Hepatic Veno-Occlusive Disease with Immunodeficiency

Clinical characteristics: Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by (1) combined immunodeficiency and (2) terminal hepatic lobular vascular occlusion and hepatic fibrosis manifesting 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 and B 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 or subcutaneous immunoglobulin (IVIG/SCIG) and Pneumocystis jirovecii prophylaxis. However, with early recognition and treatment, including the more recent use of defibrotide, there is a marked improvement in prognosis. Early hematopoietic stem cell transplantation (HSCT) using non-hepatoxic drugs in conditioning and prophylactic defibrotide is potentially curative.

Diagnosis/testing: The diagnosis of VODI is established in a proband who meets clinical diagnostic criteria or by identification of biallelic pathogenic variants in SP110 on molecular genetic testing.

Management: Targeted therapies: IVIG/SCIG; defibrotide for acute hepatic disease; HSCT with non-hepatotoxic conditioning therapy, preferably with defibrotide prophylaxis.

Supportive care: Pneumocystis jirovecii prophylaxis; prompt treatment of infections with antibacterials, antivirals, or antifungals as indicated; standard treatment for complications of liver disease; consider liver transplantation, although rate of complications may be high.

Surveillance: Assess growth every three to six months; measurement of immunoglobulin concentrations every three to six months; bronchoalveolar lavage to diagnose Pneumocystis jirovecii infection; viral and bacterial cultures and PCR as needed; serum aminotransferases, bilirubin, albumin, complete blood count, and platelet count every three to six months; pulmonary function studies annually once able to perform reliably; cerebrospinal imaging to identify leukodystrophy or other central nervous system pathology when clinically indicated.

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

Evaluation of relatives at risk: If both pathogenic variants in the family are known, it is appropriate to evaluate via molecular genetic testing sibs of a proband who are younger than age 12 months in order to identify those who would benefit from initiation of IVIG or SCIG treatment, Pneumocystis jirovecii prophylaxis, and consideration of preemptive HSCT.

Genetic counseling: VODI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SP110 pathogenic variant, each sib of an affected individual has at conception 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. Once the SP110 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for VODI are possible.