Langerhans Cell Histiocytosis

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Retrieved

2019-09-22

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Omim

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BRAF, MAPK1, MAP2K1, CD1A, EPHB2, CD207, RAF1, ZHX2, MAP2K7, S100A1, S100B, TP53, IL17A, IL1B, LHCGR, PIK3CD, TNFRSF11B, IL1A, TNF, PECAM1, ARAF, SMUG1, JAG2, SPP1, PIK3CA, AR, PIK3CB, NRAS, PIK3CG, SOST, FOXP3, RELN, CD14, CD68, CCL22, NOTCH1, CD83, TNFSF11, POSTN, GNA11, PLEKHA6, TNFRSF1A, NR0B2, TUBA1A, UCHL1, U2AF1, PDGFRA, IGK, PTPN6, STAB1, GNA14, AMACR, S100A9, TRBV20OR9-2, STK11, CCL17, FADD, FSCN1, CFLAR, AKT1, PDGFB, PAX5, HLA-A, GSN, GNAQ, FSHR, FLT3LG, DCX, CTLA4, CSF2, CSF1, CCR7, CCR6, CDKN2A, CDKN1A, CDK5, CD34, CD86, CASP8, BCL2, CCND1, HLA-DRB1, HTC2, IFNG, KITLG, PAFAH1B1, OAT, NTRK3, XIAP, MYD88, MPO, MMP12, MME, MAP3K1, IFNGR1, LYZ, LIF, KIT, KIR2DL4, JAK2, INSL3, IL1RN, IGH, SLC29A3

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Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, Anti-CD123 IgG1 humanised monoclonal antibody conjugated to N1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-N6-((S)-1-(((S)-1-((3-((((S)-8-methoxy-6-oxo-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)-5-((((S)-8-methoxy-6-oxo-12a,13-dihydro-6Hbenzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)adipamide, Vemurafenib ( ZELBORAF )

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Description

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the dysregulated proliferation of Langerhans cells and subsequent organ infiltration. Clinical manifestations range from a spontaneously healing isolated osteolytic lesion to a lymphoma-like syndrome with fatal multiorgan failure, in the absence of any cellular evidence of malignancy. Although the disease can present at any age, the peak age at diagnosis is between 1 and 3 years (summary by Arico et al., 1999).

Egeler and D'Angio (1995) presented a classification of histiocytosis syndromes in children: class I, Langerhans cell histiocytosis (LCH); class II, histiocytosis of mononuclear macrophages other than Langerhans cells, including familial hemophagocytic lymphohistiocytosis (267700); and class III, malignant histiocytic disorders, including histiocytic lymphoma.

Clinical Features

The Langerhans cell is a dendritic cell (DC) of the epidermis that was first described by a medical student, Paul Langerhans, who thought it was part of the nervous system (Langerhans, 1868). Birbeck et al. (1961) found that the Langerhans cell displays a unique electron-microscopic morphology. The discoveries that these cells are not confined to skin and that they make up a sizable portion of the cellular infiltrate in histiocytosis X (246400), along with other evidence, suggested that they play an immunologic role in protecting against environmental antigens.

LCH is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamopituitary axis (HPA). Although diabetes insipidus (DI) is a well-recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement had not been well defined, particularly in adult patients with the disease. Kaltsas et al. (2000) evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. The median age at diagnosis of DI was 34 years (range, 2-47 years); DI was the presenting symptom in 4 patients, whereas the remaining 8 each developed DI 1-20 years (median, 2 years) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 years (range, 2-22 years) after the diagnosis of DI; GH (139250) deficiency developed in 8 patients (median, 2 years; range 2-22 years), FSH/LH (see 136530) deficiency in 7 patients (median, 7 years; range, 2-22 years), and TSH (see 188540) and ACTH (see 176830) deficiency in 5 patients (median, 10 years; range, 3-16 and 3-19 years), respectively; 5 patients developed panhypopituitarism. In addition, 7 patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 years (range, 1-23 years): 5 morbid obesity (body mass index greater than 35), 5 short-term memory deficits, 4 sleeping disorders, 2 disorders of thermoregulation, and 1 adipsia. The authors concluded that in their adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 (67%) patients; these occurred over the course of 20 years. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.

Population Genetics

The reported incidence of childhood Langerhans cell histiocytosis ranges from 3.5 to 7 cases per million children per year. These figures may be spuriously low because of the failure to diagnose and report cases with a mild course or spontaneous healing of isolated lesions (cited by Arico et al., 1999).

Inheritance

Although LCH is usually considered a sporadic nonhereditary disorder, familial clustering has been described in a limited number of cases, particularly in twins reported or known to be monozygotic. Arico et al. (1999) conducted a survey to examine the possible familial nature of LCH. They identified 9 families with more than 1 affected relative: 5 with LCH-concordant twin pairs, and 4 with LCH in sibs or cousins. Three twin pairs not concordant for LCH were also studied. Because of variable confidence for twin monozygosity, they termed the twin pairs 'presumed monozygotic,' or pMZ. Overall, 4 of 5 pMZ twin pairs and 1 of 3 dizygotic (DZ) pairs were concordant for LCH. The pMZ twins had simultaneous and early disease onset (mean age, 5.4 months); onset was at 21 months in the DZ pair. Clinical features were similar in the pMZ pairs. One pair of DZ twins had disseminated LCH. The 3 healthy twins (1 pMZ, 2 DZ) remained asymptomatic 0.3, 5.9, and 4.7 years, respectively, after disease onset in their cotwins. Of the 2 families with affected nontwin sibs, one had parental consanguinity and the other possible consanguinity. Potential consanguinity was also present in 1 of the 2 families with affected first cousins.

Pathogenesis

Coury et al. (2008) detected high levels of soluble RANKL (TNFSF11; 602642) and IL17A (603149), but not IL1B (147720), IL22 (605330), or TNF (191160), in serum from patients with LCH. Immunohistochemical analysis demonstrated IL17A-positive DCs in LCH patient skin and bone lesions and in multinucleated giant cells (MGCs). Intracytoplasmic flow cytometry and ELISA identified DCs, and not T cells, as the source of IL17A in LCH. IL17A stimulation induced fusion of healthy DCs in vitro. LCH DCs behaved similarly to IL17A-stimulated healthy DCs, and transwell assays confirmed that IL17A secreted from LCH DCs was functional. Gene chip analysis showed that IL17A was responsible for expression of TRAP (ACP5; 171640), MMP9 (120361), and MMP12 (601046) by MGCs in healthy DCs. Healthy DCs treated with IL17A and LCH DCs and MGCs displayed overactivation of TRAP. IgG autoantibody to IL17A was also detected in LCH serum. Coury et al. (2008) proposed that IL17A has a major role in LCH severity and may be a therapeutic target in the disease.

In a follow-up study to Coury et al. (2008), Allen and McClain (2009) reported that they were unable to detect IL17A mRNA by RT-PCR in CD207 (604862)-positive Langerhans cells or CD3-positive T cells isolated by flow cytometry from 14 LCH biopsy samples. In addition, they could not detect significant levels of serum IL17A in LCH patients. In response, Arico et al. (2009) pointed out that they (i.e., Coury et al. (2008)) had detected IL17A in CD207-negative DCs, the majority cell population in LCH lesions, using different sets of antibodies from those used by Allen and McClain (2009). They also stated that their serum ELISA assay used a capture antibody able to outcompete autoantibodies to IL17A that are present in LCH sera. Both studies showed that serum IL17A concentrations did not correlate with LCH activity and that Th17 cells were not present in LCH lesions. Indirectly, there may also be concurrence between the studies in the statement by Arico et al. (2009) that LCH is a DC-related disease rather than a Langerhans cell-related disease.