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].

• Poor Feeding

  He presented with fever and poor feeding, lymphocytosis with thrombocytopenia and CSF pleocytosis without virological explanation. [ncbi.nlm.nih.gov]

  However 12 days after discharge she was readmitted with fever and poor feeding. Examination showed pallor and generalized skin mottling, cold peripheries and feeble pulses. Liver was palpable 3cm and spleen 2 cm. [indianpediatrics.net]

• Hypothermia

  A previously healthy neonate, first child of noncosanguineous young healthy parents, presented with hypothermia and fulminant hepatic failure at 28 days of life and succumbed short after. [ncbi.nlm.nih.gov]

• 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]

  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]

• High Arched Palate

  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]

• 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]

• 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]

• 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]

• Suggestibility

  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]

  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]

• 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]

  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]

  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]

  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]

  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]

• 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]

• 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]

• 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]

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].

• Normocytic Anemia

  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]

• 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]

  Bleeding, generalized atrophy, and brain edema may be observed. Hyperdense areas on CT may be falsely interpreted as calcifications. Life expectancy. Median survival in typical FHL, without treatment, is less than two months. [ncbi.nlm.nih.gov]

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.