Histiocytosis Syndromes




Abstract


This chapter describes the causes, clinical manifestations, diagnosis, and treatment of various types of histiocytosis disorders.




Keywords

Histiocytosis, Langerhans cell histiocytosis, Rosai–Dorfman disease, emophagocytic lymphohistiocytosis, Erdheim–Chester disease, Hand–Schüller–Christian disease, eosinophilic granuloma, Abt–Letterer–Siwe disease, Langerhans cell, dendritic cell, inus histiocytosis with massive lymphadenopathy, dermal dendrocytes, macrophages, erythrophagocytosis, infection-associated hemophagocytic syndrome, malignancy-associated hemophagocytic syndrome, macrophage activation syndrome, perforin, syntaxin, Munc genes, cytolytic granules

 


The term histiocytosis syndrome identifies a group of disorders that have in common the proliferation of cells of the mononuclear phagocyte system and/or the dendritic cell system.


Macrophages function predominantly as antigen-processing cells and dendritic cells function as accessory cells or antigen-presenting cells. Although the principal pathological cells of these syndromes are histiocytes, the term histiocytosis syndrome is a very selective term in the sense that it does not include storage diseases, hyperlipidemic xanthomatosis, or granulomatous reaction in chronic infections such as tuberculosis or foreign body granuloma.


The histiocytoses thus represent a diverse group of diseases characterized by the excess proliferation and accumulation of dendritic cells, monocytes, and macrophages in addition to other immune effector cells such as eosinophils and lymphocytes depending upon the specific type of disorder ( Table 20.1 ).



Table 20.1

Classification of Histiocytoses











  • Type I.

    Dendritic cell and dermal dendritic cell disorders



    • •

      LCH, including eosinophilic granuloma, multisystem with bone involvement, DI, and exophthalmos (formerly called Hand–Schüller–Christian syndrome) and disseminated involvement with risk organ dysfunction (formerly called Abt–Letterer–Siwe syndrome)


    • •

      Juvenile xanthogranulomatosis


    • •

      Erdheim–Chester disease




  • Type II.

    Macrophage-related disorders



    • •

      Hemophagocytic lymphohistiocytosis


    • •

      Familial erythrophagocytic lymphohistiocytosis


    • •

      Infection-associated hemophagocytic syndrome


    • •

      Malignancy-associated hemophagocytic syndrome


    • •

      Rosai–Dorfman disease




  • Type III.

    Malignant histiocytic disorders



    • •

      Dendritic cell-related histiocytic sarcoma (localized or disseminated)


    • •

      Macrophage-related histiocytic sarcoma


    • •

      Monocyte-related (monocytic leukemia or sarcoma)



Adapted from WHO committee Classification Working Group of Histiocytic Society.




Langerhans Cell Histiocytosis


Incidence


The prevalence has been estimated to be between 2 and 10 cases per million children under age 15 years annually. The male to female ratio is between 1.3 and 1.9:1. The peak incidence is between the ages of 1 and 4 years. Isolated pulmonary Langerhans cell histiocytosis (LCH) occurs primarily in adults who smoke cigarettes (>90% of cases). LCH has also been shown to be commonly concordant in identical twins and less frequently in nonidentical twin siblings and relatives.


Pathology


The characteristic histopathology required for a “presumptive diagnosis” usually shows a granulomatous-like lesion with immature dendritic-appearing cells that have characteristic bean-shaped, folded nuclei and pale cytoplasm. Often, multinucleated giant cells are present. A “definitive diagnosis” of LCH requires the immunohistochemical identification of the presence of Langerhans cell antigen expression of cell surface CD1a, CD207 (langerin) or by the presence of cells with Birbeck granules by electron microscopy ( Table 20.2 ). Early in the course of the disease the lesions are usually proliferative and locally destructive. In later or healing stages, they can become more fibrotic.



Table 20.2

Histological, Histochemical, and Electron Microscopic Diagnosis of LCH







  • 1.

    Presumptive diagnosis: light morphologic characteristics


  • 2.

    Designated diagnosis



    • a.

      Light morphologic features plus


    • b.

      Two or more supplemental positive stains for



      • i.

        Adenosine triphosphatase


      • ii.

        S-100 protein


      • iii.

        ∝-D-mannosidase


      • iv.

        Peanut lectin




  • 3.

    Definitive diagnosis



    • a.

      Light morphologic characteristics plus


    • b.

      Birbeck granules in the lesional cell with electron microscopy or CD207 expression by immunohistochemistry and/or


    • c.

      Immunohistochemical staining for CD1a antigen on the lesional cell.



Adapted from Writing Group of the Histiocyte Society ( Chu et al. 1987 ), with permission.


Pathogenesis


LCH can most accurately be considered a clonal neoplasm that arises from an immature dendritic cell or in some cases an earlier hematopoietic precursor cell. Multiple reports have furthermore now documented the presence of BRAF V600E mutations in 50–60% of cases. This mutation is nearly always monoallelic and thus appears to act like a dominant driving oncogene. There also appears to be no predilection for this BRAF V600E mutation in terms of the extent of organ involvement or age ( Badalian-Very et al., 2013 ). Of particular interest, however, is that the cases which appear not to have BRAF V600E mutations do have evidence for activation of the RAS-RAF-MEK-ERK signaling pathway. This suggested that alternative activating mutations were present, which has been confirmed with the subsequent identification of mutations involving genes encoding CSF-1 receptor, RAS, and MAP2K1. Evidence for circulating CD34-positive hematopoietic progenitors harboring V600E mutations, usually in the more severe forms of LCH, along with RNA expression patterns placing the pathologic LCH LC in a category of an activated myeloid dendritic cell rather than a epidermal Langerhans cell, have contributed to LCH now being considered an oncogene-driven neoplasm of the myeloid lineage.


Clinical Features


Clinical manifestations depend on the site of lesions, number of involved areas, and extent to which the function of key involved organs is compromised. Although replaced by more prognostic categories, the classic designations, eosinophilic granuloma, Hand–Schüller–Christian disease, and Abt–Letterer–Siwe disease, are still present in the literature and are useful descriptions of the various clinical manifestations of LCH.


Eosinophilic granuloma , solitary (SEG) or multifocal (MEG), are found predominantly in older children, as well as in young adults, usually within the first three decades of life with the incidence peaking between 5 and 10 years of age. SEG and MEG represent approximately 60–80% of all instances of LCH. Patients with systemic involvement frequently have similar bone lesions in addition to other manifestations of disease.


Hand–Schüller–Christian disease (multisystem disease) was historically described as the clinical triad of lytic lesions of bone, exophthalmos, and diabetes insipidus (DI), although this form of LCH is now usually considered to be more typical multisystem LCH without key organ dysfunction. It most commonly occurs in younger children, 2–5 years of age, and represents 15–40% of such patients; this type of involvement can be observed, however, in all ages. Signs and symptoms include bone lesions with exophthalmos due to tumor mass in the orbital cavity. This usually occurs from involvement of the roof and lateral wall of the orbital bones. Orbital involvement may sometimes result in vision loss or strabismus due to optic nerve or orbital muscle involvement, respectively. The most frequent sites of skeletal involvement include the flat bones of the skull, ribs, pelvis, and scapulae. There may be extensive involvement of the skull, with irregularly shaped, lytic lesions. Less frequently, long bones and lumbosacral vertebrae, usually the anterior portion of the vertebral body, are involved. Oral involvement commonly affects the gums and/or palate, resulting in the characteristic floating tooth seen on dental radiographs. Large sections of the mandible may be involved, with loss of bone leading to diminished height of the mandibular rami. Chronic otitis media, due to involvement of the mastoid and petrous portion of the temporal bone, and otitis externa are common.


Abt–Letterer–Siwe disease occurs in about 10% of cases and represents the most severe manifestation of LCH. Typically, patients are less than 2 years of age and present with a scaly seborrheic, eczematoid, sometimes purpuric rash that involves the scalp, ear canals, abdomen, and intertriginous areas of the neck and face. The rash may be maculopapular or nodulopapular. Ulceration may result, especially in intertriginous areas. Draining ears, lymphadenopathy, hepatosplenomegaly, and, in severe cases, hepatic dysfunction with hypoproteinemia and diminished synthesis of clotting factors can occur. Gastrointestinal involvement may give rise to diarrhea, malabsorption, and bleeding. Anorexia, irritability, failure to thrive, and significant pulmonary symptoms such as cough, tachypnea, and pneumothorax may occur as well. Involvement of the hematopoietic system, with bone marrow infiltration, can result in pancytopenia.


Other presentations of LCH are commonly seen. LCH can have a strictly nodal presentation , not to be confused with sinus histiocytosis with massive lymphadenopathy (SHML) (Rosai–Dorfman disease). This presentation is characterized by significant enlargement of multiple lymph node groups, with little or no other signs of disease. Pulmonary disease, usually seen in young adults in their third or fourth decade (occasionally in adolescents) and associated with cigarette smoking, may follow a severe and often chronic, debilitating course; patients may present with pneuomthorax. Pulmonary disease may also occur as part of multisystem disease. Cutaneous disease with no evidence of dissemination has been described in infants, children, and adults.


Involvement by Site of Disease


Skeleton


Painful bone lesions affecting hematopoietically active bones are common. Radiographically, the lesions are lytic and sometimes may have sclerotic edges or bone islands within the lytic area. They occur commonly in the skull as punched-out lytic lesions. Bone involvement of the mandible and maxilla and soft-tissue involvement of the gingivae may result in loss of teeth. Involvement of vertebrae can result in vertebral collapse (vertebra plana) and lesions of long bones can result in fractures. There is often an inability to bear weight and tender, sometimes warm, swelling due to soft-tissue infiltration overlying the bone lesions occur. Radionuclide bone scan ( 99m Tc-polyphosphate) or PET/CT may show localized increased uptake at the site of involvement. The differential diagnoses include osteomyelitis, malignant bone tumors, and bony cysts. Only rarely are bones involving the wrists, hands, and feet observed. Table 20.3 lists the distribution of the sites of bone lesions.



Table 20.3

Distribution of Bone Lesions in LCH




















































Site Incidence (%)
Skull 49
Innominate bone 23
Femur 17
Orbit 11
Ribs 8
Humerus 7
Mandible 7
Tibia 7
Vertebra 7
Clavicle 5
Scapula 3
Fibula 2
Sternum 1
Radius 1
Metacarpal 1


Skin


Cutaneous eruptions consist of:



  • 1.

    Diffuse papular scaling lesions, resembling seborrheic eczema (most common).


  • 2.

    Petechiae and purpura.


  • 3.

    Granulomatous ulcerative lesions.


  • 4.

    Xanthomatous lesions.



Lungs


Lung involvement may result in pulmonary dysfunction with tachypnea and/or dyspnea, cyanosis, cough, pneumothorax, or pleural effusion. Radiographic infiltrates consisting of diffuse cystic changes, nodular infiltrations, or extensive fibrosis can occur. The radiographic appearance may resemble miliary tuberculosis.


Liver


The liver may be enlarged with dysfunction that results in hypoproteinemia (total protein less than 5.5 g/dl and/or albumin less than 2.5 g/dl), edema, ascites, and/or hyperbilirubinemia (bilirubin level greater than 1.5 mg/dl, not attributable to hemolysis). Pretreatment liver biopsy more often reveals portal triditis and less often fibrohistiocytic infiltrates or bile duct proliferation. Sclerosing cholangitis, fibrosis, and liver failure may lead to the need for liver transplantation.


Hematopoietic System


The pathophysiology of hematopoietic dysfunction can be due to hypersplenism as well as direct involvement of the bone marrow by Langerhans cells and/or reactive macrophages.


Hematopoietic system dysfunction may consist of the following:




  • Anemia (hemoglobin level less than 10 g/dl, not due to iron deficiency or superimposed infection), leukopenia (neutrophils less than 1500/mm 3 ), or thrombocytopenia (less than 100,000/mm 3 ). Excessive number of histiocytes in the marrow aspirate is not considered evidence of dysfunction.



Lymph Nodes


Occasionally, there is massive lymph node enlargement of cervical nodes occurs without other evidence of histiocytosis.


Endocrine System


Short stature has been found in up to 40% of children with systemic LCH. Chronic illness and steroid therapy play an important role in its causation. However, short stature may also be a consequence of anterior pituitary involvement and growth hormone deficiency, which may occur in up to about half of the patients with initial anterior pituitary dysfunction. Posterior pituitary involvement with DI is characteristic of systemic LCH. Other endocrine manifestations include hyperprolactinemia and hypogonadism due to hypothalamic infiltration. Pancreatic and thyroid involvement have also been reported.


Gastrointestinal System


Gastrointestinal tract disease can occur and 2–13% of patients have biopsy-proven gastrointestinal involvement and/or digestive tract symptoms, although this may be an underestimate. Diarrhea, malabsorption, and hematochezia are common manifestations.


Central Nervous System


Four groups of patients can be clinically distinguished:



  • 1.

    Patients who present with hypothalamic pituitary system involvement.


  • 2.

    Patients who present with site-dependent symptoms of space-occupying lesions leading to headache and seizures.


  • 3.

    Patients who exhibit neurologic dysfunction characterized by a neurodegenerative picture of reflex abnormalities, ataxia, intellectual impairment, sometimes hydrocephalus, tremor, and dysarthria with variable progression to severe CNS deterioration.


  • 4.

    Patients who present with an overlap of the aforementioned symptoms.



Patients who develop CNS disease are more likely to have multisystem disease and skull lesions. Table 20.4 shows the clinical characteristics of patients with LCH who developed CNS disease compared to those who did not develop CNS disease. It reveals that patients who developed CNS disease are more likely to have multisystem disease with skull and temporal bone lesions, orbital involvement, DI, and endocrinopathies. Table 20.5 shows the classification of CNS lesions according to MRI morphology.



Table 20.4

Extent of LCH and Organs Involved in Diagnosis of Patients Who Develop CNS Disease Compared to Those Who Do Not Develop CNS Disease




































































Percentage in 38 CNS patients Percentage in 275 LCH patients
Multisystem disease 72 40
Single-system bone disease 18 53
Single-system skin, lymph node 0 7
Primary CNS disease 10 0
Bone 84 79
Skull 74 40
Temporal bone 34 8
Skin 58 25
Diabetes insipidus 31 6
Orbits 24 2
Endocrinopathies 18 3
Lungs 16 6
Gastrointestinal tract 10 5
Liver 10 11
Spleen 10 9

From Grois et al. (1998) , with permission.


Table 20.5

Classification of Central Nervous System Lesions According to Magnetic Resonance Imaging Morphology a










































































Type Number Percentage
Ia White-matter lesions without enhancement 21 55
Ib White-matter lesions with enhancement 9 24
IIa Gray-matter lesions without enhancement 19 50
IIb Gray-matter lesions with enhancement 3 8
IIIa Extraparenchymal dural based 12 32
IIIb Extraparenchymal arachnoidal based 2 5
IIIc Extraparenchymal choroid plexus based 3 8
IVa Infundibular thickening 8 21
IVb (Partial) empty sella 14 37
IVc Hypothalamic mass lesions 4 10
Va Atrophy: diffuse 10 26
Vb Atrophy: localized 6 16
VI Therapy-related with enhancement 6 15

From Grois et al. (1998) , with permission.

a LCH-CNS Study, n =38.



Histopathology of CNS Lesions


There are likely four stages of LCH involvement of the CNS as follows:



  • 1.

    Hyperplastic proliferative.


  • 2.

    Granulomatous.


  • 3.

    Xanthomatous.


  • 4.

    Fibrosis.



Lesions in the hyperplastic proliferative stage are most likely to contain the diagnostic LCH cells. In the cerebellum and cerebrum, white matter may show demyelination and there may also be destruction of Purkinje cells in the absence of histiocytes. Gliosis with plasma cell infiltrates may also be found.


Hypothalamic Pituitary Involvement





  • Signs and symptoms: Disturbances in social behavior, appetite, temperature regulation, and sleep patterns are common.



  • Posterior pituitary involvement: DI, polyuria, polydipsia.



  • Anterior pituitary involvement: Growth failure, precocious or delayed puberty, amenorrhea, hypothyroidism.



Of these, DI is the most common manifestation. The incidence of this complication ranges from 5% to 35% depending upon the extent and location of disease. Most present within 4 years of diagnosis. DI is due to infiltration by the disease into the hypothalamus with or without involvement of the posterior pituitary gland. Local tissue damage may be a consequence of IL-1 and prostaglandin E2 production. Polydipsia and polyuria may develop at presentation, during active disease (even when there is improvement in other areas), or after therapy is discontinued and there is no other apparent active disease.


Laboratory Studies for the Diagnosis of DI




  • 1.

    Water deprivation test with at least 3 h of no intake and with serum and urine electrolytes and osmolalities before and after deprivation plus arginine vasopressin levels is a definitive approach to diagnosis. Correction with a dose of desmopressin (DDAVP) further confirms the diagnosis. An early morning fasting urinalysis for specific gravity is also helpful as a screen.


  • 2.

    Gadolinium-enhanced MRI studies show thickening of the hypothalamic pituitary stalk (>2.5 mm) and absence of a posterior pituitary bright signal in T1 weighted images. These lesions are caused by pathologic infiltrates. There is no convincing evidence that established DI can be reversed by any treatment modality, but new-onset DI is considered to represent active disease and rapid initiation of treatment, usually LCH-directed chemotherapy, is recommended, although there are few data about the true response rate.



Replacement therapy with DDAVP is recommended for patients with DI. The rapid institution of effective systemic chemotherapy for disseminated disease may prevent the occurrence of DI and might be responsible for the low frequency of DI, although this has not been definitively proven. A small pituitary or empty sella indicates combined anterior and posterior pituitary insufficiency. This may be a result of disease or may be observed following cranial radiotherapy for DI.


Patients presenting with isolated idiopathic DI and morphologic changes in the suprasellar area should be closely observed. Stereotactic biopsy performed because of an enlarged pituitary stalk can distinguish a variety of conditions such as sarcoidosis, granulomatosis, tuberculosis, nonspecific lymphocytic hypophysitis, and LCH. A biopsy is not always possible. Cerebrospinal fluid (CSF) analysis for markers of germ cell tumors can be an important differentiator. Patients without a definitive diagnosis and with DI are often followed with serial contrast MRIs. If the CNS lesion enlarges and no definitive diagnosis has been made, then a biopsy may be indicated.


Space-Occupying Central Nervous System Lesions


These lesions most often arise from adjacent bone lesions, brain meninges, or choroid plexus. They usually give rise to signs and symptoms of increased intracranial pressure. They are also site-specific and size-dependent. Symptoms include headaches, vomiting, papilledema, optic atrophy, seizures, and other focal symptoms. Even diffuse meningitis-like manifestations can occur. These lesions may occur without any other evidence of LCH. Mass lesions respond well to treatment, leaving minimal or no residual defects.


Neurodegenerative Disease


The cerebellum is the second most common site of LCH CNS involvement, the first being the hypothalamic–hypophyseal axis. Neurologic symptoms occasionally predate the diagnosis of LCH. Symptoms mainly follow the pontine–cerebellar pattern, beginning as a discrete reflex abnormality or gait disturbance, and/or nystagmus. Sometimes patients may also present with hydrocephalus. They can progress to disabling ataxia. Pontine symptoms include dysarthria, dysphagia, and other cranial nerve deficits, ultimately leading to fatal neurodegeneration. On MRI, enhancing lesions involving the pons, basal ganglion, and cerebellar peduncles are observed. MRI of the cerebral hemispheres may show white-matter lesions in the periventricular area.


Biopsy shows a primarily inflammatory, lymphocyte response associated with gliosis, demyelination, and neuronal cell death. The etiology of this neurodegenerative process is unknown, but is believed to be an immune-mediated paraneoplastic response. In some cases, the onset of CNS symptoms occurs many years after the initial diagnosis of LCH.


Clinical and Laboratory Evaluation of LCH


Diagnostic Evaluation


Physical Findings: Patients should have a thorough physical examination including temperature, height, weight and head circumference, pubertal status, skin and scalp for rash, pallor or jaundice, external and middle ear, face and orbits, oropharynx, dentition, chest and lungs, abdomen for organomegaly, extremity and spine. There are few evidence-based guidelines, but the ones listed represent general best practice recommendations ( Tables 20.6 and 20.7 ).



Table 20.6

Laboratory and Radiographic Evaluation of Newly Diagnosed Patients with LCH



































































Follow-up test interval when organ system is:
Test Involved Not involved Single-bone lesion
Hemoglobin and/or hematocrit Monthly 6 months None
White blood cell count and differential count Monthly 6 months None
Platelet count Monthly 6 months None
Ferritin, iron, transferrin ESR Monthly 6 months None
Liver function tests (SGOT, SGPT, alkaline phosphatase, bilirubin, total proteins, albumin) Monthly 6 months None
Coagulation studies (PT, PTT, fibrinogen) Monthly 6 months None
Chest radiograph (PA and lateral) Monthly 6 months None
Skeletal radiograph survey a 6 months None Once, at 6 months
Urine osmolality measurement after overnight water deprivation 6 months 6 months None
Bone marrow aspirate and biopsy b
HLA-typing c

Note: SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic pyruvate transaminase; PT, prothrombin time; PTT, partial thromboplastin time; PA, posteroanterior.

Modified from Broadbent et al. (1989) .

a Radionuclide bone scan is not as sensitive as the skeletal radiograph survey in most patients. It may be performed optionally but should not replace the skeletal survey. If suspicion of lesion exists (e.g., pain) and both radiographic and radionuclide tests are negative, an MRI should be performed.


b From patients with multisystem disease.


c From patients with high-risk disease (multisystem with major organ dysfunction).



Table 20.7

Recommended Evaluations Based on Specific Clinical Indications in Patients with LCH








Clinical scenario and recommended additional testing


  • 1.

    History of polyuria or polydipsia



    • a.

      Early morning urine specific gravity and osmolality


    • b.

      Blood electrolytes


    • c.

      Water deprivation test if possible


    • d.

      MRI of the head



  • 2.

    Bicytopenia, pancytopenia, or persistent unexplained single cytopenia



    • a.

      Other cause of anemia or thrombocytopenia has to be ruled out according to standard medical practice. If no other causes are found, the cytopenia is considered LCH-related


    • b.

      Bone marrow aspirate and trephine biopsy to exclude causes other than LCH a as exposant


    • c.

      Evaluation for features of macrophage activation and hemophagocytic syndrome b (triglycerides and ferritin in addition to coagulation studies)



  • 3.

    Liver dysfunction



    • a.

      If frank liver dysfunction (liver enzymes fivefold upper limit of normal/bilirubin > fivefold upper limit of normal): consult a hepatologist and consider liver MRI which is preferable to retrograde cholangiography


    • b.

      Liver biopsy is only recommended if there is clinically significant liver involvement and the result will alter treatment (i.e., to differentiate between active LCH and sclerosing cholangitis)



  • 4.

    Lung involvement (further testing is only needed in case of abnormal chest X-ray or symptoms/signs suggestive of lung involvement, or pulmonary findings not characteristic of LCH or suspicion of an atypical infection)



    • a.

      Lung high-resolution computed tomography (HR-CT) or preferably low-dose multidetector HR-CT if available. Note that cysts and nodules are the only images typical of LCH; all other lesions are not diagnostic. In children already diagnosed with MS-LCH (see section “Clinical Classification”) low-dose CT is sufficient in order to assess extent of pulmonary involvement, and reduce the radiation exposure


    • b.

      Lung function tests (if age-appropriate)


    • c.

      Bronchoalveolar lavage (BAL): >5% CD1a+cells in BAL fluid may be diagnostic in a nonsmoker


    • d.

      Lung biopsy (if BAL is not diagnostic)



  • 5.

    Suspected craniofacial bone lesions including maxilla and mandible



    • a.

      MRI of head including the brain, hypothalamus–pituitary axis, and all craniofacial bones. If MRI not available, CT of the involved bone and the skull base in recommended



  • 6.

    Aural discharge or suspected hearing impairment/mastoid involvement



    • a.

      Formal hearing assessment


    • b.

      MRI of head or HR-CT of temporal bone



  • 7.

    Vertebral lesions (even if only suspected)



    • a.

      MRI of spine to assess for soft-tissue masses and to exclude spinal cord compression



  • 8.

    Visual or neurological abnormalities



    • a.

      MRI of head


    • b.

      Neurological assessment


    • c.

      Neuropsychometric assessment



  • 9.

    Suspected other endocrine abnormality (i.e., short stature, growth failure, hypothalamic syndromes, precocious, or delayed puberty)



    • a.

      Endocrine assessment (including dynamic tests of the anterior pituitary and thyroid)


    • b.

      MRI of head



  • 10.

    Unexplained chronic diarrhea, failure to thrive, or evidence of malabsorption



    • a.

      Endoscopy


    • b.

      Biopsy


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Jul 3, 2019 | Posted by in HEMATOLOGY | Comments Off on Histiocytosis Syndromes

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