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Rationale: Menkes disease (MD), also known as Menkes kinky hair disease, is a fatal neurodegenerative disease caused by a defect in copper metabolism. The symptoms involve multiple organ systems, such as the brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. There is currently no cure for this disease entity, and patients with the classic form of MD usually die from complications between 6 months and 3 years of age. Intracranial hemorrhage secondary to tortuous intracranial arteries is a well-known complication of MD, but spontaneous retroperitoneal hemorrhage, to the best of our knowledge, has never been reported in a patient with MD. Herein, we describe the first case of retroperitoneal hematoma as a complication of MD in a 4-year-old boy. Patient concerns: A 4-year-old Taiwanese male patient with MD was referred to the hospital and presented with a palpable epigastric mass. Diagnoses: On the basis of the findings of ultrasonography and enhanced computed tomography, the diagnosis was retroperitoneal hematoma. Interventions: Interventions included laparotomy with evacuation of the hematoma, manual compression, and suture of the bleeding vessels. Outcomes: There were no postoperative complications. Lessons: This case emphasizes that bleeding in patients with MD is possible at any site in the body owing to the unstable structure of the connective tissues. Timely diagnosis with proper imaging studies can lead to prompt and appropriate management and save patients from this life-threatening condition. Abbreviations: CPR = cardiopulmonary resuscitation, IRB = Institutional Review Board, LO = lysyl oxidase, MD = Menkes disease, MRI = magnetic resonance imaging, VUR = vesicoureteral reflux. Keywords: copper, intracranial hemorrhage, Menkes kinky hair disease, retroperitoneal hematoma, vessel tortuosity 1. Introduction enzymes, including cytochrome oxidase, dopamine beta-hydrox- ylase, lysyl oxidase (LO), sulfhydryl oxidase, superoxide Menkes disease (MD) is an X-linked disorder of copper dismutase, and tyrosinase, lead to the classic symptoms of metabolism with wide variability and clinical heterogeneity in MD. Early diagnosis is crucial; however, managing complica- its manifestations. Disrupted functions of copper-dependent tions of the disease is equally important. Severe respiratory infections and neurological deterioration are the main causes of Editor: N/A. [1] morbidity or mortality in MD. Retroperitoneal hematoma is a The authors have no conflicts of interest to disclose. rare entity in children, and most cases are caused by blunt Department of Pediatric Gastroenterology, Hepatology and Nutrition, abdominal trauma, malignancy, coagulopathies, or iatrogenic b c Department of Neonatology, Department of Pediatric General Surgery and [2,3] injuries. We describe herein the first case of MD with Urology, Department of Genetics and Metabolism, MacKay Children’s Hospital, e retroperitoneal hematoma, manifesting as an epigastric mass, and Taipei, Department of Medicine, MacKay Medical College, New Taipei City, the diagnosis was made with the aid of ultrasonography, Division of Biochemical Genetics, Department of Medical Research, MacKay Memorial Hospital, Department of Early Childhood Care, National Taipei computed tomography, and laparotomy. This case emphasizes University of Nursing and Health Sciences, MacKay Junior College of Medicine, that bleeding in patients with MD is possible at any site in the Nursing and Management, Taipei, Taiwan. body due to the unstable structure of the connective tissues. Correspondence: Chuen-Bin Jiang, MacKay Children’s Hospital, Taipei, Taiwan (e-mail: ped.dr@yahoo.com.tw). 2. Case report Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons This study was approved by the Institutional Review Board (IRB) Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial of MacKay Memorial Hospital (IRB number 17MMHIS146). and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. A 4-year-old Taiwanese boy initially presented at 5 months of age with focal seizure, hypotonia, and hypopigmented curly scalp Medicine (2018) 97:6(e9869) hair, and the diagnosis of MD was confirmed by a molecular Received: 3 December 2017 / Received in final form: 3 January 2018 / Accepted: 24 January 2018 study at 7 months of age. Subsequently, copper-histidine injections were started. Other associated problems included http://dx.doi.org/10.1097/MD.0000000000009869 1 Peng et al. Medicine (2018) 97:6 Medicine global developmental delay, epilepsy, pectus excavatum, gastro- esophageal reflux, bilateral nephrocalcinosis, vesicoureteral reflux (VUR), multiple urinary bladder diverticula, inguinal hernias, and osteopenia. He experienced cardiopulmonary resuscitation (CPR) 4 times during the ages of 3 to 4 years, and therapeutic hypothermia after CPR was performed in 1 episode. He was bedridden at home and dependent on a nasogastric tube feeding and tracheostomy ventilator. His regular medications included levetiracetam, topiramate, and vigabatrin for epilepsy, and prophylactic antibiotics for VUR. This time, he was referred to the hospital and presented with a palpable epigastric mass, and coffee-ground substance from the nasogastric tube was noted for 4 days. He had stool passage the day before admission, and there was no blood or mucus in his stool. He had no vomiting, diarrhea, cough, shortness of breath, or increase in oxygen demand. On physical examination, vital signs revealed the following: body temperature 38.1°C, blood pressure 105/51 mm Hg, heart rate 113beats/min, and Figure 1. Abdominal ultrasonography revealing a hamburger-like mass, consisting of hypoechoic “hamburger buns” and multilayered “hamburger respiratory rate 36breaths/min. He had a pale conjunctiva, filling.” and there was an elastic soft mass at the epigastrium measuring 6 cm 5cm. There was no abdominal muscle guarding, hepatosplenomegaly, skin bruises, or petechiae. Laboratory investigations indicated anemia, and other data are listed in diameters of the mass were 6.11cm 4.69cm. On the next day, Table 1. The follow-up hemoglobin level decreased from 7.8 to the follow-up abdominal ultrasonogram showed an increased 6.8g/dL within 20hours; thus, 200mL of packed red blood cells thickness of the “bottom hamburger bun,” and a blood vessel was transfused. Plain film of the abdomen showed no obvious was mapped by color Doppler, heading into the “bottom signs of intestinal obstruction. The abdominal ultrasonogram hamburger bun.” The ultrasonograms were suggestive of active revealed a hamburger-like mass at the subxiphoid area, intra-abdominal bleeding with a growing hematoma (Fig. 3). consisting of hypoechoic “hamburger buns” and multilayered Emergent laparotomy was performed. A well-capsulated hema- “hamburger filling” (Fig. 1). An enhanced computed tomography toma, composed of 3 chambers divided by pseudomembranes, scan of the abdomen showed a mass containing 3 flat ovoid was seen between the stomach and liver. The 2 superficial layers, 1 over another, the superficial 2 with low attenuation and chambers were filled with necrotic tissues and blood clots, the deepest with high attenuation (Fig. 2). The maximum whereas the deepest chamber was impacted with blood clots and Table 1 Laboratory tests results upon admission. Variables Reference range Laboratory tests results WBC count, 10 /L 4–12 14.3 Differential, % Segmented neutrophils 55–75 78.2 Lymphocytes 20–40 9.7 Bands 0–60 Hb, g/dL 11.5–14.5 7.8 MCV, fL 77–95 76 Reticulocyte, /1000 RBC 5–15 25.2 Platelet count, 10 /L 140–450 199 INR <1.2 1.19 PT, s 8.0–12.0 11.9 PTT, s 23.9–35.0 33.6 Bleeding time, min 1’00”–4’00” 4’00” Glucose, mg/dL 60–100 91 Sodium, mEq/L 134–143 134 Potassium, mEq/L 3.3–4.6 4.5 CRP, mg/dL 0.06–0.79 10.6 Ferritin, ng/mL 38–457 626.6 Coombs test Negative Negative Hb electrophoresis HbA1, % 96.8–97.8 97.5 HbF, % <2 <0.5 HbA2, % 2.2–3.2 2.5 Stool occult blood Negative 4+ Figure 2. Enhanced computed tomography scan of the abdomen showing a CRP= C-reactive protein, Hb= hemoglobin, INR= international normalized ratio, MCV= mean mass next to the stomach, containing 3 flat ovoid layers, the superficial 2 with corpuscular volume, PT= prothrombin time, PTT= partial thromboplastin time, WBC= white low attenuation and the deepest with high attenuation. blood cell. 2 Peng et al. Medicine (2018) 97:6 www.md-journal.com contributing to low serum copper and ceruloplasmin levels. Copper is an essential element in the early stages of central nervous system development and in the biosynthesis and [4] maintenance of bone and connective tissues. As a result, clinical features of MD are diverse and multisystemic, including mental retardation, optic atrophy, convulsions, feeding difficul- ties, failure to thrive, hypothermia, hypotonia, apnea, infections, bladder diverticula, peculiar facies, kinky hair, hypopigmenta- [5,6] tion, bone changes, and cutis laxa. Most patients die of complications before the age of 3 years. Copper-histidine therapy may be beneficial in preventing neurological deterioration; increasing tone; and improving sociocognitive milestones, hair changes, weight gain, and immunity in some patients, particu- larly when treatment is begun in the neonatal period or in the [7] fetus. However, the effects of long-term treatment are still [8] limited, and the overall prognosis remains poor. It is worth mentioning that connective tissue disorders comprise a major part of symptoms, which are attributed to decreased activities of LO, the key copper-dependent enzyme that works in elastin and collagen cross-linking. Parenteral adminis- tration of copper-histidine cannot improve activities of LO because the administered copper is not transported to the Golgi [4,5] apparatus, where LO combines with copper to function. In patients with MD, defective elastic fibers within the internal Figure 3. A blood vessel is mapped by color Doppler, heading into the elastic lamina, tunica media, and intimate layer of arteries and “bottom hamburger bun.” The hypoechoic circular flow within the “hamburger arterioles result in vascular tortuosity and ectasia, with greater bun” is also seen, indicating active bleeding with hematoma formation. [9] predisposition to mucosal hemorrhage. In fact, brain magnetic resonance imaging (MRI) has become an adjunct diagnostic tool for MD, as increased cerebrovascular tortuosity seems to represent an early and reliable diagnostic revealed multiple active bleeders (Fig. 4). One bleeder was [1,10] [11] biomarker of MD. According to Manara et al, elongated identified as a branch of the left gastric artery. Manual and thin-walled intracranial arteries appear on brain MRI scans compression, suture of the vessel, and surgical packing of the at as early as disease onset in most patients with MD, whereas inner side of the capsule were performed to stop the bleeding. there is no evidence of significant vessel wall change evolution The patient’s postoperative course was smooth. Nasogastric [12] during the disease course. In addition, epidural and subdural feeding was started since postoperative day 3, and the patient was [5,13] hemorrhages have been frequently reported in the literature. discharged 9 days postoperatively. One reported case in 1972 showed splitting, irregularity, and fragmentation of the internal elastic lamina of the systemic 3. Discussion arteries upon necropsy, particularly in the mesenteric vessels and [14] in the aorta and carotid, splenic, and renal arteries. MD is a lethal neurodegenerative disease caused by mutations of Nonetheless, there is a lack of literature depicting tortuosity of the ATP7A gene that lead to a defect in copper metabolism, systemic vessels, and gastrointestinal bleeding or intra-abdominal bleeding has been scarcely reported. Recurrent spontaneous subserosal hemorrhage of the ileum was reported in a 3-year-old patient with MD and led to intestinal [15] [9] obstructions. Belsha et al described a multilobulated hyperplastic polyp with extensive involvement of the antrum and pylorus of the stomach in a 5-month-old patient with MD, and it caused marked upper gastrointestinal tract bleeding. A hyperplastic polyp of such a large size in infancy is extremely rare, and it was hypothesized that mucosal redundancy owing to LO deficiency in combination with chronic pressure during gastric peristalsis at the pyloric outlet predisposed the patient to polyp [9] formation. To the best of our knowledge, spontaneous retroperitoneal hemorrhage in patients with MD has never been described; the cause of the hemorrhage and location and 3- chambered architecture of the hematoma in our case were also very unique. The common causes of retroperitoneal hemorrhage are blunt abdominal trauma, rupture of the aortic aneurysm, adrenal hemorrhage, renal hemorrhage, malignancy, coagulop- athy (hemophilia or use of anticoagulants), or iatrogenic injuries Figure 4. After removing the superficial 2 chambers of blood clots and necrotic [2,3] (after femoral catheter insertion or bone marrow biopsy). We tissues, the deepest chamber (C) with active bleeders is revealed. postulated that the formation of 3 chambers of the hematoma in 3 Peng et al. Medicine (2018) 97:6 Medicine [4] Kodama H, Fujisawa C, Bhadhprasit W. Pathology, clinical features and our patient was derived from intermittent bleeding of the friable treatments of congenital copper metabolic disorders—focus on neuro- and tortuous abdominal vessel(s) over time. Timely recognition logic aspects. Brain Dev 2011;33:243–51. of the hematoma by abdominal ultrasonography led to successful [5] Kodama H, Fujisawa C, Bhadhprasit W. Inherited copper transport surgical management, and the patient returned to his usual state disorder: biochemical mechanisms, diagnosis, and treatment. Curr Drug Metab 2012;13:237–50. uneventfully. Unfortunately, there is currently no way to prevent [6] Droms RJ, Rork JF, McLean R, et al. Menkes disease mimicking child a next episode of bleeding or any other life-threatening events in abuse. Pediatr Dermatol 2017;34:e132–4. our patient. [7] Yoganathan S, Sudhakar SV, Arunachal G, et al. Menkes disease and This case highlights the importance of considering retroperi- response to copper histidine: an Indian case series. Ann Indian Acad toneal hemorrhage as a diagnosis when a patient with MD Neurol 2017;20:62–8. [8] Tümer Z, Petris M, Zhu S, et al. A 37-year-old Menkes disease patient- presents with abdominal distention or even an abdominal mass. residual ATP7A activity and early copper administration as key factors in Abdominal ultrasonography is a useful, noninvasive, and beneficial treatment. Clin Genet 2017;92:548–53. irradiation-free modality that should be performed promptly [9] Belsha D, Narula P, Urs A, et al. Management of hyperplastic gastric in MD patients with gastrointestinal symptoms to differentiate polyp following upper gastrointestinal bleeding in infant with Menkes’ disease. World J Gastrointest Endosc 2017;9:341–5. surgical problems from nonsurgical ones. Since our patient [10] Kim OH, Suh JH. Intracranial and extracranial MR angiography in survived several episodes of severe complications and exceeds the Menkes disease. Pediatr Radiol 1997;27:782–4. average life expectancy of MD, a variety of rare complications [11] Manara R, D’Agata L, Rocco MC, et al. Neuroimaging changes in may provide unexpected challenges for clinicians in the future. Menkes disease, part 1. AJNR Am J Neuroradiol 2017;38:1850–7. [12] Verma A, Menghani K. Menkes kinky hair disease. Indian Pediatr 2016;53:86. References [13] Gandhi R, Kakkar R, Rajan S, et al. Menkes kinky hair syndrome: a rare neurodegenerative disease. Case Rep Radiol 2012;2012:684309. [1] Ojha R, Prasad AN. Menkes disease: what a multidisciplinary approach [14] Danks DM, Campbell PE, Stevens BJ, et al. Menkes’s kinky hair can do. J Multidiscip Healthc 2016;9:371–85. syndrome. An inherited defect in copper absorption with widespread [2] Chenaitia H, Abrous K, Louis F, et al. WINFOCUS (World Interactive effects. Pediatrics 1972;50:188–201. Network Focused On Critical UltraSound) Group France. Relevance [15] Weng SC, Hsu CH, Wang NL, et al. Recurrent spontaneous of sonography for retroperitoneal hematoma. Am J Emerg Med subserosal hematoma of ileum causing intestinal obstruction in a 2011;29:827–8. patient with Menkes disease: a case report. Medicine (Baltimore) [3] Monib S, Ritchie A, Thabet E. Idiopathic retroperitoneal hematoma. J 2016;95:e4842. Surg Tech Case Rep 2011;3:49–51.
Medicine – Wolters Kluwer Health
Published: Feb 1, 2018
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