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 testing 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 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].

Genotype-Phenotype Correlations

No significant difference in the clinical manifestations of VODI is observed between individuals with different pathogenic variants.

The one child with an out-of-frame duplication in exon 4 (Individual 1, Table 3) presented at age 11 months (later than average) with disseminated CMV infection, which has not been noted in other children with VODI. In addition, the numbers of memory T and B cells were normal and intracellular cytokine production was normal – findings not observed in other children with VODI.

Penetrance

Penetrance for the combined B- and T-cell immunodeficiency has been 100% in individuals confirmed to have VODI caused by pathogenic variants in SP110. Likewise, hVOD has been described in all probands or their affected sibs.

Approximately 10% of children with VODI, ascertained at a young age because of an affected sib and treated early in the disease course with IVIG, may manifest immunodeficiency only at presentation.

Nomenclature

Hepatic veno-occlusive disease alone was known previously as Jamaican bush tea disease due to a dietary and geographic association. This term is now superseded by hepatic veno-occlusive disease (hVOD) or sinusoidal obstruction syndrome (SOS), terms less limiting given the occurrence of hVOD worldwide and it being secondary to other precipitants. The combination of hVOD and a combined immunodeficiency is termed VODI.

Prevalence

VODI was described originally in Australians of Lebanese origin by Mellis & Bale [1976]. Subsequently, the majority of children reported with VODI have been of Lebanese origin. The prevalence of VODI in the Lebanese population of Sydney, Australia has been calculated at one in 2,500 [Roscioli et al 2006]. Unpublished data from Australia and Lebanon suggest that VODI associated with the SP110 exon 5 pathogenic variant c.642delC is found not infrequently in families of Lebanese background, especially in association with consanguinity. This in turn suggests that the diagnosis has been missed in expatriate Lebanese communities.

The prevalence of VODI in children of non-Lebanese origin is unknown; however, the following reports suggest that the VODI phenotype is observed in other populations. Additional reports of VODI:

• A simplex case of VODI (i.e., a single occurrence in a family) with humoral and cellular immunodeficiency in the Spanish literature
• Two Italian children with VODI [Ruga et al 2006, Cliffe et al 2012]
• A Hispanic child with VODI from the United States [Cliffe et al 2012, Wang et al 2012]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hepatic veno-occlusive disease with immunodeficiency (VODI), the following evaluations are recommended:

• Assessment of immune function including serum immunoglobulin levels, T- and B-cell numbers and percentages, and T-cell proliferative response to mitogens
• More extensive immune testing for number of memory B and T cells and intracellular cytokine (IL2, IL4, IL6, and IFNγ) responses to stimulation, if available
• Complete blood count
• Assessment of hepatic function (including serum concentrations of aminotransferases, bilirubin, and albumin) and assessment for sequelae of portal hypertension (including anemia and thrombocytopenia)
• Consultation with a clinical geneticist and/or genetic counselor

A clotting profile and a hepatic Doppler ultrasound examination should be undertaken prior to consideration of hepatic biopsy for a histologic diagnosis of hepatic veno-occlusive disease (hVOD). Evidence of impaired clotting and/or portal hypertension contraindicates hepatic biopsy.

Treatment of Manifestations

Hypogammaglobulinemia is treated via intravenous immunoglobulin (IVIG), which should commence at the diagnosis of VODI or in presymptomatic sibs confirmed to have homozygous SP110 pathogenic variants. An appropriate dose is 0.4 g/kg every four weeks adjusting the dose to maintain a trough IgG level greater than 6 g/L.

Pneumocystis jirovecii prophylaxis with cotrimoxazole pediatric suspension (5 mL = trimethoprim 40 mg and sulfamethoxazole 200 mg) should be ongoing in children with VODI who tolerate this medication. This may be administered as a single daily dose or as a single dose three days per week. The recommended dose is 5 mg trimethoprim per kg (0.625 mL/kg) or 150 mg/M² (3.75 mL/M²).

Infections with specific agents should be treated with appropriate supportive care and antibacterials or antivirals.

Hepatic transplantation may be considered, but appears to have a high rate of complications in the VODI cohort studied to date (see Other).

Bone marrow transplantation. Ganaiem et al [2013] reported that this may be an efficacious treatment modality with appropriate conditioning therapy (see Other).

Prevention of Primary Manifestations

Initiation of regular IVIG at the time of diagnosis to prevent infection related to severe hypogammaglobulinemia and cotrimoxazole prophylaxis to prevent Pneumocystis jirovecii infection is appropriate (see Treatment of Manifestations).

Prevention of Secondary Complications

Some evidence suggests that treatment of immunodeficiency early in VODI may reduce the risk for development or recurrence of hVOD.

Surveillance

The following are appropriate:

• Regular surveillance of hepatic function, platelet count, and hemoglobin level in children with VODI as hepatic failure and portal hypertension may occur
• Surveillance 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 hVOD (e.g., cyclophosphamide and senecio alkaloids/bush teas) should be avoided.

Evaluation of Relatives at Risk

It is appropriate to evaluate sibs of a proband who are younger than age 12 months in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. The majority of children with VODI present before age six months; however, as one child presented at age 11 months, testing should be considered in sibs of a proband who are younger than age 12 months.

Evaluations include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Serum immunoglobulins, full blood count and liver function tests at birth and repeated at six months if the pathogenic variants in the family are not known.

Penetrance is complete (i.e., 100%) in the individuals with VODI described to date; thus, molecular genetic testing of healthy at-risk sibs of a proband who are older than age 12 months is not recommended.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For an affected pregnant woman, ongoing intravenous immunoglobulin to prevent infection related to severe hypogammaglobulinemia and cotrimoxazole prophylaxis to prevent Pneumocystis jirovecii infection is appropriate during pregnancy. There is evidence that early treatment of a baby known to be homozygous for pathogenic SP110 pathogenic variants may result in improved long-term outcomes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Hepatic VOD (hVOD) has been reported in the Australian cohort with VODI following hematopoietic stem cell transplantation (HSCT); therefore, individuals with VODI are likely to have at least the population risk for hVOD following HSCT. The first successful HSCT was reported by Ganaiem et al [2013] suggesting that this may be an efficacious treatment modality with appropriate conditioning therapy. Ganaiem et al described a consanguineous Arab family with eight affected individuals; five individuals received HSCT, of which three were successful. All five individuals received matched sib or family member bone marrow (4 individuals) or peripheral stem cells (1 individual). All five individuals received conditioning with fludarabine and serotherapy and an alkylating agent (cyclophosphamide, busulfan, or treosulfan). The two individuals who died also received thiotepa, and following engraftment died with hVOD and multiorgan failure. One child has remained well for two years following uncomplicated HSCT in 2014. She was of consanguineous Lebanese background and presented at age four months with probable herpetic hepatitis which initially responded clinically to acyclovir, but then developed florid hVOD following a transfusion. She responded well to IVIG, prophylactic Bactrim™, and defibrotide. She was neurologically normal, but asymptomatic bilateral subdural hematomas were found on routine pre-transplant MRI despite a normal head ultrasound a week prior when coagulation studies and platelets had already normalized. At age six months she underwent an unrelated cord blood transplant with alemtuzumab, fludarabine, treosulfan and antithymocyte globulin conditioning. Defibrotide was prophylactically continued until two months post transplant. She remains neurologically normal and her MRI scan at age two years showed no anatomic abnormality [M Wong, personal communication].

In 2016, an Australian infant of consanguineous Lebanese background presented at age four months with Pneumocystis, CMV infection, and hVOD with hypogammaglobinemia. A homozygous SP110 pathogenic variant (c.642delC) was identified on molecular genetic testing. At age five months, after control of pneumonitis and hVOD, he received a haplo-identical paternal HSCT after depletion of α/β TCR and CD19+ cells. He received conditioning with fludarabine, treosulfan, and antithymocyte globulin. Defibrotide was given as hVOD prophylaxis. Two months post transplant he was well and had engrafted without GVHD or recurrence of hVOD but with moderate CMV hepatitis. Defibrotide was able to be discontinued at day 60. Both the affected individual and donor were CMV positive prior to transplant. Seventy days following HSCT he developed seizures. MRI showed extensive abnormalities throughout the brain and spinal cord, including areas of edema and ring-like enhancing lesions. CT showed widespread calcifications. CMV retinitis was apparent and both CSF and vitreous were CMV PCR positive [T Cole, J Smart, and T Soosay Raj, personal communication].

Inclusion of defibrotide prophylaxis in the transplant regimen may improve survival. Omission of a second alkylating agent in the conditioning regimen may reduce the risk for transplant-related hVOD.

Mode of Inheritance

Hepatic veno-occlusive disease with immunodeficiency (VODI) is inherited in an autosomal recessive manner. Penetrance is complete.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one SP110 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• An at-risk sib older than age 12 months and known to be unaffected has a 2/3 risk of being a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with hepatic veno-occlusive disease with immunodeficiency are obligate heterozygotes (carriers) for a pathogenic variant in SP110.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an SP110 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SP110 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives younger than age 12 months for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the SP110 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for VODI are possible.

Literature Cited

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Revision History

• 12 January 2017 (sw) Comprehensive update posted live
• 3 July 2013 (me) Comprehensive update posted live
• 15 September 2009 (me) Comprehensive update posted live
• 21 February 2007 (me) Review posted live
• 29 November 2006 (mb) Original submission