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Hepatic Veno-Occlusive Disease with Immunodeficiency

, MBBS, FRACP, PhD, , MBBS, FRACP, MD, , MBChB, PhD, FRCPA, FHGSA, and , MBBS, FRACP, FRCPA, PhD.

Author Information
, MBBS, FRACP, PhD
Clinical Geneticist, School of Women’s and Children’s Health
University of New South Wales
Sydney Children’s Hospital
Sydney, Australia
, MBBS, FRACP, MD
Clinical Immunologist, Sydney Children's Hospital
Sydney, Australia
, MBChB, PhD, FRCPA, FHGSA
Director, SEALS Molecular and Cytogenetics Laboratory
Prince of Wales Hospital
Sydney, Australia
, MBBS, FRACP, FRCPA, PhD
Clinical Immunologist and Immunopathologist, Children's Hospital Westmead
Sydney, Australia

Initial Posting: ; Last Update: July 3, 2013.

Summary

Disease 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. Diagnosis is based on low serum concentrations of IgA, IgM, and IgG for age, normal lymphocyte numbers, normal CD4 and CD8 percentages, histologic examination of the liver (or hepatic ultrasonography and Doppler ultrasonography if hepatic biopsy is not possible), and molecular genetic testing of SP110, the only gene in which mutations are known to cause VODI.

Management. Treatment of manifestations: Intravenous immunoglobulin (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 hVOD, such as cyclophosphamide and senecio alkaloids/bush teas.

Evaluation of relatives at risk: If both disease-causing mutations in the family are known, molecular genetic testing of sibs of a proband who are younger than age 12 months to allow 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 mutant allele. 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 disease-causing mutations in a family are known.

Diagnosis

Clinical Diagnosis

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 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
  • Onset usually before age six months
  • Family history consistent with autosomal recessive inheritance

Testing

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 thus should be compared against appropriate local reference ranges.
    • Normal lymphocyte numbers and CD4 and CD8 percentages
    • Low intracellular cytokine production
  • 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.
    • Histology. Features of 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). *
Figure 1

Figure

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.

Molecular Genetic Testing

Gene. SP110 is the only gene in which mutations are known to cause VODI.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Hepatic Veno-Occlusive Disease with Immunodeficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SP110Sequence analysisSequence variants 413/13 (100%) 5 

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. 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.373del (exon 4; 1 patient), c.642delC (exon 5; 8 patients), c.667dupG (exon 5; 1 patient) (See Table 4.)

Testing Strategy

Establishing/confirming 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. Sequence analysis may be performed in a tiered approach beginning with exons 2, 4, and 5, in which both mutations were identified in 100% of the thirteen individuals with VODI evaluated to date [Roscioli et al 2006, Ruga et al 2006, Cliffe et al 2012, Wang et al 2012]. 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 mutation is identified in exons 2, 4, and 5.

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).

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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, Cliffe et al 2012, Wang et al 2012].

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 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 mutations) and eight newly ascertained individuals [Cliffe et al 2012].

Table 2. Clinical and Immunologic Features of Hepatic Veno-Occlusive Disease with Immunodeficiency

PhenotypeNewly Ascertained Patients with VODI [Cliffe et al 2012] with Novel Mutations
Clinical FeaturesPatients from Sydney with VODI [Roscioli et al 2006]Comments
Presenting <6 months20/20 (100%)7/8 (Patient 1 >6 months)
Hepatic failure at initial presentation4/20 (20%)1/12 post-HSCT
3/12 no obvious precipitant
0/8
Hepatomegaly at initial presentation9/20 (45%)3/6 P. jirovecii
2/6 hepatomegaly without SOS
6/8
1/8 enterovirus & disseminated cytomegalovirus (Patient 1)
P. jirovecii infection12/20 (60%)7/12 proven
5/12 suspected
1/8 suspected (Patient 1)
1/8 proven (Patient 4)
Mucocutaneous candidiasis2/20 (10%)1/8
Other features1/20 (5%)By age 19 years1/8 lung fibrosis (Patient 2)
Death19/20 (95%)3/8 (38%)
Recovery from initial SOS4/20 (20%)1 completely well
1 chronic liver disease requiring hepatic transplantation
1 SOS post-HSCT
1 developmental disability, chronic aspiration
4/8
Neurologic abnormalities6/20 (35%)4/7 cerebral infarction
2/7 leukodystrophy
1/8 leukodystrophy
Panhypogammaglobulinemia19/19 (100%)1/18 loss of normal immunoglobulins at age 4 months5/5 tested
1/5 low normal levels of IgA and IgM after commencing IVIg
Normal number of lymphocytes10/11 (92%)8/8
Normal NK cells12/12 (100%)3/3 1
Decreased intracytoplasmic IFN-γ, IL-2, IL-4, IL-104/5 (80%)Low levels at 4 hours, normal/increased levels at 48 hours1/1 (Patient 1)
Decreased number of memory T and B cells3/4 (75%)2/3 1
These cells were present in Patient 1 (see Table 3)

Table modified from Roscioli et al [2006], Cliffe et al [2012]

HSCT = hematopoietic stem cell transplantation

IVIg = intravenous immunoglobulin

SOS = sinusoidal obstruction syndrome

1. Patients 4, 1, and 2 in Table 3: 4 = c.78_79delinsAT (p.Ile27Leu), 1 = c.319_325dup (p.Ser109trpfs*5), 2 = c.667+1dup

VODI is associated with 100% mortality in the first year of life if unrecognized and untreated with intravenous immunoglobulin (IVIG) 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 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 intravenous immunoglobulin and Pneumocystis prophylaxis. One child (Patient A II.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. Four individuals (B II.2 [Table 3] and three unrelated children) had multi-organ failure associated with extensive cerebral necrosis on post-mortem examination. A striking finding is the presence of cerebrospinal leukodystrophy in three (20%) individuals with VODI. Patient 5 had a leukodystrophy of unknown etiology and patient 6 developed this complication after a CMV-related gastroenteritis. In patient 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 to being more consistent with cerebrospinal leukodystrophy.

Table 3 outlines clinical features in individuals with a known SP110 mutation [Roscioli et al 2006, Cliffe et al 2012, Wang et al 2012, Ganaiem et al 2013].

Table 3. Clinical Features of Individuals Homozygous for SP110 Mutations

PatientSP110 MutationPresentationSerum IgsMemory T/B CellsT Cell CytokinesClinical FindingsDeceased?
A II.1 1
Lebanese
c.642delC
in exon 5
Age 5 months: immunodeficiency, thrombocytopenia, SOSN/AN/ALeft hemiparesis 3, recurrent hVOD with GVHD post-HSCTYes
B II.1 1
Lebanese
Age 7 months: immunodeficiencyN/AN/AChronic lung disease secondary to recurrent aspirationYes (age 19 years)
B II.2 1
Lebanese
Age 6 months: hepatosplenomegaly, ascites, SOSWellNo
C II.1 1
Lebanese
Age 4 months: hepatosplenomegaly, ascites, SOS, thrombocytopenia, mucocutaneous candidiasisChronic liver disease, portal hypertension post-hepatic transplantationYes
D II.1 1
Lebanese
Age 3 months: hepatosplenomegaly, ascites, SOS↓ 4Hemophagocytic syndrome post-hepatic transplantationYes
16 2
Lebanese
c.642delC
in exon 5
Age 3 months: hepatosplenomegaly, ascites, SOSPulmonary hemorrhage, multi-organ failureYes
2
Lebanese
c.642delC
in exon 5
Age 3 months, respiratory distressN/ASIADH, idiopathic cerebrospinal leukodystrophyNo
2
Lebanese
c.642delC
in exon 5
Age 3 months: chronic cough, diarrhea

Age 8 years: hepatosplenomegaly

Age ≥12 years: hVOD
N/AN/AIdiopathic left frontal lobe calcified cyst, epilepsy, CMV colitis, post-diarrheal encephalomyelitis with lower limb paralysis, cerebrospinal leukodystrophy, oesophageal candidiasis, duodenal lymphocytic infiltrateNo
2
Lebanese
c.642delC
presumed 5
Age 2 months: chronic diarrhea, failure to thrive, middle ear and respiratory infections, hepatosplenomegaly, thrombocytopeniaN/AN/AN/AMicrocephaly, hepatic biopsy consistent with SOSYes, 11 months from diarrhea leading to septic shock
2
Lebanese
c.642delC
presumed 5
Age 5 months: upper respiratory illness, age 8 months chronic diarrhea, hepatomegaly, thrombocytopeniaN/AN/AN/AHepatic biopsy consistent with SOSYes, 3.5 years from diarrhea leading to septic shock
2
Lebanese
c.642delC
presumed 5
Age 2 months: ascites, hepatomegaly, anaemia, thrombocytopeniaN/AN/AN/AHepatic biopsy consistent with SOSYes, 2.5 months otitis, diarrhea, pneumonia
E I.1 1
Lebanese
c.40delC
in exon 2
Age 3 months: immunodeficiency, thrombocytopenia, hepatosplenomegaly without definite evidence of SOSN/AN/AEnteroviral and P. jirovecii infectionYes
2
Hispanic
c.78_79delinsAT (p.Ile27Leu)
in exon 2
Age 5 months: hepatosplenomegaly, fever, respiratory distress, pancytopeniaStable and wellNo
2
Italian
c.319_325dup GGTGCTT
in exon 4
Age 11 months: hepatosplenomegaly, disseminated cytomegalovirus infection, rotavirus gastroenteritis, vulvar abscesses, SOS↓initiallyN/ARecovering from hVOD, wellNo
2
Italian
c.667+1dup
exon 5 splice site
Age 3 months: hepatosplenomegaly, failure to thrive, respiratory distress/lung fibrosis, diarrheaN/AHepatic biopsy consistent with sinusoidal dilatation, moderate central vein and perivenular subsinusoidal fibrosis; stable with improvementNo
2
Palestinian Arabic
c.373del
in exon 4
Age 3 months: diagnosis of VODI confirmed with cascade testing prior to illness onset. No hepatomegaly or liver function abnormalitiesN/AN/AN/AStable and wellNo

Modified from Roscioli et al [2006]

GVHD = graft-versus-host disease

HSCT = hematopoietic stem cell transplantation

SOS = sinusoidal obstruction syndrome

SIADH = syndrome of inappropriate antidiuretic hormone secretion

Note: Although families A, B, and C are not known to be related, they are believed to have a common ancestor. Patients included in the initial homozygosity mapping analysis: A II.1, B II.1, B II.2, C II.1, 16 (‘G’ in initial analysis), and 5 (‘J’ in initial analysis).

Patient designations are those used in the articles cited.

1. Reported in Roscioli et al [2006]

2. Reported in Cliffe et al [2012]

3. Secondary to cerebral white matter abnormality

4. IgA and IgM serum concentrations increased to lower limit of normal while on IVIG.

5. The mutation listed is a known familial mutation. While mutation analysis was not performed on this affected individual, c.642delC is presumed to be the causative mutation based on the family history.

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 Correlations

No significant difference in the clinical manifestations of VODI is observed between individuals with SP110 exon 2, 4 and exon 5 mutations.

The one child with an exon 4 duplication (Patient 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 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.

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 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:

Differential Diagnosis

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 to have hVOD alone.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

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)
  • Medical genetics consultation

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, 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 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 intravenous immunoglobulin 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 of development or recurrence of hVOD.

Surveillance

  • 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 such as cyclophosphamide and senecio alkaloids/bush teas should be avoided.

Evaluation of Relatives at Risk

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.

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 mutations may result in improved long term outcomes.

Therapies Under Investigation

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.

Other

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. Recently, three of five children with VODI were successfully treated with HSCT [Ganaiem et al 2013] suggesting that this may be an efficacious treatment modality with appropriate conditioning therapy.

Genetic Counseling

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. —ED.

Mode of Inheritance

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

Risk to Family Members

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 Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.

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 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.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Immune Deficiency Foundation (IDF)
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204
    Phone: 800-296-4433 (toll-free)
    Email: idf@primaryimmune.org
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Firside
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
    Email: info@ipopi.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org

Molecular Genetics

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

Data 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)

235550HEPATIC VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY; VODI
604457NUCLEAR BODY PROTEIN SP110; SP110

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_004509.3 (average mass 78.438 kd; transcript does not include exon 17)
  • Isoform B, NM_004510.3 (average mass 61.940 kd; transcript includes an alternate exon 15 and terminates within exon 15)
  • Isoform C, NM_080424.2 (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).

The majority of these pathogenic mutations cause a frameshift with consequent protein truncation.

Table 4. SP110 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeExonProtein Amino Acid ChangeReferenceReference Sequences
c.40delC2p.Gln14Serfs*25Roscioli et al [2006]NM_080424​.2
NP_536349​.2
c.78_79delinsAT
(78_79CA>AT)
2p.Ile27LeuCliffe et al [2012], Wang et al [2012]
c.319_325dupGGTGCTT4p.Ser109Trpfs*5Ruga et al [2006], Cliffe et al [2012]
c.373delA4p.Thr125Leufs*3Cliffe et al [2012], Ganaiem et al [2013]
c.642delC5p.Pro214Profs*14Roscioli et al [2006]
c.667+1dup5NACliffe et al [in preparation]

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

1. Variant designation that does not conform to current naming conventions

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 (amino acids 6-159), which is involved in dimerization with other Sp100 family proteins, a nuclear localization signal (amino acids 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 (amino acids 452-532), a plant homeobox domain (amino acids 537-577), and a bromodomain (amino acids 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].

The c.78_79delinsAT 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 p.Ile27Leu 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. The dinucleotide deletion/insertion mutation has been shown to produce profound effects on Sp110 protein stability [Cliffe et al 2012]. The key pathogenic event in the development of VODI in all cases reported to date therefore appears to be of the lack of fully functional Sp110 protein.

References

Literature Cited

  1. Bloch DB, Nakajima A, Gulick T, Chiche JD, Orth D, de La Monte SM, Bloch KD. Sp110 localizes to the PML-Sp100 nuclear body and may function as a nuclear hormone receptor transcriptional coactivator. Mol Cell Biol. 2000;20:6138–46. [PMC free article: PMC86089] [PubMed: 10913195]
  2. Buckley JA, Hutchins GM. Association of hepatic veno-occlusive disease with the acquired immunodeficiency syndrome. Mod Pathol. 1995;8:398–401. [PubMed: 7567938]
  3. Cliffe ST, Bloch DB, Suryani S, Kamsteeg EJ, Avery DT, Palendira U, Church JA, Wainstein BK, Trizzino A, Lefranc G, Akatcherian C, Megarbané A, Gilissen C, Moshous D, Reichenbach J, Misbah S, Salzer U, Abinun M, Ong PY, Stepensky P, Ruga E, Ziegler JB, Wong M, Tangye SG, Lindeman R, Buckley MF, Roscioli T. Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome. J Allergy Clin Immunol. 2012 Sep;130:735-742.e6. [PubMed: 22621957]
  4. Corbacioglu S, Honig M, Lahr G, Stohr S, Berry G, Friedrich W, Schulz AS. Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide. Bone Marrow Transplant. 2006;38:547–53. [PubMed: 16953210]
  5. Ganaiem H, Eisenstein EM, Tenenbaum A, Somech R, Simanovsky N, Roscioli T, Weintraub M, Stepensky P. The role of hematopoietic stem cell transplantation in SP110 associated veno-occlusive disease with immunodeficiency syndrome. Pediatr Allergy Immunol. 2013;24:250–6. [PubMed: 23448538]
  6. Kallianpur AR. Genomic screening and complications of hematopoietic stem cell transplantation: has the time come? Bone Marrow Transplant. 2005;35:1–16. [PubMed: 15489868]
  7. Kallianpur AR, Hall LD, Yadav M, Byrne DW, Speroff T, Dittus RS, Haines JL, Christman BW, Summar ML. The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2005;35:1155–64. [PubMed: 15834437]
  8. Kishi M, Maeyama S, Ogata S, Koike J, Uchikoshi T. Hepatic veno-occlusive lesions in severe alcoholic hepatitis and alcoholic liver cirrhosis: a comparative histopathological study in autopsy cases. Alcohol Clin Exp Res. 1999;23(4) Suppl:47S–51S. [PubMed: 10235278]
  9. Mellis C, Bale PM. Familial hepatic venoocclusive disease with probable immune deficiency. J Pediatr. 1976;88:236–42. [PubMed: 1249685]
  10. Roscioli T, Cliffe ST, Bloch DB, Bell CG, Mullan G, Taylor PJ, Sarris M, Wang J, Donald JA, Kirk EP, Ziegler JB, Salzer U, McDonald GB, Wong M, Lindeman R, Buckley MF. Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease. Nat Genet. 2006;38:620–2. [PubMed: 16648851]
  11. Ruga EM, Guariso G, Antiga LD, Guido M, Fassan M, Elia RD, Ziegler JB, Roscioli T, Cliffe ST, Buckley MF, Zancan L. Hepatic veno-occlusive disease with immunodeficiency syndrome: case report. Budapest, Hungary: 12th Meeting of the European Society for Immunodeficiencies. 2006.
  12. Srisirirojanakorn N, Finegold MJ, Gopalakrishna GS, Klish WJ. Hepatic veno-occlusive disease in ataxia-telangiectasia. J Pediatr. 1999;134:786–8. [PubMed: 10356154]
  13. Srivastava A, Poonkuzhali B, Shaji RV, George B, Mathews V, Chandy M, Krishnamoorthy R. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004;104:1574–7. [PubMed: 15142875]
  14. Szeszko JS, Healy B, Stevens H, Balabanova Y, Drobniewski F, Todd JA, Nejentsev S. Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis. Hum Genet. 2007;121:155–60. [PubMed: 17149599]
  15. Thye T, Browne EN, Chinbuah MA, Gyapong J, Osei I, Owusu-Dabo E, Niemann S, Rusch-Gerdes S, Horstmann RD, Meyer CG. No associations of human pulmonary tuberculosis with Sp110 variants. J Med Genet. 2006;43:e32. [PMC free article: PMC2564561] [PubMed: 16816019]
  16. Tosh K, Campbell SJ, Fielding K, Sillah J, Bah B, Gustafson P, Manneh K, Lisse I, Sirugo G, Bennett S, Aaby P, McAdam KP, Bah-Sow O, Lienhardt C, Kramnik I, Hill AV. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc Natl Acad Sci U S A. 2006;103:10364–8. [PMC free article: PMC1502463] [PubMed: 16803959]
  17. Wang T, Ong P, Roscioli T, Cliffe ST, Church JA. Hepatic veno-occlusive disease with immunodeficiency (VODI): first reported case in the U.S. and identification of a unique mutation in Sp110. Clin Immunol. 2012;145:102–7. [PubMed: 22982295]
  18. Washington K, Gossage DL, Gottfried MR. Pathology of the liver in severe combined immunodeficiency and DiGeorge syndrome. Pediatr Pathol. 1993;13:485–504. [PubMed: 8372033]
  19. Watashi K, Hijikata M, Tagawa A, Doi T, Marusawa H, Shimotohno K. Modulation of retinoid signaling by a cytoplasmic viral protein via sequestration of Sp110b, a potent transcriptional corepressor of retinoic acid receptor, from the nucleus. Mol Cell Biol. 2003;23:7498–509. [PMC free article: PMC207568] [PubMed: 14559998]

Chapter Notes

Revision History

  • 3 July 2013 (me) Comprehensive update posted live
  • 15 September 2009 (me) Comprehensive update posted live
  • 21 February 2007 (me) Review posted to live Web site
  • 29 November 2006 (mb) Original submission
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