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Home , Ascites, Hepatosplenomegaly, Jaundice, Splenomegaly

| Case Presentation | No. 22-2018 | A 17-month-old girl presented with , , and scaly erythematous lesion

Sayma Rahman Munmun, A. S. M. Bazlul Karim, Rezina Parveen, Md. Benazamin, Md. Shafikul Alam Tanim and Manmohan Bir Shrestha

results, the case was provisionally diagnosed. Article Info Presentation of Case Department of Pediatric Gastroenterol- Dr. Rezina Parveen: A 17-month-old girl, only ogy and Nutrition, Faculty of , issue of non-consanguineous parents, hailing Bangabandhu Sheikh Mujib Medical Provisional Diagnosis University, Shahbag, Dhaka, Bangladesh from Sirajgonj, Bangladesh immunized as per (SRM, ASMBK, RP, MB); Department of EPI schedule got admitted to the inpatient Chronic with , Faculty of Basic Science and department with the history of abdominal with pneumonia Paraclinical Science, Bangabandhu distension, jaundice, not growing well along Sheikh Mujib Medical University, Chronic Shahbag, Dhaka, Bangladesh (MSAT); with scaly skin lesion over scalp, chest, palm Department of and Imaging, and sole for 9 months. She was reasonably well The is a disease process of Faculty of Medicine, Bangabandhu 9 months back. Then she developed abdominal the liver that involves a process of progressive Sheikh Mujib Medical University, distention which was increasing day-by-day Shahbag, Dhaka, Bangladesh (MBS) destruction and regeneration of liver paren- associated with gradually deepening jaundice. chyma leading to fibrosis and and in For Correspondence: There was also a history of irregular fever and some cases . Unlike Sayma Rahman Munmun cough for 1 month. Fever was high-grade irre- [email protected] adults, there is no time duration of illness that gular in nature, subsided by taking antipyretics defines the chronic liver disease. All the inheri- Received: 21 September 2018 in conjunction with non-productive cough. ted metabolic and genetic conditions even Accepted: 13 October 2018 There was no history of contact with the when diagnosed at birth could have the Available Online: 25 December 2018 patient, any or dental advance liver disease. The common causes of procedure, family history of liver disease, but chronic liver in children are ISSN: 2224-7750 (Online) the history of one unit . 2074-2908 (Print) (chronic B or C), metabolic liver On physical examinations, she was dyspnic, disease (Wilson disease, α1 antitrypsin deficien- DOI: 10.3329/bsmmuj.v11i4.38382 febrile, mildly pale and icteric (Figure 1). The cy, glycogen storage disease, lipid abnormali- ties, cystic fibrosis), developmental/genetic respiratory rate was 48 breaths/min, SPO2 95% (, congenital hepatic fibrosis, Keywords: Ascites; Hepatosplenomeg- without O2. The blood pressure was within aly; Jaundice; Langerhans’cell histiocyto- normal limit. The digital clubbing, multiple red ), immune-related (auto- sis; Liver; Scaly erythematous; papular non-itchy skin lesion on both palm and immune hepatitis, sclerasing cholangitis), vas- sole and diffuse scaly lesion on the scalp, and cular (Budd chiari syndrome, hepatic veno- Cite this article: BCG mark were present. There was no occlusive disease, portal vein ), etc. Munmun SR, Karim ASMB, Parveen R, Benazamin M, Tanim MSA, Shrestha lymphadinopathy. She was severely wasted, Patients with chronic liver disease clinically MB. A 17-month-old girl presented with stunted and underweight. On systemic may present with , jaundice, bleeding jaundice, hepatosplenomegaly, ascites examination, the abdominal distention with manifestations and other stigmata of chronic and scaly erythematous skin lesion. huge hepatosplenomegaly and ascites were liver disease (palmar erythema, nail clubbing, Bangabandhu Sheikh Mujib Med Univ J. found. The wheeze and crackles were present 2018; 11: 304-309. spider nevi), ascites, features of hypersplenism on both lung fields. with .1 In this case, anemia, jaun- Copyright: dice, clubbing, hepatoslenomegaly and ascites The laboratory data (Table I) showed anemia The copyright of this article is retained are in favor of chronic liver disease but the by the author(s) [Atribution CC-By 4.0] (: 8.6 g/dL), markedly raised characteristic skin lesion and lung findings are erythrocyte sedimentation rate (120 mm in 1st Available at: against the diagnosis of chronic liver disease. hour), grossly impaired liver function (serum www.banglajol.info alanine aminotransferase: 238 U/L, total : 9.2 mg/dL, serum 27 g/L). The X-ray chest showed consolidation (Figure 2). The Mantoux test was 2 mm. Dr. Md. Benzamin: The patient presented with The abdominal ultrasonography showed heter- jaundice, gradual and ogenous echotexture of the liver with multiple failure to thrive. There was a history of cough nodular lesion. After evaluating the clinical and irregular fever. The child was dyspneic, data, physical findings and investigation febrile, mildly pale and icteric. Digital clubbing BSMMU J 2018; 11: 304-309 305

and the Mantoux test was negative. These go against the diagnosis of tuber- culosis. Tuberculosis Tuberculosis is an important global health problem and Bangladesh is one of the high tuberculosis burden countries in the world. It includes the pulmonary and extrapulmonary form. Studies from Bangladesh showed that extrapulmonary form is commoner in children.2, 3 Disseminated tuberculosis is defined as tuberculous infection involving the bloodstream, bone marrow, liver, or involvement of two or more non-contiguous sites, or .4 It is a potentially life-threatening form 4, 5 A B of tuberculosis. The incidence of disseminated tuberculosis ranges from 1-3% of all tuberculosis cases.6, 7 It is common among the infants and children.8 Dr. Sayma Rahman Munmun: After evaluating the patient’s presenting features, physical findings and the laboratory test results she was considered for further investigation because the skin lesions remained unexplained. For this, the skin biopsy was done and the tissue was sent for histopathology.

C D Dr. Md. Shafikul Alam Tanim: The histopathological examination of the biopsy specimen taken from the Figure 1: The patient with jaundice (A), abdominal distension (B), erythematous scalp following anesthesia revealed mixed infiltrate over scalp and face (C), and hand (D) of Langerhans cells, lymphocytes and occasional eosinophils in the upper dermis. However, a was present. She was severely wasted and under- variable number of neutrophils and plasma cells weight. On systemic examination, wheeze and were also found in many other cases. Immuno- crackles were present in both lung fields. Huge histochemical analysis was performed with anti- hepatosplenomegaly with ascites was also present. CD1a, S100 and CD68 primary . Langer- Investigations showed high erythrocyte sedimenta- hans cells organized in groups and singly showed tion rate and consolidation on the chest X-ray. After brown immunohistochemical stain for CD1a and evaluating the clinical data, physical findings and S100 protein, but not for CD68 protein. In immuno- investigations report we differentially considered it histochemical examination, CD1a and S100 posi- as a case of disseminated tuberculosis. But there tivity confirmed the diagnosis of Langerhans cell was no history of contact with the tuberculosis histiocytosis (Figure 3). patient, BCG mark was present. There was no Dr. Munmun: After getting the histopathology report, we did the skeletal survey to see the bone involvement. We also did the bone marrow puncture which was normal and planned for the but could not do that as because the parents did not give consent. Dr. Manmohan Bir Shrestha: Patient’s X-ray of the right leg revealed well-defined round intramedu- llary non-expansile lucent lesion with marginal sclerosis in the metadiaphyseal region of the proximal shaft of tibia. Radiological differentials for this type of lesion includes benign bone (i.e. simple bone , enchondroma, chondro- blastoma), Brodie’s , Langerhans cell histio- cytosis, brown tumor of hyperparathyroidism and A B . In Langerhans cell histiocytosis, the Figure 2: Consolidation of lungs (A) and lytic lesion over tibia (B) as shown by common locations include the skull and long bones. arrows In the case of long bones, Langerhans cell 306 BSMMU J 2018; 11: 304-309

histiocytosis. After considering the history, physical Table I examination, biopsy and immunohistochemistry findings we reached a diagnosis of Langerhans cell Laboratory investigations of the patient histiocytosis. Parameter Findings References Langerhans cell histiocytosis Hemoglobin (g/dL) 8.6 12.2-14.8 This is a rare disease of Langerhans cell where 9 WBC count (×10 /L) 10 4-10 multiple systems like skin, bones, nodes, Differentials pituitary gland, bone marrow, liver, spleen, lungs Neutrophil (%) 65 40-80 etc. can be affected. Langerhans cell histiocytosis was previously called histiocytosis X, which inclu- Lymphocyte (%) 28 20-40 ded three entities named , Eosinophil (%) 3 1-6 Hand-Schuller-Christian disease, Letterer-Siwe Monocyte (%) 8 2-10 disease.9-13 These are, now, replaced by single- count (109/L) 150 150-400 system single site, single-system multisite, and multisystem disease.14-17 Erythrocyte sedimentation rate 120 0-10 (mm in 1st hour) Single-system disease Peripheral blood film Microcytic hypo- Single-system disease is the commonest form chromic anemia (65%).18-20 Single-system single site disease can be Serum bilirubin total (mg/dL) 9.2 0-1 defined as involvement of one system with the Serum (U/L) 238 0-55 unifocal lesion. The unifocal form is usually benign, affects older children and adults and is (g/L) 27 35-50 characterized by a solitary bone lesion, usually in (sec) 14 12-16 the skull or spine.21 But less commonly it can also INR 1.2 involve the skin, , lungs, hypothalamic- pituitary/, etc. According to Mantoux test (tuberculin test) Negative the older terminology, the unifocal form corres- Chest X-ray Consolidation in ponds to eosinophilic granuloma. When multiple both lung fields sites of a single system is involved, then it will be X-ray skull (both view) Normal termed as single-system multisite disease. Multi- focal form of Langerhans cell histiocytosis is more X ray of both hip joint, knee joint Lytic lesion in right tibia and left femur invasive and affects infants and several bone lesions and ankle joint and involvement of the adjacent soft tissue are seen Ultrasonography of whole abdo- with coarse echotexture in it. This disease corresponds to Hand-Schuller- men with multiple ill defined nodules in both Christian disease.22 lobes of the liver Bone marrow study Mature marrow with increase erythroid Multisystem disease Involvement of two or more organ/system is called multisystem disease. Multisystem disease can occur histiocytosis usually involves diaphysis or with or without the risk organ involvement. Bone metadiaphysis. Patient’s chest X-ray anteroposterior marrow, liver, spleen and lungs are the high-risk view revealed almost round dense homogenous organs, whereas skin, bones, lymph nodes, pituitary opacity in the right mid zone at suprahilar region, gland are recognized as low risk organs.9, 10, 14, 16 But possibly consolidation. lungs are not defined as risk organs.23 The Dr. Munmun: Radiological findings of the patient multisystem disease was previously called as was also in favor of the Langerhans cell Letterer-Siwe disease.

A B C

Figure 3: Histopathological feature of the skin biopsy H & E 200x showing the Langerhans’cell histiocytosis (A, within circles); Immuno- histochemistry 400x showing the CD1a (B) and 100x showing S100 (C) positivity (arrows) BSMMU J 2018; 11: 304-309 307

Our patient had liver, spleen, skin, lungs and bone motting. Magnetic resonance imaging involvement. So, she can be classified as multi- and computed tomography scan may reveal system disease with the risk organ involvement. infiltration in sella turcica. Assessment of endocrine function and bone marrow biopsy are also performed when indicated. Dr. Munmun’s Diagnosis Treatment may be local or systemic, depending on the number and location of lesions. Systemic Langerhans’cell histiocytosis chemotherapy is the treatment of choice for single system multiorgan and multisystem disease as well as for special localizations. Systemic chemotherapy Discussion includes an initial intensive phase consisting of a standard two drugs regimen with vinblastine and Dr. A. S. M. Bazlul Karim: Langerhans cell histiocy- prednisone for 6–12 weeks followed by main- tosis is an uncommon disease with an annual tenance and the total treatment duration 13, 15, 20, 24 incidence of 2-9 per million of children. In should be at least 12 months.14 Salvage therapy with Bangladesh this disease is also diagnosed as only cytarabine, cladribine, clofarabine or combinations 2% of all childhood in a tertiary care of these as well as bone marrow and/ 25 center. Here, clonal proliferation and migration of or solid are the treatment of 26 Langerhans cells occur, and these cells can choice for the non-responders, progressive disease infiltrate almost every tissue or organ. Langerhans in a high-risk organ.10, 31-33 Single system single site cell histiocytosis was previously termed as disease confined to the skin can be observed for histiocytosis X. The term X denotes for its unknown spontaneous remission, if not then topical steroids, origin. However, there is a paucity of information nitrogen mustard, psoralen combined with ultra- about the etiology and pathogenesis of Langerhans violet A therapy can be applied. For localized bone cell histiocytosis. It is not caused by a known lesions surgical curettage is the usual treatment. infection, is not contagious, nor it is believed to Radiotherapy, intralesional steroids, bisphospho- be inherited. Although available data suggest that nates, early chemotherapy (vinblastine and predni- the growth of immature Langerhans cells possibly solone) are used for the bony lesions at crucial due to BRAF V600E gene mutation is responsible for anatomical sites. Surgical excision is for single about 50% of the cases there remain debates among nodes with Langerhans cell histiocytosis. Regional the experts as to whether it is definitively or node involvement may respond to a course of 27, 28 not. It occurs at any age but it mostly affects systemic steroids and chemotherapy for nodes children and young adults and the peak age is in resistant to treatment. between 1 to 4 years.29 It is more common in boys. The male : female ratio is approximately 2:1.30 The Systemic therapy with two-drug regimen (vinblas- clinical presentation is highly variable which can tin, prednisolone) was started in our patient. range from self-limiting single system disease to Dr. Kamrun Nahar: What endocrine problem(s) may potentially fatal multisystem disease. General occur in this patient? symptoms are fever, lethargy, weight loss, growth failure, etc. More specific symptoms depend on the Dr. Parveen: Endocrine involvement is uncommon involvement of different organ and it includes in Langerhans cell histiocytosis. It can involve painful bone lesion (80%), seborrhoeic erythema- pituitary gland, hypothalamus, thyroid gland. The tous rash, hemorrhagic rash (60%), swollen lymph most common problem is diabetes incipidus. Others nodes (33%), feature of diabetes insipidus, short include short stature, . The common stature (25%), hepatomegaly, liver dysfunction symptoms are the excessive thirst, excessive (15%), anemia, jaundice, clubbing, proptosis, dental urination, , fatigue, sweating, carries, splenomegaly, ascites, otitis media, cranial temperature changes, weight gain/loss, early or nerve palsy, etc. Young children often present with delayed/absent puberty. multisystem disease having fever and symptoms of failure in various organs.9, 17 The diagnosis of Dr. Luthfun Nahar: What type of liver derangement Langerhans cell histiocytosis is done on the basis of occur? histological criteria determined by the Histiocyte Dr. Karim: Liver involvement is rare and can occur Society in 1987.14 A definitive diagnosis includes in the form of isolated hepatomegaly, sclerosing identification of characteristic cells and the presence cholangitis, liver cirrhosis, etc. Involvement of of markers eg. CD1a and/or CD207 (langerin). hepatic hilar lymph nodes may give rise to Other supportive investigations such as full blood hepatomegaly. The feature of organ dysfunction count, liver function test, skeletal survey, ultra- such as raised liver enzyme, (<30 sonogram of abdomen etc. are done for the deter- g/dL), clotting factor deficiencies and secondary mination of disease extent and exclusion of other , ascites, jaundice, etc. may accompany causes. Osteolytic bone lesions can be present in the hepatomegaly.14, 16 Imaging studies of the liver skeletal survey and chest X-ray may show miliary (ultrasonography, computed tomography scan and 308 BSMMU J 2018; 11: 304-309

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