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Familial Hemophagocytic Lymphohistiocytosis

HLH

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disease that is inherited in an autosomal recessive manner. It results in the hyperactivation of macrophages and T lymphocytes. FHL is mainly diagnosed in early childhood.


Presentation

Familial hemophagocytic lymphohistiocytosis (FHL) is a condition that is usually diagnosed in infants. In a minority of cases, the condition manifests later in childhood or adulthood [1].

FHL is also referred to as primary hemophagocytic lymphohistiocytosis and is a genetic disease inherited in an autosomal recessive pattern. It has been reported more frequently in children of consanguineous parents. Most cases of FHL results from mutations in the PRF1 (perforin 1) and UNC13D (unc-13 homolog D) genes [2]. It is a contrast compared to secondary hemophagocytic lymphohistiocytosis, which is often triggered by an inflammatory process such as an infection, malignancy, or by a low immunity. Manifestations result from the abnormal function of macrophages and T lymphocytes [3]. The condition may prove fatal if untreated.

Because FHL affects numerous organ systems, there is a wide range of possible presenting manifestations. The typical clinical characteristics of FHL are a prolonged fever that is accompanied by hepatomegaly, elevated liver enzymes, cytopenias, and less commonly, a rash and lymphadenopathy. About half of patients have abnormal cerebrospinal fluid (CSF) findings [4]. Neurological signs have also been described and can include increased or decreased tone, seizures, ataxia, cranial nerve palsies, and signs of raised intracranial pressure. Patients may also exhibit a reduced level of consciousness, neck stiffness, and loss of vision. Another defining feature of the disease is the phagocytosis of several lines of blood cells in the bone marrow by overactive histocytes.

In older individuals, the course of the illness may be acute, or gradual and recurrent, with some episodes resolving spontaneously. It is not uncommon for FHL to be misdiagnosed as an infection, as it can manifest with non-specific symptoms. Moreover, FHL has been reported to sometimes occur together with infections such as those caused by the herpes virus or Leishmania parasites [5].

Easy Bruising
  • A reduction in platelets may cause easy bruising and abnormal bleeding.The brain may also be affected in familial hemophagocytic lymphohistiocytosis.[icdlist.com]
  • A reduction in platelets may cause easy bruising and abnormal bleeding. The brain may also be affected in familial hemophagocytic lymphohistiocytosis .[ghr.nlm.nih.gov]
  • Some of the more common symptoms of HLH include the following: Frequent, high fevers Enlargement of the spleen, liver or lymph nodes Easy bruising or bleeding Feeling very tired Headaches, irritability or other neurological changes Red skin rash or tiny[stjude.org]
Splenomegaly
  • We report the case of a 3-year-old boy who presented with splenomegaly and normocytic anemia 4 months after returning to the US from a region endemic for Leishmania infection.[ncbi.nlm.nih.gov]
  • The clinical findings mainly include high fever, cytopenia, splenomegaly, phagocytosis, and proliferation of histiocytes in lymphoreticular tissue.[ncbi.nlm.nih.gov]
  • Diagnosis is challenging because it mimics severe sepsis by demonstrating hepatomegaly, splenomegaly, persistent fever, central nervous system involvement, and cytopenias.[ncbi.nlm.nih.gov]
  • We describe a 7-year-old male who presented with fever resistant to antibiotic therapy, pancytopenia, splenomegaly, hypertriglyceridemia, and hyperferritinemia. Bone marrow aspirate showed hemophagocytosis.[ncbi.nlm.nih.gov]
  • Some literature suggests that the presence of fever, splenomegaly, and thrombocytopenia is enough to suspect FHL if leukemia has been eliminated as a possible alternative diagnosis.[symptoma.com]
Hepatosplenomegaly
  • Reported here is the case of a 12-year-old boy, from a poor family, with a 6-year history of visual loss and fever for 5 months, and transient hemiparesis with hepatosplenomegaly and pancytopenia.[ncbi.nlm.nih.gov]
  • Examination revealed fever, lymphadenopathy, and hepatosplenomegaly. Ultrasound examination revealed hepatosplenomegaly and free intra-abdominal fluid. HLH was revealed on bone marrow aspiration biopsy.[ncbi.nlm.nih.gov]
  • We describe a 10-year-old boy with a 9-year history of prolonged fever and progressive hepatosplenomegaly who was diagnosed as having hemophagocytic lymphohistiocytosis 2, being homozygote to a previously described mutation in the PRF1 gene, and cured[ncbi.nlm.nih.gov]
  • Familial hemophagocytic lymphohistiocytosis (FHL) is a rapidly fatal illness, usually encountered in infancy, characterized by fever, hepatosplenomegaly, pancytopenia, and central nervous system involvement.[ncbi.nlm.nih.gov]
  • Symptoms include prolonged fever, hepatosplenomegaly and cytopenias. Allogeneic stem cell transplant appears to provide the best overall cure rate in this disease.[ncbi.nlm.nih.gov]
Hepatomegaly
  • Diagnosis is challenging because it mimics severe sepsis by demonstrating hepatomegaly, splenomegaly, persistent fever, central nervous system involvement, and cytopenias.[ncbi.nlm.nih.gov]
  • The typical clinical characteristics of FHL are a prolonged fever that is accompanied by hepatomegaly, elevated liver enzymes, cytopenias, and less commonly, a rash and lymphadenopathy.[symptoma.com]
  • Symptoms and Signs Common early manifestations of hemophagocytic lymphohistiocytosis include fever, hepatomegaly, splenomegaly, rash, lymphadenopathy, and neurologic abnormalities (eg, seizures, retinal hemorrhages, ataxia, altered consciousness or coma[merckmanuals.com]
  • Abdominal examination revealed firm non tender hepatomegaly of 6 cm and massive splenomegaly of 9 cm. Other systems were within normal limits.[mjdrdypu.org]
  • Signs and symptoms include fever, lymphadenopathy, hepatomegaly, splenomegaly, and pancytopenia.[icd10data.com]
Seizure
  • This disorder can affect multiple organ systems, and neurologic manifestations include irritability, seizures, impaired consciousness, meningismus, and cranial nerve palsies.[ncbi.nlm.nih.gov]
  • The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia.[uniprot.org]
  • Neurological signs have also been described and can include increased or decreased tone, seizures, ataxia, cranial nerve palsies, and signs of raised intracranial pressure.[symptoma.com]
  • Children with HLH often develop low blood counts, bleeding and seizures. HLH may be inherited (familial HLH) or it may be caused by infections or the use of immune suppressing drugs (secondary HLH).[bmt.umn.edu]
  • As a result, affected individuals may experience irritability, delayed closure of the bones of the skull in infants, neck stiffness, abnormal muscle tone, impaired muscle coordination, paralysis, blindness, seizures, and coma.[icdlist.com]
Irritability
  • Cerebellar swelling with obstructive hydrocephalus is a rare but life threatening condition, associated with different etiologies, familial hemophagocytic lymphohistiocytosis (HLH) being rarely one of them. 2-year-7-month old boy presented with irritability[ncbi.nlm.nih.gov]
  • FHLH, initially known as familial hemophagocytic reticulosis (FHR), is rare and without proper treatment is invariably rapidly fatal, usually accompanied by fever, anorexia, vomiting, irritability and pallor.[ncbi.nlm.nih.gov]
  • This disorder can affect multiple organ systems, and neurologic manifestations include irritability, seizures, impaired consciousness, meningismus, and cranial nerve palsies.[ncbi.nlm.nih.gov]
  • The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia.[uniprot.org]
  • As a result, affected individuals may experience irritability, delayed closure of the bones of the skull in infants, neck stiffness, abnormal muscle tone, impaired muscle coordination, paralysis, blindness, seizures, and coma.[icdlist.com]
Neck Stiffness
  • Patients may also exhibit a reduced level of consciousness, neck stiffness, and loss of vision. Another defining feature of the disease is the phagocytosis of several lines of blood cells in the bone marrow by overactive histocytes.[symptoma.com]
  • As a result, affected individuals may experience irritability, delayed closure of the bones of the skull in infants, neck stiffness, abnormal muscle tone, impaired muscle coordination, paralysis, blindness, seizures, and coma.[icdlist.com]
  • The symptoms may change in a wide spectrum, ranging from irritability, bulging fontanelle, neck stiffness, headache, convulsions, cranial nerve palsies, ataxia, hemiplegia/tetraplegia, and stupor to coma.[pediatricneurosciences.com]
Downbeat Nystagmus
  • We describe a unique case of hemophagocytic lymphohistiocytosis in which downbeat nystagmus developed due to cerebellar swelling with compression of the cervicomedullary junction.[ncbi.nlm.nih.gov]
Opisthotonus
  • Here we describe a case of familial hemophagocytic lymphohistiocytosis with distinct facial abnormalities including full cheeks, shallow orbits, and high arched palate, opisthotonus with clenched hands and feet; in addition to a family history of a female[ncbi.nlm.nih.gov]

Workup

The diagnosis of familial hemophagocytic lymphohistiocytosis is based on the clinical picture and genetic testing to detect mutations [6]. Family history is important as patients may have siblings with the same disease, or siblings who died of an obscure illness or infection. Furthermore, if there is parental consanguinity, the diagnosis of FHL is even more likely. Clinical criteria as stipulated by the Histocyte Society must be met [7]. According to the criteria, at least five of a given list of possible signs and symptoms should be present, namely prolonged fever lasting over 7 days, cytopenia of multiple blood lineages observed through peripheral smear, low hemoglobin, platelets or neutrophils, raised triglyceride levels, splenomegaly, fibrinogen less than 1.5 g/L, and hemophagocytosis.

Further investigations that can be carried out include:

  • CSF analysis: This may show an increased number of inflammatory cells as well as high protein content.
  • Bone marrow analysis: Rules out leukemia, which is one of the main differential diagnoses.
  • Blood tests: Elevated plasma ferritin and D-dimers support the diagnosis of FHL.
  • Magnetic resonance imaging (MRI): There are certain features on MRI that, if observed, are suggestive of FHL. These include inflammatory lesions in the brain, demyelination, intracranial hemorrhage, generalized atrophy, and brain edema [8].
  • Computed tomography (CT) and ultrasonography: These imaging techniques may detect ascites, pleural effusions, and other changes that can take place in FHL.

The disease typically presents within the first year of life, however, cases of late presentations are being reported more frequently [9]. Some literature suggests that the presence of fever, splenomegaly, and thrombocytopenia is enough to suspect FHL if leukemia has been eliminated as a possible alternative diagnosis [10].

Erythroblast
  • Furthermore, cultured erythroblasts from patients with FHL-5 display defective erythropoiesis characterized by decreased CD235a expression and aberrant cell morphology. Copyright 2015 ISEH - International Society for Experimental Hematology.[ncbi.nlm.nih.gov]
Staphylococcus Aureus
  • Here, we report that FHL-5 neutrophils have a profound defect in granule mobilization, resulting in inadequate bacterial killing, in particular, of gram-negative Escherichia coli, but not of Staphylococcus aureus, which rather depends on intact reduced[ncbi.nlm.nih.gov]
Brain Edema
  • These include inflammatory lesions in the brain, demyelination, intracranial hemorrhage, generalized atrophy, and brain edema.[symptoma.com]

Treatment

  • These results suggest that nonmyelotoxic treatments for FHL may be safe, effective, and worthy of further investigation; they also support the key role of T lymphocytes in the disease.[ncbi.nlm.nih.gov]
  • Improvements in recognition and treatment have been substantial for both diseases in the past decade, although early and late morbidity continue to be major concerns.[ncbi.nlm.nih.gov]
  • Our hypothesis was that the application of MSCs could be effective in the treatment of FHL, since MSCs possess a broad repertoire of immunomodulating mechanisms impacting both innate and adaptive immunity pathways.[ncbi.nlm.nih.gov]
  • Future prospective trials are needed to evaluate this treatment strategy.[ncbi.nlm.nih.gov]
  • Initial treatment consists of immune suppression, whereas definitive treatment requires hematopoietic cell transplantation. Copyright 2015 Elsevier Inc. All rights reserved.[ncbi.nlm.nih.gov]

Prognosis

  • The presence of central nervous system involvement has a profound impact on the prognosis, treatment, and clinical outcome of the disease.[ncbi.nlm.nih.gov]
  • The role of EBV infection in the prognosis of FHL is discussed.[ncbi.nlm.nih.gov]
  • With recent progress in the molecular diagnosis of FHL, prompt and most appropriate therapeutic measures should be introduced to improve the prognosis of FHL patients.[ncbi.nlm.nih.gov]
  • Considering the markedly improved prognosis of FHL due to recent advances made in the molecular diagnosis and in the management including allogeneic hematopoietic stem cell transplantation, auditor by screening might be warranted for surviving FHL patients[ncbi.nlm.nih.gov]
  • The prognosis for patients with familial hemophagocytic lymphohistiocytosis (FHL) is poor, but the survival of affected children has been markedly prolonged by treatment with the epipodophyllotoxin derivatives etoposide and teniposide and by bone marrow[ncbi.nlm.nih.gov]

Etiology

  • The etiologies of hemophagocytic lymphohistiocytosis have been well established through the identification of 3 causative genetic mutations.[ncbi.nlm.nih.gov]
  • Cerebellar swelling with obstructive hydrocephalus is a rare but life threatening condition, associated with different etiologies, familial hemophagocytic lymphohistiocytosis (HLH) being rarely one of them. 2-year-7-month old boy presented with irritability[ncbi.nlm.nih.gov]
  • An infectious etiology was excluded, and brain, liver, and bone marrow biopsies were nonspecific but consistent with hemophagocytic lymphohistiocytosis.[ncbi.nlm.nih.gov]
  • The result of our study indicates that not much evidence is present concerning a correlation between perforin gene defects and familial hemophagocytic lymphohistiocytosis etiology in these cases.[ncbi.nlm.nih.gov]
  • VL in HLH patients does not exclude a genetic etiology and requires structured clinical management.[ncbi.nlm.nih.gov]

Epidemiology

  • Dengue hemophagocytic syndrome: A systematic review and meta‐analysis on epidemiology, clinical signs, outcomes, and risk factors. Reviews in medical virology. 2018 Nov;28(6):e2005. a b Wysocki CA (December 2017).[en.wikipedia.org]
  • Etiology and Epidemiology HLH can be broadly categorized into primary and secondary forms, with respective subtypes. Primary HLH, also known as familial HLH (F-HLH), has autosomal recessive inheritance and incomplete penetrance.[healio.com]
Sex distribution
Age distribution

Pathophysiology

  • Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may[ncbi.nlm.nih.gov]
  • This could reflect survival versus elimination of B-EBV cells (ie, the source of NK-cell stimulation) in patients versus healthy control subjects, thus mimicking the pathophysiologic scenario of FHL.[ncbi.nlm.nih.gov]
  • On the basis of the immunologic pathophysiology of familial hemophagocytic lymphohistiocytosis, we propose a therapy with a combination of antithymocyte globulins with corticosteroids, cyclosporin A, and intrathecal injections of methotrexate.[ncbi.nlm.nih.gov]
  • It brings together the pathophysiology of disease with detailed clinical guidance on diagnosis and management for the full range of childhood cancers, including aspects important in optimal supportive care.[books.google.com]
  • Much of what is known about the pathophysiology of HLH has been discovered in the context of F-HLH.[healio.com]

Prevention

  • The aim of this report was to emphasize the importance of blood products irradiation in the prevention of the development of graft versus host disease especially among high-risk subjects such as newborns with HLH.[ncbi.nlm.nih.gov]
  • HLH include: Fever Cytopenias—low count of one or more of the types of blood cells: Neutropenia: low count of white blood cells that fight infection Anemia : low count of red blood cells that carry oxygen Thrombocytopenia : low count of platelets that prevent[danafarberbostonchildrens.org]
  • There is no way to prevent HLH, but as healthcare providers continue to learn more about it, treatment improves. Most children who are successfully treated go on to live normal lives.[hopkinsmedicine.org]
  • Additionally, your doctor may give medications that help prevent and/or treat any infections.[cincinnatichildrens.org]

References

Article

  1. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794-5798.
  2. Sieni E, Cetica V, Mastrodicasa E, et al. Familial hemophagocytic lymphohistiocytosis: a model for understanding the human machinery of cellular cytotoxicity. Cell Mol Life Sci. 2012;69(1):29–40.
  3. Feldmann J, Le Deist F, Ouachee-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. 2002;117(4):965-972.
  4. Horne A, Trottestam H, Arico M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140(3):327-335.
  5. Imashuku S, Ueda I, Teramura T, et al. Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients. Eur J Pediatr. 2005;164(5):315-319.
  6. Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002;100(6):2266-2267.
  7. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.
  8. Filipovich AH. The expanding spectrum of hemophagocytic lymphohistiocytosis. Curr Opin Allergy Clin Immunol. 2011;11(6):512-516.
  9. Manno EC, Salfa I, Palma P, et al. Familial hemophagocytic lymphohistiocytosis type 3 diagnosed at school age: a case report. J Pediatr Hematol Oncol. 2014;36(2):e128–130.
  10. Sieni E, Cetica V, Santoro A, et al. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3. J Med Genet. 2011;48(5):343-352.

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Last updated: 2019-07-11 19:56