SPECIAL ARTICLE

Pediatric Dermatology Vol. 9 No. 1 66-76

Proceedings of the 16th Annual Meeting of the Society for Pediatric Dermatoiogy

WiUiamsburg, Virginia June 3a-July 3, 1991

Eleanor £. Sahn, M.D. Medical University of South Carolina Charleston, South Carolina A. Howiand Hartley, M.D. Children's Hospital National Medical Center Washington, D.C. Stephen Gellis, M.D. Children's Hospital Medical Center Boston, Massachusetts James E. Rasmussen, M.D. University of Michigan Medical Center Ann Arbor, Michigan Monday, July 1, 1991 ture by the newspaper account he received, dated December 17, 1799, telling of General George Dr. Alfred T. Lane (Stanford University) orga- Washington's death. We learn the story of General nized the sixteenth annual meeting of the Society Washington's rapid demise, probably from bacterial for Pediatric Dermatology, held in Wiliiamsburg, infection, hastened by the medical treatments of the Virgitiia. The seventh annual Sidney Hurwitz Lec- day, including frequent and copious blood letting. ture was delivered by Dr. Rona M. MacKie (Uni- There was a current saying, "more people died an- versity of Glasgow) on "Melanoma: Risk Factors in nually from lancets than from swords." Dysplastic Nevus Syndrome." President Anne Lucky (Cincinnati, Ohio) welcomed the society MELANOMA: RISK FACTORS AND members to Wiliiamsburg and introduced the first DYSPLASTIC NEVUS SYNDROME speaker. Dr. Rona MacKie first discussed risk factors in mel- anoma, citing several large case control studies car- COLONIAL MEDICINE ried out in western Canada, Scotland, Scandinavia, Dr. Tor A. Shwayder (Henry Ford Hospital) pre- and Germany. The frequency of melanoma has dou- sented a delightful and professional "Character In- bled each decade in Scandinavia, the United King- terpreter Portrayal of Iseiac Shwayder, Medical dom, and Germany. The frequency increases with Doctor (circa 1799)." Complete in eighteenth- high altitudes, low latitudes, pale skin, outdoor rec- century costume, including three-cornered hat and reation, and total number of banal, nondysplastic silk hose. Dr. Shwayder discussed the art and sci- nevi. Other risk factors are the tendency to freckle, ence of medicine as it evolved in colonial Willisuns- a history of severe sunburn, three or more clinically burg. However, he became distracted from his lec- atypical nevi, and fair hair. Factors that are associ-

No reprints available.

66 Proceedings 67 ated with acquisition of large numbers of banal nevi nevus at the site. The melanomas that developed on include one or more years of childhood spent in the these nevi tended to be thick. Dr. MacKie recom- tropics, Mediterranean holidays when less than 5 mended a photographic record of dysptastic nevi in years old, light skin that bums rather than tatis, se- children, and removing those that developed char- vere sunburn in childhood, and freckling. The acteristics suggestive of melanoma. working hypothesis is that these early childhood events act as initiating factors that may induce be- HERPES SIMPLEX INFECTIONS IN CHILDREN nign meianocytic lesions. Later, further sun expo- Dr. J. Clark Huff (University of Colorado) dis- sure may lead to both promotion and progression, cussed the four types of herpes simplex virus (HSV) with the development of melanoma. infection in children: initial (primary) infection; re- An additional risk factor for the development of activation (recurrent) infection; infection in the im- melanoma is the presence of clinically atypical and munocompromised host; and herpes-associated er- pathologically dysplastic nevi (DN). There is much ythema multiforme (EM). confusion regarding the use of the term "dysplastic Initial or primary HSV infection is most com- nevus" because experts do not agree on pathologic motily subclinical or unrecognized. Older literature criteria. Elder's clinical criteria are size greater than stated that 95% of the United States population was 5 mm, irregular outline, "fried egg" profile, varie- seropositive, but current studies revised this figure gated pigmentation, and erythema. His pathologic to 52% to 65%. criteria are basilar meianocytic hyperplasia, cyto- Neonatal HSV infection occurs in about 1 in 14(X) logic meianocytic atypia, fusion of meianocytic live births—that is, 1500 to 2200 affected infants per nests, lymphocytic infiltrate, lamellar or concentric year in the United States. Seventy percent of the fibroplasia, and rete ridge elongation. cases are due to HSV-2. Risk factors for neonatal The four categories of DN according to the NIH HSV infection are thought to include asymptomatic Consensus Conference are (A) sporadic; (B) famil- shedding from the maternal genital tract, especially ial nevi with no melanoma; (C) sporadic personal the cervix, at the time of delivery; recently acquired melanoma (not in the fEunily, patient only); (D,) fa- subclinical first episode infection; reactivation milial nevi with personal melanoma and one family herpes with shedding (although risk is only about member with melanoma, and (D2) familial nevi with 3% in these infants); and the absence of maternal personal melanoma and two family members with antibodies to HSV-2. Neonatal HSV localized to melanoma. The increased risk of melanoma de- the skin, eye, or mucous membrane is associated pending on the type of dysplastic nevus is as fol- with no mortality. When encephalitis is present, lows: type A, 4-fold increase; type B, 7-fold in- mortality is 15%, and of those who survive, 64% crease; type C, 80-fold increase; type D, 108-fold have severe sequelae, usually mental retardation. If increase. It was noted that melanoma was ex- the infection is disseminated but no encephalitis is tremely rare prepubertally, but in the few patients present, mortality is 57% and morbidity at one year in whom it has occurred, 50% developed in giant is 41%. Treatment is acyclovir 30 mg/kg/day intra- meianocytic nevi. venously for 10 days. In Dr. MacKie's current study of melanomas in An HSV infection in the immunocompromised individtials under age 30 years, a significant associ- host is often extremely severe. Treatment is intra- ation exists between the presence of a nevus since venous acyclovir 30 mg/kg/day for 10 days. early life and the development of melanoma at that The HSV-associated EM is usually a minor form site. This suggests that a portion of congenital or of EM, and follows recurrent HSV by 3 to 21 days. early-onset small nevi have the potential for malig- The polymerase chain reaction (PCR) has been used nant change. Continuing studies wiU attempt to es- to identify herpes virus DNA in skin lesions of EM. tabhsh the rate at which this occurs and guidehnes In HSV-associated EM, 100% of lesions had HSV for the management of small congenital nevi. Be- DNA. Fifty percent of patients with idiopathic EM cause these melanomas do not seem to develop had evidence of HSV DNA in lesions. Prophylaxis prior to puberty—approximately 1 chance in 100 ex- includes oral acyciovir 400 to 800 mg/day. ists that a smdl congenital nevus will become ma- The diagnosis of HSV can be made on culture, lignant by 13 years of age—it is reasonable to offer which is usually positive in one to two days. A new excision of small congenital nevi at puberty. Of 95 technique involves culturing for 24 to 48 hours and patients who developed melanoma at age 30 or less, then fluorescent antibody staining. Tzanck prepara- 44% had evidence of a preexisting, small congenital tion is reliable in new vesicles. Immunocytology, 68 Pediatric Dermatology Vol. 9 No. 1 March 1992 enzyme-linked immunosorbent assay of blister nychia, angular stomatitis, glossitis, and alopecia fluid, and spin amplification techniques are avail- often are present. Impaired wound healing, growth able at some institutions. retardation, marked irritability, diarrhea, and im- mune abnormalities may be seen. NUTRITIONAL DEFICIENCY COAGULATION DISORDERS Dr. Moise L. Levy (Baylor College) discussed the cutaneous signs of four types of nutritional defi- Dr. Hazel Vemon (Medical College of Virginia) dis- ciency: protein-energy malnutrition, vitamin defi- cussed three coagulation disorders with manifesta- ciencies, essential fatty acid deficiency, and trace tions in the skin: protein C deficiency, purpura ful- element deficiency. Protein-energy malnutrition is minans, and the Kasabach-Merritt syndrome. the most common worldwide and is recognized clin- Homozygous protein C deficiency is extremely ically as kwashiorkor or marasmus. Either can fol- rare, with only 17 confirmed cases in the United low poor dietary intake, maiabsorption, or catabolic States and Europe. Protein C activity is usually less state. than 1%, with protein C antigen ranging from less The skin in kwashiorkor shows hypopigmenta- than 1% to 30%. The three major clinical findingsi n tion and diffuse pitting edema. Waxy elevated these newboms are the onset of ecchymoses and plaques ("enamel paint") or erosions ("flaky necrotic lesions within 2 to 12 hours of birth, central paint") are often seen. In marasmus the skin is dry, nervous system thromboses, and blindness. Hema- wrinkled, and loose, often producing "monkey tologic studies show a picture of disseminated intra- facies." The hair is reddish and thin in kwashior- vascular coagulation with decreased platelets and kor, and alternating periods of adequate and inade- fibrinogens, elevated fibrin split products, and pro- quate nutrition are reflected in alternate bands of longed activated partial thromboplastin and pro- color in the hair, the so-called flag sign. In maras- thrombin times. PVotein C levels are low or absent. mus the hair is also thin and slow growing, and Histologic examination of a skin biopsy specimen lanugo hair may be seen. reveals extensive thrombosis with fibrinoid necro- Deficiencies of vitamins A, B, and C also pro- sis of vessel walls and hemorrhage into subcutane- duce skin signs. Vitamin A deficiency produces foi- ous fat, but without vasculitis. Treatment includes hcular papules, so-called phrynoderma. Xerosis is fresh-frozen plasma given daily, or protein C and S prominent, as are ophthalmologic abnormalities in- concentrates. Warfarin may also be given. cluding Bitot spots and keratomalacia, with iris pro- Purpura fulminans is characterized by the sudden lapse in severe cases. onset of hemorrhagic necrosis of the skin and dis- Vitamin C deficiency produces scurvy, and most seminated intravascular coagulation, as well as cases are due to inadequate intake. Skin manifesta- widespread cutaneous thrombosis. It usually arises tions include corkscrew hairs (secondary to de- in the setting of an overwhelming infection due to crease in disuUide bonds in the affected hairs), Haemophilus influenzae, or meningococcal, strep- perifoUictilar hemorrhage, gingival edema and hem- tococcal, or staphylococcal infection. Tumor necro- orrhage, weakness, depression, diarrhea, and ane- sis factor is thought to act as a procoagulant, to- mia. gether with bacterial endotoxin. Treatment includes Essential fatty acid deficiency occurs in prema- eradicating the infectious cause and supporting the ture itifants with inadequate adipose stores. Unsat- child with platelets and fresh-frozen plasma. Hepa- urated fatty acids that cannot be synthesized by hu- rin, dextran, steroids, plasmapheresis, and uroki- mans are necessary for membrane structure and the nase have been used in the treatment of purpura ful- production of eicosanoids. Linoleic acid is the pri- minans. mary nutrient for treating or preventing this defi- Kasabach-Merritt syndrome is a localized con- ciency. Clinically, alopecia, xerosis, and scaling are sumption coagulopathy occurring within a very present. The infants have retarded growth and show large hemangioma, most commonly on the extrem- an increased susceptibility to infection. ity. The median age of onset of the syndrome is 5 Trace element deficiency is correctable when the weeks (range birth-73 yrs). The mortality rate is deficiency is in iron, copper, zinc, chromium, man- 21%. Usually the size of the hemangioma increases ganese, or iodine. Zinc deficiency is caused by in- suddenly, with the development of petechiae or ec- adequate intake, including breast milk deficient in chymoses elsewhere, and gastrointestinal bleeding. zinc, increased excretion, or a genetic factor. Clin- Laboratory studies show a picture of disseminated ically, acral and pehorficial dermatitis occur. Paro- intravascular coagulation. Current recommenda- Proceedings 69 tions for therapy include high-dose prednisone (2-4 tron microscopy. Good prognostic factors include mg/kg/day), expecting improvement within several age less than 1 year, stage I or IV-S tumors, loca- days. Surgery can be attempted if the lesion is ac- tion above the diaphragm (not involving adrenal cessible and relatively small. Epsilon-aminocaproic glands), and well-differentiated morphology (all acid (Amicar) can be used to allow the hemangioma markers present). Polyploidy by DNA flow cytom- to clot and scar, with a response seen after two etry is associated with a poor prognosis, whereas weeks. Finally, intermittent pneumatic compres- aneuploidy is associated with increased survival. sion can be tried if the hemangioma is in an appro- Genomic amplification of the N-myc oncogene is priate location. It is used 24 hours per day until in- associated with rapid tumor progression. volution begins and then is used nightly. Dr. Julie Francis (University of Washington) dis- cussed a white newborn boy who, after a vacuum CLINICOPATHOLOGIC CONFERENCE extraction delivery, was noted to have a large ceph- Dr. Loren Golitz (University of Colorado) pre- alohematoma on the left parietal scalp. All scalp sented clinicopathologic cases submitted by mem- hair was present and no erosions were noted. At 4 bers of the Society. Drs. Lawrence Eichenfield and days of age, erosions with yellow crusting devel- Paul Honig (University of Pennsylvania) reported a oped and continued to enlarge. At 2 months of age, 14-year-oid boy with foUicular mucinosis. He had a raised, flesh-colored plaque developed peripher- developed a scaling, annular plaque above the right ally around the erosions, and the erosions contin- eyebrow eight months previously, and hairs were ued to heal. At the present time, the plaque mea- absent within the involved area. The lesion was un- sures 3 X 3 cm with central atrophy, peripheral responsive to topical antibiotics and hydrocorti- flesh-colored papules, crusting, and complete hair sone. loss within the scarred area. Bacterial and herpes FoUicular mucinosis causes grouped, foUicular cultures were negative, as were maternal ANA and papules, nodules, or patches of hair loss. Mycosis SSA. Examination of skin biopsy specimens fungoides (MF) occurs in 15% or less of patients but showed fibrosis consistent with scar and a large for- has never been reported in an individual less than 20 eign body granuloma reaction to keratin remnants years of age. It was noted that three reports de- of hair follicles. Hair foUicles were decreased in scribed children with foUicular mucinosis who later number as well, suggesting a diagnosis of aplasia developed Hodgkin disease. cutis congenita. In the discussion. Dr. Wesley Ga- Drs. Andrea Dominey, Moise Levy, and H. len (New Orleans) reported that she has seen six Hawkins (Texas Children's Hospital) submitted a similar cases after vacuum extraction with a defec- case of congenital neuroblastoma. A newborn had tive machine by the same obstetrician. She thinks numerous cutaneous nodules that rapidly increased these are secondary to trauma and resulting celluli- in size, as weU as an intraabdomina! mass and he- tis, and not to aplasia cutis congenita. patomegaly. Examination of bone marrow and skin biopsies revealed a round cell tumor consistent with CASES OF THE YEAR neuroblastoma. The infant underwent exploratory The presentation of cases of the year was organized laparotomy, at which time a nonresectable retroper- by Dr. Samuel Weinberg (New York University). itoneal tumor was found, with hepatic involvement Drs. Teresita Laude (SUNY-Brooklyn) and Brad but no adrenal gland involvement. Singman (Staten Island, New York) discussed twin Congenital neuroblastoma is the most common boys bom at 34 weeks with anhydrotic ectodermal malignant tumor in neonates and represents 8% to dysplasia. They had large square foreheads with 10% of all cancers in children up to 15 years of age. bossing, beaked nose, increased scalp vascularity, In neonates, cutaneous metastases may produce a and decreased eccrine glands on skin biopsy. Anhy- "blueberry muffin" appearance. Because one-third drotic ectodermal dysplasia is an X-linked recessive of children have metastases at the time of diagnosis, disorder characterized by anhydrosis, abnormal the prognosis is poor. Neuroblastoma is the proto- dentition, and hypotrichosis. type of small, round, blue ceU tumors, the others Dr. Rhonda Schnur (Children's Hospital of Phil- being rhabdomyosarcoma, Ewing sarcoma, and adelphia) discussed a child with hypohidrotic ecto- non-Hodgkin lymphoma. Marker studies in neuro- dermal dyspiasia who^Jiad minima! sweating ability, blastoma usually are negative for B and T cells and hypoplastic nipples, and hypotrophic dentition, and fHJsitive for neuron-specific enolase. Dense core whose mother had small breasts and abnormal teeth granules (neurosecretory granules) are seen on elec- and nails. Because of recent advances in molecular 70 Pediatric Dermatology Vol. 9 No. 1 March 1992 genetics, DNA analysis of linked RFLPs may be a have HSV and treated with acyclovir. All cultures useful adjunct for genetic counseling in some of the and Tzanck preparations were negative, but exami- ectodermal dysplasias. nation of a skin biopsy specimen was reported as Dr. Maureen Rogers (The Children's Hospital, "viral Infection." As blistering continued, a repeat Camperdown, Australia) presented a case of Neth- biopsy was performed at age 11 days and inter- erton syndrome in an infant girl who at birth had preted as erythema multiforme. Oral prednisone erythema and scaling resembling congenital ichthy- was begun and the blistering ceased. The pattern of osiform erythroderma. Her hair, including eye- peripheral blisters around a central buUa ("crown of brows, failed to grow until she was 7 month old, at jewels") was noted and a skin biopsy specimen was which time examination of a hair pluck showed the sent for DIF. Examination revealed linear IgA at typical "ball in a cup" (bamboo hair) picture of the basement membrane zone. The child was Netherton syndrome. The disorder is autosomal re- treated with dapsone and by 6 months of age had cessive, with skin manifestations most commonly only residual mild scarring of the skin with milia, of ichthyosis linearis circumflexa, and occasionally but severe eye sequelae and blindness. The two of ichthyosiform erythroderma, as in this child. points to be learned from this case are first, immu- Atopic dermatitis may be present, and hypema- nobuUous disease can occur in the neonate; and tremia has been reported. Because the hair often second, the younger the age at onset of chronic bul- does not grow until later, diagnosis is often delayed. lous disease of childhood, the more significant the The point was made that if present, an eyebrow hair sequelae tend to be. can be plucked and the characteristic changes found Dr. Allison Holm (Batavia, New York) presented there as well. a case of rash with Epstein-Barr virus (EBV) infec- Dr. Lawrence Eichenfield reported a case of tion and amoxicillin therapy. An 8-year-old boy de- aplasia cutis congenita (ACC) in association with fe- veloped fever, lymphadenopathy, hepatomegaly, tus papyraceous. Fetal death of a twin occurred at and jaundice. He had been treated with amoxiciUin 13 weeks, and the mummified fetus was noted at two weeks earlier and developed a diffuse morbiUi- birth. The viable twin was bom with a scalp lesion form eruption. The mono spot test was negative, of ACC as weU as linear lesions on the arms and and a broad differential diagnosis was considered, flank. The disorder in association with fetus papy- including Kawasaki disease and leptospirosis. The raceous or placental infarct is classified as group V child was suspected of having virus-associated he- ACC. One theory of pathogenesis is that embolic or mophagocytic syndrome or X-linked lymphoprolif- thromboplastic material is transferred from the erative syndrome; however, he recovered with VP- dead fetus through the placenta to the surviving 16 and intravenous gammaglobuiin. It is important twin. It is unclear why lesions are symmetric. to remember that in childhood mononucleosis, the Drs. Lynn Williams and Linda Rabinowitz mono spot test is frequently negative and EBV- (Thomas Jefferson University) discussed a case of specific serologies must be obtained. tyrosinemia II (Richner-Hanhart syndrome). The patient was bom at 35 weeks and throughout in- Tuesday, July 2, 1991 fancy refused to eat meats. He developed photo- RESEARCH AWARD phobia and tearing at an early age, and at 2 years of The Resident/Fellow Pediatric Dermatology Re- age developed painful plantar keratoderma. The di- search Award was presented to Steven Shpall, agnosis of tyrosinemia II was made by finding a M.D. (University of California, San Francisco) for high tyrosine level on plasma amino acid screening. his study, "The Risk of Melanoma in Black Pa- Urinary tyrosine metabolites were also increased. tients." He found that the number of blacks with at Tyrosinemia II is due to deficiency of the hepatic least one congenital nevocytic nevus (CNN) was cytosolic enzyme tyrosine aminotransferase. This 1.8%. Malignant transformation was strongly age patient was treated with avoidance of all dairy prod- dependent. For those under 15 years old, the risk ucts, and showed improvement in the eye and skin was 1 in 10,000 (0.01%), and for the group age 15 to symptoms within two weeks. A low-tyrosine, iow- 35 years it was I in 3700 (0.027%). The overall risk phenylalanine diet in infancy is beneficial, and older was 0.61%. These data assume that all melanomas children may be maintained on a low-protein diet if arise in CNN and, therefore, may overestimate the tyrosine levels do not exceed 10 mg/dl. risk by 10- to 100-fold. Dr. Shpall concluded that Dr. Susan MaUory (St. Louis Children's Hospi- removal of CNN is not recommended in black pa- tal) described a newborn with blisters thought to tients, especially those under age 35. Proceedings 71

CASES IN SEARCH OF A DIAGNOSIS ma (increased with heat), eczema, unilateral cafe au lait macuies, and one axillary freckle. The famUy Dr. William Weston (University of Colorado) pre- history was unremarkable, and results of chromo- sented four "Cases in Search of a Diagnosis." The some studies were normal. The consensus of the au- first, from Dr. Maureen Rogers, was a 6-year-old dience was that this most likely represented a chro- with unusual annular erythema beginning at 1 hour mosomal abnormality not yet identified by gene of age and consisting of intensely pruritic rings mapping. within rings, largely on the trunk. The child's gen- eral health has been unaffected. Results of exhaus- tive laboratory studies were unremarkable; a biopsy ATOPIC DERMATITIS specimen showed an infiltrate with a predominance of eosinophils and neutrophils, with distinct flame ln her lecture on atopic dermatitis. Dr. Rona figures as seen in Well syndrome. Spirochetes MacKie focused on European research and experi- present on one specimen stained with Warthin- ence. She cited a 1989 study by Cookson at Oxford Starry could not be found in subsequent specimens. that linked IgE to chromosome llq, and showed The long list of treatments that failed included pred- that specific allergic responses are linked to the ma- nisone, cromolyn, antihistamines, antibiotics, dap- jor histocompatibility complex. The abnormal regu- sone, phototherapy, and elimination diet. Members lation and overproduction of IgE is secondary to a of the audience mentioned three separate cases with preferential expansion of a subset of T helper cells similar lesions. These children went on to have se- with a relative reduction of gamma-interferon- vere liver and renal disease, but no diagnosis. Be- producing T helper cells. Basic research has shown cause the lesions in Dr. Rogers' patient cleared only that the mononuclear cells in atopic patients are with fever, the use of alpha-interferon was sug- defective in controlling production of interleukin gested. (IL)-4. A high level of IgE is the result of IL-4 over- Dr. Elaine Siegfried (University of Iowa) dis- production. Thus, in atopic dermatitis the cytokine- cussed an unusual port-wine stain present at birth mediated immune response is distorted. with extensive localized loss of subcutaneous fat. In studies of dust mite aUergy Dutch researchers Biopsy was unremarkable. Diagnosis of atypical cu- have shown the likely role for aUergen-specific T tis marmorata telangiectatica congenita or atypical helper response. The importance of Langerhans lipodystrophy was proposed. Dr. Anne Lucky ceUs in trapping igE-antigen complexes and antigen noted that in similar cases, the atrophic component presentation was stressed. gradually resolved without treatment. Dr. MacKie reviewed several treatment modali- A second case from Dr. Siegfried was that of a ties for atopic dermatitis. Work in her own labora- child with acquired erythema of one cheek after a tory has centered on the role of Staphylococcus au- four-day febrile illness. Biopsy showed an exuber- reus in initiating and perpetuating atopic dermatitis ant lichenoid infiltrate extending deeply into fat. On lesions. Although other microorganisms are not sig- direct immunofiuorescence, there was granular IgM nificant, the number of S. aureus organisms (espe- at the basement membrane zone. Remarkable labo- cially phage type III) have a quantitative relation- ratory study results included erythrocyte sedimen- ship to disease activity. Based on these tation rate 72, platelets 607,000, and negative ANA observations, studies of topical mupiricin were the and Ro antibodies. Numerous treatments from top- next step and yielded highly statistically significant ical steroids to laser yielded nothing. Audience reduction in S. aureus colonization and significant members suggested Jessner benign lymphocytic in- clinical improvement. filtrate, foreign body reaction (e.g., fiberglass),con - Unpublished information on the use of Chinese nective tissue disease, and panniculitis as possible herbal medicine included a study of 47 children, diagnoses. which showed improvement in 51% of atopies with For the last case. Dr. Amy Paller (Northwestern no effect on asthma or IgE levels. Until analysis of University) asked, "What's this syndrome?" Bom the herbs is completed, concern over the safety of prematurely, the child had microcephaly, unusual this therapy remains. Finally, Dr. MacKie dis- facies, abnormal tooth enamel, mental retardation, cussed the striking clinical improvement noted with absence of the corpus callosum, retinitis pigmento- subcutaneously injected gamma-interferon. It is hy- sa, strabismus, deafness, renal fsdlure, and hyper- pothesized that gamma-interferon controls IgE pro- tension. Cutaneous findings included facial erythe- duction by its action on mononuclear cells. 72 Pediatric Dermatology Vol. 9 No. 1 March 1992

SCLERODERMA AND MORPHEA baseline studies in neurofibromatosis type 1 (NF-1). Dr. Jouni Uitto (Thomas Jefferson University) dis- TraditionaUy, CT has been weak, whereas MRI cussed scleroderma and morphea in children. He finds "too much." Unidentified bright objects pose reported that at least 14 different coUagens are clas- a dilemma for the radiologist. These probably rep- sified and that five new geneticaUy distinct ones resent hamartomas in most cases and, in general, have recently been discovered, all with alpha require intervention only if there is a mass effect. In chains. In reviewing fibrotic diseases. Dr. Uitto NF-2 MRI is definitely superior to CT, and very im- stressed that the common pathway and haUmark of portant in identifying tumors of the eighth nerve. In these conditions are connective tissue deposition diagnosing tuberous sclerosis, CT is a good tool for and primary collagen accumulation, respectively. identifying cerebral calcification; MRI is helpful in detecting malignant transformation. In addition, CT In his research using abundantly available tissue is the best method for detecting the characteristic of keloid scars as a model. Dr. Uitto has shown that serpiginous train-track calcifications of Sturge- mRNA of types I and IV coUagen is increased. Weber syndrome. For the classic hemangioblas- Transforming growth factor-beta increases coUagen toma of von Hippel-Lindau, angiography has been deposition. Its origin is probably vascular, either replaced by MRI. from platelets or endothelial cells. Turning to treatment. Dr. Uitto discussed several VASCULITIC DISEASES drugs. PeniciUamine is believed to prevent intramo- lecular cross-linking. It is effective in progressive Vasculitic diseases of childhood were addressed by systemic sclerosis and linear morphea, but takes six Dr. Thomas Lehman (Cornell University). In his to eight months to work and must be started early in broad overview he stressed that many specialists the disease course. Side effects are abundant. Cor- may be required to diagnose and care for these chil- ticosteroids probably act by increasing coUagenase dren, who may not fit into any neat category. Key activity and reducing cross-linking. Although their points included the fact that children with linear systemic use has been disappointing, topical ste- scleroderma en coup de sabre may have vasculitis roids are useful in softening lesions. Gamma- in the underlying brain. Also, en coup de sabre may interferon antagonizes transforming growth factor- be easily confused with Parry-Romberg syndrome beta activity. Preliminary data indicate that it may (progressive facial hemiatrophy). The latter is dis- be useful. In anecdotal reports, phenytoin improved tinguished by tongue involvement. linear morphea, but Dr. Uitto is not impressed with In summation. Dr. Lehman gave the foUowing its effectiveness. In the United States, penicillin is take home messages: (!) disease expression is a di- administered only to patients with increased Borre- rect consequence of the size of the vessel involved; lia titers, but in Europe all patients with morphea or (2) each vessel type has its own characteristics with systemic sclerosis are treated with high dosages. regard to pressure, flow, cellular makeup, and ana- Photopheresis may be worth a try in rapidly pro- tomic distribution; and (3) disease manifestations gressive SS but studies to date have not been con- are influenced by the size (and several other char- vincing. acteristics) of the antigen or inciting agent, and the host's genetic makeup. IMAGING NEUROCUTANEOUS SYNDROMES NEUROFIBROMATOSIS Dr. Rich Towbin (Pittsburgh Children's Hospital) spoke on imaging studies in neurocutaneous syn- In the first of two lectures. Dr. Vincent Riccardi dromes. In deciding whether to use computerized (Alfigen, Pasadena, California) gave a fascinating tomography (CT) or magnetic resonance imaging review of new developments and important charac- (MRI), he stressed that CT is stilt an excellent teristics of neurofibromatosis (NF). Based on his method and costs one-third of what MRI does. The observations of hundreds of patients, he had many latter is particularly useful for posterior fossa le- clinical pearls. The macromelanosomes of cafe au sions, craniocervical junction, leukoencephalopa- lait macules (CALM) are not helpful in diagnosis thy, temporal lobe lesions, and spinal cord lesions. due to their presence in healthy subjects and the However, it is somewhat problematic in children great difficulty in identifying them in children and due to the extended time required and the confining all black patients. He maintains that there is no rea- nature of the equipment. son to biopsy patients to make the diagnosis of NF. Controversy remains over the desirability of Axillary freckling, which occurs early in NF, must Proceedings 73 be a cluster of at least 10 or 12 to be diagnostic. the need for controUed studies to determine the ef- Acquired freckling in NF is a different phenome- ficacy and safety of this treatment. She outlined the non, occurring in areas of friction (e.g., neck, axil- collaborative study she has begun in order to an- lae) due to environmental factors, not genetics. swer these questions. The macules are highly variable: they may be two-tone or spotted, ragged or smooth in outline, of ECTODERMAL DYSPLASIA: DIAGNOSIS huge size, and darken with sun exposure. In gen- AND MANAGEMENT eral, the darker the background skin, the darker the Dr. Virginia Sybert (University of Washington) out- CALM. The "Riccardi sign" is the presence of an lined an approach to the ectodermal dysplasias. abnormal hair whorl overlying the spine in NF-1, These are defined as disorders in which there are indicating the presence of either vertebral dysplasia two or more abnormalities in ectodermal deriva- or plexiform neurofibroma underneath. This finding tives: hair, teeth, nails, sebaceous glands, sweat is significant because it shows that NF-1 is a defect and mucous glands, and lens and conjunctiva of the with onset in embryonic development. The pres- eye. One system of classification used by Freire- ence of juvenile xanthogranuloma is an important Maia and Pinheiro in their textbook Ectodermal sign of NF-1 in young children, present in up to 1%. Dysplasia numbers the ectodermal structures: 1, This lesion may lead the child to the dermatologist, trichodystrophy; 2, dental defects; 3, onychodys- with eventual discovery of NF. Another important trophy; 4, dyshidrosis; and 5, other abnormalities. association is chronic myeiogenous leukemia, seen Hypohidrotic ectodermal dysplasia (Christ- in 0.5% of children with NF. Dr. Riccardi believes Siemens-Touraine syndrome) was reviewed. It is an that almost all children with NF-1 can be diagnosed X-linked recessive disorder. The mutation is lo- on clinical grounds by age 1. Infants with CALM cated on the proximal portion of the long arm of the should simply be followed closely and considered X chromosome. It affects approximately 1 in as having presumptive NF-1 until proved other- 100,000 males bom. Affected individuals have wise. sparse to absent scalp and vellus body hair, hy- podontia or adontia. a paucity of sweat glands, and CLINICOPATHOLOGIC CONFERENCE decreased mucus production in the respiratory tree. Although previously referred to as anhidrotic, pa- Concluding the day's program. Dr. Loren Golitz tients have some ability to sweat. The nails are nor- presented the CPC with cases of blue rubber bleb mal. Patients may suffer from eczema, frequent up- syndrome. Sweet syndrome, and non-X histiocyto- per respiratory tract infections, and difficulty sis. lacrimating. They have characteristic facies with a saddle nose, midfacial hypoplasia, and periorbital Wedn«sday, July 3, 1991 hyperpigmentation. The diagnosis in newboms may CONTROVERSIES IN be difficult to make if there has been no prior family PEDIATRIC DERMATOLOGY history. One clue is the presence of peeling skin that Dr. Alvin Jacobs (Stanford University) reviewed may be mistaken for a coUodion membrane. If the the epidemiology, natural history, clinical features, diagnosis is missed at birth, the infant often experi- and treatment of hemangiomas. With many superb ences bouts of unexplained fever due to inability to illustrations from his own practice, he demon- sweat. A dental panoramic x-ray demonstrates the strated the complete regression of many untreated absent primary teeth and peg-shaped incisors. By lesions. He cautioned those who embark on new puberty many patients develop some ability to therapies to remember the dictum of primum non sweat and also acquire secondary sexual hair. In nocere. When he sees an infant whose hemangioma their management, it is important to have them fit- will spontaneously regress without treatment, he ted for dentures by 3 to 5 years of age. spends additional time reassuring the parents by Other forms of ectodermal dysplasia include the showing them examples of others that involuted Clouston syndrome, which is known as the hidrotic spontaneously. He photographs the infant's heman- form. It is an autosomal dominant disorder charac- gioma and schedules frequent follow-up visits to il- terized by normal sweating and normal teeth, but lustrate to the parents the progress of the lesion. abnormal nails, hair, Eind mucous glands. Rapp- Dr. Karen Rothman (Westboro, Massachusetts) Hodgkin ectodermal dysplasia is an autosomal discussed the experimental use of the pulsed-dye la- dominant condition with hypotrichosis, hypohidro- ser for treatment of hemangiomas. She emphasized sis, onychodystrophy, and cleft lip and palate. 74 Pediatric Dermatology Voi. 9 No. 1 March 1992

Ankyloblepharon-ectodermal dysplasia-cleft lip and zyme. Diagnosis is made by measuring copper lev- palate (AEC) and ectrodactyly-ectodermal dysplasia- els. cleft lip and palate (EEC) are two other autosomal Abnormalities of elastic fibers were reviewed. dominant conditions. The former may develop pyo- Elastic fibers are a minor constituent of normal genic granuloma-like lesions in the scalp. skin, making up 2% to 4% of the extracellular ma- Information for patients and their physicians is trix. They are composed of two components: elas- available from the National Foundation for Ecto- tin, an amorphous-appearing protein, and a distinct dermal Dysplasias, 219 East Main Street, Mas- microfibrillar protein. The gene for elastin is on a couteh, IL 62258. chromosome that was recently cloned. It is very complex and susceptible to deletions. Elastin un- HERITABLE DISORDERS OF dergoes posttranslational modification by cross- CONNECTIVE TISSUE linking of molecules mediated by lysyioxidase, a Dr. Jouni Uitto reviewed the biochemistry of the copper-dependent enzyme. coUagen molecule. Functional alterations in colla- Heritable diseases in which elastic structures are gen affect the cornea, tendon, cortical bones, carti- structurally abnormal include pseudoxanthoma lage, lungs, and liver. Molecular defects in collagen elasticum, Buschke-Ollendorff syndrome, cutis molecules give rise to the various clinical pheno- laxa, alpha|-antitrypsin deficiency, Ehlers-Danlos types of Ehlers-Danlos disease (ED). The 11 dis- type IX, Menkes syndrome, and Marfan syndrome. tinct forms show a wide spectrum of involvement, In alphaj-antitrypsin deficiency there is a deficiency although some overlap is seen among them. Clini- in the inhibitor of elastase. Elastic structures are de- cally, ED is characterized by loose-jointedness, hy- stroyed in the lung. Both Menkes syndrome and perextensible skin, and eye problems including stra- type IX ED show low copper levels but have signif- bismus and fragile comeas. The inheritance in the icantly different outcomes. An abnormal mi- various forms of ED may be autosomal dominant, crofibrillar component of the elastic fiber recently autosomal recessive, or X-linked recessive. Fifty was shown in Marfan syndrome. percent of patients cannot be easUy classified into a Cutis laxa, characterized by loose skin, with specific type. The prevalence of these disorders de- variable inheritance can also be an acquired condi- pends on the sensitivity of the diagnostic criteria. tion, as seen in severe drug eruption or sun damage. Types IV, VI, VII, IX have been characterized Skin biopsy specimens show a loss of elastin. The biochemically as coUagen defects. Type IV ED is mechanism of the inherited disorder is unknown. due to a deficiency of type 3 collagen, which is Possibilities include reduced synthesis, nonfunc- abundant in skin and vascular connective tissue. tional fibers, defective cross-linking, and increased This explains the increased frequency of major gas- degradation. trointestinal or aortic rupture in these patients. It is important to establish an accurate diagnosis. This INTERVENTIONAL RADIOLOGIC can be done by analyzing the coUagen in a skin bi- TREATMENT OF opsy specimen. VASCULAR MALFORMATIONS Type VI ED is an autosomal recessive disorder Dr. Rich Towbin chronicled the advances in radio- characterized by scleral fragility leading to blind- logic imaging and in biosynthetic material that have ness, marked hyperextensible skin, and musculo- created a new role for embolotherapy. Patients with skeletal deformities. It is due to a deficiency of lysyl vascular malformations that include arteriovenous hydroxylase. This can be confirmed by measuring malformations and fistulas, who are symptomati- hydroxylysine in a skin biopsy specimen. Some pa- caUy at risk, can be offered treatment that may tients have altered ability to use the cofactor ascor- achieve palliation. The biosynthetic materials in- bic acid. The deficiency can be overcome by treat- clude poly vinyl alcohol (Ivelon), dehydrated alco- ment with high amounts of ascorbic acid in the hol, gel foam, and glues. Several types of coils for range of 2 to 4 g/day. occlusion can be introduced by variable-stiffness Typie VII Ehlers-Danlos is characterized by de- microcatheters that are soft and spaghetti-Hke. fective conversion of the precursor molecule These procedures are mostly used in vascular mal- procoU£igen to a mature product. formations of the head and neck. In their prese- Type IX disease is caused by a deficiency in ly- lected group of patients they successfully obtained syloxid£^e. The primary defect is the altered coppei palliation in all and cures (five yrs without recur- metabolism, since copper is a cofactor for the en- rence) in 25%. The other area of use is in vascular Proceedings 75 tumors pdor to surgery to control blood loss. These He feels that this is not necessarily due to an estro- procedures are not without complications, such as gen effect, but may have something to do with the stroke, facial weakness, pain, and revasculariza- presence of erectile tissue or highly vascular tissue. tion. Neurofibromas are rarely seen over the shins, glans penis, and upper Up. This may be due to lack of fat BIOLOGIC BASE OF ICHTHYOSIS in these areas and the associated change in temper- ature. Another peculiarity of location was demon- Dr. Joseph McGuire (Stanford University) re- strated in a patient with extensive neurofibromas viewed the events in terminal differentiation of the who had no lesions in an area of motor and sensory epidermis. It has been known for some time that deficit. The last example was a patient who devel- ceU division is accelerated in some forms of ichthy- oped numerous lesions in the area of a donor site for osis. Although much effort has been expended in a skin graft. studying the synthesis of keratin, it does not appear to piay much of a role in the ichthyoses. Filaggrin is Patients with NF-2 have findings that may mimic an important molecule that probably is involved in other disorders. They do not all have cafe au lait ichthyosis vulgaris and the retention of scale. In one macules. If skin tumors are present, they are theory, as the keratinocyte matures it loses or- schwannomas and may have overlying hyperpig- ganelles. The filaggrin (stratum corneum basic pro- mentation and hypertrichosis. Four cases of NF-2 tein) disease is included. Little is known of the basic have been discovered in patients who had nasola- abnormalities in the most common ichthyoses such bial neurofibromas. This appears to be an important as ichthyosis vulgaris. pathognomonic sign. Patients should be cautioned to avoid swimming or diving alone since they are at Lamellar ichthyosis, which often is manifested as risk of becoming disoriented under water from the a collodion baby, is a heterogeneous group that has vestibular schwannomas. also remained an enigma. On the other hand, Dr. Riccardi briefly discussed his management of X-linked ichthyosis provided the major break- children with neurofibromatosis and outlined a through for experimental biologists with the discov- yearly screen that includes cranial imaging in the ery of the steroid sulfatase deficiency in this disor- asymptomatic patient. He admitted that this was der. The scale of patients with X-linked ichthyosis controversial. contains increased cholesterol sulfate that has been circumstantially linked to the delay in cell separa- The molecular biology of the disease was dis- tion. Other lipid disorders have been associated cussed. The genes for NF-1 and NF-2 have been lo- with ichthyosis. Another exciting discovery has calized to the long arm of chromosomes 17 and 22, been the identification of a defect in fatty alcohol respectively. The NF-1 gene has been cloned. It is a oxidoreductase in Sjogren-Larsson syndrome, an large gene with 300,000 KB. In a study of 300 pa- autosomal recessive condition with ichthyosis, tients with NF-1 the exact mutation was recognized spastic quadriplegia, seizures, mental retardation, in only 3%. Buried in the NF gene are three other and glistening retinal spots. Patients improve when genes. Two of them are known as EVIS (equotropic they receive medium-chain lipids. Dorfman de- viral insertion site) and are associated with murine scribed a disorder of neutral lipid storage associated chronic myeiogenous leukemia (CML). This may be with ichthyosis, myopathy, neurosensory deafness, important since 0.5% of patients with NF develop cataracts, and a fatty liver. Refsum syndrome in- CML. Another gene buried within the NF gene is cludes ichthyosis, cerebeUar ataxia, and retinitis the OMGP (oligodendrocyte myelin glycoprotein). pigmentosa. lt is due to a deficiency of phytanic Some patients with NF-1 develop a poly neuropathy acid oxidase. If dietary phytanic acid is restricted, that might relate to aberrant expression of this bur- the ichthyosis improves. ied gene. In addition, the NF-1 gene is an activating protein for guanosine triphosphatase, affecting growth control through RAS and with a number of NEUROFIBROMATOSIS IN CHILDHOOD other oncogenes. The NF-2 gene is probably a Dr. Vincent Riccardi continued his review of the tumor-suppressor gene. Dr. Riccardi speculated clinical manifestation of neurofibromatosis by dis- that the target area of this mutant gene may be the cussing some of the peculiarities in the location of secretory processes of the intemal cell membranes. neurofibromas. The lesions have a proclivity to de- Evidence for this may be found in the giant melano- velop on the areolae and nipples of 90% of adult somes of neurofibromatosis arising from the Golgi women with neurofibromatosis and 10% of males. apparatus and the endoplasmic reticulum. 76 Pediatric Dermatology Vol. 9 No. 1 March 1992

ALOPECIA AREATA IN CHILDHOOD pathology revealed a spindle cell neoplasm with small, spindle-shaped, vascular spaces. There have Dr. Eleanor Sahn (Medical University of South been two different interpretations: neurogenic sar- CaroUna) reviewed the clinical manifestations of coma and congenital fibrosarcoma. alopecia areata in childhood. She cited a frequency Dr. Andrea Dominey reported two infants with of 17 cases per 1,000,000, with 63% having onset congenital self-healing reticulohistiocytosis before age 20. Five percent of patients advance to (Hashimoto-Pritzker disease). They had ulcerated alopecia totalis and 1% to alopecia universalis. She lesions appearing at birth, resolving spontaneously discussed the heredity, with a positive family his- over several months. Their skin biopsy specimens tory in up to 27% of patients, the association with were typical, with histiocytic infiltrates surrounded atopy in 18% of children, and the 5% association of by reticulum fibers. Electron microscopy revealed autoimmune disorders such as vitiligo and thyroid Birbeck granules and laminated dense bodies. disease in alopecia areata. The various theories of pathogenesis include infection, neurologic factors, Dr. Robert Silverman (Annandale, Virginia) dis- vascular changes, and immune dysfunction. Im- cussed a 29-year-old man with Down syndrome mune dysfunctions that have been cited are the who had generalized syringomas that became more presence of autoantibodies, decreased T cell prominent with anxiety or activity. He cited an ear- counts, anergy, and decreased mitogen response. lier study that found syringomas in 18% of those Therapy was reviewed, such as corticosteroids with Down syndrome. (topical, intralesional, systemic), anthraUn, topical Dr. Karen Wiss (Boston Children's Hospital) de- immunotherapy with diphencyprone, PUVA, cy- scribed a 5-month-old who was born with yellowish closporin, thymopentin, minoxidil, inosoplex, red plaques and nodules involving the nose, fore- isotretinoin, and the use of wigs and psychologic head, and cheeks, spreading to the extremities. Le- support. The address of the National Alopecia sions over the extremities were covered with an in- Areata Foundation is 714 C Street, Suite 216, San creased density of hair. Except for hoarseness and Raphael, CA 94901; telephone (415) 456-4644. nasal stuffiness the child was well. Laboratory stud- ies showed only an elevated sedimentation rate and a mild microcytic anemia. Ear, nose, and throat ex- CASES OF THE YEAR amination revealed an enlarged uvula. The family history was significant in that the patient's father, Dr. Uona Frieden (University of California, San brother, paternal aunt, and cousin had similar le- Francisco) reported a newborn with macrocephaly sions at birth that resolved spontaneously. Only a who on day 6 of life developed macular erythema paternal uncle has persistent lesions. He has a diag- over the left side of the face. A CT examination nosis of sarcoidosis. A skin biopsy specimen from showed hydrocephalus consistent with a Dandy- the patient revealed sheets and nodular aggregates Wtdker cyst. At 5 weeks of age the vascular lesion of histiocytoid cells. Macrophage markers were had developed Into an ulcerated hemangioma that markedly positive, and Langerhans ceU markers required systemic steroids. An additional finding were focally positive. Electron microscopy showed was a choroidal angioma of the eye. A review of the no true Birbeck granules. Invaginations of the literature revealed 18 other cases of facial hemangi- plasma membrane appeared to represent incom- omas, abnormalities of the posterior fossa, and ab- pletely formed Birbeck granules. The whole picture normal eye findings. was interpreted as an indeterminate ceU prolifera- Dr. Bemard Cohen (Johns Hopkins University) tion. Because of progressive deformity of the skin, described a child with blue rubber bleb nevus syn- the child was treated with topical steroids, topical drome who had repeated episodes of acute anemia nitrogen mustard, and vinblastine, with no re- requiring several transfusions. The anemia was not sponse. due to gastrointestinal blood loss but seemed to be Maira Alvarez-Franco (Children's Memorial due to a hemolytic anemia with a localized dissem- Hospital, Chicago) discussed a Fusarium infection inated intravascular coagulation. in an 18-year-old leukemic that caused oral lesions Dr. Steven Resnick (University of North Caro- and a lip ulceration. Within several days a general- lina) described a newbom who had a large, tense ized rash developed. A biopsy specimen showed nodule on the buttock thought to be a hemangioma. fungal hyphae and cultures grew Fusarium. The pa- When it began to hemorrhage, it was excised. The tient died despite treatment with amphotericin.