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:

• Clinical evidence of primary immunodeficiency
• Hepatomegaly or evidence of hepatic failure in a proband or a first-degree relative
• Onset usually before age six months
• 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 diagnosis for pregnancies at increased risk are possible if both pathogenic variants in a family are known.

Suggestive Findings

Hepatic veno-occlusive disease with immunodeficiency (VODI) should be suspected in individuals with the following.

Clinical diagnostic criteria

• Clinical evidence of immunodeficiency with bacterial and opportunistic infections including Pneumocystis jirovecii infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections
• Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first degree relative (hepatic veno-occlusive disease is usually present and pathognomonic but may not be found, or may have resolved)
• Onset usually before age six months
• Family history consistent with autosomal recessive inheritance

Laboratory features

• Low serum concentrations of IgA, IgM, and IgG
  Note: Immunoglobulin levels are age specific and laboratory specific and thus should be compared against appropriate local reference ranges.
• Normal lymphocyte numbers and CD4 and CD8 percentages
• Normal lymphocyte proliferative responses to mitogens
• Low intracellular cytokine production

Radiographic features

• Hepatic ultrasonography. Features consistent with hepatic veno-occlusive disease (hVOD) may include hepatosplenomegaly, gallbladder wall thickening, increased portal vein diameter, reduced hepatic vein diameter, ascites, and re-canalization of the ligamentum teres.
• Doppler ultrasound examination. Features consistent with hVOD may include reduced portal venous flow, flow in the para-umbilical vein, and increased resistance in the hepatic artery.

Histopathologic features

• hVOD (also known as sinusoidal obstruction syndrome) may include fibrous concentric narrowing of zone 3 terminal hepatic venules, centrilobular hepatocyte necrosis, and sinusoidal congestion (see Figure 1).
• Note: If hepatic biopsy is contraindicated, hepatic ultrasonography and Doppler ultrasonography may provide supportive evidence of hVOD.

Figure 1.

Hepatic biopsy showing vascular obliteration, perivenular fibrosis, zone 3 fibrosis and hepatocyte dropout from a girl who presented at age five months with hepatomegaly and ascites (Picro-Mallory stain 100x)

Establishing the Diagnosis

The diagnosis of VODI is established in a proband with the above clinical diagnostic criteria. Identification of biallelic pathogenic variants in SP110 on molecular genetic testing establishes the diagnosis if clinical features are inconclusive (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

• Single-gene testing. Sequence analysis of SP110 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  Targeted analysis for the c.642delC pathogenic variants can be performed first in individuals of Lebanese ancestry.
  Sequence analysis of SP110 may be performed in a tiered approach beginning with exons 2, 4, 5 and 8 (reference sequence: LRG_109). Sequencing of the entire coding region of 19 exons and an alternatively spliced exon 15 in the Sp110c isoform is performed if neither or only one pathogenic variant is identified in exons 2, 4, 5 and 8.
• A multigene panel that includes SP110 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes SP110) fails to confirm a diagnosis in an individual with features of VODI. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Hepatic veno-occlusive disease with immunodeficiency (VODI) is a primary immunodeficiency associated with terminal hepatic lobular vascular occlusion and hepatic lobule zone 3 fibrosis. All children in the cohort from Sydney, Australia presented prior to age six months, the majority with sequelae of the immunodeficiency either alone or concurrently with features of hepatic veno-occlusive disease (hVOD) (see Table 2).

Immunodeficiency is characterized by 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 [Roscioli et al 2006]. Bacterial and opportunistic infections including Pneumocystis jirovecii infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections occur.

Hepatic veno-occlusive disease (hVOD). Ninety percent of the children with VODI present ab initio either with hepatomegaly (83% with preceding infection) or hepatic failure (53% with preceding infection). Typically, an infant has been unwell for several weeks, has become tachypneic, is failing to thrive, is admitted with interstitial pneumonitis caused by Pneumocystis jirovecii, is found to be jaundiced with ascites, has hypogammaglobulinemia and thrombocytopenia, and has evidence of hVOD.

Neurologic. Overall, 30% of children with VODI had neurologic involvement; none of the individuals were reported to have veno-occlusive disease of the brain. Four individuals (sister of B II.1 and B II.2 [Table 3] and 3 unrelated children) had multiorgan failure associated with extensive cerebral necrosis on postmortem examination. A striking finding is the presence of cerebrospinal leukodystrophy in three individuals (20%) with VODI. Individual 5 had a leukodystrophy of unknown etiology and individual 6 developed this complication after a CMV-related gastroenteritis. In individual A II.1, the initial diagnosis of a cerebrovascular accident with a right-sided cerebral white matter lesion – presumed to be Toxoplasma or a porencephalic cyst – was revised as more consistent with cerebrospinal leukodystrophy. Individual B II.2 remained well on intravenous immunoglobulin (IVIG) and cotrimoxazole prophylaxis until age 18 years when she suddenly developed paraparesis and urinary retention associated with cerebral lesions. No infective cause or evidence of veno-occlusive disease was found on extensive investigation. There was partial response to high-dose IVIG and steroid therapy, suggesting an inflammatory etiology [MW Lin and M Wong, personal communication].

Other features. Infants and children with VODI do not have dysmorphic features. Thrombocytopenia is frequent at presentation but may improve with resolution of the hVOD. One child had the syndrome of inappropriate ADH secretion, presumably as a manifestation of his cerebral leukodystrophy.

Morbidity/mortality. VODI is associated with 100% mortality in the first year of life if unrecognized and untreated with IVIG or subcutaneous immunoglobulin (SCIG) replacement and Pneumocystis jirovecii prophylaxis, and a 90% mortality overall by the mid-teenage years [Roscioli et al 2006]. However, there have been only three deaths among eight recently ascertained affected individuals older than age one year, representing a markedly improved prognosis with early recognition and treatment [Cliffe et al 2012]. Should hVOD recovery occur, recurrence of hVOD appears to be prevented by continuation of IVIG and Pneumocystis jirovecii prophylaxis. However, there may be an ongoing risk for neurologic inflammatory complications (B II.2). One child (Individual A II.1, Table 3) died following recurrence of hVOD after bone marrow transplantation at age six years. Table 2 summarizes the clinical and immunologic features of the 20 individuals from Sydney with the clinical diagnosis of VODI (including the 11 individuals who were able to be investigated by molecular analysis confirming the presence of SP110 pathogenic variants) and eight newly ascertained individuals [Cliffe et al 2012].

Table 3 outlines clinical features in individuals with identified homozygous SP110 pathogenic variants [Roscioli et al 2006, Cliffe et al 2012, Wang et al 2012, Ganaiem et al 2013].