Hepatic veno-occlusive disease with immunodeficiency
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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 before age 12 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 jerovici infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections occur. VODI is associated with 90% mortality overall and 100% mortality if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jerovici prophylaxis.
The 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
Additional investigations that support the diagnosis of VODI include the following (in suggested order):
- Immunologic investigations
- Low 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 production
- SP110 molecular testing
- Hepatic investigations
- 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.
- 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) *
Figure 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.
Gene. 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 Immunodeficiency
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method 1 | Test Availability |
| SP110 | Sequence analysis | Sequence variants 2 | 12/12 (100%) 3 | Clinical Image testing.jpg |
- Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.
- 1. The ability of the test method used to detect a mutation that is present in the indicated gene
- 2. 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.
Establishing 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.
Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).
No 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.
Hepatic 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)
| Phenotype | Patients I, F, H with Novel Mutations 1 | ||
| Clinical Features | Patients from Sydney with VODI | Comments | |
| Presenting <6 months | 20/20 | 2/3 | |
| Hepatic failure at initial presentation | 4/20 | 1/12 post HSCT 3/12 no obvious precipitant |
0/3 |
| Hepatomegaly at initial presentation | 9/20 | 3/6 P. jerovici 2/6 hepatomegaly without SOS |
2/3 1/3 enterovirus and disseminated CMV (F) |
| P. jerovici infection | 12/20 | 7/12 proven 5/12 suspected |
1/3 suspected (F) 1/3 proven (I) |
| Mucocutaneous candidiasis | 2/20 | 1/3 | |
| Other features | 1/20 | By age 19 years | 1/3 lung fibrosis (H) |
| Death | 19/20 | 0/3 | |
| Recovery from initial SOS | 4/20 | 1 completely well 1 chronic liver disease requiring hepatic transplantation 1 SOS post HSCT 1 developmental disability, chronic aspiration |
3/3 |
| Neurologic abnormalities | 6/20 | 4/7 cerebral infarction 1/7 Toxoplasma? 1/7 porencephalic cyst |
0/3 |
| Panhypogammaglobulinemia | 19/19 | 1/18 loss of normal immunoglobulins at age 4 mos | 3/3 1/3 low normal levels of IgA and IgM after commencing IVIg |
| Normal number of lymphocytes | 10/11 | 3/3 | |
| Normal NK cells | 12/12 | 3/3 | |
| Decreased intracytoplasmic IFNγ, IL2, IL4, IL10 | 4/5 | Low levels at 4 hours, normal/increased levels at 48 hours | 1/1 (F) |
| Decreased number of memory T and B cells | 3/4 | 2/3 (I,H) |
- Table modified from Roscioli et al [2006]
- HSCT= hematopoietic stem cell transplantation
- CMV= cytomegalovirus
- SOS= 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 Mutations
| Patient | SP110 Mutation | Presentation | Serum Igs | Memory T/B Cells | T-Cell Cytokines | Clinical Findings | Deceased? |
| AII.1 1 | c.642delC | Age 5 mos: immunodeficiency, thrombocytopenia, hVOD | ↓ | — | — | Left hemiparesis 2 , recurrent hVOD with GVHD post HSCT | Yes |
| BII.1 1 | Age 7 mos: immunodeficiency | ↓ | — | — | Chronic lung disease secondary to recurrent aspiration | Yes (age 19 yrs) | |
| BII.2 1 | Age 6 mos: hepatosplenomegaly, ascites, hVOD | ↓ | ↓ | ↓ | Well | ||
| CII.1 1 | Age 4 mos: hepatosplenomegaly, ascites, hVOD, thrombocytopenia, mucocutaneous candidiasis | ↓ | ↓ | ↓ | Chronic liver disease, portal hypertension post hepatic transplantation | Yes | |
| DII.1 1 | Age 3 mos: hepatosplenomegaly, ascites, hVOD | ↓ initially 3 | ↓ | ↓ | Hemophagocytic syndrome post hepatic transplantation | Yes | |
| G | Age 3 mos: hepatosplenomegaly, ascites, hVOD | ↓ | ↓ | ↓ | Pulmonary hemorrhage, multi-organ failure | Yes | |
| J | Age 3 mos: respiratory distress | ↓ | ↓ | N/A | SIADH, idiopathic cerebrospinal leukodystrophy | No | |
| EI.1 1 | c.40delC | Age 3 mos: immunodeficiency, thrombocytopenia, hepatosplenomegaly without definite evidence of hVOD | ↓ | N/A | N/A | Enteroviral and Pneumocystis jerovici infection | Yes |
| I | c.78_79delinsAT (p.Ile27Leu) | Age 3 mos: hepatosplenomegaly, hVOD, fever, respiratory distress | ↓ | ↓ | ↓ | Stable and well | No |
| F | c.319_325dup GGTGCTT | Age 11 mos: hepatosplenomegaly disseminated CMV infection, rotavirus gastroenteritis, vulvar abscesses, hVOD | ↓ initially | ↓ | N/A | Recovering from hVOD, well | No |
| H | c.667+1dup | Age 3 mos: hepatosplenomegaly, failure to thrive, respiratory distress/lung fibrosis, diarrhea | ↓ | ↓ | N/A | Hepatic biopsy consistent with sinusoidal dilatation, moderate central vein and perivenular subsinusoidal fibrosis; stable with improvement | No |
- Modified 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.
No 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.
Penetrance for the combined B and T-cell immunodeficiency has been 100% in individuals confirmed to have VODI caused by mutations in SP110. Likewise, hVOD has been described in all probands or their affected siblings.
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.
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.
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 to be one in 2,500 [Roscioli et al 2006].
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 VOD (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; Author, unpublished data]
- A Hispanic child with hVOD and immunodeficiency from the United States on whom molecular genetic testing is in progress [Cliffe et al, unpublished data]
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Although 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.
To 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.
Hypogammaglobulinemia 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).
Initiation 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).
Some evidence suggests that treatment of immunodeficiency early in VODI may reduce the risk of development or recurrence of hVOD.
- Regular 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 known to predispose to hVOD such as cyclophosphamide and senecio alkaloids/bush teas should be avoided.
Bone marrow transplantation is not recommended.
The 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.
Search 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.
Contact information for voluntary patient registries is provided by GeneReviews staff.
European Society for Immunodeficiencies (ESID) Registry University Medical Center Freiburg Centre of Chronic Immunodeficiency Phone: 49-761-270-34450 Email: registry@esid.org Web: www.esid.org
Hepatic 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 have 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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Hepatic veno-occlusive disease with immunodeficiency (VODI) is inherited in an autosomal recessive manner.
Parents of a proband
- The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
- Heterozygotes (carriers) are asymptomatic.
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.
- Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
- Heterozygotes (carriers) are asymptomatic.
- Penetrance is complete; asymptomatic homozygous individuals have not been identified.
Offspring of a proband. The offspring of an individual with hepatic veno-occlusive disease with immunodeficiency are obligate heterozygotes (carriers) for a disease-causing mutation in SP110.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.
See Management, Evaluation of Relatives at Risk for information on testing 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See Image testing.jpg for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately 11 to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see Image testing.jpg.
Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).
Information 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 Databases
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
| SP110 | 2q37.1 | Sp110 nuclear body protein | Resource of Asian Primary Immunodeficiency Diseases (RAPID) | SP110 |
Table B. OMIM Entries for Hepatic Veno-Occlusive Disease with Immunodeficiency (View All in OMIM)
Normal 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.Gln14SerfsX25)
- Exon 2: NM_080424.2:c.78_79delinsAT (p.Ile27Leu) (a)
- Exon 4: NM_080424.2:c.319_325dup (p.Ser109trpfsX5) (b)
- Exon 5: NM_080424.2:c.642del (p.Ser215AlafsX14)
- 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 SP110
| Mutation | Exon | Reference |
| c.40delC (p.Q14SfsX25) |
2 | Roscioli et al 2006] |
| c.78_79delinsAT (p.Ile27Leu) | 2 | Cliffe et al [unpublished data] |
| c.319_325dupGGTGCTT (p.S109WfsX5) |
4 | Ruga et al [2006] |
| c.642delC (p.P214PfsX14) |
5 | Roscioli et al [2006] |
| c.667+1dup | 5 | Cliffe 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].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.