(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]

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