolaryngol. 2:17, 1973. 21. Maisel, R. H., and Ogura, J.H.: Neurofibromatosis with laryngeal involvement. Laryngoscope 84:132, 1974.

3. Crowe, F. W., Schull, W. J., and Neel, J. V.: Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis. Springfield, Charles C Thomas, 1956.

4. Sergeyev, A. S.: On the mutation rate of neurofibromatosis. Humangenetik 28:129, 1975.

5. Swapp, G. H., and Main, R. A,: Neurofibromatosis in pregnancy. Br. J. Dermatol. 88:431, 1973.

6. Lever, W. F., and Schaumberg-Lever, G: Histopathology of the Skin. Fifth edition. Philadelphia, J. B. Lippincott Co., 1975.

7. Waggener, J. D.: Ultrastructure of benign peripheral nerve sheath tumors. Cancer 19:699, 1966.

8. Weber, K, and Braun-Falco, 0.:Zur Ultrastruktur der Neurofibromatose. Hautarzt 23:116, 1972. E. H., and Miller, R. H.: Sarcomas of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (von Recklinghausen's disease). Cancer 16:1015, 1963.

El. D'Agostino, A. N., Soule,

10. Brasfield, R. D., and Das Gupta, T. K.: Von Recklinghausen's disease: A clinicopathological study. Ann. Surg. 175:86, 1972.

11. Rosman, N. P., and Pearce, j.: The brain in multiple neurofibromatosis (von Recklinghausen's disease):

22. Jafek, B. W., and Stern, F. A,: Neurofibroma of the larynx occurring with von Recklinghausen disease: Report of a case. Arch. Otolaryngol. 98:77, 1973. 23. Gold, B. M.: Neurofibromatosisof the bladder and vagina. Am. J.Obstet. Gynecol. 113:1055, 1972. 24. Pessin, J. I., and Bodian, M: Neurofibromatosis of the pelvic autonomic plexuses. Br. j. Urol. 36:510, 1964. 25. Cameron, K. M.: Neurofibromatosisof the bladder. Br. J. Urol. 36:77, 1964. 26. Howat, J. M.: Neurofibromatosis of the bladder. J. Roy. Coll. Surg. Edinb. 18:244, 1973. 27. Carlson, D. H., and Wilkinson, R. H.:Neurofibromatosis of the bladder in children. Radiology 105:401, 1972. 28. Hochberg, F. H., Dasilva, A. B., Galdabini, J., and Richardson, E. P., jr.: Gastrointestinal involvement i n von Recklinghausen's neurofibromatosis. Neurology 24:1144, 1974. 29. Devereux, R. B., Koblenz, L. W., Cipriano, P., and Gray G. F.: Gastrointestinal hemorrhage: An unusual manifestation of neurofibromatosis. Am. J. Med. 58: 135, 1975.

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30. Sivak, M. V., Jr, Sullivan, B. H., jr, and Farmer, R. G.: Neurogenic tumors of the small intestine: Review of the literature and report of a case with endoscopic removal. Gastroenterology 68:374, 1975. 31. Ginsburg, L. D.: Eccentric polyposis of the small bowel: A possible radiologic sign of plexiform neurofibromatosis of the small bowel and its mesentery. Radiology 116:561, 1975. 32. Orcel, L., Luboinski, J., and Natali, I.:Etude anatomique et histog6nCtique d’une localisation rectale de neurofibromatose de Recklinghausen. Arch. Anat. PGhol. 20:163, 1972. 33. Khubchandani, 1. T., Trirnpi, H. D., and Sheets, J. A.: Von Recktinghausen’s disease with involvement of the rectum: Report of a case. Dis. Colon Rectum 15:459, 1972. 34. Neiman, H. L., Mena, E, Holt, J. F., Stern, A. M., and Perry, B. L.: Neurofibromatosis and congenital heart disease. Am. J. Roentgenol. Radium Ther. Nucl. Med. 122:146, 1974. 35. Feyrter, F.: U k r ein sehr einfaches Verfahren der Markscheidenfarbung, zugleich eine neue Art der Farberei. Virchows Arch. (Pathol. Anat.) 296:645, 1936. 36. Schurch, W.,ksserli, F. H.,Genest,J., Lefebvre, R., Roy, P., Cartier, P., and Rojo-Ortega, J. M.: Arterial hypertension and neurofibromatosis: Renal artery stenosis and coarctation of abdominal aorta. Can. Med. Assn. 1. 113379, 1975. 37 Halpern, M., and Currarino, G.: Vascular lesions causing hypertension in neurofibromatosis. N. Engl. J. Med. 273:248, 1965. 38 Rowen, M., Dorsey, T. J.,Kegel, S. M., and Ostermiller, W. E., Jr: Thoracic coarctation associated with neurofibrornatosis. Am. J. Dis. Child. 129:113, 1975. 39 Itzchak, Y., Katznelson, D., Boichis, H., Jona, A., and Deutsch, V.: Angiographic features of arterial lesions in neurofibromatosis. Am. J. Roentgenol. Radium Ther. Nucl. Med. 122:643, 1974. 40. Lynch, J. D., Sheps, S. G., Bernatz, P. E., ReMine, W. H., and Harrison, E. G., Jr.: Neurofibromatosis and hypertension. Minn. Med. 55:25, 1972. 41 Crowe, F. W.: Axillary freckling as a diagnostic aid in neurofibromatosis. Ann. Intern. Med. 61 :1142, 1964. 42 Benedict, P. H., SzaM, G., Fitzpatrick, T. B., and Sinesi, S. 1.: Melanotic macules in Albright’s syndrome and in neurofibromatosis. JAMA 205:618, 1968. 43. Johnson, B. L., and Charneco, D. R.: Cafe au lait spot in neurofibromatosis and in normal individuals. Arch. Dermatol. 102:442, 1970. 44. Jimbow, K., Srabo, G., and Fitzpatrick,T. 6.: UItrastructure of the giant pigment granules (macromelanosomes) i n the cutaneous pigmented macules of nevrofibromatosis. J. Invest. Dermatol. 61 :300, 1973.

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45. Konrad, K., and Wolff, K.: Cited by limbow, K. et a1.44 46. Saxena, K. M.: Endocrine manifestations of neurofibromatosis in children. Am. J. Dis. Child. 120:265, 1970. 47. Lee, H. Y., and Garber, P. E.: Von Recklinghausen’s disease associated with pheochromocytoma and carcinoid tumor. Ohio State Med. J. 66:583, 1970. 48. Arnesjo, B., Idvall, I., ihse, K., Telenius, M., and Tyl6n U.: Concomitant occurrence of neurofibromatosis and carcinoid of the intestine. Scand. J. Gastroenterol. 8:637, 1973. 49. Sizemore, G . W., Beahrs, 0. H., Capen, C. C., Cloutier, M. D., Gordon, H.,Perry, H. O., Robertson, D. M., Sayre, G. P., Sheps, S. G., and Weiland, L. H.: Multiple endocrine neoplasia, type 26: Afamilial syndrome of mucosal neuromas and connective tissue abnormalities with C-cell hyperplasia or medullary carcinoma of the thyroid gland, pheochromocytoma, and normal parathyroid glands. Submitted for publication. 50. Block, M. B., Roberts, J. P., Kadair, R. G., Seyfer, A. E., Hull, S. F., and Nofeldt, F. D.: Multiple endocrine adenomatosis type Ilb: Diagnosis and treatment. JAMA 234:710, 1975. 51. Sipple, J. H.: The association of pheochromocytoma with carcinoma of the thyroid gland. Am. J. Med. 31:163, 1961. 52. Pearse, A.G.E.: The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J. Histochem. Cytochem. 17:303, 1969. 53. Romer, A. S.: The Vertebrate Body. Fourth edition. Philadelphia, W. B. SaundersCo, 1970, pp. 22-26. 54. Fialkow, P. J., Sagebiel, R. W., Gartler, S. M., and Rimoin, D. L.: Multiple cell origin of hereditary neurofibromas. N. Engl. J. Med. 284:298, 1971. 55. Schenkein, I., Bueker, E. D., Helson, L., Axelrod, F., and Dancis, I.: Increased nerve-growth-stimulating activity in disseminated neurofibromatosis.N. Engl. J. Med. 290:613, 1974. 56. Siggers, D. C., Boyer, S. H., and Eldridge, R: Nerve-growth factor in disseminated neurofibromatosis (letter to the editor). N. Engl. J. Med. 292:1134, 1975.. 57. Patchefsky, A. S., Atkinson, W. G., Hoch, W. S., Gordon, G., and Lipshitz, H.I.: Interstitial pulmonary fibrosis and von Recklinghausen’s disease: An ultrastructural and immunofluorescent study. Chest 64:459, 1973. 58. Nordmann, J., and Brini, A,: Von Recklinghausen’s disease and melanoma of the uvea. Br. J. Ophthalmol. 54:641, 1970. 59. Cernea, P., and Dobrescu, G.: Melanome malin uveal, manifestation de la maladie de Recklinghausen. Ophthalrnologica 166:161, 1973. 60. Okisaka, S., Ono, H., Asaoka, I., and Uemura, Y.: A case of neurofibromatosis with juvenile xantho-

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granuloma and congenital glaucoma. Folia Ophthalmol. lap. 21 :273, 1970. 61. Jensen, N. E., Sabharwal, S., and Walker, A. E.: Naevoxanthoendothelioma and neu rofi brornatosis. Br. J. Dermatol. 85:326, 1971. 62. Sourreil, P., Beylot, C., and Bioulac, P.: L'association du xantho-granulomejuvCnile etda la maladie de Recklinghausen: A propos de trois cas. J. Med. Lyon 53:1165, 1972. 63. Pihbl Aguade, J., Ferrando, B. J., and Fernandez Morillo, N.: Xantogranuloma juvenile asociado a enfermedad de V. Recklinghausen. Actas Dermosifiliogr. 64:213, 1974. 64. Stout, A. P.: The peripheral manifestations of the specific nerve sheath tumor (neurilemoma). Am. J. Cancer 24:751, 1935. 65. Izumi, A. K., Rosato, F. E., and Wood, M. G.: Von Recklinghausen's disease associated with multiple neurolemomas. Arch. Dermatol. 104:172, 1971. 66. DeAngelis, P., and Cirillo, C.: Un caso di neurofibromatosi di von Recklinghausen associata a sindrome di Ehlers-Danlos. Pediatria (Napoli) 76:134, 1968. 67. Zarbaeva, S. F.: Sluchai sochetanua boleznei Burnevillia i Reklingauzena. Vestn. Oftalmol. 5:83, 1971. 68. Ranneberg, K. M.: Gleichzeitiges Vorkommen von M. Pringle und M. Recklinghausen? Med. Welt. 23:841, 1972. 69. Fraumeni, J. F., Jr.: Neurofibromatosis and childhood leukemia. Br. Med. J. 4:489, 1971. 70. Lagos, J.C., and Gomez, M. R.: Tuberoussclerosis: Reappraisal of a clinical entity. Mayo Clin. Proc. 42:26, 1967. 71. Bundey, S.: Geneticfact0rs.h neurological disease: Tuberous sclerosis (summary). Proc. Roy. SOC. [email protected]:185, 1971.

72. Fitzpatrick, T. B., Szab6, G., Hori, Y., Simone, A. A,, Reed, W. B., and Greenberg, M. H.: White leafshaped macules: Earliest visible sign of tuberous sclerosis. Arch. Dermatol. 98:1, 1968.

73* limbow, K., Fitzpatrick, T. B., Szab6, G., and Hori,

-

Y.: Conaenital circumscribed hvoomelanosis: A characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J. Invest. Dermatol. 64:50, 1975. I .

74. Nickel, W. R., and Reed, W. B.: Tuberous sclerosis. Arch. Dermatol. 85:209, 1962. 75. Adams, R. D., and Reed, W. 6.: Neurocutanmus diseases. In Dermatology in General Medicine. Edited by Fitzpatrick, T. B., Arndt, K. A., Clark, W. H., Jr., Eisen, A. Z., Van Scott, E. J., and Vaughan, J, H., New York, McGraw-Hill, 1971, pp. 13861393. 76. Schafer, J. A,, Berg, B. O., and Norman, D.: Cerebellar calcification in tuberous sclerosis. Arch. Neurol. 32:642, 1975. 77. Brown, J. M.: Tuberose sclerosis with malignant astrocytoma. Med. J. Aust. 1 :811, 1975.

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78. Roth, J.C., and Epstein, C. 1.: Infantile spasms and hypopigmented macules: Early manifestations of tuberous sclerosis. Arch. Neurol. 25547, 1971. 79. Fowler, G. W., and Williams, J. P.: Technetium brain scans in tuberous sclerosis. J. Nucl. Med. 14:215, 1973. 80. Herz, D. A., Liebeskind, A., Rosenthal, A., and Schechter, M. M.: Cerebral angiographic changes associated with tuberous sclerosis. Radiology 115:647, 1975. 81. Gomez, M. R., Mellinger, J. F., and Reere, D. F.: The use of computerized transaxial tomography in the diagnosis of tuberous sclerosis. Mayo Clin. Proc. 50:553, 1975. 82. Prompitak, A,, Maberley, A. L., and Shea, M.: An abortive case of tuberous sclerosis without mental deficiency or epilepsy in an adult. Am. J. Ophthalmol. 76:255, 1973. 83. OCallaghan, T. I.,Edwards, J. A., Tobin, M., and Mookerjee, B. K.: Tuberous sclerosis with striking renal involvement in a family. Arch. Intern. Med. 135:1082, 1975. 84. Rosenburg, J. C., Bernstein, J., and Rosenberg, B.: Renal cystic disease associated with tuberous sclerosis complex: renal failure treated by cadaveric kidney transplantation. Clin. Nephrol. 4:109, 1975.

85. Reed, W. B., Nickel, W. R., and Campion, G.: Internal manifestations of tuberous sclerosis. Arch. Dermatol. 87:715, 1963. 86. Jochimsen, P. R., Braunstein, P. M., Najarian, J. S.: Renal allotransplantation for bilateral renal tumors. JAMA 210:1721, 1969. 87. Chonko, A. M., Weiss, S. M., Stein, J. H., and Ferris, T. F.: Renal involvement in tuberous sclerosis. Am. J. Med. 56:124, 1974. 88. Sood, S., Mancini, A. A,, and Kropp, K.: Tuberous sclerosis: Emphasis on the angiographic findings. J. Urol. 114:185, 1975. 89. Mori, M., Ikeda, T., and Onoe, T.: Blastic Schwann cells in renal tumor of tuberous sclerosis complex: An electron microscopic study. Acta Pathol. lap. 21:121, 1971. 90. Inglis, K.: The relation of the renal lesions to the cerebral lesions in the tuberous sclerosis complex. Am. J. Pathol. 30:739, 1954. 91. Tsakraklides, V., Burke, B., Mastri, A., Runge, W., Roe, E., and Anderson, R.: Rhabdomyomas of heart: A report of four cases. Am. J. Dis. Child. 128:639, 1974. 92. Dwyer, J. M., Hickie, J . B., and Garvan, J.: Pulmonary tuberous sclerosis. Quart. J. Med. 40:115, 1971. 93. Malik, S. K., Pardee, N., and Martin, C. I.: Involvement of the lungs in tuberous sclerosis. Chest 58:538, 1970. 94. Valensi, Q. J.: Pulmonary lymphangiomyoma, a probable forme frust of tuberous sclerosis: A case

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report and survey of the literature. Am. Rev. Respir. Dis. 108:1411, 1973. 95. Sareen, C. K., Ruvalcaba, R. H.A,, Scotvold, M. J., Mahoney, C. P., and Kelley, V. C.: Tuberous sclerosis: Clinical, endocrine, and metabolic studies. Am. J. Dis. Child. 123:34, 1972.

96. Tod, P. A,: Radiological findings in tuberose sclerosis. j. Coll. Radiol. Aust. 6:42, 1962. 97. Papanayotou, P., and Vezirtzi, E.: Tuberous sclerosis with gingival lesions: Report of a case. Oral Surg. 39:578, 1975.

98. Mackler, S. B., Shoulars, H. W., and Burkes, E. I.,Jr.: Tuberous sclerosis with gingival lesions. Oral Surg.

34:619, 1972. 99. Hoff, M., van Grunsven, M. F., Jongebloed, W. L.,

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(Sturge-Weber syndrome). Acta Derm. Venereol.

52:386, 1972. 112. Wilkins, R. H., and Brody, I. A,: Sturge-Weber syndrome. Arch. Neurol. 21 :554, 1969. 11 3. Borns, P. F., and Rancier L. F.: Cerebral calcification in childhood leukemia mimicking SturgeWeber syndrome: Report of two cases. Am. j. Roentgenol. Radium Ther. Nucl. Med. 122:52,

1974. 114. Guseo, A.: Ultrastructure of calcification in Sturge-Weber disease. Virchows Arch. Pathol. Anat. 366:353, 1975. 11 5. Bentson, I. R., Wilson, G. H., and Newton, T. H.: Cerebral venous drainage pattern of the SturgeWeber syndrome. Radiology 101 :111, 1971.

and 's-Gravenmade, E. 1.: Enamel defects associated with tuberous sclerosis: A clinical and scanning-electron-microscope study. Oral Surg.

116. Kuhl, D. E., Bevilacqua, j. E., Mishkin, M. M., and

40:261, 1975. 100. Darden, J. W., Teeslink, R., and Parrish, R. A,:

11 7. Chang, J.C., Jackson, G. L., and Baltz, R.: Isotope cisternography i Sturge Weber syndrome. J. Nucl. Med. 11:551, l%O. 118. Susac, j. O., Smith, J. L., and Scelfo, R. j.: The

Hamartoma of the spleen: A manifestation of tuberous sclerosis. Am. Surg. 41 :564, 1975.

101. Rundle, A. T., Atkin, J., and Dollimore, J.: Serum and tissue proteins in tuberous sclerosis. II. Immunoglobulin levels. Humangenetik 28:147, 1975.

102. David, T. j.: Palmar dermatoglyphs in tuberous sclerosis. J. Med. Genet. 9:443, 1972. 103. Rook, A,: Naevi and other developmental defects: Sturge-Weber syndrome. In Textbook of Dermatology. Vol 1. Second edition. Edited by Rook, A,, Wilkinson, D. S., and Ebling, F. J. C. London, Blackwell, 1972, pp. 146-147. 104. Sturge, W.: A case of partial epilepsy, apparently due to a lesion of one of the vaso-motor centres of the brain. Clin. SOC. London Trans. 12:162, 1879. 105. Weber, F. P.: Right-sided hemi-hypotrophy resulting from right-sided congenital spastic hemiplegia, with a morbid condition of the left side of the brain, revealed by radiograms. J. Neurol. Psychopathol.

3:134, 1922. 106. Teller, H., Lindner, B., and Gotze, W.: Konkordanter doppelseitiger Trigeminusnaevus bei eineiigen Zwillingen mit gleichartigen elektroenzephalographischen Befunden. Dermatol. Wochenschr. 127:488, 1953.

107. Peterman, A. F., Hayles, A. B., Dockerty, M. B., and Love, j. G.: Encephalotrigeminal angiomatosis (Sturge-Wekr disease): Clinical study of thirty-five cases. JAMA 167:2169, 1958.

108. Lund, M.: On epilepsy in Sturge-Weber's disease. Acta Psychiatr. Neurol. 24:569, 1949. 109. Furukawa, T., Igata, A,, Toyokura, Y., and Ikeda, S.: Sturge-Weber and Klippel-Trenaunay syndrome with nevus of ota and ito. Arch. Dermatol. 102:640,

1970.

Sanders, T. P.: The brain scan in Sturge-Weber syndrome. Radiology 103:621, 1972.

"tomato-catsup" fundus in Sturge-Weber syndrome. Arch. Ophthalmol. 92:69, 1974.

119. Watzke, R. C.: Cryotherapy for retinal angiomatosis: A clinicopathologic report. Arch. Ophthalmol. 92:399, 1974.

120. Weiss, D. 1.: Dual origin of glaucoma in encephalotrigeminal haemangiomatosis: A pathogenetic concept based upon histopathologic and haernodynamic considerations. Trans. Ophthalmol. SOC. UK 93:477, 1973.

121. Kiely, 1. M., and Perry, H.0.: Sturge-Weber syndrome associated with multiple myeloma. Arch. Dermatol. 100:63, 1969.

122. Von Hippel, E.: Uber eine sehr seltene Erkrankung der Netzhaut: Klinische Beobachtungen. Albrechi von Graefes. Arch. Ophthalmol. 59:83, 1904.

123. Lindau, A.: Studien uber Kleinhirncysten: Bau, Pathogenese und Beziehungen zur Angiomatosis Retinae. Acta Pathol. Microbiol. Scand. (Suppll):l,

1926. 124. Dan, N. G., and Smith, D. E.: Pituitary hemangioblastoma in a patient with von Hippel-Lindau disease: Case report. J. Neurosurg. 42:232, 1975.

125. Hattner, R. S.: Posterior fossa scintiangiography: Documentation of genetic penetrance of von Hippel-Lindau syndrome in a clinically unaffected girl and her father. J. Nucl. Med. 16:828, 1975.

126. Krantz, S. B.: Current status of erythropoietin. Med. Clin. North Am. 54:173, 1970. 127. Carpenter, G., Schwartz, H., and Walker, A. E.: Neurogenic polycythemia. Ann. Intern. Med.

19:470, 1943.

110. Noriega-Sanchez, A,, Markand, 0. N., and Herndon, J. H.: Oculocutaneous melanosis as-

128. Goldberg, M. F., and Koenig, S.: Argon laser treatment of von Hippel-Lindau retinal angiomas. I.

sociated with the Sturge-Weber syndrome. Neurology 22:256, 1972.

Clinical and angiographic findings. Arch. Ophthalmol. 92:121, 1974.

11 1. Solomon, L. M., and Bolat, I. H.: Adenoma

129. Malek, R. S., and Greene, L. F.: Urologic aspects of Hippel-Lindau syndrome. J. Urol. 106:800, 1971.

sebaceum in encephalofacial angiomatosis

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130. Murphy, C. P., Kenny, C. M., and Mirand, E. A,: Erythropoietin levels in patients with renal tumors or cysts. Cancer 26:191, 1970. 131. Silver, M. L.: Hereditary. vascular tumors of the nervous system. JAMA 156: 1053, 1954. 132. Wise, K. S., and Gibson, J.A.: Von Hippel-Lindau’s disease and phaeochromocytoma. Br. Med. J. 1:441, 1971. 133. Sharp, W. V., and Platt, R . L.: Familial pheo-

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chromocytoma: Association with von HippelLindau’s disease. Angiology 22:141, 1971. 134. Tishler, P. V.: A family with coexistent von Recklinghausen’s neurofibromatosis and von H ippel-Li ndau’s d isease: Diseases possibly derived from a common gene. Neurology 25:840, 1975. 135. Shokeir, M. H. K.: Von Hippel-Lindau syndrome: A report on three kindreds. J. Med. Genet. 7:155, 1970.

Brooklyn Dermatological Society The Brooklyn Dermatological Society was formed in 1924 by the outstanding dermatologists of Brooklyn, namely, Walzer, Graham, Thorne, Berkowitz, Guavain, Best, Skeer, Rulison, et al. The first metings were held in members’ homes and offices, until the Society expanded in membership, when the Society moved the meetings to the Kings County Medical Society Building. After the 1929 crash, permission was granted to hold the meetings in the clinic building of the Brooklyn Hospital. We met there for many years, then we transferred to the Kings County Hospital, Building B and finally, we transferred to the Downstate Medical School. At the meetings, members would bring patients from their private and clinic practices and they would be meticulously examined by every member, orally and physically. Then the fun began! The Society went into executive discussion of each and every case. Needless to say, unanimity was not easily arrived at. When dermatologic giants like Walzer, Chargin, Satenstein and Best expressed themselves, quoting the Handbuch and the Wochenshchrift at great length, it was a sight to behold and to listen to-especially to us tyros just starting in the field of dermatology. We wondered what was before us and how we could assimilate and absorb all the various opinions, comments, suggestions, and diagnoses. Although the expressions of differences were quite vehement at times, we all wound u p at Joe’s Restaurant for a late snack o f sandwiches, tea, coffee and dessert.-Price, C. f : Brooklyn Dermatological Society 1924- 1974. In journal of the Brooklyn Dermatologic Society. Edited by f . S. Clickman, Brooklyn, private printing, 1974, p . 5 . Deposited in the American Academy of Dermatology Collection at the Library of the College of Physicians of Philadelphia.