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].

• Anemia

  This case report highlights the difficulty in managing posttransplant autoimmune hemolytic anemia. [ncbi.nlm.nih.gov]

• Infectious Mononucleosis

  Here we report the case of a 17-month-old girl with prolonged symptomatic EBV infectious mononucleosis and clinical symptoms of hemophagocytic syndrome. In vitro functional analysis pointed to a degranulation defect. [ncbi.nlm.nih.gov]

  Serological test for infectious mononucleosis, viral hepatitis, dengue, Brucella More Details, enteric fever, leptospira, syphilis, and human immunodeficiency virus were negative. [mjdrdypu.org]

  The medical history of patient 525 revealed tonsillectomy at the age of 5 years and two other similar 'infectious mononucleosis like' bouts at the age of 7 and 22 years, which resolved spontaneously. [journals.plos.org]

  A Japanese study performed genetic analysis of the SH2D1A gene in 40 male patients presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and chronic EBV infection, finding mutations in a [dovepress.com]

• 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]

  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]

• 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]

  The features of this condition may include: [1] [2] [3] [4] Fever Enlarged liver and/or spleen Skin rash Lymph node enlargement Breathing problems Easy bruising and/or abnormal bleeding Kidney abnormalities Heart problems Increased risk for certain cancers [rarediseases.info.nih.gov]

• Pleural Effusion

  Benign-looking lymphohistiocytic infiltrates with varying degrees of hemophagocytosis were present in the bone marrow, pleural effusion, cerebrospinal fluid (CSF), liver, and brain. [ncbi.nlm.nih.gov]

  Computed tomography (CT) and ultrasonography: These imaging techniques may detect ascites, pleural effusions, and other changes that can take place in FHL. [symptoma.com]

  However, a month later he was readmitted with a similar picture, ascites and pleural effusion. HLH was suspected and confirmed by the functional and genetic study. [journals.plos.org]

  Patient B:1 proved to be thrombocytopenic, along with a prolonged coagulation profile, bloody pleural effusions, and petechiae. Patient B:2 was similarly thrombocytopenic, had a prolonged coagulation profile, and developed petechiae. [bloodjournal.org]

• 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]

• 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]

• Petechiae

  Patient B:1 proved to be thrombocytopenic, along with a prolonged coagulation profile, bloody pleural effusions, and petechiae. Patient B:2 was similarly thrombocytopenic, had a prolonged coagulation profile, and developed petechiae. [bloodjournal.org]

• Eczema

  Abe J, Izawa K, Nishikomori R, Awaya T, Kawai T, Yasumi T, Hiragi N, Hiragi T, Ohshima Y, Heike T Rheumatology (Oxford, England) 52(2) 406-408 Feb 2013 [Refereed] Effect of eczema on the association between season of birth and food allergy in Japanese [researchmap.jp]

• 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

  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]

  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]

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].

• Ferritin Increased

  […] pressure Rise in pressure inside skull 0002516 Increased LDL cholesterol concentration Increased circulating LDL level Increased LDL cholesterol [ more ] 0003141 Increased serum ferritin Elevated serum ferritin High ferritin level Increased ferritin [rarediseases.info.nih.gov]

• Pleural Effusion

  Benign-looking lymphohistiocytic infiltrates with varying degrees of hemophagocytosis were present in the bone marrow, pleural effusion, cerebrospinal fluid (CSF), liver, and brain. [ncbi.nlm.nih.gov]

  Computed tomography (CT) and ultrasonography: These imaging techniques may detect ascites, pleural effusions, and other changes that can take place in FHL. [symptoma.com]

  However, a month later he was readmitted with a similar picture, ascites and pleural effusion. HLH was suspected and confirmed by the functional and genetic study. [journals.plos.org]

  Patient B:1 proved to be thrombocytopenic, along with a prolonged coagulation profile, bloody pleural effusions, and petechiae. Patient B:2 was similarly thrombocytopenic, had a prolonged coagulation profile, and developed petechiae. [bloodjournal.org]

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]

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]

The etiologies of hemophagocytic lymphohistiocytosis have been well established through the identification of 3 causative genetic mutations. [ncbi.nlm.nih.gov]

Dengue hemophagocytic syndrome: A systematic review and meta‐analysis on epidemiology, clinical signs, outcomes, and risk factors. [en.wikipedia.org]

Epidemiology Frequency International Incidence is reported to be 1.2 cases per million persons per year. [emedicine.medscape.com]

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]

[…] where the incidence of FHL is estimated at 1 in 50,000 live births. 14, 30 Overall, an estimate of HLH in children 31 Other large series have been described in Hong Kong and Taiwan; however, worldwide, the incidence of FHL is unknown, and even less epidemiologic [dovepress.com]

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]

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]

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]

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.