Hepatic Veno-Occlusive Disease with Immunodeficiency

Excerpt

Clinical characteristics: Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by: (1) primary immunodeficiency; and (2) terminal hepatic lobular vascular occlusion and hepatic fibrosis manifest as hepatomegaly and/or hepatic failure. Onset is usually before age six months. The immunodeficiency comprises severe hypogammaglobulinemia, clinical evidence of T-cell immunodeficiency with normal numbers of circulating T cells, absent lymph node germinal centers, and absent tissue plasma cells. Bacterial and opportunistic infections including Pneumocystis jirovecii infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections occur. In the past the prognosis for affected individuals was poor, with 100% mortality in the first year of life if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jirovecii prophylaxis. However, with early recognition and treatment there is a marked improvement in prognosis.

Diagnosis/testing: The diagnosis of VODI is established in a proband with the following clinical diagnostic criteria:

1. Clinical evidence of primary immunodeficiency

2. Hepatomegaly or evidence of hepatic failure in a proband or a first-degree relative

3. Onset usually before age six months

4. Family history consistent with autosomal recessive inheritance

Identification of biallelic pathogenic variants in SP110 on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management: Treatment of manifestations: IVIG and Pneumocystis jirovecii prophylaxis as soon as the diagnosis of VODI is established; appropriate, prompt treatment of infections; consider hepatic transplantation, although rate of complications may be high; bone marrow transplantation may be efficacious with appropriate conditioning therapy.

Prevention of primary manifestations: IVIG and Pneumocystis jirovecii prophylaxis.

Surveillance: Regular monitoring of hepatic function, platelet count, and hemoglobin level; routine monitoring of serum and urine electrolytes as the syndrome of inappropriate anti-diuretic hormone (SIADH) may occur; measurement of immunoglobulin concentrations prior to IVIG infusions; broncho-alveolar lavage to diagnose Pneumocystis jirovecii infection; viral cultures or lung function studies as needed; cerebrospinal imaging to diagnose leukodystrophy when clinically indicated.

Agents/circumstances to avoid: Agents known to predispose to hepatic veno-occlusive disease (hVOD) including cyclophosphamide and senecio alkaloids/bush teas.

Evaluation of relatives at risk: If both pathogenic variants in the family are known, molecular genetic testing of sibs of a proband who are younger than age 12 months to allow for early diagnosis and treatment.

Genetic counseling: VODI is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (carriers) and therefore carry one pathogenic variant. Heterozygotes are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants in a family are known.