- Case Study
- Open Access
Langerhans-cell histiocytosis (LCH) a presentation of two siblings with two different entities
© Aboud and Kadhim. 2015
- Received: 26 February 2015
- Accepted: 7 July 2015
- Published: 16 July 2015
Langerhans cell histiocytosis (LCH) as a term encompasses eosinophilic granuloma and two clinical syndromes: Letterer–Siwe disease and Hand–Schüller–Christian. All these syndromes seem to represent similar processes in which the proliferating cells have the structural and functional features of Langerhans cells. In reviewing the literature found that this disease does indeed occur in some families more often than would be expected. We present two boys, siblings with LCH in a single family with two different entities (There were no other siblings) and this paper is presented to emphasize the very rare familial occurrence of EG and the other one with Letterer–Siwe disease in our single family. The first patient, first child for consanguineous parents, 15 month boy, was born following an uncomplicated cesarean section, fullterm pregnancy. He developed well on bottle feed. At 13 months of age, he was noted to have a low hemoglobin concentration, mild fever, painful tender swellings and redness over the left lower chest wall a small subcutaneous mass was found. After clinical, radiological and histopathologic review, it was diagnosed as eosinophilic granuloma. Their second child, 6 month boy after a second cesarean section. At 5 month of age he developed a scaly, erythematous rash on his back spread to his shoulders, limbs and upper chest wall. The diagnostic conclusion from the clinical, skin biopsy, histopathology and bone marrow study was histiocytosis X and the diagnosis of Letterer–Siwe disease was established. Many studies listed a number of reported families with a disease which, though not considered as Letterer–Siwe disease by the authors, must certainly belong to the histiocytosis group. Many families reported have had more than one child affected with the generalized form of histiocytosis X. No case did a known relative other than a sibling have a similar disease, one family with known consanguinity, the parents were cousins. No such previous report presented these two rare different entities in two siblings as in our family.
- Fibrous Dysplasia
- Eosinophilic Granuloma
- Bone Marrow Study
- Mediastinal Lymph Node Enlargement
Langerhans cell histiocytosis (LCH) as a term encompasses eosinophilic granuloma and two clinical syndromes: Letterer–Siwe disease and Hand–Schüller–Christian. These entities enrolled in similar processes in which the proliferating cells have the structural and functional features of Langerhans cells. In fact these three basic conditions represent clinical stages of the same process, but they differ in their proliferating properties, ranging from a solitary focus (eosinophilic granuloma) to disseminated multifocal skeletal (Hand–Schuller–Christian) and disseminated multifocal skeletal and extraskeletal disease (Letterer–Siwe disease). Eosinophilic granuloma (EG) or benign focal histiocytosis-X is one of these clinical entities, which involves the reticuloendothelial system known as histiocytosis-X, and was reported in 1953 (Willets et al. 1998). EG frequently occurs in the flat bones such as skull, pelvis, scapula, and the ribs (Raijman 1998). Many modalities of treatment has been reported for solitary eosinophilic granuloma of bone, including observation, injections of steroid, local excision and curettage with or without bone grafting, chemotherapy and irradiation. All of these treatments are reported to give satisfactory results with a recurrence rate of less than 20% (Ioannidis et al. 2011; Stull et al. 1992; Satter et al. 2008; Bechan et al. 2006). The age of the patients in these series varies widely. LCH in its other systemic manifestations includes Hand–Schüller–Christian disease with a triad of exophthalmos, diabetes insipidus and osteolytic lesions of the skull, and Letterer–Siwe disease with skin rash, fever, lymphadenopathy, hepatosplenomegaly, anaemia and thrombocytopenia (Lichtenstein 1964). In reviewing the literature found that this disease does indeed occur in some families more often than would be expected (Falk and Gellei 1957).
We present two boys, siblings with LCH in a single family with two different entities (there were no other siblings), managed at the pediatric surgery unit, the maternity and Child Teaching Hospital, Al Qadisiya, Iraq, this paper is presented to emphasize the very rare familial occurrence of EG and the other one with Letterer–Siwe disease in our single family. The clinical course in these two infants is described. Written informed consent was obtained from the parents for publication of the reported cases and any accompanying images.
In term LCH represents a childhood disease and the others multisystem forms of the disease, formerly called Hand–Schüller–Christian and Letterer–Siwe disease (Ioannidis et al. 2011), appear almost exclusively in children between 1 to 5 years old and younger than 2 years, respectively (Stull et al. 1992). Eosinophilic granuloma is usually seen in children 5–15 years old (Stull et al. 1992) and seldom in adults. The etiology and pathogenesis of the disease still remains unknown. In some literatures have been reclassified as single organ system disease, unifocal or multifocal, and multisystem disease, complicated or not by organ dysfunction (Satter and High 2008). A clinicopathologic results offers the diagnosis, based on classical findings of clinical and histologic/immunohistochemical criteria. Reactive normal Langerhans cells found within nodes, to avoid misdiagnosis, they may present as a response to a variety of diseases including neoplasms (Bechan et al. 2006; Beverley et al. 2005). In literatures all the forms of LCH are characterized by clonal proliferation of CD1+ histiocytes and the absolute criteria for diagnosis depended on finding CD1a by immunohistochemistry or Birbeck granules by electron microscopy. Positivity of one or both of these finding now defines the Langerhans cell phenotype (Romani et al. 2003; Sidler et al. 2000; Chu 2001). Despite infections, immune and neoplastic causes have been postulated (Moon et al. 2009; Plasschaert et al. 2002), the pathogenesis is not completely understood. Near 80% of histiocytosis X lesions in children are of solitary EG type and about 90% occur in children (Jayaprakash et al. 2012). Usually Letterer–Siwe disease occurs in infants less than 2 years old and presents clinical symptoms such as fever, skin rush, anemia, hepatosplenomegaly, lymphadenopathy, and bleeding diathesis. The clinical course is rapid and fatal. Despite the tropism of skin lesions to flexures also suggests that external stimuli may trigger inflammation (Weitzman and Egeler 2008). However, the nature of the initiating event(s), and the mechanisms of local tissue destruction by LCH and other inflammatory cells are still largely unknown.
Until the recent time the specific genetic abnormalities of LCH were not consistently observed, in one study a genetic component is suggested by a higher concordance rate between monozygotic twins compared with dizygotic twins (Arico et al. 1999). Many studies listed a number of reported families with a disease which, though not considered as Letterer–Siwe disease by the authors, must certainly belong to the histiocytosis group (Freundlich et al. 1972). Juberg et al. 1970 suggested by analyzing the occurrence of Letterer–Siwe disease in monozygotic twins, siblings, and consanguineous matings that this disease results from an autosomal recessive gene with low penetrance (Satoshi and Masaru 1990). Clonality of LCH granulomas has been reported in 1994 (Willman et al. 1994; Yu et al. 1994). Takashi et al. (2012) described a mutant alleles in some family groups and he mentioned specifically his finding with the clinical features of patients with B-RAF mutations V600EB-RAF mutations were found both in children with granuloma of bones or isolated skin disease, and in infants with early-onset multi-organ disease and he mentioned that the somatic mutation in some patients confirmed despite the mother with the same allele, was in good health and did not report a personal history of LCH. This is the same story with our cases but unfortunately we have no such facilities to study the precise genetic background of the family. Recently some studies considered eosinophilic granuloma and Hand–Schuller–Christian disease as a single disease entity (Satoshi and Masaru 1990; Forssman and Rudberg 1960), many investigators describe Letterer–Siwe disease as an entity distinct from eosinophilic granuloma and Hand–Schuller–Christian disease as the disease considered to be a malignant, fulminant lymphomatous disease of infants. Important study mentioned to good support that Hand–Schuller–Christian disease and eosinophilic granuloma are different clinical expressions of the same disease entity, despite the rarity in familial occurrence, while it is frequent in Letterer–Siwe disease (Satoshi and Masaru 1990; Vogel and Vogel 1972). Many families reported have had more than one child affected with the generalized form of histiocytosis X. Some of them had three affected children, others families have each had two affected children. No case did a known relative other than a sibling have a similar disease, one family with known consanguinity, the parents were cousins (Volker 1963).
No such previous report presented these two rare different entities in two siblings as in our family. As the background of all modalities of LCH may enrolled in the same process, further studies suggest to verify and obtain a precise data about the genetic, cellular, immunological, environmental and clinical profile of pedigree or parent with diseased sibling.
We are grateful for the editors to review this article managed at the Maternity and Child Teaching Hospital. The Study conducted on the terms and policy of the institution and the College of Medicine, they announced their agreement for participants, a printed, optical, electronic document and database designed to record all of the written information. The rarity of such presentation made our decision to declare the cases, hope to have more precise study and investigation with qualified resources to obtain more knowledge about the occurrence of the disease among the family siblings.
MJA and MMK were involved with study development and co-ordination, data collection, and writing the article. MMK performed all immunological profiles and immunohistochemistry studies. Both authors read and approved the final manuscript.
The author expresses sincere gratitude to all the Pediatric Surgery Unit staff at the Maternity and Child Teaching Hospital, Al-Qadisiya, Iraq, for their assistance. Thanks also go to Medical Microbiology and Clinical immunology laboratory staff at the college of medicine, Al Qadisiya University for there efforts to obtain the results and all colleagues in radiology, dermatology and pediatric units.
Compliance with ethical guidelines
Competing interests The authors declare that they have no competing interests.
Consent for publication Written informed consent was obtained from the parents for publication of the reported cases and any accompanying images.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Arico M, Nichols K, Whitlock JA, Arceci R, Haupt R, Mittler U et al (1999) Familial clustering of Langerhans cell histiocytosis. Br J Haematol 107:883–888View ArticleGoogle Scholar
- Bechan GI, Egeler RM, Arceci RJ (ed) (2006) Biology of Langerhans cells and Langerhans cell histiocytosis. Int Rev Cytol 254:1–43Google Scholar
- Beverley PC (2005) The Nikolas symposia and histiocytosis. Nat Rev Cancer 5:488–494View ArticleGoogle Scholar
- Chu T (ed) (2001) Langerhans cell histiocytosis. Australas J Dermatol 42(4):237–242Google Scholar
- Falk W, Gellei B (1957) The familial occurrence of Letterer–Siwe disease. Acta Paediat 46:471–480View ArticleGoogle Scholar
- Forssman H, Rudberg B (ed) (1960) Study of consanguinity in twenty-one cases of Hand–Schuller–Christian disease (systemic reticuloendothelial granuloma). Acta Med Scand 168:427–429Google Scholar
- Freundlich E, Amit S, Montag Y (ed) (1972) Familial occurrence of Letterer–Siwe disease. Arch Dis Child 47(251):122–125View ArticleGoogle Scholar
- Ioannidis O, Sekouli A, Paraskevas G, Chatzopoulos S, Kotronis A, Papadimitriou N et al (ed) (2011) Long term follow up of eosinophilic granuloma of the rib. Klin Onkol 24(6):460–464Google Scholar
- Jayaprakash Shetty K, Ajith Kumar, Shantharam Shetty, Kishan Prasad HL, Chandrika Rao (ed) (2012) An unusual presentation of langerhans cell histiocytosis, NUJHS 2(4):77–79Google Scholar
- Juberg RC, Kloepfer HW, Oberman HA (ed) (1970) Genetic determination of acute disseminated histiocytosis X (Letterer–Siwe syndrome). Pediatrics 45:753–765Google Scholar
- Lichtenstein L (ed) (1964) Histiocytosis X (eosinophilic granuloma of bone, ‘Letterer–Siwe disease and Schuller–Christian disease’): further observations of pathological and clinical importance. J Bone Joint Surg [Am] 46-A:76–90Google Scholar
- Moon TY, Lee J, Lee IS, Choi KU, Chae JM, Kim J et al (ed) (2009) MRI and histopathologic classification of Langerhans cell histiocytosis. Curr Med Imaging Rev 5:14–18Google Scholar
- Plasschaert F, Craig C, Bell R (ed) (2002) Eosinophilic granuloma. A different behaviour in children than in adults. J Bone Joint Surg 84:870–872Google Scholar
- Raijman I (ed) (1998) Endoscopic management of esophagorespiratory fistulas: expanding our options with expandable stents. Am J Gastroenterol 93(4):496–499Google Scholar
- Romani N, Holzmann S, Tripp CH, Koch F, Stoitzner P (ed) (2003) Langerhans cells—dendritic cells of the epidermis. APMIS 111:725–740Google Scholar
- Satoh T, Smith A, Sarde A, Lu H, Mian S, Trouillet C et al (ed) (2012) B-RAF mutant alleles associated with langerhans cell histiocytosis, a granulomatous Pediatric disease. PLoS One 7(4):e33891Google Scholar
- Satoshi, Masaru (ed) (1990) Eosinophilic granuloma of the skull in identical twins case report. Neurol med chir (Tokyo) 30:1034–1046Google Scholar
- Satter EK, High WA (ed) (2008) Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society. Pediatr Dermatol 25(3):291–295Google Scholar
- Sidler AK, Huston bM, Livasy C (ed) (2000) Pathological case of the month. Eosinophilic granuloma (Langerhans cell histiocytosis). Arch Pediatr Adolesc Med 154(10):1057–1058Google Scholar
- Stull MA, Kransdorf MI, Devaney KO (ed) (1992) Langerhans cell histiocytosis of bone. Radiographics 12(4):801–823Google Scholar
- Vogel JM, Vogel P (ed) (1972) Idiopathic histiocytosis. A discussion of eosinophilic granuloma, the Hand–Schuller–Christian syndrome, and the Letterer–Siwe syndrome. Semin Hematol 9:349–369Google Scholar
- Volker W (ed) (1963) Familial occurrance of Letterer–Siwe disease. Pediatrics 32:1055–1063Google Scholar
- Weitzman S, Egeler RM (ed) (2008) Langerhans cell histiocytosis: update for the pediatrician. Curr Opin Pediatr 20:23–29Google Scholar
- Willman CL, Busque L, Griffith BB, Favara BE, McClain KL, Duncan MH et al (ed) (1994) Langerhans’-cell histiocytosis (histiocytosis X)—a clonal proliferative disease. N Engl J Med 331:154–160Google Scholar
- Willets JE, Dudley NE (ed) (1998) Endoscopic treatment of recurrent tracheo-esophageal fistulae: long-term results. Pediatr Surg Int 13(4):256–258Google Scholar
- Yu RC, Chu C, Buluwela L, Chu AC (ed) (1994) Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343:767–768Google Scholar