DiagnosisClinical DiagnosisThe clinical diagnostic criteria for hepatic veno-occlusive disease with immunodeficiency (VODI) syndrome include the following: Clinical evidence of immunodeficiency with bacterial and opportunistic infections including Pneumocystis jerovici 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 Onset before age 12 months Family history consistent with autosomal recessive inheritance TestingAdditional investigations that support the diagnosis of VODI include the following (in suggested order): Immunologic investigationsLow serum concentrations of IgA, IgM, and IgG
Note: Immunoglobulin levels are age-specific and laboratory-specific and so should be compared against appropriate local reference ranges.Normal lymphocyte numbers and CD4 and CD8 percentages Low intracellular cytokine productionSP110 molecular testing Hepatic investigationsHepatic 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. Histologic features of hepatic veno-occlusive disease (hVOD), also known as sinusoidal obstruction syndrome, including fibrous concentric narrowing of zone 3 terminal hepatic venules, centrilobular hepatocyte necrosis, and sinusoidal congestion (see Figure 1) * FigureFigure 1. Hepatic biopsy showing vascular obliteration, peri-venular fibrosis, zone 3 fibrosis and hepatocyte dropout from a girl who presented at age five months with hepatomegaly and ascites (Picro-Mallory stain 100x) * If hepatic biopsy is contraindicated, hepatic ultrasonography and Doppler ultrasonography may provide supportive evidence of hVOD. Molecular Genetic TestingGene. SP110 is the only gene known to be associated with VODI. Clinical testing Sequence analysis Sequence analysis of exons 2, 4, and 5 detected both mutations in 100% of the eight individuals with VODI evaluated to date [Roscioli et al 2006, Ruga et al 2006].Sequencing of the entire coding region of 19 exons and an alternatively spliced exon 15 in the Sp110c isoform is performed if no mutations are identified in exons 2, 4, and 5. Table 1. Summary of Molecular Genetic Testing Used in Hepatic Veno-Occlusive Disease with ImmunodeficiencyView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilitySP110Sequence analysisSequence variants 212/12 (100%) 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Mutations identified to date: c.40delC (exon 2, 1 patient), c.78_79CA>AT (exon 2, 1 patient), c.319_325dupGGTGCTT (exon 4, 1 patient), c.642delC (exon 5, 8 patients), and c.667dupG (exon 5, 1 patient)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyEstablishing the diagnosis in a proband requires the detection of mutations in SP110. which should be undertaken concurrently with immune investigations if the clinical presentation is consistent with the diagnosis. Suggested order for investigations:1.Measure serum immunoglobulin concentrations and CD4/CD8 percentages.2.If serum concentration of immunoglobulins is low for age, hepatic imaging should be performed to detect evidence of hVOD.3.Perform SP110 molecular genetic testing. Note: If not contraindicated, hepatic biopsy should be considered to prove the basis of hepatic pathology.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder, i.e., there is no phenotype in heterozygotes.Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo allelic Mendelian disorders for SP110 or contiguous gene disorders including the SP110 region associated with hVOD or immunodeficiency have been described. Tosh et al [2006] reported transmission disequilibrium for alleles of SP110 in Mycobacterium tuberculosis infection in individuals of West African heritage. However, a replication study in a population derived from the same region did not identify an association between SP110 alleles and Mycobacterium tuberculosis infection [Thye et al 2006]. A well-designed and well-executed study by Szeszko et al [2007] failed to detect a significant association between alleles of SP110 and Mycobacterium tuberculosis infection in a population of European Russians. It is notable that the three studies cited compare Mantoux-positive and Mantoux-negative individuals rather than disease progression in individuals known to be exposed to Mycobacterium tuberculosis.}

Natural HistoryHepatic veno-occlusive disease (hVOD) with immunodeficiency (VODI) is a primary immunodeficiency associated with terminal hepatic lobular vascular occlusion and hepatic lobule zone 3 fibrosis.The 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]. The number of children known to have VODI secondary to SP110 mutations is small (Table 2 and Table 3) [Roscioli et al 2006, Ruga et al 2006]. 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 hVOD (see Table 2). Ninety percent of the children with VODI present ab initio either with hepatomegaly (83% with preceding infection) or hepatic failure (53% with preceding infection). Table 2 summarizes the clinical and immunologic features of 20 individuals with the clinical diagnosis of VODI (including the 11 individuals who were able to be investigated by molecular analysis confirming the presence of SP110 mutations).Table 2. Clinical and Immunologic Features of Hepatic Veno-Occlusive Disease with Immunodeficiency (VODI)View in own windowPhenotypePatients I, F, H with Novel Mutations ^{1Clinical FeaturesPatients from Sydney with VODICommentsPresenting <6 months20/20 2/3 Hepatic failure at initial presentation4/20 1/12 post HSCT
3/12 no obvious precipitant0/3Hepatomegaly at initial presentation9/20 3/6 P. jerovici2/6 hepatomegaly without SOS2/3
1/3 enterovirus and disseminated CMV (F) P. jerovici infection12/20 7/12 proven
5/12 suspected1/3 suspected (F)
1/3 proven (I)Mucocutaneous candidiasis2/20 1/3Other features1/20 By age 19 years1/3 lung fibrosis (H)Death19/20 0/3 Recovery from initial SOS4/201 completely well
1 chronic liver disease requiring hepatic transplantation
1 SOS post HSCT
1 developmental disability, chronic aspiration3/3 Neurologic abnormalities6/204/7 cerebral infarction
1/7 Toxoplasma?
1/7 porencephalic cyst0/3Panhypogammaglobulinemia19/191/18 loss of normal immunoglobulins at age 4 mos3/3
1/3 low normal levels of IgA and IgM after commencing IVIgNormal number of lymphocytes10/113/3 Normal NK cells12/123/3 Decreased intracytoplasmic IFNγ, IL2, IL4, IL104/5Low levels at 4 hours, normal/increased levels at 48 hours1/1 (F)Decreased number of memory T and B cells3/42/3 (I,H)Table modified from Roscioli et al [2006]HSCT= hematopoietic stem cell transplantationCMV= cytomegalovirusSOS= sinusoidal obstruction syndrome 1. See Table 3. VODI is associated with 100% mortality in the first year if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jerovici prophylaxis and a 90% mortality overall by the mid-teenage years [Roscioli et al 2006]. Should hVOD recovery occur, recurrence of hVOD appears to be prevented by continuation of intravenous immunoglobulin and Pneumocystis prophylaxis. One child (Patient AII.1, Table 3) died following recurrence of hVOD after bone marrow transplantation at age six years. Overall, 30% of children with VODI had neurologic involvement. In no case was veno-occlusive disease of the brain reported. One affected child (Patient BII.1, Table 3) had intellectual disability associated with a porencephalic cyst of uncertain origin; a second child in the same sibship and three others had multi-organ failure associated with extensive cerebral necrosis on post-mortem examination. Patient AII.1 (Table 3) experienced a cerebrovascular accident associated with a right-sided cerebral white matter lesion, presumed to be Toxoplasma gondii infection. Table 3 outlines clinical features in individuals with a known SP110 mutation [Roscioli et al 2006].Table 3. Clinical Features of Individuals Homozygous for SP110 MutationsView in own windowPatientSP110 MutationPresentationSerum IgsMemory T/B CellsT-Cell CytokinesClinical FindingsDeceased?AII.1 1 c.642delCAge 5 mos: immunodeficiency, thrombocytopenia, hVOD↓——Left hemiparesis 2 , recurrent hVOD with GVHD post HSCTYesBII.1 1 Age 7 mos: immunodeficiency↓——Chronic lung disease secondary to recurrent aspirationYes (age 19 yrs)BII.2 1 Age 6 mos: hepatosplenomegaly, ascites, hVOD↓↓↓WellCII.1 1 Age 4 mos: hepatosplenomegaly, ascites, hVOD, thrombocytopenia, mucocutaneous candidiasis↓↓↓Chronic liver disease, portal hypertension post hepatic transplantationYesDII.1 1 Age 3 mos: hepatosplenomegaly, ascites, hVOD↓ initially 3 ↓↓Hemophagocytic syndrome post hepatic transplantationYesGAge 3 mos: hepatosplenomegaly, ascites, hVOD↓↓↓Pulmonary hemorrhage, multi-organ failureYesJAge 3 mos: respiratory distress↓↓N/ASIADH, idiopathic cerebrospinal leukodystrophyNoEI.1 1 c.40delCAge 3 mos: immunodeficiency, thrombocytopenia, hepatosplenomegaly without definite evidence of hVOD↓N/AN/AEnteroviral and Pneumocystis jerovici infectionYesIc.78_79delinsAT (p.Ile27Leu)Age 3 mos: hepatosplenomegaly, hVOD, fever, respiratory distress↓↓↓Stable and wellNoFc.319_325dup GGTGCTTAge 11 mos: hepatosplenomegaly disseminated CMV infection, rotavirus gastroenteritis, vulvar abscesses, hVOD↓ initially↓N/ARecovering from hVOD, well NoHc.667+1dupAge 3 mos: hepatosplenomegaly, failure to thrive, respiratory distress/lung fibrosis, diarrhea↓↓N/AHepatic biopsy consistent with sinusoidal dilatation, moderate central vein and perivenular subsinusoidal fibrosis; stable with improvementNoModified from Roscioli et al [2006] GVHD = graft vs host disease HSCT = hematopoietic stem cell transplantation Families A, B, and C are not known to be related but are believed to have a common ancestor.1. Reported in Roscioli et al [2006]; individuals AII.1, BII.1, BII.2, and CII.1 were included in the initial homozygosity mapping analysis.2. Secondary to cerebral white matter abnormality (presumed cerebral toxoplasmosis)3. IgA and IgM serum concentrations increased to lower limit of normal while on IVIG.Pathophysiology. It is currently unknown whether the hVOD is a direct manifestation of SP110 sequence variants, related to altered apoptosis in the hepatic sinusoid, or secondary to infection; however, hVOD appears to develop after infections occur.}

Genotype-Phenotype CorrelationsNo significant difference in the clinical manifestations of VODI is observed between individuals with SP110 exon 2 and exon 5 mutations.The one child with an exon 4 duplication (Patient F, 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.

Differential DiagnosisAlthough sinusoidal obstruction syndrome in association with severe combined immunodeficiency (SCID) was described in one case reported by Washington et al [1993], and in one post-mortem HIV cohort reported by Buckley & Hutchins [1995], the lack of a recognized and replicated association of immunodeficiency with hepatic veno-occlusive disease (hVOD) in other classes of immunodeficiency suggests that hVOD may be a primary feature of VODI rather than secondary to an immunodeficiency per se. No other associations of hVOD with immunodeficiency have been reported. The primary differential diagnosis for hVOD alone would be environmental alkaloid or sinusoidal cell toxicity. However, hVOD has also been reported in association with alcoholic cirrhosis [Kishi et al 1999], ataxia-telangiectasia [Srisirirojanakorn et al 1999], osteopetrosis [Corbacioglu et al 2006] (see CLCN7-related osteopetrosis), and hypereosinophilic syndrome. HIV should also be considered as a differential diagnosis for the immune phenotype.Previous case-control studies using single-nucleotide polymorphisms (SNPs) have also reported associations between hVOD and SNPs in the carbamyl phosphate synthetase 1 (CPS1) (see Urea Cycle Disorders Overview), factor V Leiden (FVL), HFE (see HFE-Associated Hereditary Hemochromatosis), and glutathione S-transferase (GSTM1 and GSTT1) genes. Relative risks of 8.6 for the homozygous HFE Cys282Tyr allele and 4.12 for the GSTM1 null allele have been reported [Srivastava et al 2004, Kallianpur 2005, Kallianpur et al 2005]. No independent replication of these findings has been performed. There has been no report of SP110 mutations in individuals described as having hVOD alone.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease 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 (CBC) Assessment of hepatic function (including serum concentrations of aminotransferases, bilirubin, and albumin) and assessment for sequelae of portal hypertension (including anemia and thrombocytopenia) 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 are contraindications to hepatic biopsy. Treatment of ManifestationsHypogammaglobulinemia is treated via intravenous immunoglobulin, which should commence at the diagnosis of hepatic veno-occlusive disease with immunodeficiency (VODI) or in presymptomatic siblings confirmed to have homozygous SP110 mutations. An appropriate dose is 0.4g/kg every four weeks adjusting the dose to maintain a trough IgG level greater than 6 g/L.Pneumocystis jerovici 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.HSCT and hepatic transplantation may be considered, but appear to have a high rate of complications in the VODI cohort studied to date (see Other).Prevention of Primary ManifestationsInitiation of regular intravenous immunoglobulin at the time of diagnosis to prevent infection related to severe hypogammaglobulinemia and cotrimoxazole prophylaxis to prevent Pneumocystis jerovici infection is appropriate (see Treatment of Manifestations). Prevention of Secondary ComplicationsSome evidence suggests that treatment of immunodeficiency early in VODI may reduce the risk of development or recurrence of hVOD. SurveillanceRegular surveillance of hepatic function, platelet count, and hemoglobin level in children with VODI as hepatic failure and portal hypertension may occur Measurement of immunoglobulin concentrations prior to IVIG infusions Broncho-alveolar lavage to diagnose Pneumocystis jerovici infection; viral cultures or lung function studies as needed Agents/Circumstances to AvoidAgents known to predispose to hVOD such as cyclophosphamide and senecio alkaloids/bush teas should be avoided. Bone marrow transplantation is not recommended.Evaluation of Relatives at RiskThe majority of children with VODI present before age six months; however, as one child presented at age 11 months, molecular genetic testing should be considered in sibs of a proband who are younger than age 12 months. 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.Therapies Under InvestigationSearch ClinicalTrials.gov 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.OtherHepatic VOD has been reported in the Australian cohort with VODI following HSCT; therefore, individuals with VODI are likely to have at least the population risk of hVOD after HSCT. Other transplant modalities may also involve an increased risk of other complications. Another child with VODI developed hemophagocytic syndrome after hepatic transplantation. The safety of these two transplant modalities in children with VODI compared to HSCT in other settings is not yet known.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hepatic Veno-Occlusive Disease with Immunodeficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSP1102q37​.1Sp110 nuclear body proteinResource of Asian Primary Immunodeficiency Diseases (RAPID)
SP110 homepage - Mendelian genesSP110Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hepatic Veno-Occlusive Disease with Immunodeficiency (View All in OMIM) View in own window 235550HEPATIC VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY; VODI 604457NUCLEAR BODY PROTEIN SP110; SP110Normal allelic variants. SP110 is expressed primarily in leukocytes and spleen; it is induced by interferon gamma and all-trans retinoic acid (ATRA). The Sp110 nuclear body protein has three described major isoforms: Sp110 isoform A, NM_004509 (average mass 78.438 kd; transcript does not include exon 17)Isoform B, NM_004510 (average mass 61.940 kd; transcript includes an alternate exon 15 and terminates within exon 15)Isoform C, NM_080424 (average mass 81.211 kd; full-length transcript including exon 17 and terminating at exon 19)The Sp110b protein isoform has been described as showing activity as a potent transcriptional co-repressor of retinoic acid receptor alpha (RARα) perhaps via competitive exclusion of activators at receptor [Watashi et al 2003].Pathologic allelic variants (see Table 4). SP110 mutations associated with VODI have been described in the following: Exon 2: NM_080424.2:c.40delC (p.Gln14Serfs*25)Exon 2: NM_080424.2:c.78_79delinsAT (p.Ile27Leu) (a)Exon 4: NM_080424.2:c.319_325dup (p.Ser109trpfs*5) (b)Exon 5: NM_080424.2:c.642del (p.Ser215Alafs*14)Exon 5: NM_080424.2:c.667+1dup(c) The majority of these pathogenic mutations cause a frameshift with consequent protein truncation. The one exception to date is the c.78_79CA>AT mutation. This dinucleotide substitution mutation includes the silent third base of codon 26 (GCC>GCA, both of which encode alanine) and the adjacent first base of codon 27 (ATA>TTA). The predicted isoleucine to leucine substitution is a relatively conservative change and is ordinarily well tolerated by proteins; however, in this instance, the mutation is located within the highly conserved Sp100 domain of the SP110 protein which mediates dimerization of SP110 with other gene family members. A multispecies alignment of the protein sequence in this region shows that isoleucine27 is almost absolutely conserved, suggesting that this residue has a significant functional role in protein:protein interactions and may mediate the Sp140 related recruitment of Sp110 into the nuclear body.Table 4. VODI-Causing Mutations in SP110View in own windowMutationExonReferencec.40delC
(p.Q14Sfs*25)2Roscioli et al 2006]c.78_79delinsAT (p.Ile27Leu)2Cliffe et al [unpublished data]c.319_325dupGGTGCTT
(p.S109Wfs*5)4Ruga et al [2006] c.642delC
(p.P214Pfs*14)5Roscioli et al [2006] c.667+1dup5Cliffe et al [unpublished data]Normal gene product. The Sp110 nuclear body protein is a member of the Sp100/Sp140 promyelocytic leukemia nuclear body (PML NB) protein family. The protein has an Sp100 domain (AA 6-159), which is involved in dimerization with other Sp100 family proteins, a nuclear localization signal (AA 288-306) and a nuclear hormone interaction domain (LXXLL type), which may act as an ATRA response element. Other domains that are common features of modular proteins involved in chromatin-mediated gene transcription include a SAND domain (AA 452-532), a plant homeobox domain (AA 537-577), and a bromodomain (AA 606-674) [Bloch et al 2000]. The Sp110 nuclear body protein is associated with the PML NB, a nuclear macromolecular complex, which is deployed to areas of active host or viral DNA replication, transcription, and repair and has been reported to be involved in apoptosis, cell cycle control, and the immune response.Abnormal gene product. EBV-transformed B cells from an individual with VODI and a homozygous inactivating SP110 mutation have shown an absence of nuclear Sp100-specific immunolabeling in a setting of normal numbers of PML nuclear bodies. This finding is consistent with Sp110 protein having an important role in the immune response without being essential for PML nuclear body formation [Roscioli et al 2006].