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Latest revision as of 00:03, 30 July 2012

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S

Overview

Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by Primary immunodeficiency and 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. Hepatic veno-occlusive disease with immunodeficiency (also called VODI) is a hereditary disorder of the liver and immune system. Its signs and symptoms appear after the first few months of life.

Hepatic veno-occlusive disease is a condition that blocks (occludes) small veins in the liver, disrupting blood flow in this organ. This condition can lead to enlargement of the liver (hepatomegaly), a buildup of scar tissue (hepatic fibrosis), and liver failure.^[1]

Children with VODI are prone to recurrent infections caused by certain bacteria, viruses, and fungi. The organisms that cause infection in people with this disorder are described as opportunistic because they ordinarily do not cause illness in healthy people. These infections are usually serious and may be life-threatening. In most people with VODI, infections occur before hepatic veno-occlusive disease becomes evident.

Pathophysiology

Genetics

This condition is inherited in an autosomal recessive pattern

VODI results from mutations in the SP110 gene. This gene provides instructions for making a protein called SP110 nuclear body protein, which is involved in the normal function of the immune system. This protein likely helps regulate the activity of genes needed for the body's immune response to foreign invaders (such as viruses and bacteria).

Mutations in the SP110 gene prevent cells from making functional SP110 nuclear body protein, which impairs the immune system's ability to fight off infections. It is unclear how a lack of this protein affects blood flow in the liver.

Epidemiology and Demographics

VODI appears to be a rare disorder; approximately 20 affected families have been reported worldwide. Most people diagnosed with the condition have been of Lebanese ancestry. However, the disorder has also been identified in several individuals with other backgrounds in the United States and Italy.

Natural History, Complications and Prognosis

Many people with VODI live only into childhood, although some affected individuals have lived to early adulthood. VODI is associated with 90% mortality overall and 100% mortality if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jerovici prophylaxis.

Treatment

Evaluations Following Initial Diagnosis^[2]

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.

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 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

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 jerovici infection is appropriate

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
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 Avoid

Agents 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 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.

References

↑ http://ghr.nlm.nih.gov/condition/hepatic-veno-occlusive-disease-with-immunodeficiency
↑ Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, Roscioli T, Ziegler JB, Buckley M, Wong M. [[]]. PMID 20301448. Missing or empty |title= (help); |access-date= requires |url= (help)

Template:WH Template:WS

[1] ttp://ghr.nlm.nih.gov/condition/hepatic-veno-occlusive-disease-with-immunodeficiency

[pmid20301448-2] Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, Roscioli T, Ziegler JB, Buckley M, Wong M. [[]]. PMID 20301448. Missing or empty |title= (help); |access-date= requires |url= (help)

[1]

[2]

@@ Line 1: / Line 1: @@
-{{CMG}}
+__NOTOC__
+{{SI}}
+{{CMG}} '''Assosciate Editor(s)-In-Chief:''' [[User: Prashanthsaddala|Prashanth Saddala M.B.B.S]]
 ==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.
+Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by Primary immunodeficiency and terminal hepatic lobular vascular occlusion and hepatic fibrosis manifest as hepatomegaly and/or hepatic failure.
-<div>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 jerovici'' infection, mucocutaneous candidiasis, and enteroviral or cytomegalovirus infections
-* Hepatomegaly or evidence of hepatic failure not explained by other factors in the [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected] individual or a first degree relative
-* Onset before age 12 months
-* Family history consistent with [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/ autosomal recessive] inheritance
-</div><div>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 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 [http://www.ncbi.nlm.nih.gov/books/NBK1271/figure/vodi.F1/?report=objectonly Figure 1]) *
-<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/figure/vodi.F1/?report=objectonly [[Image:vodiFig1.gif|Figure 1]]]<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/figure/vodi.F1/?report=objectonly 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)
-</div></div>
-* If hepatic biopsy is contraindicated, hepatic ultrasonography and Doppler ultrasonography may provide supportive evidence of hVOD.
-<div>Molecular Genetic Testing
-'''Gene.''' ''SP110'' is the only [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/ 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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al 2006], [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.ruga.2006.1 Ruga et al 2006]].
-** Sequencing of the entire [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/coding-region/ coding region] of 19 exons and an alternatively spliced [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/ exon] 15 in the Sp110c isoform is performed if no mutations are identified in exons 2, 4, and 5.
-<div><div>
-Table 1. Summary of Molecular Genetic Testing Used in Hepatic Veno-Occlusive Disease with Immunodeficiency
-</div><div>
-{|
-|-
-| Gene Symbol
-| Test Method
-| Mutations Detected
-| Mutation Detection Frequency by Test Method <sup>1</sup>
-| Test Availability
-|-
-| colspan="1" rowspan="1" | ''SP110''
-| colspan="1" rowspan="1" | Sequence analysis
-| colspan="1" rowspan="1" | Sequence variants <sup>2</sup>
-| colspan="1" rowspan="1" | 12/12 (100%) <sup>3</sup>
-| colspan="1" rowspan="1" | Clinical<br />[http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/272071?db=genetests [[Image:testing.jpg|Image testing.jpg]]]
-|}
-</div><div><div>
-: Test Availability refers to availability in the [http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTests 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/ mutation] that is present in the indicated [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/ gene]
-: 2. Examples of mutations detected by [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/ sequence analysis] may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.
-: 3. Mutations identified to date: c.40delC ([http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/ 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)
-</div></div></div>
-'''Interpretation of test results.''' For issues to consider in interpretation of [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/ sequence analysis] results, click [http://www.ncbi.nlm.nih.gov/books/n/gene/app2/ here].
-</div></div><div>Testing Strategy
-'''Establishing the diagnosis in a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/ 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'' [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/ 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/ autosomal recessive] disorder and are not at risk of developing the disorder, i.e., there is no [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/ 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).
-</div><div>Genetically Related (Allelic) Disorders
-No allelic Mendelian disorders for ''SP110'' or contiguous [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/ gene] disorders including the ''SP110'' region associated with hVOD or immunodeficiency have been described.
-[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.tosh.2006.10364 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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.thye.2006.e32 Thye et al 2006]].
-A well-designed and well-executed study by [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.szeszko.2007.155 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''.
-</div><div><div>Clinical Description<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/# Go to:]</div></div><div>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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al 2006]]. The number of children known to have VODI secondary to ''SP110'' mutations is small ([http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_and_immunologic_features/?report=objectonly Table 2] and [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_features_of_individuals_/?report=objectonly Table 3]) [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al 2006], [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.ruga.2006.1 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 [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_and_immunologic_features/?report=objectonly 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). [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_and_immunologic_features/?report=objectonly 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).
-<div><div>
-Table 2. Clinical and Immunologic Features of Hepatic Veno-Occlusive Disease with Immunodeficiency (VODI)
-</div><div>
-{|
-|-
-| Phenotype
-| Patients I, F, H with Novel Mutations <sup>1</sup>
-|-
-| Clinical Features
-| Patients from Sydney with VODI
-| Comments
-|-
-| colspan="1" rowspan="1" | Presenting <6 months
-| colspan="1" rowspan="1" | 20/20
-| colspan="1" rowspan="1" |
-| colspan="1" rowspan="1" | 2/3
-|-
-| colspan="1" rowspan="1" | Hepatic failure at initial presentation
-| colspan="1" rowspan="1" | 4/20
-| colspan="1" rowspan="1" | 1/12 post HSCT<br />3/12 no obvious precipitant
-| colspan="1" rowspan="1" | 0/3
-|-
-| colspan="1" rowspan="1" | Hepatomegaly at initial presentation
-| colspan="1" rowspan="1" | 9/20
-| colspan="1" rowspan="1" | 3/6 ''P. jerovici''<br />2/6 hepatomegaly without SOS
-| colspan="1" rowspan="1" | 2/3<br />1/3 enterovirus and disseminated CMV (F)
-|-
-| colspan="1" rowspan="1" | ''P. jerovici'' infection
-| colspan="1" rowspan="1" | 12/20
-| colspan="1" rowspan="1" | 7/12 proven<br />5/12 suspected
-| colspan="1" rowspan="1" | 1/3 suspected (F)<br />1/3 proven (I)
-|-
-| colspan="1" rowspan="1" | Mucocutaneous candidiasis
-| colspan="1" rowspan="1" | 2/20
-| colspan="1" rowspan="1" |
-| colspan="1" rowspan="1" | 1/3
-|-
-| colspan="1" rowspan="1" | Other features
-| colspan="1" rowspan="1" | 1/20
-| colspan="1" rowspan="1" | By age 19 years
-| colspan="1" rowspan="1" | 1/3 lung fibrosis (H)
-|-
-| colspan="1" rowspan="1" | Death
-| colspan="1" rowspan="1" | 19/20
-| colspan="1" rowspan="1" |
-| colspan="1" rowspan="1" | 0/3
-|-
-| colspan="1" rowspan="1" | Recovery from initial SOS
-| colspan="1" rowspan="1" | 4/20
-| colspan="1" rowspan="1" | 1 completely well <br />1 chronic liver disease requiring hepatic transplantation<br />1 SOS post HSCT<br />1 developmental disability, chronic aspiration
-| colspan="1" rowspan="1" | 3/3
-|-
-| colspan="1" rowspan="1" | Neurologic abnormalities
-| colspan="1" rowspan="1" | 6/20
-| colspan="1" rowspan="1" | 4/7 cerebral infarction<br />1/7 ''Toxoplasma''?<br />1/7 porencephalic cyst
-| colspan="1" rowspan="1" | 0/3
-|-
-| colspan="1" rowspan="1" | Panhypogammaglobulinemia
-| colspan="1" rowspan="1" | 19/19
-| colspan="1" rowspan="1" | 1/18 loss of normal immunoglobulins at age 4 mos
-| colspan="1" rowspan="1" | 3/3 <br />1/3 low normal levels of IgA and IgM after commencing IVIg
-|-
-| colspan="1" rowspan="1" | Normal number of lymphocytes
-| colspan="1" rowspan="1" | 10/11
-| colspan="1" rowspan="1" |
-| colspan="1" rowspan="1" | 3/3
-|-
-| colspan="1" rowspan="1" | Normal NK cells
-| colspan="1" rowspan="1" | 12/12
-| colspan="1" rowspan="1" |
-| colspan="1" rowspan="1" | 3/3
-|-
-| colspan="1" rowspan="1" | Decreased intracytoplasmic IFNγ, IL2, IL4, IL10
-| colspan="1" rowspan="1" | 4/5
-| colspan="1" rowspan="1" | Low levels at 4 hours, normal/increased levels at 48 hours
-| colspan="1" rowspan="1" | 1/1 (F)
-|-
-| colspan="1" rowspan="1" | Decreased number of memory T and B cells
-| colspan="1" rowspan="1" | 3/4
-| colspan="1" rowspan="1" |
-| colspan="1" rowspan="1" | 2/3 (I,H)
-|}
-</div><div><div>
-: Table modified from [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al [2006]]
-: HSCT= hematopoietic stem cell transplantation
-: CMV= cytomegalovirus
-: SOS= sinusoidal obstruction syndrome
-: 1. See [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_features_of_individuals_/?report=objectonly Table 3].
-</div></div></div>
-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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 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, [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_features_of_individuals_/?report=objectonly 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected] child (Patient BII.1, [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_features_of_individuals_/?report=objectonly 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 ([http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_features_of_individuals_/?report=objectonly Table 3]) experienced a cerebrovascular accident associated with a right-sided cerebral white matter lesion, presumed to be ''Toxoplasma gondii'' infection.
-[http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_features_of_individuals_/?report=objectonly Table 3] outlines clinical features in individuals with a known ''SP110'' [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/ mutation] [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al 2006]].
-<div><div>
-Table 3. Clinical Features of Individuals Homozygous for ''SP110'' Mutations
-</div><div>
-{|
-|-
-| Patient
-| ''SP110'' Mutation
-| Presentation
-| Serum Igs
-| Memory T/B Cells
-| T-Cell Cytokines
-| Clinical Findings
-| Deceased?
-|-
-| colspan="1" rowspan="1" | AII.1 <sup>1</sup>
-| colspan="1" rowspan="7" | c.642delC
-| colspan="1" rowspan="1" | Age 5 mos: immunodeficiency, thrombocytopenia, hVOD
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | —
-| colspan="1" rowspan="1" | —
-| colspan="1" rowspan="1" | Left hemiparesis <sup>2</sup> , recurrent hVOD with GVHD post HSCT
-| colspan="1" rowspan="1" | Yes
-|-
-| colspan="1" rowspan="1" | BII.1 <sup>1</sup>
-| colspan="1" rowspan="1" | Age 7 mos: immunodeficiency
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | —
-| colspan="1" rowspan="1" | —
-| colspan="1" rowspan="1" | Chronic lung disease secondary to recurrent aspiration
-| colspan="1" rowspan="1" | Yes (age 19 yrs)
-|-
-| colspan="1" rowspan="1" | BII.2 <sup>1</sup>
-| colspan="1" rowspan="1" | Age 6 mos: hepatosplenomegaly, ascites, hVOD
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | Well
-| colspan="1" rowspan="1" |
-|-
-| colspan="1" rowspan="1" | CII.1 <sup>1</sup>
-| colspan="1" rowspan="1" | Age 4 mos: hepatosplenomegaly, ascites, hVOD, thrombocytopenia, mucocutaneous candidiasis
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | Chronic liver disease, portal hypertension post hepatic transplantation
-| colspan="1" rowspan="1" | Yes
-|-
-| colspan="1" rowspan="1" | DII.1 <sup>1</sup>
-| colspan="1" rowspan="1" | Age 3 mos: hepatosplenomegaly, ascites, hVOD
-| colspan="1" rowspan="1" | ↓ initially <sup>3</sup>
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | Hemophagocytic syndrome post hepatic transplantation
-| colspan="1" rowspan="1" | Yes
-|-
-| colspan="1" rowspan="1" | G
-| colspan="1" rowspan="1" | Age 3 mos: hepatosplenomegaly, ascites, hVOD
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | Pulmonary hemorrhage, multi-organ failure
-| colspan="1" rowspan="1" | Yes
-|-
-| colspan="1" rowspan="1" | J
-| colspan="1" rowspan="1" | Age 3 mos: respiratory distress
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | N/A
-| colspan="1" rowspan="1" | SIADH, idiopathic cerebrospinal leukodystrophy
-| colspan="1" rowspan="1" | No
-|-
-| colspan="1" rowspan="1" | EI.1 <sup>1</sup>
-| colspan="1" rowspan="1" | c.40delC
-| colspan="1" rowspan="1" | Age 3 mos: immunodeficiency, thrombocytopenia, hepatosplenomegaly without definite evidence of hVOD
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | N/A
-| colspan="1" rowspan="1" | N/A
-| colspan="1" rowspan="1" | Enteroviral and ''Pneumocystis jerovici'' infection
-| colspan="1" rowspan="1" | Yes
-|-
-| colspan="1" rowspan="1" | I
-| colspan="1" rowspan="1" | c.78_79delinsAT (p.Ile27Leu)
-| colspan="1" rowspan="1" | Age 3 mos: hepatosplenomegaly, hVOD, fever, respiratory distress
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | Stable and well
-| colspan="1" rowspan="1" | No
-|-
-| colspan="1" rowspan="1" | F
-| colspan="1" rowspan="1" | c.319_325dup GGTGCTT
-| colspan="1" rowspan="1" | Age 11 mos: hepatosplenomegaly disseminated CMV infection, rotavirus gastroenteritis, vulvar abscesses, hVOD
-| colspan="1" rowspan="1" | ↓ initially
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | N/A
-| colspan="1" rowspan="1" | Recovering from hVOD, well
-| colspan="1" rowspan="1" | No
-|-
-| colspan="1" rowspan="1" | H
-| colspan="1" rowspan="1" | c.667+1dup
-| colspan="1" rowspan="1" | Age 3 mos: hepatosplenomegaly, failure to thrive, respiratory distress/lung fibrosis, diarrhea
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | ↓
-| colspan="1" rowspan="1" | N/A
-| colspan="1" rowspan="1" | Hepatic biopsy consistent with sinusoidal dilatation, moderate central vein and perivenular subsinusoidal fibrosis; stable with improvement
-| colspan="1" rowspan="1" | No
-|}
-</div><div><div>
-: Modified from [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 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 [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 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.
-</div></div></div>
-'''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.
-</div><div>Genotype-Phenotype Correlations
-No significant difference in the clinical manifestations of VODI is observed between individuals with ''SP110'' [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/ exon] 2 and exon 5 mutations.
-The one child with an [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/ exon] 4 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/duplication/ duplication] (Patient F, [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.clinical_features_of_individuals_/?report=objectonly 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.
-</div><div>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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected] siblings.
-Approximately 10% of children with VODI, ascertained at a young age because of an [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected] sib and treated early in the disease course with IVIG, may manifest immunodeficiency only at presentation.
+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.
-</div><div>Nomenclature
+Hepatic veno-occlusive disease with immunodeficiency (also called VODI) is a hereditary disorder of the liver and immune system. Its signs and symptoms appear after the first few months of life.
-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.
+Hepatic veno-occlusive disease is a condition that blocks (occludes) small veins in the liver, disrupting blood flow in this organ. This condition can lead to enlargement of the liver (hepatomegaly), a buildup of scar tissue (hepatic fibrosis), and liver failure.<ref>http://ghr.nlm.nih.gov/condition/hepatic-veno-occlusive-disease-with-immunodeficiency</ref>
-</div><div>Prevalence
-VODI was described originally in Australians of Lebanese origin by [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.mellis.1976.236 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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al 2006]].
+Children with VODI are prone to recurrent infections caused by certain bacteria, viruses, and fungi. The organisms that cause infection in people with this disorder are described as opportunistic because they ordinarily do not cause illness in healthy people. These infections are usually serious and may be life-threatening.  In most people with VODI, infections occur before hepatic veno-occlusive disease becomes evident.
-The prevalence of VODI in children of non-Lebanese origin is unknown; however, the following reports suggest that the VODI [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/ phenotype] is observed in other populations.
+==Pathophysiology==
+===Genetics===
+This condition is inherited in an autosomal recessive pattern
-Additional reports of VODI:
+VODI results from mutations in the SP110 gene.  This gene provides instructions for making a protein called SP110 nuclear body protein, which is involved in the normal function of the immune system. This protein likely helps regulate the activity of genes needed for the body's immune response to foreign invaders (such as viruses and bacteria).
-* A [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/simplex-case/ simplex case] of VOD (i.e., a single occurrence in a family) with humoral and cellular immunodeficiency in the Spanish literature
+Mutations in the SP110 gene prevent cells from making functional SP110 nuclear body protein, which impairs the immune system's ability to fight off infections.  It is unclear how a lack of this protein affects blood flow in the liver.
-* Two Italian children with VODI [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.ruga.2006.1 Ruga et al 2006]; Author, unpublished data]
-* A Hispanic child with hVOD and immunodeficiency from the United States on whom [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/ molecular genetic testing] is in progress [Cliffe et al, unpublished data]
-</div></div><div><div>Differential Diagnosis<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/# Go to:]</div></div>
-''For current information on availability of genetic testing for disorders included in this section, see ''[http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTests ''GeneTests Laboratory Directory'']''.'' —ED.
+==Epidemiology and Demographics==
+VODI appears to be a rare disorder; approximately 20 affected families have been reported worldwide.  Most people diagnosed with the condition have been of Lebanese ancestry. However, the disorder has also been identified in several individuals with other backgrounds in the United States and Italy.
-Although sinusoidal obstruction syndrome in association with severe combined immunodeficiency (SCID) was described in one case reported by [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.washington.1993.485 Washington et al [1993]], and in one post-mortem HIV cohort reported by [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.buckley.1995.398 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.
+==Natural History, Complications and Prognosis==
+Many people with VODI live only into childhood, although some affected individuals have lived to early adulthood.
+VODI is associated with 90% mortality overall and 100% mortality if unrecognized and untreated with intravenous immunoglobulin (IVIG) and Pneumocystis jerovici prophylaxis.
-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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.kishi.1999.47S Kishi et al 1999]], [http://www.ncbi.nlm.nih.gov/books/n/gene/ataxia-telangiectas/ ataxia-telangiectasia] [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.srisirirojanakorn.1999.786 Srisirirojanakorn et al 1999]], osteopetrosis [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.corbacioglu.2006.547 Corbacioglu et al 2006]] (see [http://www.ncbi.nlm.nih.gov/books/n/gene/clcn7/ ''CLCN7''-related osteopetrosis]), and hypereosinophilic syndrome. HIV should also be considered as a differential diagnosis for the immune [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/ phenotype].
+==Treatment==
-Previous case-control studies using single-[http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/nucleotide/ nucleotide] polymorphisms (SNPs) have also reported associations between hVOD and SNPs in the carbamyl phosphate synthetase 1 ''(CPS1'') (see [http://www.ncbi.nlm.nih.gov/books/n/gene/ucd-overview/ Urea Cycle Disorders Overview]), [http://www.ncbi.nlm.nih.gov/books/n/gene/factor-v-leiden/ factor V Leiden] (FVL), ''HFE'' (see [http://www.ncbi.nlm.nih.gov/books/n/gene/hemochromatosis/ ''HFE''-Associated Hereditary Hemochromatosis]), and glutathione S-transferase ''(GSTM1'' and ''GSTT1'') genes. Relative risks of 8.6 for the homozygous ''HFE'' Cys282Tyr [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/ allele] and 4.12 for the ''GSTM1'' [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/null-allele/ null allele] have been reported [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.srivastava.2004.1574 Srivastava et al 2004], [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.kallianpur.2005.1 Kallianpur 2005], [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.kallianpur.2005.1155 Kallianpur et al 2005]]. No independent replication of these findings has been performed.
+'''Evaluations Following Initial Diagnosis'''<ref name="pmid20301448">{{cite journal |author=Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, Roscioli T, Ziegler JB, Buckley M, Wong M |title= |journal=[[]] |volume= |issue= |pages= |year= |pmid=20301448 |doi= |url= |accessdate=2012-07-29}}</ref>
-There has been no report of ''SP110'' mutations in individuals described as having hVOD alone.
-</div><div><div>Management<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/# Go to:]</div></div><div>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:
@@ Line 371: / Line 40: @@
 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.
-</div><div>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.
+'''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 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/M<sup>2</sup> (3.75 mL/M<sup>2</sup>).
-'''''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/M<sup>2</sup> (3.75 mL/M<sup>2</sup>).
+Infections with specific agents should be treated with appropriate supportive care and antibacterials or antivirals.
-'''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
-'''HSCT and hepatic transplantation''' may be considered, but appear to have a high rate of complications in the VODI cohort studied to date (see [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.Other Other]).
+'''Prevention of Primary Manifestations'''
-</div><div>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 jerovici'' infection is appropriate (see [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.Treatment_of_Manifestations Treatment of Manifestations]).
+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
-</div><div>Prevention of Secondary Complications
+'''Prevention of Secondary Complications'''
 Some evidence suggests that treatment of immunodeficiency early in VODI may reduce the risk of development or recurrence of hVOD.
-</div><div>Surveillance
+'''Surveillance'''
 * Regular surveillance of hepatic function, platelet count, and hemoglobin level in children with VODI as hepatic failure and portal hypertension may occur
@@ Line 396: / Line 69: @@
 Bone marrow transplantation is not recommended.
-</div><div>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, [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/ molecular genetic testing] should be considered in sibs of a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/ proband] who are younger than age 12 months.
-Penetrance is complete (i.e., 100%) in the individuals with VODI described to date; thus, [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/ molecular genetic testing] of healthy at-risk sibs of a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/ proband] who are older than age 12 months is not recommended.
-See [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.Related_Genetic_Counseling_Issues Genetic Counseling] for issues related to testing of at-risk relatives for [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genetic-counseling/ genetic counseling] purposes.
-</div><div>Therapies Under Investigation
-Search [http://clinicaltrials.gov/ 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.
-</div><div>Registries
-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:''' [http://www.esid.org/registry www.esid.org]
-</div><div>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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/population-risk/ 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 [http://www.ncbi.nlm.nih.gov/sites/GeneTests/clinic?db=GeneTests GeneTests Clinic Directory].
-'''See '''[http://www.ncbi.nlm.nih.gov/sites/GeneTests?Db=genetests&Cmd=DiseaseResourcesList&TermToSearch=27207199 '''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.
-</div></div><div><div>Genetic Counseling<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/# Go to:]</div></div>
-''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 ''[http://www.ncbi.nlm.nih.gov/sites/GeneTests/clinic?db=GeneTests ''GeneTests Clinic Directory'']''.''
-<div>Mode of Inheritance
-Hepatic veno-occlusive disease with immunodeficiency (VODI) is inherited in an [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/ autosomal recessive] manner.
-</div><div>Risk to Family Members
-'''Parents of a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/ proband]'''
-* The parents of an [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected] child are obligate heterozygotes and therefore carry one mutant [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/allele/ allele].
-* Heterozygotes (carriers) are asymptomatic.
-'''Sibs of a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/ proband]'''
-* At conception, each sib of an [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected] individual has a 25% chance of being affected, a 50% chance of being an asymptomatic [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/ carrier], and a 25% chance of being [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/ unaffected] and not a carrier.
-* Once an at-risk sib is known to be [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/ unaffected], the risk of his/her being a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/ carrier] is 2/3.
-* Heterozygotes (carriers) are asymptomatic.
-* Penetrance is complete; asymptomatic homozygous individuals have not been identified.
-'''Offspring of a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/ proband].''' The offspring of an individual with hepatic veno-occlusive disease with immunodeficiency are obligate heterozygotes (carriers) for a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/disease-causing-mutation/ disease-causing mutation] in ''SP110''.
-'''Other family members of a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/proband/ proband].''' Each sib of the proband's parents is at a 50% risk of being a [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/ carrier].
-</div><div>Carrier Detection
-Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.
-</div><div>Related Genetic Counseling Issues
-See Management, [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.Evaluation_of_Relatives_at_Risk 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/ carrier] status, and discussion of the availability of prenatal testing is before pregnancy.
-* It is appropriate to offer [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genetic-counseling/ genetic counseling] (including discussion of potential risks to offspring and reproductive options) to young adults who are [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected], are carriers, or are at risk of being carriers.
-'''[http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna-banking/ 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ affected] individuals. See [http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_lab_service_id/2561?db=genetests [[Image:testing.jpg|Image testing.jpg]]] for a list of laboratories offering DNA banking.
-</div><div>Prenatal Testing
-Prenatal diagnosis for pregnancies at increased risk is possible by analysis of [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/ 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/ 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 [http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_lab_service_id/3036?db=genetests [[Image:testing.jpg|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).
-</div></div><div><div>Molecular Genetics<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/# Go to:]</div></div>
-''Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —''ED.
-<div><div>
-Table A. Hepatic Veno-Occlusive Disease with Immunodeficiency: Genes and Databases
-</div><div>
-{|
-|-
-| Gene Symbol
-| Chromosomal Locus
-| Protein Name
-| Locus Specific
-| HGMD
-|-
-| [http://www.ncbi.nlm.nih.gov/gene/3431 ''SP110'']
-| [http://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?taxid=9606&chr=2&query=SP110&qstr=SP110&maps=snp,genes-r,pheno&zoom=2 2q37.1]
-| [http://www.uniprot.org/uniprot/Q9HB58 Sp110 nuclear body protein]
-| [http://rapid.rcai.riken.jp/RAPID/mutation?pid_id=AGID_122 Resource of Asian Primary Immunodeficiency Diseases (RAPID)]
-| [http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SP110 SP110]
-|}
-</div><div><div>
-: Data are compiled from the following standard references: gene symbol from 		[http://www.genenames.org/index.html HGNC]; 	chromosomal locus, locus name, critical region, complementation group from 		[http://www.omim.org/ OMIM]; 	protein name from [http://www.uniprot.org/ UniProt]. For a description of databases (Locus Specific, HGMD) to which links are provided, click [http://www.ncbi.nlm.nih.gov/books/n/gene/app1/ here].
-</div></div></div><div><div>
-Table B. OMIM Entries for Hepatic Veno-Occlusive Disease with Immunodeficiency ([http://www.ncbi.nlm.nih.gov/omim/235550,604457 View All in OMIM])
-</div><div>
-{|
-|-
-| [http://www.ncbi.nlm.nih.gov/omim/235550 235550]
-| HEPATIC VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY; VODI
-|-
-| [http://www.ncbi.nlm.nih.gov/omim/604457 604457]
-| NUCLEAR BODY PROTEIN SP110; SP110
-|}
-</div></div>
-'''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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/isoforms/ isoforms]:
-* Sp110 isoform A, NM_004509 (average mass 78.438 kd; transcript does not include [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/ exon] 17)
-* Isoform B, NM_004510 (average mass 61.940 kd; transcript includes an alternate [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/ exon] 15 and terminates within exon 15)
-* Isoform C, NM_080424 (average mass 81.211 kd; full-length transcript including [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/exon/ 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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.watashi.2003.7498 Watashi et al 2003]].
-'''Pathologic allelic variants''' (see [http://www.ncbi.nlm.nih.gov/books/NBK1271/table/vodi.T.vodicausing_mutations_in_sp110/?report=objectonly 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/ mutation]. This dinucleotide substitution mutation includes the silent third base of [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/codon/ 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/domain/ domain] of the SP110 protein which mediates dimerization of SP110 with other [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/ 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.
-<div><div>
+'''Evaluation of Relatives at Risk'''
-Table 4. VODI-Causing Mutations in ''SP110''
-</div><div>
-{|
-|-
-| Mutation
-| Exon
-| Reference
-|-
-| colspan="1" rowspan="1" | c.40delC <br />(p.Q14SfsX25)
-| colspan="1" rowspan="1" | 2
-| colspan="1" rowspan="1" | Roscioli et al 2006]
-|-
-| colspan="1" rowspan="1" | c.78_79delinsAT (p.Ile27Leu)
-| colspan="1" rowspan="1" | 2
-| colspan="1" rowspan="1" | Cliffe et al [unpublished data]
-|-
-| colspan="1" rowspan="1" | c.319_325dupGGTGCTT <br />(p.S109WfsX5)
-| colspan="1" rowspan="1" | 4
-| colspan="1" rowspan="1" | [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.ruga.2006.1 Ruga et al [2006]]
-|-
-| colspan="1" rowspan="1" | c.642delC <br />(p.P214PfsX14)
-| colspan="1" rowspan="1" | 5
-| colspan="1" rowspan="1" | [http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al [2006]]
-|-
-| colspan="1" rowspan="1" | c.667+1dup
-| colspan="1" rowspan="1" | 5
-| colspan="1" rowspan="1" | Cliffe et al [unpublished data]
-|}
-</div></div>
-'''Normal [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene-product/ 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/domain/ 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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/transcription/ transcription] include a SAND domain (AA 452-532), a plant homeobox domain (AA 537-577), and a bromodomain (AA 606-674) [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.bloch.2000.6138 Bloch et al 2000]].
+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.
-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 [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/ DNA] replication, [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/transcription/ transcription], and repair and has been reported to be involved in apoptosis, cell cycle control, and the immune response.
+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.
-'''Abnormal [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene-product/ gene product].''' EBV-transformed B cells from an individual with VODI and a homozygous inactivating ''SP110'' [http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/ 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 [[http://www.ncbi.nlm.nih.gov/books/NBK1271/#vodi.REF.roscioli.2006.620 Roscioli et al 2006]].
+==References==
-</div><div><div>Resources<div>[http://www.ncbi.nlm.nih.gov/books/NBK1271/# Go to:]</div></div>
+{{Reflist|2}}
-''See ''[http://www.ncbi.nlm.nih.gov/sites/GeneTests?Db=genetests&Cmd=DiseaseResourcesList&TermToSearch=27207199 ''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.
+[[Category:Disease]]
-</div>
+{{WH}}
+{{WS}}