Clinical Guidance

Hypomorphic pathogenic variants in PRF1, MUNC13-4, and STXBP2 have been associated with mild and late-onset (i.e., adult) fHLH . PRF1. The PRF1 (p.Ala91Var) variant has been reported in individuals with late-onset adult fHLH . Nonsense variants are associated with younger age at onset than missense variants . UNC13D. Biallelic truncating variants are associated with younger age at onset than missense variants .

Source: GeneReviews — "Familial Hemophagocytic Lymphohistiocytosis"

Diagnostic Criteria

The diagnosis of familial hemophagocytic lymphohistiocytosis (fHLH) is based on suggestive clinical and laboratory findings and is established by identification of biallelic pathogenic variants in one of four genes: PRF1, STX11, STXBP2, and UNC13D.

Suggestive Findings

Familial HLH (fHLH) should be suspected in young children with the following clinical findings, supportive laboratory findings, and suggestive family history.

Clinical Findings

Common

• Prolonged fever

• Hepatosplenomegaly

• Skin rash

• Lymphadenopathy

• Neurologic abnormalities including:

• Increased intracranial pressure, irritability, coma

• Neck stiffness

• Hypotonia, hypertonia

• Seizures

• Cranial nerve palsies

• Ataxia

• Hemiplegia/quadriplegia

• Blindness

Less common

Source: GeneReviews — "Familial Hemophagocytic Lymphohistiocytosis"

Differential Diagnosis

Several inherited inborn errors of immunity include the hemophagocytic lymphohistiocytosis (HLH) phenotype (resembling familial HLH) as a predominant feature due to defects in lymphocyte cytotoxicity or regulation of the inflammasome, a multi-protein complex that is essential for activation of inflammatory responses . Hyperinflammation in these conditions is often triggered by infection. Children with the HLH phenotype may require investigation for these errors of immunity, particularly if they have a history of prior, recurrent, chronic, and/or severe infections. Table 4a. Inherited Immune Disorders to Consider in the Differential Diagnosis of Familial Hemophagocytic Lymphohistiocytosis

Management Guidelines

No clinical practice guidelines specifically for familial hemophagocytic lymphohistiocytosis (fHLH) have been published; however, a report by the Steering Committee of the Histiocyte Society provides recommendations on the use of etoposide-containing therapies such as the HLH-94 protocol and hematopoietic stem cell transplantation (HSCT) for individuals with HLH, including those with fHLH . Evaluations Following Initial Diagnosis To establish the extent of disease and treatment needs in an individual diagnosed with fHLH, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Familial Hemophagocytic Lymphohistiocytosis: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Familial Hemophagocytic Lymphohistiocytosis"

Clinical Guidance

The following should be avoided:

• Live vaccines

• Exposure to infections

• Acetaminophen in individuals with liver failure

• Nonsteroidal anti-inflammatory drugs in individuals with thrombocytopenia

• Areas of construction or soil manipulation, which increase the risk for fungal infection for individuals with neutropenia

• Transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT, per institutional guidelines

Source: GeneReviews — "Familial Hemophagocytic Lymphohistiocytosis"

Therapies Under Investigation

Emapalumab (NI-0501), an anti-interferon-gamma antibody, was approved by the FDA in 2018 for children and adults with fHLH who have refractory, recurrent, or progressive disease or intolerance of conventional HLH therapy . The drug is under investigation for individuals with newly diagnosed fHLH as well as individuals with nonfamilial HLH. Ruxolitinib, a janus kinase (JAK) 1 and 2 inhibitor, was shown to sensitize immune cells to glucocorticoid-induced apoptosis in vitro and dampen hyperinflammation in a mouse fHLH model .

Source: GeneReviews — "Familial Hemophagocytic Lymphohistiocytosis"

Surveillance Guidelines

Individuals responding to treatment and HSCT are technically not at risk for other organ system involvement. Surveillance focuses on potential complications of HSCT. Surveillance for changes in neurologic manifestations, respiratory function, GI tract manifestations, renal function, and other systems is per standard of care by primary care health care providers or specialty clinicians.

Source: GeneReviews — "Familial Hemophagocytic Lymphohistiocytosis"