Yung-Chieh Huang, MD,a,​ b​ Jiaan-Der Wang, MD, PhD,a​ Fang-Yi Lee, MD,c​ Lin-Shien Fu, MDa,​d

Pediatric Malignant Atrophicabstract Papulosis Malignant atrophic papulosis (MAP), also known as Degos disease, is an extremely rare disease that is characterized by its unique skin presentation (namely, central, porcelain-white atrophic with a telangiectatic rim). MAP has the following 2 variants: cutaneous MAP is manifested in the skin alone, whereas systemic MAP affects the , , , and other internal organs. Some patients who presented with only cutaneous symptoms at first may develop systemic symptoms several years later. Although the exact pathologic mechanisms – are unclear, Magro et al suggested in a recent study that MAP is a vascular α injury syndrome that involves complement component C5b 9 complex deposition and high expression of interferon- . The prognosis of systemic – MAP is poor and typically fatal within a few years. Nonetheless, because Departments of aPediatrics and cPathology and Laboratory Medicine, Taichung Veterans General Hospital, the C5b 9 complex is detected in MAP, some researchers have suggested Taichung, Taiwan; bDivision of Pediatrics, Puli Branch, combined treatment with (a humanized monoclonal antibody Taichung Veterans General Hospital, Nantou, Taiwan; and d against C5) and (a prostacyclin analog). Here, we report on a Department of Pediatrics, National Yang-Ming University, Taipei, Taiwan girl with systemic MAP who had severe central nervous system involvement and responded to eculizumab. Dr Huang drafted the initial manuscript; Drs Fu and Wang conceptualized and designed the study CASE REPORT and critically reviewed the manuscript; Dr Lee provided the pathologic photographs and wrote papules occurred during her infancy the description of pathological findings in the and gradually increased in number. manuscript; and all authors approved the final A 4-year-old girl was admitted to manuscript as submitted. our hospital because of a sudden Neurologic examination revealed left – DOI: https://​doi.​org/​10.​1542/​peds.​2016-​4206 onset of ptosis of the left eyelid. The ptosis, lateral deviation of the left eye, Accepted for publication Apr 28, 2017 patient was born with middle ring and mydriasis without light reflex. No – finger syndactyly in both hands and decreased muscle power or sensory Address correspondence to Lin-Shien Fu, MD, Department of Pediatrics, Taichung Veterans middle fourth toe syndactyly in both loss was observed. The complete blood count, serum biochemistry, and General Hospital, 1650 Taiwan Blvd Sect. 4, feet. The patient had undergone web Taichung, Taiwan 40705. E-mail: linshienfu@yahoo. release and reconstruction at the coagulation function tests yielded com.tw normal results. An emergency brain age of 2 years. Two weeks before PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, this admission, she had 1 episode CT scan showed effusion in the 1098-4275). frontoparietotemporal area of the of severe ; however, Copyright © 2018 by the American Academy of blood examination and abdominal bilateral hemisphere (which was more Pediatrics prominent in the left side) and several computed tomography (CT) revealed FINANCIAL DISCLOSURE: The authors have no remarkable findings. Her symptoms calcification spots in the left cerebral indicated they have no financial relationships were relieved after supportive cortex (Fig 2). relevant to this article to disclose. treatment. Her family history was FUNDING: Supported by the Taiwan Foundation for The patient underwent an emergency unremarkable. Rare Disorders (Case: TFRD104MS09-03). operation of the left blur hole on POTENTIAL CONFLICT OF INTEREST: The authors At the pediatric emergency the left frontal scalp with external have indicated they have no potential conflicts of department, the patient was alert and drainage on the same day. Her interest to disclose. oriented, with normal psychomotor cerebrospinal fluid (CSF) collected development. On examination, we during surgery revealed elevated To cite: Huang Y-C, Wang J-D, Lee F-Y, et al. Pedia­ observed several porcelain-white protein concentration (776 mg/dL) tric Malignant Atrophic Papulosis. Pediatrics. 2018; atrophic papules with rims of only. The patient still showed left 141(s5):e20164206 erythema on her trunk and thighs ptosis and no pupil light reflex in (Fig 1). According to her parents, the the left eye for the next few days. Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number s5, April 2018:e20164206 CASE REPORT FIGURE 1 FIGURE 4 Porcelain-white atrophic papules with rims of Immunohistochemical staining of the MAC on erythema on the trunk. the skin specimen (original magnification ×200).

patient was diagnosed as having malignant atrophic papulosis (MAP). The first dose of eculizumab FIGURE 3 (300 mg) was administered 2 Hematoxylin and eosin staining (original magni­ months after her admission. The fication ×200) of the skin biopsy spec­imen revealed focal fibrinous necrosis of the vascular protocol was approved by the wall (A) and thrombotic microang­iopathy Institutional Review Board of the under a microscope (B). Taichung Veteran General Hospital, Taiwan (No. SF15161A) and the Food and Drug Administration of Taiwan (No. 1040035623). FIGURE 2 her left frontal lobe and left high Meanwhile, we administered Emergency brain CT scan showed effusion in frontoparietal junction with marked enoxaparin subcutaneously as the frontoparietotemporal area of the bilateral subdural effusion and calcification ’ an anticoagulant and depakine hemisphere and several calcification spots in in the cortex, as mentioned. Within the left cerebral cortex. orally as an antiepileptic drug. 2 weeks, the patient s neurologic Her rate returned to normal symptoms deteriorated to aphasia, within 2 days. The continuous loss of swallowing ability, and total administration of eculizumab every Subsequently, a skin biopsy was paralysis; she did not respond to 2 weeks markedly improved her performed, of which the specimen pain or other stimuli. An additional neurologic function. After 18 months revealed the focal loss of elastic episode of abdominal distention and of regular eculizumab, enoxaparin, fiber integrity in the upper dermis gastric occurred 2 weeks and rehabilitation, the patient had and superficial perivascular later, with bowel distention and minimal facial paralysis, normal lymphocytic infiltration in the ileus observed on the radiograph swallowing and speaking ability, and dermis. Furthermore, focal fibrinoid film. For the following month, the muscle power grades 4 for the left necrosis of the vascular wall (Fig 3A) patient was awake but completely limbs and 3 for the right limbs. and thrombotic paralyzed and could trace moving objects only with her right eye. She were observed microscopically (Fig The patient presented with exhibited tachycardia of up to 130 3B). We screened for an antinuclear sudden generalized and to 150 beats per minute with sinus antibody, the complement bilateral pupil dilation during a rhythm, intermittent abdominal components C3 and C4, and 2-day trip. She was transferred to fullness with indigestion, and antiphospholipid antibodies, and our emergency department from intermittent -like movements. the results revealed no signs of another hospital in a few hours, Immunohistochemical staining of autoimmune disease. and her brain CT scan revealed membrane attack complexes (MACs) multiple intracranial hemorrhages, in her skin biopsy specimen revealed A total of 10 days after her admission, intraventricular hemorrhage with MAC deposition in the vessel walls the patient developed right facial hydrocephalus, subdural effusion (Fig 4). paralysis and right arm and leg in the left frontoparietal region, and weakness. An emergency brain CT According to clinical presentation multiple calcifications in the CSF scan revealed acute infarction in and pathologic findings, the space. Her parents refused additional Downloaded from www.aappublications.org/news by guest on October 1, 2021 S482 HUANG et al ACKNOWLEDGMENTS resuscitation or operation, and she favorable responses15 in a few cases died within a few hours. later. Magro et al administered The eculizumab treatment protocol DISCUSSION eculizumab to a 46-year-old man was approved by the Institutional with MAP for more than 2 years. ∼ Review Board of the Taichung The clinical condition of the patient Veteran General Hospital, Taiwan To date, 200 cases of MAP have markedly improved after the initial (No. SF15161A). been reported worldwide. The treatment and remained stable; ∼ ABBREVIATIONS however, he still experienced 2 average1 age of disease onset– is 35.4 years,​ and 30 cases involved2 4 episodes of acute abdominal pain, children or adolescents. ‍ ‍ Only which required surgery. The tissue CNS: central nervous system 1 case reported eculizumab and biopsy specimen showed no more CSF: cerebrospinal fluid treprostinil treatment of the central MAC deposits but persistently CT: computed tomography nervous system5 (CNS) manifestation high type I interferon signature11 MAC: membrane attack complex of this disease. and . Oliver et al MAP: malignant atrophic examined a 55-year-old woman The presentation of MAP varies papulosis with MAP who presented with among patients. Studies have– abdominal symptoms for 5 years. REFERENCES reported neurologic involvement1,6​ 8 in 20% to 64% of patients. ‍ ‍ ‍ After eculizumab treatment for 6 1. Theodoridis A, Konstantinidou A, Makrantonaki E, Zouboulis CC. However, neurologic involvement months, the patient experienced Malignant and benign forms of was more frequent in the only 1 minor episode5 of abdominal pain. Shapiro et al reported marked atrophic papulosis (Köhlmeier-Degos pediatric group4 in 1 study (11 of disease): systemic involvement effects of treprostinil in a patient 14 patients). The presentations determines the prognosis. Br J with MAP combined with severe of CNS involvement included Dermatol. 2014;170(1):110–115 subdural effusions, hemorrhagic pulmonary . They later administered treprostinil to a 2. Gutiérrez-Pascual M, Hernández-Martín or ischemic , disabling A, Colmenero I, Garc a-Pe as JJ, L pez- 17-year-old patient who presented í ñ ó polyradiculoneuropathy, and other Pino MA, Torrelo A. Malignant atrophic nonspecific neurologic symptoms. with recurrent abdominal pain, papulosis: a case report with severe In our case, the first neurologic hematuria, and neurologic symptoms visual and neurological impairment. symptoms were ptosis of the left despite eculizumab treatment; Pediatr Dermatol. 2011;28(3): eyelid and subdural effusion, which the patient has subsequently been 302 305 ğ – were similar to a pediatric case symptom-free. Thus, a long-term ’ 3 3. Karaoğlu P, Topçu Y, Bayram E, et al. reported by Karao lu et al. Elevated treatment combination of treprostinil1 Severe neurologic involvement of protein in the patient s CSF indicated3,9​ and eculizumab is suggested. Degos disease in a pediatric patient. J Child Neurol. 2014;29(4):550 554 a chronic meningovascular10 process. ‍ – Caviness et al reported vessel Before the introduction of 4. Wilson J, Walling HW, Stone MS. involvement in dural biopsy in a eculizumab and treprostinil, no Benign cutaneous Degos disease in previous study. studies had reported an effective a 16-year-old girl. Pediatr Dermatol. 2007;24(1):18 24 MAP has been treated by several treatment of neurologic involvement – medical treatments, including in MAP, and surgical drainage had 5. Shapiro LS, Toledo-Garcia AE, Farrell JF. Effective treatment of malignant antiplatelet agents (aspirin, not been found to 3,be10​ effective for atrophic papulosis (K hlmeier-Degos dipyridamole, and clopidogrel), subdural effusion. ‍ However, the ö disease) with treprostinil early anticoagulants (heparin and combination treatment may entail – experience. Orphanet J Rare Dis. a considerable economic burden warfarin), and immunosuppressants– 2013;8:52 (corticosteroids, azathioprine, and on the patient and family. Although 11 13 6. Subbiah P, Wijdicks E, Muenter M, methotrexate). ‍‍ Nonetheless, no our patient died after 18 months of Carter J, Connolly S. Skin treatment has yielded satisfactory eculizumab treatment, her initial with a fatal neurologic outcome responses before the introduction of response was impressive, and 14 (Degos’ disease). Neurology. eculizumab. In 2011, Magro et al neurologic function showed gradual – ’ 1996;46(3):636–640 reported the pathologic findings of improvement. This case reveals that 7. Assier H, Chosidow O, Piette JC, et al. extensive deposits of C5b 9 within eculizumab can improve patients Absence of antiphospholipid and CNS manifestations, although its long- the cutaneous vasculature, and anti-endothelial cell antibodies in they proposed that inhibition of C5 term effectiveness and combined use malignant atrophic papulosis: a study might be a therapeutic approach with treprostinil require additional to this disease. Eculizumab yielded clinical examination. 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Downloaded from www.aappublications.org/news by guest on October 1, 2021 S484 HUANG et al Pediatric Malignant Atrophic Papulosis Yung-Chieh Huang, Jiaan-Der Wang, Fang-Yi Lee and Lin-Shien Fu Pediatrics 2018;141;S481 DOI: 10.1542/peds.2016-4206

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