(Primary) Familial Hemophagocytic Lymphohistiocytosis– aka Familial Erythrophagocytic Lymphohistiocytosis

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Acronym:
1° HLH/ FHL

SAID group:
Macrophage Activation Diseases

Gene:
PRF1, STX11, STXBP2, MUNC13-4 , RAB27A, UNC13D; X linked: SH2D1A,

Inheritance:
Autosomal recessive, but if X-linked: inheritance is dominant.

Ethnicity:
Affects all races. 80% of African Americans and 20% of patients with European decent have PRF1 mutations. [47] [48]

Frequency:
1° HLH affects 1:50,000 people worldwide. [48]

Timing of symptoms:
Fevers often > 39°C 1-2 times/day for >2 weeks, most often occurring in the evening with arthralgia, rash and other symptoms.

Age of onset:
Onset <1yr: often by 6 months to early childhood. Some in utero or late childhood cases. A few adult-onset cases. [47] [48] [49]

Skin cutaneous:
40% with transient maculopapular, nodular or purpuric skin rashes during bouts of high fever. Jaundice. [47] [48]

Neurologic:
High fevers. Increased CSF protein. High intracranial pressure (ICP). Multifocal inflammation of the gray and white matter, intracranial bleeding, generalized atrophy or brain edema, seizures and/or coma. [47]

Auditory:
Not noted. [47] [48] [49]

Ophthalamic:
Blindness due to brain inflammation. [48]

Cardiopulmonary:
High risk for respiratory infections triggering fevers, edema, systemic inflammation and macrophage activation syndrome (MAS). [49]

Abdominal:
Hepatomegaly, splenomegaly, or hepatosplenomegaly. Liver disease (hepatitis) is common. High risk of death from multi-organ failure in 2+ months if untreated. [49]

Lymphatic:
Lymphoma. Hemophagocytosis– spleen and lymph nodes. Splenomegaly. [49]

Joints bones muscles cartilage:
Hemophagocytosis in the bone marrow. Delayed closure of the bones of the skull in infants, with a bulging fontanel often noted. Neck stiffness, abnormal muscle tone, impaired muscle coordination, paralysis. [48] [49]

Vasculitis:
Not noted. [47] [48] [49]

Amyloidosis:
Not noted. [47] [48] [49]

Abnormal labs:
High: ESR, CRP, triglycerides, liver Function tests (LFTs), especially ALT, soluble CD25, ferritin, sIL2r. Low: platelets, fibrinogen. Low NK cell cytotoxic function, neutropenia, anemia. [49]

Search Keywords:
ferritin, sIL2r, Familial Hemophagocytic Lymphohistiocytosis, Familial Erythrophagocytic Lymphohistiocytosis, Macrophage Activation Diseases, macrophage activation syndrome, MAS, PRF1, STX11, STXBP2, MUNC13-4 , RAB27A, UNC13D, SH2D1A, evening fever, recurrent fever, daily fever, fever rash MAS, fever rash hemophagocytosis, jaundice, maculopapular, nodular, purpuric, maculopapular rash, cerebellar atrophy, brain edema, seizures, coma, triggered, respiratory infections, hepatomegaly, splenomegaly, hepatosplenomegaly. hepatitis, multi-organ failure, organ failure, lymphoma, hemophagocytosis, bulging fontanel, intracranial pressure, ICP, paralysis, muscle coordination, triglycerides, liver function tests, LFTs, anemia, muscle tone, muscle weakness, pulmonary, respiratory, pneumonia, respiratory distress, blindness, histiocytosis


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Photo credit:

Autoinflammatory Alliance image collection. Voluntarily offered by patients. Image use restricted, Contact karen@autoinflammatory.org

Resources:

Leading center in the US for HLH is Cincinnati Children's.

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