🏷

Classifications

Harrison's Part

⚙

Pathophysiology

5

Maternal Rubella Viremia and Transplacental Viral Entry

Primary maternal rubella infection in a non-immune pregnant host produces systemic viremia that seeds the placenta, allowing rubella virus to cross the placental barrier and enter fetal tissues during critical first-trimester windows of embryogenesis.

Viral entry into host cell GO:0046718 ↑ INCREASED

Placenta UBERON:0001987

Downstream

Placental Chorionic Villus Endothelial Infection and Angiogenic Impairment Maternal rubella viremia infects placental chorionic villus endothelial cells.

Fetal Cytopathic Apoptosis and Mitotic Inhibition During Organogenesis Transplacental viral dissemination establishes persistent infection in developing fetal organs, triggering capsid-mediated mitochondrial injury, apoptosis, and reduced cell proliferation.

Disseminated Fetal Reticuloendothelial Infection and Extramedullary Hematopoiesis Transplacental viral spread seeds the fetal liver, spleen, and bone marrow, driving hepatosplenic inflammation, thrombocytopenia, and compensatory dermal erythropoiesis.

Show evidence (2 references)

PMID:37327049 SUPPORT BACKGROUND Other

"Some pathogens can be extremely harmfull during pregnancy as they can cross the placenta, infect the fetus, and go on to cause congenital birth defects, miscarriages and stillbirths (Pereira, 2018)."

Establishes transplacental pathogen crossing and fetal infection as the upstream mechanism of congenital defects.

PMID:37327049 SUPPORT Other

"the fetus is most vulnerable to the rubella virus during the first trimester of pregnancy, due to the lack of immune defense in the developing fetus"

Supports transplacental fetal infection during the first trimester.

Placental Chorionic Villus Endothelial Infection and Angiogenic Impairment

Rubella virus infects placental endothelial cells and induces a strong type I and type III interferon response with secretion of angiostatic chemokines such as CXCL10, reducing endothelial migratory and angiogenic capacity and impairing placental vascular development and fetal growth.

Endothelial cell CL:0000115

Angiogenesis GO:0001525 ↓ DECREASED Defense response to virus GO:0051607 ↑ INCREASED

Placenta UBERON:0001987

Downstream

Intrauterine Growth Restriction Impaired placental endothelial angiogenesis and villous vascular insufficiency restrict fetal nutrient and oxygen delivery, causing low birth weight and intrauterine growth restriction.

Fetal Cytopathic Apoptosis and Mitotic Inhibition During Organogenesis Infected placental endothelium facilitates viral shedding into the fetal circulation and systemic fetal organ seeding.

Show evidence (1 reference)

GEO:GSE225949 SUPPORT In vitro / ex vivo

"Endothelial cells (EC) of the placenta are infected by rubella virus (RuV). RuV reduced angiogenic and migratory capacity of primary human EC whereas cell cycle and apoptosis rate were not affected. Next generation sequencing analysis revealed an induction of antiviral type I and III interferons..."

Demonstrates that rubella virus infects placental endothelial cells and impairs angiogenesis via type I/III interferon-induced CXCL10.

Fetal Cytopathic Apoptosis and Mitotic Inhibition During Organogenesis

Within infected fetal tissues (developing lens, retina, cochlear organ of Corti, cardiac outflow tract, and brain), rubella virus capsid protein binds host protein p32, disrupting mitochondrial distribution and morphology, inducing apoptosis, and inhibiting cell population proliferation. In the developing brain, rubella virus infects microglia within heterogeneous neural environments and provokes a profound interferon response in surrounding neurons and neural progenitor cells. This arrest of organogenesis produces the classical Gregg triad of congenital cataracts (along with pigmentary retinopathy), sensorineural deafness, and congenital heart defects as well as microcephaly and intellectual disability.

Microglial cell CL:0000129

Apoptotic process GO:0006915 ↑ INCREASED Cell population proliferation GO:0008283 ↓ DECREASED

Lens UBERON:0000965 Retina UBERON:0000966 Cochlea UBERON:0001844 Heart UBERON:0000948 Brain UBERON:0000955

Downstream

Congenital Cataract Viral invasion and cytopathic apoptosis of embryonic lens fibers arrest lens development and cause congenital nuclear cataract.

Pigmentary Retinopathy Viral infection and focal pigmentary degeneration of the retinal pigment epithelium produce the classic "salt-and-pepper" pigmentary retinopathy.

Sensorineural Hearing Impairment Cytopathic injury to the developing cochlear stria vascularis and organ of Corti causes bilateral or unilateral sensorineural deafness.

Branch Pulmonary Artery Stenosis Viral inhibition of arterial wall elastogenesis and endothelial proliferation produces branch pulmonary artery stenosis.

Patent Ductus Arteriosus Disruption of ductal arterial smooth muscle and elastic lamina development prevents postnatal closure of the ductus arteriosus.

Microcephaly Microglial infection, interferon-mediated neural progenitor perturbation, and mitotic arrest reduce cerebral cortical growth.

Intellectual Disability Fetal neurodevelopmental disruption and microglial-neuronal inflammatory signaling cause lifelong cognitive impairment.

Postnatal Rubella Viral Persistence and Delayed Autoimmune Endocrinopathy Chronic viral persistence in fetal tissues seeds long-term tissue injury and delayed autoimmune and ocular sequelae.

Show evidence (4 references)

PMID:16051872 SUPPORT In vitro / ex vivo

"capsid expression has been reported to cause apoptosis in certain cell types, suggesting that this protein may play a role in the cytopathic effect of the virus"

Demonstrates that rubella capsid expression induces apoptosis, explaining cytopathic fetal tissue injury.

PMID:16051872 SUPPORT In vitro / ex vivo

"The distribution and morphology of mitochondria are dramatically affected during infection with rubella virus (RV)."

Demonstrates rubella virus-induced mitochondrial disruption via capsid-p32 interaction.

PMID:37327049 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo

"We show that in human brain slices, rubella virus predominantly infects microglia. This infection occurs in a heterogeneous population but not in a highly microglia-enriched monoculture in the absence of other cell types. By using an organoid-microglia model, we further demonstrate that rubella..."

Demonstrates microglial tropism of rubella virus in human fetal brain models and downstream interferon-driven perturbation of neurons and neural progenitor cells.

+ 1 more reference

Disseminated Fetal Reticuloendothelial Infection and Extramedullary Hematopoiesis

Systemic fetal viremia involves the liver, spleen, bone marrow, and dermis, causing reticuloendothelial hyperplasia, cholestatic/hemolytic jaundice, megakaryocyte suppression with neonatal thrombocytopenic purpura, and compensatory dermal erythropoiesis presenting as "blueberry muffin" skin lesions.

Liver UBERON:0002107 Spleen UBERON:0002106 Skin UBERON:0002097

Downstream

Hepatosplenomegaly Disseminated viral replication and reticuloendothelial hyperplasia enlarge the neonatal liver and spleen.

Dermal Extramedullary Hematopoiesis (Blueberry Muffin Lesions) Persistent compensatory dermal erythropoiesis produces infiltrative blue-red macules and papules.

Neonatal Thrombocytopenic Purpura Viral bone marrow suppression and peripheral platelet consumption cause neonatal purpura.

Neonatal Jaundice Hepatic viral involvement and hemolysis produce early neonatal hyperbilirubinemia and jaundice.

Show evidence (2 references)

PMID:35367004 SUPPORT Human clinical

"congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"

Documents the disseminated neonatal manifestations of jaundice, purpura, and hepatosplenomegaly in CRS.

PMID:25654000 SUPPORT Human clinical

"The baby had blueberry muffin skin lesions, long bone metaphysitis and congenital heart defects."

Documents cutaneous extramedullary hematopoiesis (blueberry muffin lesions) in neonatal CRS.

Postnatal Rubella Viral Persistence and Delayed Autoimmune Endocrinopathy

Chronic persistence of rubella virus in tissues after birth, shortened cellular lifespan, progressive vascular damage, and virus-triggered autoimmune responses against endocrine organs and ocular structures lead to delayed-onset CRS manifestations years to decades later, notably insulin-dependent diabetes mellitus, thyroid disorders, and late-onset glaucoma.

Cell population proliferation GO:0008283 ↓ DECREASED Autoimmune response GO:0006955 ⚠ ABNORMAL

Pancreas UBERON:0001264 Thyroid gland UBERON:0002046 Eye UBERON:0000970

Downstream

Delayed-Onset Diabetes Mellitus Chronic viral persistence and autoimmune pancreatic islet injury cause delayed-onset diabetes mellitus in childhood or adulthood.

Delayed-Onset Thyroid Disease Infection-stimulated autoimmune thyroiditis and chronic tissue injury cause delayed-onset hypothyroidism and thyroid dysfunction in childhood or adulthood.

Congenital or Delayed-Onset Glaucoma Persistent ocular viral damage and trabecular meshwork injury lead to congenital or delayed-onset glaucoma.

Show evidence (2 references)

PMID:4001724 SUPPORT Human clinical

"Several mechanisms of pathogenesis of the damage have to be considered for the delayed manifestations, including growth of the virus in tissues, resulting in a reduced growth rate and shortened life-span of the cells; autoimmune responses, initially stimulated by the infection; genetic..."

Details the mechanisms driving delayed CRS manifestations, including chronic tissue viral persistence, reduced cellular growth rate, vascular damage, and infection-stimulated autoimmunity.

PMID:12463994 SUPPORT Human clinical

"The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"

60-year longitudinal follow-up confirming markedly elevated prevalence of late-onset diabetes and endocrine disorders in CRS survivors.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Blood 2

Dermal Extramedullary Hematopoiesis (Blueberry Muffin Lesions) HP:0001978

Show evidence (1 reference)

PMID:25654000 SUPPORT Human clinical

"The baby had blueberry muffin skin lesions, long bone metaphysitis and congenital heart defects."

Documents neonatal blueberry muffin skin lesions in congenital rubella syndrome.

Neonatal Thrombocytopenic Purpura HP:0000979

Show evidence (1 reference)

PMID:35367004 SUPPORT Human clinical

"congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"

Documents purpura as a classic neonatal manifestation of congenital rubella syndrome.

Cardiovascular 3

Branch Pulmonary Artery Stenosis HP:0004415

Show evidence (1 reference)

PMID:19697432 SUPPORT Human clinical

"Of the 121 patients in the 10 studies with catheterization data, 78% had branch pulmonary artery stenosis, and 62% had a PDA."

Quantifies branch pulmonary artery stenosis as the most common cardiac malformation in CRS (78%).

Patent Ductus Arteriosus HP:0001643

Show evidence (1 reference)

PMID:19697432 SUPPORT Human clinical

"Of the 121 patients in the 10 studies with catheterization data, 78% had branch pulmonary artery stenosis, and 62% had a PDA."

Quantifies patent ductus arteriosus in 62% of catheterized CRS patients.

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:35367004 SUPPORT Human clinical

"congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"

Lists hepatosplenomegaly as a classic neonatal CRS sign.

Digestive 1

Neonatal Jaundice HP:0000952

Show evidence (1 reference)

PMID:35367004 SUPPORT Human clinical

"congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"

Documents neonatal jaundice as a core clinical manifestation of congenital rubella syndrome.

Ear 1

Sensorineural Hearing Impairment HP:0000407

Show evidence (2 references)

PMID:35367004 SUPPORT Human clinical

"congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"

Lancet seminar identifying sensorineural hearing impairment as a core CRS manifestation.

PMID:19249974 SUPPORT Human clinical

"Gregg first described the triad of deafness, cataracts and cardiac disease as the classical clinical manifestations of congenital rubella syndrome (CRS)"

Documents deafness as a primary component of the classical CRS triad.

Endocrine 2

Delayed-Onset Diabetes Mellitus HP:0000819

Show evidence (2 references)

PMID:4001724 SUPPORT Human clinical

"The delayed manifestations are not present in early life and include the following: endocrinopathies: diabetes, thyroid disease, and growth hormone deficiency"

Establishes diabetes as a delayed-onset endocrine manifestation of congenital rubella syndrome.

PMID:12463994 SUPPORT Human clinical

"The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"

Quantifies a 22% prevalence of diabetes mellitus in adult survivors of congenital rubella syndrome.

Delayed-Onset Thyroid Disease Hypothyroidism HP:0000821

Show evidence (2 references)

PMID:4001724 SUPPORT Human clinical

"The delayed manifestations are not present in early life and include the following: endocrinopathies: diabetes, thyroid disease, and growth hormone deficiency"

Establishes thyroid disease as a delayed-onset endocrine manifestation of congenital rubella syndrome.

PMID:12463994 SUPPORT Human clinical

"The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"

Quantifies a 19% prevalence of thyroid disorders in adult survivors of congenital rubella syndrome.

Eye 3

Congenital Cataract HP:0000518

Show evidence (3 references)

PMID:12463994 SUPPORT Human clinical

"In 1941, a Sydney ophthalmologist, Norman McAlister Gregg, correctly identified the link between congenital cataracts in infants and maternal rubella early in pregnancy."

Historic cohort study establishing congenital cataract as the founding hallmark of CRS.

PMID:19249974 SUPPORT Human clinical

"Gregg first described the triad of deafness, cataracts and cardiac disease as the classical clinical manifestations of congenital rubella syndrome (CRS)"

Confirms cataract as part of the classical CRS triad.

PMID:31745134 SUPPORT Human clinical

"One-hundred-and-eight children with CRS were enrolled. Cardiac defects (99%), cataracts (72%), and hearing impairment (7%) were detected."

Documents congenital cataracts in 72% of a 108-child clinical cohort with CRS.

Pigmentary Retinopathy HP:0000580

Show evidence (2 references)

PMID:28012878 SUPPORT REVIEW SYNTHESIS Other

"Pigmentary retinopathy is developed in about 20%–60% of children with congenital rubella syndrome."

Establishes the 20%–60% prevalence of pigmentary retinopathy in children with congenital rubella syndrome.

PMID:28012878 SUPPORT REVIEW SYNTHESIS Other

"Congenital rubella causes a progressive pigmentary retinopathy that is characterized by a “salt and pepper” fundus."

Documents the characteristic "salt-and-pepper" fundus appearance of rubella pigmentary retinopathy.

Congenital or Delayed-Onset Glaucoma HP:0000501

Show evidence (1 reference)

PMID:4001724 SUPPORT Human clinical

"ocular damage: glaucoma, keratic precipitates, keratoconus, corneal hydrops, and absorption of the cataractous lens"

Documents glaucoma as a delayed ocular manifestation of congenital rubella.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:35367004 SUPPORT Human clinical

"congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"

Lists microcephaly among the core clinical features of CRS.

Nervous System 1

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:16051872 SUPPORT BACKGROUND Human clinical

"Symptoms of CRS include low birth weight, deafness, cataracts, mental retardation, and heart disease (10)."

Documents intellectual disability (historically termed mental retardation) as a classic manifestation of CRS.

Growth 1

Intrauterine Growth Restriction Intrauterine growth retardation HP:0001511

Show evidence (2 references)

PMID:31745134 SUPPORT Human clinical

"CRS-PDA patients had smaller median birthweight (p < 0.001), more frequent pulmonary (p < 0.001) and aortic stenosis (p < 0.001), higher main pulmonary artery pressure, and higher aortic pressure in systole/diastole (p < 0.001 for each) than did non-CRS-PDA patients."

Demonstrates significantly smaller median birthweight in infants with CRS-associated patent ductus arteriosus compared with non-CRS controls.

PMID:16051872 SUPPORT BACKGROUND Human clinical

"Symptoms of CRS include low birth weight, deafness, cataracts, mental retardation, and heart disease (10)."

Lists low birth weight as a classic clinical feature of congenital rubella syndrome.

💊

Medical Actions

2

Pre-Conception and Childhood Live-Attenuated Rubella Vaccination (MMR)

Action: vaccination Ontology label: Vaccination NCIT:C15346

Platform: Vaccine

Immunization of children and non-pregnant women of childbearing age with live-attenuated rubella-containing vaccine (RA 27/3 strain, typically delivered as MMR) induces durable anti-E1 neutralizing IgG antibodies that prevent maternal rubella viremia and transplacental transmission, eliminating congenital rubella syndrome.

Mechanism Target:

INHIBITS Maternal Rubella Viremia and Transplacental Viral Entry — Pre-existing vaccine-induced neutralizing antibodies block maternal rubella viremia and prevent transplacental viral seeding of the placenta and fetus.

Show evidence (1 reference)

PMID:35367004 SUPPORT Human clinical

"Rubella and congenital rubella syndrome can be prevented by rubella-containing vaccines, which are commonly administered in combination with measles vaccine."

Establishes that rubella-containing vaccines prevent primary maternal rubella and congenital rubella syndrome.

Show evidence (1 reference)

PMID:35367004 SUPPORT Human clinical

"Rubella and congenital rubella syndrome can be prevented by rubella-containing vaccines, which are commonly administered in combination with measles vaccine."

Lancet seminar establishing rubella-containing vaccines as the primary means of preventing congenital rubella syndrome.

Multidisciplinary Supportive, Surgical, and Rehabilitative Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Management of affected infants requires inpatient medical care and interventional or surgical repair of structural congenital defects, notably transcatheter occlusion therapy for patent ductus arteriosus alongside ophthalmologic and audiologic care.

Show evidence (2 references)

PMID:31745134 SUPPORT Human clinical

"Tubular-type PDA was frequently seen in patients with CRS and accompanied by pulmonary/systemic hypertension and pulmonary/aortic stenosis; in these patients, more cautious device selection is needed for transcatheter PDA closure."

Clinical management conclusion demonstrating that transcatheter device closure of tubular-type patent ductus arteriosus in CRS patients with concomitant pulmonary/systemic hypertension and pulmonary/aortic stenosis requires cautious device selection.

PMID:31745134 SUPPORT Human clinical

"We reviewed the medical records of patients with CRS who were admitted to the Children's Hospital 1 in Vietnam between December 2010 and December 2012, and patients with CRS who underwent PDA transcatheter occlusion therapy at the cardiology department between December 2009 and December 2015."

Documents inpatient care and transcatheter occlusion therapy for patent ductus arteriosus in children with congenital rubella syndrome.

🔬

Diagnosis

3

Rubella-Specific IgM Serology

Detection of rubella-specific IgM antibody in neonatal or maternal serum is the primary serological test for confirming congenital rubella infection or maternal primary rubella in pregnancy; because IgM does not cross the placenta, neonatal rubella IgM indicates fetal infection, while maternal IgM reactivity in low-prevalence settings requires confirmatory testing.

Rubella IgM LOINC:31616-6

The qualitative serum presence code is bound; no numerical reference_ranges apply to a qualitative presence assay.

Show evidence (2 references)

PMID:28412379 SUPPORT Other

"Laboratory investigation heavily relies on specific IgM serology and increasingly on virus detection by reverse transcription (RT)-PCR, but other methods such as IgG avidity testing and genetic characterization of virus strains have gained in importance."

Establishes rubella-specific IgM serology as the core laboratory diagnostic method alongside RT-PCR and IgG avidity.

PMID:33316569 SUPPORT Human clinical

"In case of seroconversion for RV-IgG and/or positive RVIgM during pregnancy, laboratories usually send serum samples to the French National Reference Laboratory (FNRL) for Rubella in order to perform complementary investigations and confirm or exclude rubella infection during pregnancy."

Documents maternal rubella IgM and IgG seroconversion testing as the diagnostic trigger for prenatal rubella evaluation.

Maternal Rubella IgG Avidity Testing

Measurement of rubella-specific IgG avidity in maternal serum distinguishes acute primary rubella infection (low avidity) from pre-existing immunity or reinfection (high avidity) when evaluating congenital rubella risk during pregnancy.

Rubella IgG avidity LOINC:34421-8

Assay-specific low/high avidity cutoffs vary by commercial kit and eluting agent, so no universal reference_ranges are recorded.

Show evidence (1 reference)

PMID:33316569 SUPPORT Human clinical

"Additional serological tests were performed, mainly immunoblot (to look for the presence of anti-E1 protective antibody) and RV-IgG avidity (to exclude or confirm primary infection)."

Confirms the role of rubella IgG avidity testing in confirming or excluding maternal primary infection during pregnancy.

Rubella Virus Reverse Transcription PCR (RT-PCR)

Direct detection of rubella viral RNA by reverse transcription polymerase chain reaction (RT-PCR) in clinical specimens provides molecular confirmation of infection and enables viral genotyping for epidemiological tracking.

polymerase chain reaction NCIT:C17003

Show evidence (2 references)

PMID:21116802 SUPPORT Other

"Direct detection of viral genomic material using reverse transcription polymerase chain reaction (RT-PCR) methodologies can play an important role for laboratory confirmation of acute infections."

Establishes RT-PCR detection of rubella viral RNA for laboratory confirmation.

PMID:28412379 SUPPORT Other

"Laboratory investigation heavily relies on specific IgM serology and increasingly on virus detection by reverse transcription (RT)-PCR, but other methods such as IgG avidity testing and genetic characterization of virus strains have gained in importance."

Confirms the increasing diagnostic role of RT-PCR virus detection and genetic characterization.

📈

Progression

2

Congenital and Neonatal Presentation

Age: First-trimester fetal onset with neonatal presentation

Fetal vulnerability is highest during first-trimester maternal primary rubella infection, producing structural embryopathy (cataracts, pigmentary retinopathy, sensorineural hearing impairment, branch pulmonary artery stenosis, patent ductus arteriosus, microcephaly) and extended newborn signs (intrauterine growth restriction, hepatosplenomegaly, jaundice, thrombocytopenic purpura, and dermal extramedullary hematopoiesis).

Show evidence (2 references)

PMID:4001724 SUPPORT Human clinical

"The manifestations of congenital rubella syndrome (CRS) can be grouped according to time of onset into newborn, extended, and delayed CRS."

Defines the temporal progression of CRS into newborn, extended, and delayed phases.

PMID:37327049 SUPPORT Other

"the fetus is most vulnerable to the rubella virus during the first trimester of pregnancy, due to the lack of immune defense in the developing fetus"

Establishes the first trimester as the critical window for congenital onset.

Delayed-Onset Childhood and Adult Sequelae

Age: Late childhood through adulthood

Years to decades after congenital infection, survivors develop delayed manifestations driven by chronic viral persistence, vascular stenosis, and autoimmunity, including diabetes mellitus, thyroid disorders, and late-onset glaucoma.

Show evidence (2 references)

PMID:4001724 SUPPORT Human clinical

"The delayed manifestations are not present in early life and include the following: endocrinopathies: diabetes, thyroid disease, and growth hormone deficiency"

Documents delayed-onset endocrine manifestations emerging after early life.

PMID:12463994 SUPPORT Human clinical

"The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"

Demonstrates adult-onset endocrine and metabolic sequelae 60 years after congenital rubella infection.

🦠

Infectious Agent

1

Rubella virus

Rubella virus (Rubivirus rubellae; family Matonaviridae) is an enveloped, single-stranded positive-sense RNA virus whose E1 and E2 envelope glycoproteins mediate host cell entry and serve as the targets of neutralizing maternal and vaccine-induced antibodies, while the viral capsid protein interacts with host mitochondrial protein p32 to perturb mitochondrial distribution and trigger cytopathic apoptosis in developing fetal tissues.

Rubella virus NCBITaxon:11041

Show evidence (2 references)

PMID:16051872 SUPPORT BACKGROUND Human clinical

"Rubella virus (RV) is the causative agent of the disease known as rubella or German measles in humans."

Establishes rubella virus as the causative agent of rubella in humans.

PMID:35367004 SUPPORT Human clinical

"Rubella is an acute illness caused by rubella virus and characterised by fever and rash."

Establishes rubella virus as the etiologic pathogen.

↔️

Transmission

1

Transplacental (vertical) transmission

Following maternal respiratory acquisition and systemic viremia during early gestation, rubella virus infects the placental chorionic villous endothelium and crosses the placental barrier to establish chronic infection in the developing fetus, which lacks mature adaptive immune defenses during the first trimester.

Show evidence (2 references)

PMID:35367004 SUPPORT Human clinical

"primary rubella virus infection in early pregnancy can result in congenital rubella syndrome, which has serious medical and public health consequences"

Establishes early-pregnancy maternal rubella infection as the route to congenital rubella syndrome.

PMID:37327049 SUPPORT Other

"the fetus is most vulnerable to the rubella virus during the first trimester of pregnancy, due to the lack of immune defense in the developing fetus"

Documents first-trimester fetal vulnerability to transplacental rubella infection.

📊

Related Datasets

1

Rubella virus infection in endothelial cells reduces angiogenesis via interferon betainduced CXCL10 geo:GSE225949

Rubella virus infection during pregnancy can result in abortion, stillbirth and severe defects in embryogenesis resulting in congenital rubella syndrome (CRS). Low vaccination coverage in developing regions results in estimated 100,000 CRS cases in infants per year with a mortality rate over 30%. The molecular pathomechanisms and potential treatments remain largely unexplored. Endothelial cells (EC) of the placenta are infected by rubella virus (RuV). RuV reduced angiogenic and migratory capacity of primary human EC whereas cell cycle and apoptosis rate were not affected.

human BULK RNA SEQ n=19

Identified by GEO DataSets index search for Rubella; directly profiles placental endothelial cell infection relevant to congenital rubella syndrome.

{ }

Source YAML

click to show

name: Congenital Rubella Syndrome
creation_date: "2026-11-01T00:00:00Z"
category: Infectious Disease
synonyms:
- CRS
- Fetal rubella syndrome
- Gregg syndrome
description: >
  Congenital rubella syndrome (CRS) is a severe teratogenic disorder resulting from
  maternal primary infection with rubella virus during early pregnancy, with the
  highest risk of congenital anomalies occurring during the first trimester.
  Transplacental viral transmission leads to placental chorionic villus endothelial
  infection with interferon-driven angiogenic impairment, persistent fetal infection,
  and capsid-p32-mediated mitochondrial disruption, apoptosis, and mitotic arrest
  during organogenesis. Classically described by Norman Gregg in 1941 as a triad of
  sensorineural deafness, congenital cataracts, and congenital heart disease (most
  commonly branch pulmonary artery stenosis and patent ductus arteriosus), CRS also
  presents with intrauterine growth restriction, microcephaly, intellectual
  disability, hepatosplenomegaly, neonatal jaundice, thrombocytopenic purpura,
  "blueberry muffin" lesions of dermal extramedullary hematopoiesis, and delayed-onset
  manifestations including diabetes mellitus and glaucoma. Universal immunization with
  live-attenuated rubella-containing vaccines (RA 27/3 strain in MMR) prevents
  maternal rubella viremia and transplacental transmission.
disease_term:
  preferred_term: congenital rubella syndrome
  term:
    id: MONDO:0017361
    label: congenital rubella syndrome
parents:
- Congenital infection
- Teratogenic syndrome
infectious_agent:
- name: Rubella virus
  infectious_agent_term:
    preferred_term: Rubella virus
    term:
      id: NCBITaxon:11041
      label: Rubella virus
  description: >
    Rubella virus (Rubivirus rubellae; family Matonaviridae) is an enveloped,
    single-stranded positive-sense RNA virus whose E1 and E2 envelope glycoproteins
    mediate host cell entry and serve as the targets of neutralizing maternal and
    vaccine-induced antibodies, while the viral capsid protein interacts with host
    mitochondrial protein p32 to perturb mitochondrial distribution and trigger
    cytopathic apoptosis in developing fetal tissues.
  evidence:
  - reference: PMID:16051872
    reference_title: "Interactions between rubella virus capsid and host protein p32 are important for virus replication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Rubella virus (RV) is the causative agent of the disease known as rubella or German measles in humans."
    explanation: Establishes rubella virus as the causative agent of rubella in humans.
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rubella is an acute illness caused by rubella virus and characterised by fever and rash."
    explanation: Establishes rubella virus as the etiologic pathogen.
transmission:
- name: Transplacental (vertical) transmission
  description: >
    Following maternal respiratory acquisition and systemic viremia during early
    gestation, rubella virus infects the placental chorionic villous endothelium and
    crosses the placental barrier to establish chronic infection in the developing
    fetus, which lacks mature adaptive immune defenses during the first trimester.
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "primary rubella virus infection in early pregnancy can result in congenital rubella syndrome, which has serious medical and public health consequences"
    explanation: Establishes early-pregnancy maternal rubella infection as the route to congenital rubella syndrome.
  - reference: PMID:37327049
    reference_title: "The dangers of rubella virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the fetus is most vulnerable to the rubella virus during the first trimester of pregnancy, due to the lack of immune defense in the developing fetus"
    explanation: Documents first-trimester fetal vulnerability to transplacental rubella infection.
pathophysiology:
- name: Maternal Rubella Viremia and Transplacental Viral Entry
  description: >
    Primary maternal rubella infection in a non-immune pregnant host produces systemic
    viremia that seeds the placenta, allowing rubella virus to cross the placental
    barrier and enter fetal tissues during critical first-trimester windows of
    embryogenesis.
  locations:
  - preferred_term: Placenta
    term:
      id: UBERON:0001987
      label: placenta
  biological_processes:
  - preferred_term: Viral entry into host cell
    modifier: INCREASED
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  downstream:
  - target: Placental Chorionic Villus Endothelial Infection and Angiogenic Impairment
    description: Maternal rubella viremia infects placental chorionic villus endothelial cells.
  - target: Fetal Cytopathic Apoptosis and Mitotic Inhibition During Organogenesis
    description: Transplacental viral dissemination establishes persistent infection in developing fetal organs, triggering capsid-mediated mitochondrial injury, apoptosis, and reduced cell proliferation.
  - target: Disseminated Fetal Reticuloendothelial Infection and Extramedullary Hematopoiesis
    description: Transplacental viral spread seeds the fetal liver, spleen, and bone marrow, driving hepatosplenic inflammation, thrombocytopenia, and compensatory dermal erythropoiesis.
  evidence:
  - reference: PMID:37327049
    reference_title: "The dangers of rubella virus."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Some pathogens can be extremely harmfull during pregnancy as they can cross the placenta, infect the fetus, and go on to cause congenital birth defects, miscarriages and stillbirths (Pereira, 2018)."
    explanation: Establishes transplacental pathogen crossing and fetal infection as the upstream mechanism of congenital defects.
  - reference: PMID:37327049
    reference_title: "The dangers of rubella virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the fetus is most vulnerable to the rubella virus during the first trimester of pregnancy, due to the lack of immune defense in the developing fetus"
    explanation: Supports transplacental fetal infection during the first trimester.
- name: Placental Chorionic Villus Endothelial Infection and Angiogenic Impairment
  description: >
    Rubella virus infects placental endothelial cells and induces a strong type I and
    type III interferon response with secretion of angiostatic chemokines such as
    CXCL10, reducing endothelial migratory and angiogenic capacity and impairing
    placental vascular development and fetal growth.
  locations:
  - preferred_term: Placenta
    term:
      id: UBERON:0001987
      label: placenta
  cell_types:
  - preferred_term: Endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Angiogenesis
    modifier: DECREASED
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: Defense response to virus
    modifier: INCREASED
    term:
      id: GO:0051607
      label: defense response to virus
  downstream:
  - target: Intrauterine Growth Restriction
    description: Impaired placental endothelial angiogenesis and villous vascular insufficiency restrict fetal nutrient and oxygen delivery, causing low birth weight and intrauterine growth restriction.
  - target: Fetal Cytopathic Apoptosis and Mitotic Inhibition During Organogenesis
    description: Infected placental endothelium facilitates viral shedding into the fetal circulation and systemic fetal organ seeding.
  evidence:
  - reference: GEO:GSE225949
    reference_title: "Rubella virus infection in endothelial cells reduces angiogenesis via interferon betainduced CXCL10"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Endothelial cells (EC) of the placenta are infected by rubella virus (RuV). RuV reduced angiogenic and migratory capacity of primary human EC whereas cell cycle and apoptosis rate were not affected. Next generation sequencing analysis revealed an induction of antiviral type I and III interferons (IFN) that induced angiogenesis-inhibiting cytokines such as CXCL10."
    explanation: Demonstrates that rubella virus infects placental endothelial cells and impairs angiogenesis via type I/III interferon-induced CXCL10.
- name: Fetal Cytopathic Apoptosis and Mitotic Inhibition During Organogenesis
  description: >
    Within infected fetal tissues (developing lens, retina, cochlear organ of
    Corti, cardiac outflow tract, and brain), rubella virus capsid protein binds
    host protein p32, disrupting mitochondrial distribution and morphology,
    inducing apoptosis, and inhibiting cell population proliferation. In the
    developing brain, rubella virus infects microglia within heterogeneous neural
    environments and provokes a profound interferon response in surrounding neurons
    and neural progenitor cells. This arrest of organogenesis produces the
    classical Gregg triad of congenital cataracts (along with pigmentary
    retinopathy), sensorineural deafness, and congenital heart defects as well as
    microcephaly and intellectual disability.
  locations:
  - preferred_term: Lens
    term:
      id: UBERON:0000965
      label: lens of camera-type eye
  - preferred_term: Retina
    term:
      id: UBERON:0000966
      label: retina
  - preferred_term: Cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  - preferred_term: Heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: Brain
    term:
      id: UBERON:0000955
      label: brain
  cell_types:
  - preferred_term: Microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: Apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: Cell population proliferation
    modifier: DECREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Congenital Cataract
    description: Viral invasion and cytopathic apoptosis of embryonic lens fibers arrest lens development and cause congenital nuclear cataract.
  - target: Pigmentary Retinopathy
    description: Viral infection and focal pigmentary degeneration of the retinal pigment epithelium produce the classic "salt-and-pepper" pigmentary retinopathy.
  - target: Sensorineural Hearing Impairment
    description: Cytopathic injury to the developing cochlear stria vascularis and organ of Corti causes bilateral or unilateral sensorineural deafness.
  - target: Branch Pulmonary Artery Stenosis
    description: Viral inhibition of arterial wall elastogenesis and endothelial proliferation produces branch pulmonary artery stenosis.
  - target: Patent Ductus Arteriosus
    description: Disruption of ductal arterial smooth muscle and elastic lamina development prevents postnatal closure of the ductus arteriosus.
  - target: Microcephaly
    description: Microglial infection, interferon-mediated neural progenitor perturbation, and mitotic arrest reduce cerebral cortical growth.
  - target: Intellectual Disability
    description: Fetal neurodevelopmental disruption and microglial-neuronal inflammatory signaling cause lifelong cognitive impairment.
  - target: Postnatal Rubella Viral Persistence and Delayed Autoimmune Endocrinopathy
    description: Chronic viral persistence in fetal tissues seeds long-term tissue injury and delayed autoimmune and ocular sequelae.
  evidence:
  - reference: PMID:16051872
    reference_title: "Interactions between rubella virus capsid and host protein p32 are important for virus replication."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "capsid expression has been reported to cause apoptosis in certain cell types, suggesting that this protein may play a role in the cytopathic effect of the virus"
    explanation: Demonstrates that rubella capsid expression induces apoptosis, explaining cytopathic fetal tissue injury.
  - reference: PMID:16051872
    reference_title: "Interactions between rubella virus capsid and host protein p32 are important for virus replication."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The distribution and morphology of mitochondria are dramatically affected during infection with rubella virus (RV)."
    explanation: Demonstrates rubella virus-induced mitochondrial disruption via capsid-p32 interaction.
  - reference: PMID:37327049
    reference_title: "The dangers of rubella virus."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "We show that in human brain slices, rubella virus predominantly infects microglia. This infection occurs in a heterogeneous population but not in a highly microglia-enriched monoculture in the absence of other cell types. By using an organoid-microglia model, we further demonstrate that rubella virus infection leads to a profound interferon response in non-microglial cells, including neurons and neural progenitor cells"
    explanation: Demonstrates microglial tropism of rubella virus in human fetal brain models and downstream interferon-driven perturbation of neurons and neural progenitor cells.
  - reference: PMID:28012878
    reference_title: "Viral posterior uveitis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Retinopathy caused by rubella is usually associated with congenital rubella syndrome, characterized by a triad of auditory, ocular (cataracts, microphthalmos and pigmentary retinopathy) and cardiac defects."
    explanation: Documents rubella-induced pigmentary retinopathy alongside cataracts, auditory, and cardiac defects as part of the congenital rubella embryopathy triad.
- name: Disseminated Fetal Reticuloendothelial Infection and Extramedullary Hematopoiesis
  description: >
    Systemic fetal viremia involves the liver, spleen, bone marrow, and dermis,
    causing reticuloendothelial hyperplasia, cholestatic/hemolytic jaundice,
    megakaryocyte suppression with neonatal thrombocytopenic purpura, and
    compensatory dermal erythropoiesis presenting as "blueberry muffin" skin lesions.
  locations:
  - preferred_term: Liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: Spleen
    term:
      id: UBERON:0002106
      label: spleen
  - preferred_term: Skin
    term:
      id: UBERON:0002097
      label: skin of body
  downstream:
  - target: Hepatosplenomegaly
    description: Disseminated viral replication and reticuloendothelial hyperplasia enlarge the neonatal liver and spleen.
  - target: Dermal Extramedullary Hematopoiesis (Blueberry Muffin Lesions)
    description: Persistent compensatory dermal erythropoiesis produces infiltrative blue-red macules and papules.
  - target: Neonatal Thrombocytopenic Purpura
    description: Viral bone marrow suppression and peripheral platelet consumption cause neonatal purpura.
  - target: Neonatal Jaundice
    description: Hepatic viral involvement and hemolysis produce early neonatal hyperbilirubinemia and jaundice.
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"
    explanation: Documents the disseminated neonatal manifestations of jaundice, purpura, and hepatosplenomegaly in CRS.
  - reference: PMID:25654000
    reference_title: "Congenital rubella syndrome with blueberry muffin lesions and extensive metaphysitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The baby had blueberry muffin skin lesions, long bone metaphysitis and congenital heart defects."
    explanation: Documents cutaneous extramedullary hematopoiesis (blueberry muffin lesions) in neonatal CRS.
- name: Postnatal Rubella Viral Persistence and Delayed Autoimmune Endocrinopathy
  description: >
    Chronic persistence of rubella virus in tissues after birth, shortened cellular
    lifespan, progressive vascular damage, and virus-triggered autoimmune responses
    against endocrine organs and ocular structures lead to delayed-onset CRS
    manifestations years to decades later, notably insulin-dependent diabetes
    mellitus, thyroid disorders, and late-onset glaucoma.
  notes: >-
    Gene Ontology (GO) was searched for a biological process term specific to
    autoimmune response and none exists; GO:0006955 (immune response) with
    modifier: ABNORMAL is used as the closest available GO anchor for delayed
    autoimmune endocrinopathy.
  locations:
  - preferred_term: Pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  - preferred_term: Thyroid gland
    term:
      id: UBERON:0002046
      label: thyroid gland
  - preferred_term: Eye
    term:
      id: UBERON:0000970
      label: eye
  biological_processes:
  - preferred_term: Cell population proliferation
    modifier: DECREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: Autoimmune response
    modifier: ABNORMAL
    term:
      id: GO:0006955
      label: immune response
  downstream:
  - target: Delayed-Onset Diabetes Mellitus
    description: Chronic viral persistence and autoimmune pancreatic islet injury cause delayed-onset diabetes mellitus in childhood or adulthood.
  - target: Delayed-Onset Thyroid Disease
    description: Infection-stimulated autoimmune thyroiditis and chronic tissue injury cause delayed-onset hypothyroidism and thyroid dysfunction in childhood or adulthood.
  - target: Congenital or Delayed-Onset Glaucoma
    description: Persistent ocular viral damage and trabecular meshwork injury lead to congenital or delayed-onset glaucoma.
  evidence:
  - reference: PMID:4001724
    reference_title: "Delayed manifestations of congenital rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several mechanisms of pathogenesis of the damage have to be considered for the delayed manifestations, including growth of the virus in tissues, resulting in a reduced growth rate and shortened life-span of the cells; autoimmune responses, initially stimulated by the infection; genetic susceptibility; vascular damage by the viral infection with further stenosis or occlusion of the vessels later; reactive hypervascularization; and chronic persistence of the virus in the tissue with subsequent extension of the infection to other areas."
    explanation: Details the mechanisms driving delayed CRS manifestations, including chronic tissue viral persistence, reduced cellular growth rate, vascular damage, and infection-stimulated autoimmunity.
  - reference: PMID:12463994
    reference_title: "Gregg's congenital rubella patients 60 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"
    explanation: 60-year longitudinal follow-up confirming markedly elevated prevalence of late-onset diabetes and endocrine disorders in CRS survivors.
phenotypes:
- name: Congenital Cataract
  description: >
    Congenital nuclear or total cataract resulting from rubella viral invasion of the
    developing embryonic lens vesicle; one of the three classical manifestations of
    Gregg's triad.
  category: Ophthalmologic
  diagnostic: true
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:12463994
    reference_title: "Gregg's congenital rubella patients 60 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 1941, a Sydney ophthalmologist, Norman McAlister Gregg, correctly identified the link between congenital cataracts in infants and maternal rubella early in pregnancy."
    explanation: Historic cohort study establishing congenital cataract as the founding hallmark of CRS.
  - reference: PMID:19249974
    reference_title: "Congenital rubella syndrome: progress and future challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gregg first described the triad of deafness, cataracts and cardiac disease as the classical clinical manifestations of congenital rubella syndrome (CRS)"
    explanation: Confirms cataract as part of the classical CRS triad.
  - reference: PMID:31745134
    reference_title: "Characteristics of Patent Ductus Arteriosus in Congenital Rubella Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One-hundred-and-eight children with CRS were enrolled. Cardiac defects (99%), cataracts (72%), and hearing impairment (7%) were detected."
    explanation: Documents congenital cataracts in 72% of a 108-child clinical cohort with CRS.
- name: Pigmentary Retinopathy
  description: >
    Bilateral "salt-and-pepper" pigmentary retinopathy affecting 20%–60% of
    children with congenital rubella syndrome, characterized by mottled areas of
    retinal pigment epithelium hypopigmentation and hyperpigmentation in the
    posterior pole and macula.
  category: Ophthalmologic
  diagnostic: true
  phenotype_term:
    preferred_term: Pigmentary retinopathy
    term:
      id: HP:0000580
      label: Pigmentary retinopathy
  evidence:
  - reference: PMID:28012878
    reference_title: "Viral posterior uveitis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pigmentary retinopathy is developed in about 20%–60% of children with congenital rubella syndrome."
    explanation: Establishes the 20%–60% prevalence of pigmentary retinopathy in children with congenital rubella syndrome.
  - reference: PMID:28012878
    reference_title: "Viral posterior uveitis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Congenital rubella causes a progressive pigmentary retinopathy that is characterized by a “salt and pepper” fundus."
    explanation: Documents the characteristic "salt-and-pepper" fundus appearance of rubella pigmentary retinopathy.
- name: Sensorineural Hearing Impairment
  description: >
    Bilateral or unilateral sensorineural deafness caused by viral cytopathic damage
    to the cochlear stria vascularis and organ of Corti; the single most common and
    frequently isolated manifestation of congenital rubella syndrome.
  category: Otologic
  diagnostic: true
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"
    explanation: Lancet seminar identifying sensorineural hearing impairment as a core CRS manifestation.
  - reference: PMID:19249974
    reference_title: "Congenital rubella syndrome: progress and future challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gregg first described the triad of deafness, cataracts and cardiac disease as the classical clinical manifestations of congenital rubella syndrome (CRS)"
    explanation: Documents deafness as a primary component of the classical CRS triad.
- name: Branch Pulmonary Artery Stenosis
  description: >
    Stenosis of the main or branch pulmonary arteries, the most frequent
    cardiovascular malformation documented by cardiac catheterization in patients
    with congenital rubella syndrome.
  category: Cardiovascular
  phenotype_term:
    preferred_term: Pulmonary artery stenosis
    term:
      id: HP:0004415
      label: Pulmonary artery stenosis
  evidence:
  - reference: PMID:19697432
    reference_title: "An update on cardiovascular malformations in congenital rubella syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 121 patients in the 10 studies with catheterization data, 78% had branch pulmonary artery stenosis, and 62% had a PDA."
    explanation: Quantifies branch pulmonary artery stenosis as the most common cardiac malformation in CRS (78%).
- name: Patent Ductus Arteriosus
  description: >
    Persistence of the fetal ductus arteriosus due to rubella-induced disruption of
    ductal arterial wall elastogenesis and smooth muscle closure; one of the two
    signature cardiac lesions of CRS.
  category: Cardiovascular
  diagnostic: true
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:19697432
    reference_title: "An update on cardiovascular malformations in congenital rubella syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 121 patients in the 10 studies with catheterization data, 78% had branch pulmonary artery stenosis, and 62% had a PDA."
    explanation: Quantifies patent ductus arteriosus in 62% of catheterized CRS patients.
- name: Intrauterine Growth Restriction
  description: >
    Fetal growth restriction and low birthweight resulting from placental chorionic
    villous endothelial infection, impaired placental angiogenesis, and direct fetal
    mitotic inhibition.
  category: Growth
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:31745134
    reference_title: "Characteristics of Patent Ductus Arteriosus in Congenital Rubella Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CRS-PDA patients had smaller median birthweight (p < 0.001), more frequent pulmonary (p < 0.001) and aortic stenosis (p < 0.001), higher main pulmonary artery pressure, and higher aortic pressure in systole/diastole (p < 0.001 for each) than did non-CRS-PDA patients."
    explanation: Demonstrates significantly smaller median birthweight in infants with CRS-associated patent ductus arteriosus compared with non-CRS controls.
  - reference: PMID:16051872
    reference_title: "Interactions between rubella virus capsid and host protein p32 are important for virus replication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Symptoms of CRS include low birth weight, deafness, cataracts, mental retardation, and heart disease (10)."
    explanation: Lists low birth weight as a classic clinical feature of congenital rubella syndrome.
- name: Microcephaly
  description: >
    Congenital microcephaly resulting from viral inhibition of neural progenitor
    proliferation and microvascular injury in the developing fetal brain.
  category: Neurological
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"
    explanation: Lists microcephaly among the core clinical features of CRS.
- name: Intellectual Disability
  description: >
    Neurodevelopmental impairment and intellectual disability secondary to fetal
    central nervous system rubella infection, microglial activation, and neuronal
    interferon signaling.
  category: Neurological
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:16051872
    reference_title: "Interactions between rubella virus capsid and host protein p32 are important for virus replication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Symptoms of CRS include low birth weight, deafness, cataracts, mental retardation, and heart disease (10)."
    explanation: Documents intellectual disability (historically termed mental retardation) as a classic manifestation of CRS.
- name: Hepatosplenomegaly
  description: >
    Neonatal enlargement of the liver and spleen reflecting disseminated congenital
    viral infection and extramedullary hematopoiesis.
  category: Hepatic
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"
    explanation: Lists hepatosplenomegaly as a classic neonatal CRS sign.
- name: Dermal Extramedullary Hematopoiesis (Blueberry Muffin Lesions)
  description: >
    Neonatal blue-red infiltrative macules and papules ("blueberry muffin" rash)
    representing persistent dermal erythropoiesis in response to congenital rubella
    infection.
  category: Dermatologic
  phenotype_term:
    preferred_term: Extramedullary hematopoiesis
    term:
      id: HP:0001978
      label: Extramedullary hematopoiesis
  evidence:
  - reference: PMID:25654000
    reference_title: "Congenital rubella syndrome with blueberry muffin lesions and extensive metaphysitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The baby had blueberry muffin skin lesions, long bone metaphysitis and congenital heart defects."
    explanation: Documents neonatal blueberry muffin skin lesions in congenital rubella syndrome.
- name: Neonatal Thrombocytopenic Purpura
  description: >
    Neonatal petechiae and purpura resulting from congenital rubella-associated
    thrombocytopenia and megakaryocytic injury.
  category: Hematologic
  phenotype_term:
    preferred_term: Purpura
    term:
      id: HP:0000979
      label: Purpura
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"
    explanation: Documents purpura as a classic neonatal manifestation of congenital rubella syndrome.
- name: Neonatal Jaundice
  description: >
    Early-onset neonatal hyperbilirubinemia and jaundice associated with congenital
    rubella hepatitis and hemolysis.
  category: Hepatic
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly"
    explanation: Documents neonatal jaundice as a core clinical manifestation of congenital rubella syndrome.
- name: Delayed-Onset Diabetes Mellitus
  description: >
    Autoimmune or insulin-deficient diabetes mellitus emerging in late childhood or
    adulthood as a delayed endocrine sequela of congenital rubella infection.
  category: Endocrine
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:4001724
    reference_title: "Delayed manifestations of congenital rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The delayed manifestations are not present in early life and include the following: endocrinopathies: diabetes, thyroid disease, and growth hormone deficiency"
    explanation: Establishes diabetes as a delayed-onset endocrine manifestation of congenital rubella syndrome.
  - reference: PMID:12463994
    reference_title: "Gregg's congenital rubella patients 60 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"
    explanation: Quantifies a 22% prevalence of diabetes mellitus in adult survivors of congenital rubella syndrome.
- name: Delayed-Onset Thyroid Disease
  description: >
    Autoimmune thyroiditis and hypothyroidism developing in late childhood or
    adulthood as a delayed endocrine manifestation of congenital rubella
    syndrome.
  category: Endocrine
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:4001724
    reference_title: "Delayed manifestations of congenital rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The delayed manifestations are not present in early life and include the following: endocrinopathies: diabetes, thyroid disease, and growth hormone deficiency"
    explanation: Establishes thyroid disease as a delayed-onset endocrine manifestation of congenital rubella syndrome.
  - reference: PMID:12463994
    reference_title: "Gregg's congenital rubella patients 60 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"
    explanation: Quantifies a 19% prevalence of thyroid disorders in adult survivors of congenital rubella syndrome.
- name: Congenital or Delayed-Onset Glaucoma
  description: >
    Ocular hypertension and glaucoma developing either in infancy or as a late
    ophthalmologic manifestation of congenital rubella syndrome.
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:4001724
    reference_title: "Delayed manifestations of congenital rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular damage: glaucoma, keratic precipitates, keratoconus, corneal hydrops, and absorption of the cataractous lens"
    explanation: Documents glaucoma as a delayed ocular manifestation of congenital rubella.
progression:
- phase: Congenital and Neonatal Presentation
  age_range: First-trimester fetal onset with neonatal presentation
  notes: >
    Fetal vulnerability is highest during first-trimester maternal primary rubella
    infection, producing structural embryopathy (cataracts, pigmentary retinopathy,
    sensorineural hearing impairment, branch pulmonary artery stenosis, patent
    ductus arteriosus, microcephaly) and extended newborn signs (intrauterine growth
    restriction, hepatosplenomegaly, jaundice, thrombocytopenic purpura, and dermal
    extramedullary hematopoiesis).
  evidence:
  - reference: PMID:4001724
    reference_title: "Delayed manifestations of congenital rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The manifestations of congenital rubella syndrome (CRS) can be grouped according to time of onset into newborn, extended, and delayed CRS."
    explanation: Defines the temporal progression of CRS into newborn, extended, and delayed phases.
  - reference: PMID:37327049
    reference_title: "The dangers of rubella virus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the fetus is most vulnerable to the rubella virus during the first trimester of pregnancy, due to the lack of immune defense in the developing fetus"
    explanation: Establishes the first trimester as the critical window for congenital onset.
- phase: Delayed-Onset Childhood and Adult Sequelae
  age_range: Late childhood through adulthood
  notes: >
    Years to decades after congenital infection, survivors develop delayed
    manifestations driven by chronic viral persistence, vascular stenosis, and
    autoimmunity, including diabetes mellitus, thyroid disorders, and late-onset
    glaucoma.
  evidence:
  - reference: PMID:4001724
    reference_title: "Delayed manifestations of congenital rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The delayed manifestations are not present in early life and include the following: endocrinopathies: diabetes, thyroid disease, and growth hormone deficiency"
    explanation: Documents delayed-onset endocrine manifestations emerging after early life.
  - reference: PMID:12463994
    reference_title: "Gregg's congenital rubella patients 60 years later."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of diabetes (22%), thyroid disorders (19%), early menopause (73%) and osteoporosis (12.5%) was increased compared with the Australian population"
    explanation: Demonstrates adult-onset endocrine and metabolic sequelae 60 years after congenital rubella infection.
diagnosis:
- name: Rubella-Specific IgM Serology
  description: >
    Detection of rubella-specific IgM antibody in neonatal or maternal serum is the
    primary serological test for confirming congenital rubella infection or maternal
    primary rubella in pregnancy; because IgM does not cross the placenta, neonatal
    rubella IgM indicates fetal infection, while maternal IgM reactivity in
    low-prevalence settings requires confirmatory testing.
  measurements:
  - preferred_term: Rubella IgM
    term:
      id: LOINC:31616-6
      label: Rubella virus IgM Ab [Presence] in Serum
  notes: >
    The qualitative serum presence code is bound; no numerical reference_ranges apply
    to a qualitative presence assay.
  evidence:
  - reference: PMID:28412379
    reference_title: "Challenges of measles and rubella laboratory diagnostic in the era of elimination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Laboratory investigation heavily relies on specific IgM serology and increasingly on virus detection by reverse transcription (RT)-PCR, but other methods such as IgG avidity testing and genetic characterization of virus strains have gained in importance."
    explanation: Establishes rubella-specific IgM serology as the core laboratory diagnostic method alongside RT-PCR and IgG avidity.
  - reference: PMID:33316569
    reference_title: "Positive predictive value of seroconversion or positive rubella IgM in diagnosis of maternal rubella infection: Seven-years review of French National Reference Laboratory for Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In case of seroconversion for RV-IgG and/or positive RVIgM during pregnancy, laboratories usually send serum samples to the French National Reference Laboratory (FNRL) for Rubella in order to perform complementary investigations and confirm or exclude rubella infection during pregnancy."
    explanation: Documents maternal rubella IgM and IgG seroconversion testing as the diagnostic trigger for prenatal rubella evaluation.
- name: Maternal Rubella IgG Avidity Testing
  description: >
    Measurement of rubella-specific IgG avidity in maternal serum distinguishes acute
    primary rubella infection (low avidity) from pre-existing immunity or reinfection
    (high avidity) when evaluating congenital rubella risk during pregnancy.
  measurements:
  - preferred_term: Rubella IgG avidity
    term:
      id: LOINC:34421-8
      label: Rubella virus IgG Ab avidity [Ratio] in Serum
  notes: >
    Assay-specific low/high avidity cutoffs vary by commercial kit and eluting agent,
    so no universal reference_ranges are recorded.
  evidence:
  - reference: PMID:33316569
    reference_title: "Positive predictive value of seroconversion or positive rubella IgM in diagnosis of maternal rubella infection: Seven-years review of French National Reference Laboratory for Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional serological tests were performed, mainly immunoblot (to look for the presence of anti-E1 protective antibody) and RV-IgG avidity (to exclude or confirm primary infection)."
    explanation: Confirms the role of rubella IgG avidity testing in confirming or excluding maternal primary infection during pregnancy.
- name: Rubella Virus Reverse Transcription PCR (RT-PCR)
  description: >
    Direct detection of rubella viral RNA by reverse transcription polymerase chain
    reaction (RT-PCR) in clinical specimens provides molecular confirmation of
    infection and enables viral genotyping for epidemiological tracking.
  diagnosis_term:
    preferred_term: polymerase chain reaction
    term:
      id: NCIT:C17003
      label: Polymerase Chain Reaction
  evidence:
  - reference: PMID:21116802
    reference_title: "Detection of measles, mumps, and rubella viruses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Direct detection of viral genomic material using reverse transcription polymerase chain reaction (RT-PCR) methodologies can play an important role for laboratory confirmation of acute infections."
    explanation: Establishes RT-PCR detection of rubella viral RNA for laboratory confirmation.
  - reference: PMID:28412379
    reference_title: "Challenges of measles and rubella laboratory diagnostic in the era of elimination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Laboratory investigation heavily relies on specific IgM serology and increasingly on virus detection by reverse transcription (RT)-PCR, but other methods such as IgG avidity testing and genetic characterization of virus strains have gained in importance."
    explanation: Confirms the increasing diagnostic role of RT-PCR virus detection and genetic characterization.
treatments:
- name: Pre-Conception and Childhood Live-Attenuated Rubella Vaccination (MMR)
  description: >
    Immunization of children and non-pregnant women of childbearing age with
    live-attenuated rubella-containing vaccine (RA 27/3 strain, typically delivered
    as MMR) induces durable anti-E1 neutralizing IgG antibodies that prevent maternal
    rubella viremia and transplacental transmission, eliminating congenital rubella
    syndrome.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: Maternal Rubella Viremia and Transplacental Viral Entry
    treatment_effect: INHIBITS
    description: >-
      Pre-existing vaccine-induced neutralizing antibodies block maternal rubella
      viremia and prevent transplacental viral seeding of the placenta and fetus.
    evidence:
    - reference: PMID:35367004
      reference_title: "Rubella."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rubella and congenital rubella syndrome can be prevented by rubella-containing vaccines, which are commonly administered in combination with measles vaccine."
      explanation: Establishes that rubella-containing vaccines prevent primary maternal rubella and congenital rubella syndrome.
  evidence:
  - reference: PMID:35367004
    reference_title: "Rubella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rubella and congenital rubella syndrome can be prevented by rubella-containing vaccines, which are commonly administered in combination with measles vaccine."
    explanation: Lancet seminar establishing rubella-containing vaccines as the primary means of preventing congenital rubella syndrome.
- name: Multidisciplinary Supportive, Surgical, and Rehabilitative Care
  description: >
    Management of affected infants requires inpatient medical care and
    interventional or surgical repair of structural congenital defects, notably
    transcatheter occlusion therapy for patent ductus arteriosus alongside
    ophthalmologic and audiologic care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31745134
    reference_title: "Characteristics of Patent Ductus Arteriosus in Congenital Rubella Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tubular-type PDA was frequently seen in patients with CRS and accompanied by pulmonary/systemic hypertension and pulmonary/aortic stenosis; in these patients, more cautious device selection is needed for transcatheter PDA closure."
    explanation: Clinical management conclusion demonstrating that transcatheter device closure of tubular-type patent ductus arteriosus in CRS patients with concomitant pulmonary/systemic hypertension and pulmonary/aortic stenosis requires cautious device selection.
  - reference: PMID:31745134
    reference_title: "Characteristics of Patent Ductus Arteriosus in Congenital Rubella Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We reviewed the medical records of patients with CRS who were admitted to the Children's Hospital 1 in Vietnam between December 2010 and December 2012, and patients with CRS who underwent PDA transcatheter occlusion therapy at the cardiology department between December 2009 and December 2015."
    explanation: Documents inpatient care and transcatheter occlusion therapy for patent ductus arteriosus in children with congenital rubella syndrome.
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:35367004
      reference_title: "Rubella."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rubella is an acute illness caused by rubella virus"
      explanation: Congenital rubella syndrome is a vertical infectious disease caused by rubella virus.
datasets:
- accession: geo:GSE225949
  title: Rubella virus infection in endothelial cells reduces angiogenesis via interferon betainduced CXCL10
  description: Rubella virus infection during pregnancy can result in abortion, stillbirth and severe defects in embryogenesis resulting in congenital rubella syndrome (CRS). Low vaccination coverage in developing regions results in estimated 100,000 CRS cases in infants per year with a mortality rate over 30%. The molecular pathomechanisms and potential treatments remain largely unexplored. Endothelial cells (EC) of the placenta are infected by rubella virus (RuV). RuV reduced angiogenic and migratory capacity of primary human EC whereas cell cycle and apoptosis rate were not affected.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 19
  notes: Identified by GEO DataSets index search for Rubella; directly profiles placental endothelial cell infection relevant to congenital rubella syndrome.

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Congenital Rubella Syndrome. Core disease mechanisms, molecular and cellul...

Asta Scientific Corpus Retrieval 20 citations 2026-11-01T17:56:53.597613

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Congenital Rubella Syndrome. Core disease mechanisms, molecular and cellul...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Susceptibility to Rubella Infection and Incidence of Congenital Rubella Infection: 6 Years Retrospective Study

Authors: R. AlDossary, Sarah Althuwaiqeb, K. Alkharsah, N. H. Wanni, Basavaraja C Hunasemaranda et al.
Year: 2022
Venue: International Journal of General Medicine
URL: https://www.semanticscholar.org/paper/efd9cc520f2e42e899c16a96608b60f75a3612ab
DOI: 10.2147/IJGM.S353867
PMID: 35401012
PMCID: 8985818
Citations: 3
Summary: The level of Rubella immunity in the population is 91% and is less than the WHO target for rubella control therefore, risk of resurge of cases is present, indicating the need for continued national surveillance and more efforts to improve vaccination coverage in the kingdom.
Evidence snippets:
Snippet 1 (score: 0.472) > Rubella was initially considered a mild childhood exanthematous disease characterized by fever, faint maculopapular rash and lymphadenopathies which resolve in few days with no major sequels. 1 But with the observation of an Australian ophthalmologist, Sir Norman McAlister Gregg in 1941 of a cluster of 1 infants born with cataract and cardiac defect which was associated with maternal history of rubella infection in early pregnancy, rubella was then identified as a major cause of congenital defects. 2 Rubella, which is also known as German measles, is caused by Rubella virus, a member of the Togaviridae, genus Rubivirus. Rubella infection or vaccination commonly leads to lifelong immunity, as the virus has only one serotype. 3 ubella virus targets almost all organs of the body leading to a wide range of clinical manifestations. It utilizes myelin oligodendrocyte glycoprotein (MOG) as its receptor along with other yet to be discovered receptors. 1 Following primary infection of non-immune pregnant women, rubella virus spreads to the placenta, and from there to the developing fetus causing systemic inflammation and interference with organ development. Rubella virus is believed to cause congenital defects via multiple mechanisms, including necrosis of chorionic epithelium and endothelial cells, inhibition of cell division, and development and induction of immunopathological events. 4 nfants born with congenital rubella infection display a variety of manifestations including fetal death, ocular complications (cataract, glaucoma, pigmentary retinopathy, microphthalmia and chorioretinitis), auditory complications (sensorineural hearing loss) and cardiac complications (patent ductus arteriosus, ventricular septal defect and pulmonary artery stenosis). 5 Infants born with laboratory evidence of rubella infection in addition to clinical manifestations are referred to as suffering from congenital rubella syndrome (CRS). In addition, infants who survive intrauterine rubella infection, can suffer from developmental and endocrinal problems including autism and insulin dependent diabetes mellitus. 6

[2] Alterations in Cell Mechanics by Actin Cytoskeletal Changes Correlate with Strain-Specific Rubella Virus Phenotypes for Cell Migration and Induction of Apoptosis

Authors: Martin Kräter, Jiranuwat Sapudom, N. C. Bilz, T. Pompe, J. Guck et al.
Year: 2018
Venue: Cells
URL: https://www.semanticscholar.org/paper/98f96455050ff25eaf032e945dd3468e44ea19e4
DOI: 10.3390/cells7090136
PMID: 30217036
PMCID: 6162683
Citations: 29
Summary: Infection with rubella virus (RV) strains is analyzed with respect to phenotypes in cellular mechanical properties, cell movement, and viral cytopathogenicity to emphasize RT-DC technology as a sensitive means to characterize viral cell populations and to implicate alterations of cell mechanical properties with cell functions.
Evidence snippets:
Snippet 1 (score: 0.427) > Rubella virus (RV) is the only member of the genus Rubivirus of the Togavirus family. The single-stranded RNA genome in plus-strand orientation encodes two non-structural (P150 and P90) and three structural (the envelope glycoproteins E1 and E2 and the capsid protein) proteins. While postnatal infections are generally mild or asymptomatic, perinatal infections of susceptible women during the first trimester of pregnancy can result in severe malformations of the unborn child known as congenital rubella syndrome (CRS). Besides abnormalities in the heart, eye, and ear, vascular and endothelial pathologies have been noted [1][2][3][4]. Despite the availability of an effective vaccine, RV is still a cause of outbreaks [5,6] and CRS cases occur even in countries of the Western world [7]. Although these cases are mainly import-related, it emphasizes that RV as an efficient teratogen is of ongoing relevance. The mechanisms and signaling pathways that lead to the strictly human-specific pathophysiological mechanisms behind CRS are still unknown, but contributing factors were discussed [4,8]. Among those factors was the reduction and rearrangement of actin filaments in discrete clumps in viral protein-enriched areas [9]. Furthermore, filamentous actin (F-actin) stress fibers are disrupted at late time points of RV infection [10]. All viral proteins involved in RV replication, namely the replicase proteins P90 and P150, and the capsid protein [11], were found to co-localize with the actin cytoskeleton [10,12]. > F-actin is a major contributor to cellular mechanics [13]. This is a physical property of a cell, which can be altered in response to cellular stress or changes in cell functions. Thus, it is hypothesized that cell functional alterations by RV infection can be assessed by the cell mechanical phenotype to define features of virus populations.

[3] Skin Development and Disease: A Molecular Perspective

Authors: I. Dermitzakis, Despoina Chatzi, Stella Aikaterini Kyriakoudi, Nikolaos Evangelidis, E. Vakirlis et al.
Year: 2024
Venue: Current Issues in Molecular Biology
URL: https://www.semanticscholar.org/paper/3b0d602b335c265102e2a9f169bab20f51343212
DOI: 10.3390/cimb46080487
PMID: 39194704
PMCID: 11353016
Citations: 24
Influential citations: 1
Summary: By delving into the molecular mechanisms implicated in developmental processes, as well as in the pathogenesis of diseases, a comprehensive understanding of these aspects paves the way for developing innovative targeted therapies and personalised treatment approaches for various skin conditions.
Evidence snippets:
Snippet 1 (score: 0.418) > Understanding the molecular mechanisms underlying congenital skin diseases and cancer has significantly advanced in recent years, providing crucial insights into the pathogenesis of these conditions. Researchers have uncovered key genetic mutations, signalling cascades, and cellular interactions that drive the development and progression of these disorders by unravelling the intricate molecular pathways affected. This section emphasises that the various molecular signals involved in embryonic development are also implicated in the pathophysiology of certain congenital skin diseases and types of cancer. Analysing these connections provides valuable insights into the molecular mechanisms underlying both skin development and the pathogenesis of skin cancers, such as basal cell and squamous cell carcinoma. Skin cancers often stem from disruptions in essential biological pathways that are also involved in normal skin development. Therefore, identifying these specific molecules can pave the way for developing new targeted therapies through laboratory-based interventions.

[4] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, P. A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 40
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.399) > However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[5] Immunolocalization and Distribution of Rubella Antigen in Fatal Congenital Rubella Syndrome

Authors: Mihaela Lazăr, L. Perelygina, R. Martines, P. Greer, C. Paddock et al.
Year: 2015
Venue: EBioMedicine
URL: https://www.semanticscholar.org/paper/8774bd7e95f0a8b881b1b79037f2f3b4adaeb4d7
DOI: 10.1016/j.ebiom.2015.11.050
PMID: 26870820
PMCID: 4739417
Citations: 55
Influential citations: 1
Summary: Cell types positive for rubella virus (RV) in CRS infants are identified and infection of each cell type is consistent with abnormalities which have been identified in patients with CRS, in the heart, large blood vessels, and brain.
Evidence snippets:
Snippet 1 (score: 0.392) > Background An estimated 100,000 cases of congenital rubella syndrome (CRS) occur worldwide each year. The reported mortality rate for infants with CRS is up to 33%. The cellular mechanisms responsible for the multiple congenital defects in CRS are presently unknown. Here we identify cell types positive for rubella virus (RV) in CRS infants. Methods Cells and organs involved in RV replication were identified in paraffin-embedded autopsy tissues from three fatal case-patients by histopathologic examination and immunohistochemical (IHC) staining using a rabbit polyclonal RV antibody. Normal rabbit antisera and RV antisera preabsorbed with highly purified RV served as negative controls. Results RV antigen was found in interstitial fibroblasts in the heart, adventitial fibroblasts of large blood vessels, alveolar macrophages, progenitor cells of the outer granular layer of the brain, and in capillary endothelium and basal plate in the placenta. The antibody specificity was verified by IHC staining of multiple tissue sections from other infectious disease cases. RV infection of each cell type is consistent with abnormalities which have been identified in patients with CRS, in the heart, large blood vessels, and brain. Antigen distribution was consistent with inflammatory response to vascular injury and systemic spread of RV. Conclusions The identification of RV positive cell types in CRS is important to better understand the pathology and pathogenesis of CRS.

[6] Relationship between HLA Polymorphisms and Gamma Interferon and Interleukin-10 Cytokine Production in Healthy Individuals after Rubella Vaccination

Authors: I. Ovsyannikova, R. Jacobson, J. E. Ryan, N. Dhiman, R. Vierkant et al.
Year: 2007
Venue: Clinical and Vaccine Immunology
URL: https://www.semanticscholar.org/paper/69ffc02225e174fb075b0b7d236474a0455c63ed
DOI: 10.1128/CVI.00247-06
PMID: 17215337
Citations: 34
Summary: Results provide additional evidence that HLA genes may influence Th1- and Th2-specific cytokine response(s) following rubella immunization, which in turn can influence both cellular and humoral immune responses to rubella vaccination.
Evidence snippets:
Snippet 1 (score: 0.381) > The class I A0201 and A6801 alleles were associated with both IFN-␥ and IL-10 secretion. These tentative associations need to be validated in larger studies with subjects of differing ethnicities. These results provide additional evidence that HLA genes may influence Th1-and Th2-specific cytokine response(s) following rubella immunization, which in turn can influence both cellular and humoral immune responses to rubella vaccination. > Rubella, a viral infection, is still a major health concern in developing countries, with approximately 100,000 cases of congenital rubella syndrome reported worldwide each year (3,11,38). Although rare in the United States, the disease exists elsewhere and is imported into developed countries. For this reason, it is important to continue to vaccinate children and women of childbearing age to induce protective immunity and prevent congenital rubella syndrome. The cost of containing and treating rubella cases in developing countries is high (39), and rubella cases continue to be brought into the United States (8,9,12). > The vaccine currently used in the United States and in other developed countries consists of the Wistar RA 27/3 strain, attenuated by cold adaptation and serial passage through human diploid cells (37). Immunogenicity trials reveal rates of seroconversion of 92 to 98% (17,21,40,45). Efficacy and immunogenicity studies have shown failure rates of 3 to 14% (5,16,20,40,43), and borderline or subprotective levels of rubella antibody may exist in percentages ranging from 4 to 23% of vaccinees 6 to 16 years after rubella vaccination (10,25,31,32). The molecular mechanism for this low immune response is unknown; therefore, it is important to understand the immunogenetic mechanisms underlying poor immune response to the vaccine. > Two main CD4 T-helper-cell patterns in response to viral stimulation have been recognized (27,28). Type 1 helper T cells produce cytokines favoring T-cell-mediated immunity and are classically assessed by measuring gamma interferon (IFN-␥) (or interleukin-2 [IL-2]).

[7] Next-Generation Sequencing Technologies and Neurogenetic Diseases

Authors: Hui Sun, Xia Shen, Z. Fang, Zong-zhi Jiang, Xiaojing Wei et al.
Year: 2021
Venue: Life
URL: https://www.semanticscholar.org/paper/610176b2538c442811882df5f33353d4c4fff4d4
DOI: 10.3390/life11040361
PMID: 33921670
PMCID: 8072598
Citations: 26
Summary: An overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases is provided and examples of N GS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot–Marie–Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis are provided.
Evidence snippets:
Snippet 1 (score: 0.372) > In a rare and extreme condition, patients exhibit phenotypes of two congenital diseases. Thus, when confronting diseases that are difficult to diagnose, it is suggested that monism should be used to explain the etiological factors. Congenital myasthenia syndrome (CMS), comprising a group of monogenetic disorders that affect neuromuscular junction, offers a sound explanation for this condition. Among the 32 known genes in CMS, the phenotypes associated with DOK7, MUSK, DPAGT1, CHRNE, and GMPPB can coincide with muscular diseases, such as MD, limb-girdle muscular dystrophy (LMD), and myopathy [116]. Some patients with GMPPB or CHRNE mutations present with MD-like symptoms [117]. The myopathy-like clinical and pathological manifestations of CHRNE, which are involved in slow-channel congenital myasthenic syndrome, are primarily caused by calcium overload due to the delayed closure of slow ion channels [118]. In contrast to the pathway associated with CHRNE, defects in protein glycosylation caused by GMPPB lead to AChR subunits incorrectly settled, and expressed, on the surface of cells [119]. Approximately 40 genes are associated with MD and are primarily involved in extracellular matrix and basement membrane proteins [120]. GMPPB is also involved in N-glycation and O-mannose glycation pathways [121]. In the case of GMPPB, pathological changes of muscular and neuromuscular junctions can be present simultaneously, with the clinical manifestations of LMD and CMS overlapping, or concealing, each other. Therefore, in the complex background of neurogenetic diseases, the pathological mechanisms of different diseases may intersect. Hence, NGS is extremely important for diseases with more than one congenital disease phenotype, with the genes screened by WGS potentially providing insights into new mechanisms. A similar example is that of GARS, which causes distal upper limb dyspraxia and was not only found in CMT, but also in autism spectrum disorder, mitochondrial disease, and motoneuron disease [122][123][124].

[8] Assembly, maturation and three-dimensional helical structure of the teratogenic rubella virus

Authors: Vidya Mangala Prasad, T. Klose, M. Rossmann
Year: 2017
Venue: PLoS Pathogens
URL: https://www.semanticscholar.org/paper/4a271555a243f5b5f3ccd27ed657de160b85afb8
DOI: 10.1371/journal.ppat.1006377
PMID: 28575072
PMCID: 5470745
Citations: 35
Influential citations: 3
Summary: These results present the first known example of a helical membrane-enveloped virus, while also providing a structural basis for its assembly and maturation pathway.
Evidence snippets:
Snippet 1 (score: 0.362) > Rubella virus is an airborne human pathogen that causes a contagious disease with measleslike symptoms in children and adults. Rubella infection in pregnant women can lead to fetal death or severe life-long disabilities such as mental retardation, deafness, cataracts and heart defects in the new-born infants, collectively referred to as congenital rubella syndrome [1]. Despite the availability of an effective vaccine for rubella since the 1960s, the virus is still a global health concern with over 100,000 babies born with congenital rubella syndrome every year [2]. > Rubella virus is an enveloped, positive-stranded RNA virus with virions ranging from 500 Å to 900 Å in diameter [3]. The virions form a variety of shapes that range from nearly spherical to elongated tube-like structures [3,4]. The structural components of rubella virus are comprised of three proteins, glycoproteins E1 (58kDa), E2 , and the capsid protein (31kDa) [5,6]. The glycoproteins are type I transmembrane proteins [5,7] that form heterodimers on the virion surface [8]. E1 is responsible for recognition and attachment to cellular receptors [9]. It is also involved in membrane fusion in the presence of low pH and calcium ions [10][11][12]. E2 is required for efficient folding and transportation of E1 through cellular compartments [7,8]. Of the two glycoproteins, only the structure of the E1 ectodomain in its trimeric, post-fusion conformation is known [13]. The rubella E1 ectodomain has an elongated structure, similar to the post-fusion conformations of the alphavirus E1 and flavivirus E glycoproteins [13]. The E1 ectodomain has three domains DI, DII and DIII. DII contains two conserved hydrophobic fusion loops at one end of the rubella E1 structure, whereas DI and DIII form the other end [13].

[9] Congenital Rubella Syndrome - A Major Review and Update

Authors: Nure Ishrat Nazme, M. Hussain, Ashith Chandra Das
Year: 2015
Venue: Delta Medical College Journal
URL: https://www.semanticscholar.org/paper/da7d6a68ccce33b52d959b9570b93891f115a754
DOI: 10.3329/DMCJ.V3I2.24429
Citations: 7
Summary: The epidemiology of CRS is characterized; the patho-phyisiology, clinical features and laboratory testing for the disease are described, and measures needed for prevention of rubella and CRS are discussed.
Evidence snippets:
Snippet 1 (score: 0.361) > Rubella is a major public health problem which is usually a mild rash illness in children and adults. However, it has devastating systemic consequences when rubella virus crosses the placental barrier and infects fetal tissue resulting in congenital rubella syndrome (CRS). Congenital rubella syndrome is an under-recognized public health problem in Bangladesh and the burden of the disease weighs heavily on patients and society; therefore, routine vaccination and other preventative strategies are strongly encouraged. Extensive surveillance studies should be conducted to eliminate CRS from our country. In this review, we will characterize the epidemiology of CRS; describe the patho-phyisiology, clinical features and laboratory testing for the disease, and discuss measures needed for prevention of rubella and CRS. Delta Med Col J. Jul 2015; 3(2): 89-95

[10] Discovering cell types underlying rare disease phenotypes using scRNA-seq data from non-diseased tissues

Authors: Jorge Novoa, F. Pazos, M. Chagoyen
Year: 2025
Venue: bioRxiv
URL: https://www.semanticscholar.org/paper/c038b1472f7b42b58e9068eae4b0b0bf3970657e
DOI: 10.64898/2025.12.09.693155
Summary: Applied across diverse tissues and phenotypes, Cell4Rare was validated against literature-based associations and highlights the potential of computational analyses of non-diseased scRNA-seq data to uncover the cellular basis of rare disease phenotypes, paving the way for improved diagnostics and therapeutic strategies.
Evidence snippets:
Snippet 1 (score: 0.360) > Rare diseases, despite their individual low prevalence, collectively affect millions worldwide and pose persistent challenges for both diagnosis and treatment. The majority of these conditions have a genetic basis, with mutations that disrupt molecular and cellular pathways, ultimately manifesting as distinct and often severe phenotypes. Experimental approaches such as CRISPR-Cas9 gene editing, animal models, patient-derived iPSCs, and in vitro functional assays have become indispensable tools for validating the pathogenicity of specific variants and establishing the molecular and cellular pathways disrupted (MacArthur et al., 2014). These strategies provide critical insights into disease etiology by enabling the direct interrogation of gene function and phenotype. However, they are often limited by high costs, extended timelines, and scalability challenges-particularly in the context of rare diseases, where patient samples and resources are scarce. These limitations underscore the urgent need for robust, scalable computational tools that make use of the more abundant healthy omics data to facilitate the discovery and understanding of rare disease-causing mechanisms. > A major obstacle in rare disease research is determining the specific cellular contexts in which pathogenic genetic variants exert their effects. This is especially challenging given that many rare disease-associated genes are broadly expressed across tissues but lead to phenotypes that are restricted to a small subset of cell types (Feiglin et al., 2017). Pinpointing these relevant cellular targets is crucial for understanding disease mechanisms and for designing effective, targeted therapies. Recent advances in single-cell transcriptomics, along with growing databases of genotype-phenotype associations, offer an unprecedented opportunity to study gene activity at cellular resolution. Yet, for most rare diseases-many of which have pediatric onset-single-cell data from affected individuals remain unavailable, making traditional case-control approaches impractical. > In this context, computational methods that extract mechanistic insights from single-cell data derived from non-diseased tissues offer a valuable alternative. These approaches can help infer the cellular consequences of genetic alterations and guide the selection of the most relevant experimental systems for downstream validation.

[11] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

Authors: Lina Zhu, Yang Li, Yi-Yao Bao
Year: 2026
Venue: Current Issues in Molecular Biology
URL: https://www.semanticscholar.org/paper/a5e1ddccfa7d333834c4d32be123c71bfd573f83
DOI: 10.3390/cimb48040422
PMID: 42042082
PMCID: 13114623
Summary: A comprehensive framework to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome is provided.
Evidence snippets:
Snippet 1 (score: 0.356) > Molecular genetic research on Bartter syndrome has made remarkable strides, elucidating the principal BS genes SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 and their corresponding protein defects, thereby refining the molecular framework of disease classification while separating CaSR-associated Bartter-like disease from the core canonical BS spectrum. This progress has significantly deepened our understanding of the underlying pathophysiology and provided an essential framework for correlating genotypes with clinical phenotypes. However, the intricate relationship between genetic mutations and clinical manifestations remains complex and multifaceted, reflecting the profound heterogeneity of the syndrome. Addressing these diagnostic challenges and refining disease classification beyond traditional clinical criteria requires an integrative approach that seamlessly balances high-throughput sequencing technologies with rigorous functional studies. > The mechanisms by which these genetic mutations lead to protein dysfunction are diverse, encompassing critical defects in protein expression, impaired membrane localization, and direct functional impairments. Notably, aberrant protein folding, endoplasmic reticulum-associated degradation (ERAD), and splicing abnormalities have emerged as critical pathogenic pathways. These mechanistic insights not only enhance our fundamental understanding of the disease but also highlight highly promising therapeutic targets. While current treatments remain predominantly symptomatic, focusing primarily on managing electrolyte imbalances and associated complications, they inherently fail to address the underlying molecular defects driving the disease. > The precise identification of specific molecular defects opens innovative avenues for the development of targeted interventions aimed at correcting or compensating for specific protein abnormalities. For instance, molecular chaperones that assist in protein folding, agents that modulate aberrant splicing, and future gene-based strategies represent important experimental directions for mechanism-based therapy. Consequently, the future of Bartter syndrome management may increasingly move toward precision medicine tailored to the molecular pathology of individual patients. However, the transition from concept to clinical implementation will require substantial additional functional, translational, and trial-level evidence. Such mechanism-based strategies promise not only to alleviate clinical symptoms but to fundamentally modify disease progression, thereby drastically improving long-term prognosis and quality of life for patients.

[12] Cardiac Phenotype and Gene Mutations in RASopathies

Authors: M. Faienza, G. Meliota, D. Mentino, R. Ficarella, Mattia Gentile et al.
Year: 2024
Venue: Genes
URL: https://www.semanticscholar.org/paper/a4087d3b73d20a6e2f46b7fb87eed4017ec9a9be
DOI: 10.3390/genes15081015
PMID: 39202376
PMCID: 11353738
Citations: 12
Influential citations: 1
Summary: The molecular mechanisms underlying the development of cardiac diseases associated particularly with NS are clarified, and the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM are discussed.
Evidence snippets:
Snippet 1 (score: 0.351) > Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype–cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype–phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype–phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

[13] Psychoneurological Disorders in Children with Congenital Aniridia and PAX6-Associated Syndromes

Authors: O. Kupriyanova, G. A. Karkashadze, N. V. Zhurkova, Leila S. Namova-Baranova, A. Mamedyarov
Year: 2023
Venue: Current Pediatrics
URL: https://www.semanticscholar.org/paper/49aa23fa97f42cd1b38c09d9c9f2b9c8cad00cb0
DOI: 10.15690/vsp.v22i4.2611
Summary: It is crucial to review new relevant data within the context of previously obtained information to gather full picture of the clinical signs of the disease and to improve the management of children with congenital aniridia.
Evidence snippets:
Snippet 1 (score: 0.348) > Congenital aniridia manifests with total or partial absence of the iris. The association of the disease with the PAX6 gene has been proven. Changes in the PAX6 structure lead to intrauterine pathology, visual organ malformation, malformation of master regulator proteins of organogenesis affecting various cells’ differentiation (central nervous system cells included). Such disorders result into the development of PAX6-associated syndromes with various brain malformations, neurological disorders, and systemic pathology (thyroid pathology, Wilms tumor, glucose intolerance). Isolated congenital aniridia is also accompanied by psychoneurological disorders. It can be associated with brain structures’ disorders during embryogenesis and with impact of external stress factors on the child (frequent medical checkup, surgical treatments). The psychoneurological disorders’ pathogenesis as well as congenital aniridia’s genetic mechanisms remain unclear. Thus, it is crucial to review new relevant data within the context of previously obtained information to gather full picture of the clinical signs of the disease and to improve the management of children with congenital aniridia.

[14] Targeted drug development in fragile X syndrome: Molecular medicine as a key tool in clinical pharmacology

Authors: D. Protic, Maja Stojković, D. Budimirovic
Year: 2025
Venue: Medicinska istrazivanja
URL: https://www.semanticscholar.org/paper/60152d25d5ba7ab0db96bf9c44890ab070ed508f
DOI: 10.5937/medi0-60213
Citations: 1
Summary: Key molecular pathways relevant to FXS are presented, and the potential synergy between clinical pharmacology and molecular medicine is discussed as a means to promote the advancement of tailored therapeutic approaches.
Evidence snippets:
Snippet 1 (score: 0.346) > The full mutation and epigenetic silencing of the FMR1 gene lead to a deficiency of its protein, FMRP , resulting in Fragile X Syndrome (FXS). Although significant advances have been made in understanding the molecular mechanisms underlying FXS, no cure or targeted pharmacological treatments have yet been approved for this neurodevelopmental disorder. Current clinical management primarily relies on symptomatic therapies, which often offer limited benefits and do not address the core molecular causes of the condition, especially given the multifaceted roles of the FMRP. This review highlights the crucial role of molecular insights in guiding the development of drugs for FXS. It provides an overview of existing pharmacotherapies, discusses their benefits and limitations, and emphasizes the unmet need for interventions that target the specific pathways disrupted by FMR1 dysfunction. Recent and ongoing clinical trials were examined, focusing on how a deeper understanding of FXS molecular biology can inform the design of more effective and precise therapeutic strategies. In summary, key molecular pathways relevant to FXS are presented, and the potential synergy between clinical pharmacology and molecular medicine is discussed as a means to promote the advancement of tailored therapeutic approaches.

[15] Are there environmental forms of systemic autoimmune diseases?

Authors: E. Hess
Year: 1999
Venue: Environmental Health Perspectives
URL: https://www.semanticscholar.org/paper/a02203af72c6c6565fa996ecaceb76c0926278a2
DOI: 10.1289/ehp.99107s5709
PMID: 10502535
PMCID: 1566256
Citations: 13
Summary: It is important for physicians and others involved in health care to recognize the potential associations of these diseases of unknown cause or causes.
Evidence snippets:
Snippet 1 (score: 0.343) > The mechanisms by which these drugs and/or their metabolites, the chemicals and their breakdown products, and the other environ- mental factors and their various structures are as diverse as the entire immune system itself. Literally hundreds of papers have examined the drugs and other factors listed in this arti- cle and about every conceivable effect has been noted. It is not possible to define a spe- cific role or pathway that would result in the varied immunologic and clinical syndromes seen. For drugs such as hydralazine and pro- cainamide, the specific metabolites that react with specific immune cells have been well demonstrated (18,19). Other proposed mechanisms for a number of the compounds include the possibility of cross-reactive anti- gens, interference with various tolerance mechanisms, potential alteration of DNA by the drugs or their metabolites, and the role of the genetics of the various metabolic pathways of the compounds, in particular the P450 enzyme system. Studies of the actual drug structures for any commonality have not been very productive. Basically, the various drugs often fall under three different struc- tural groups: hydrazines, aromatic amines, and phenols. Studies to date of the various environmental factors again have not revealed any major commonality. > Another factor that has to be considered in humans and experimental animals is the possible inciting or potentiating effect of infectious agents. Myxoviruses, retroviruses, measles, rubella, parainfluenza, Epstein-Barr, Type C oncarnoviruses, and Type C retro- viruses could all play a role and must be con- sidered when looking at mechanisms of cross-reactive antigens (20). Among the bac- teria under consideration are streptococcal cell wall products, lipopolysaccharides, and adjuvant components. > The genetics of the immune system in autoimmune diseases and phenomena is increasingly complex. It would appear that for any one compound or environmental agent, genetic factors may differ. There is also the added complication of the genetics of the host response as manifested in the expression of different disease states.

[16] Editorial: Genetic Kidney Diseases of Childhood

Authors: M. Schmidts, M. Liebau
Year: 2018
Venue: Frontiers in Pediatrics
URL: https://www.semanticscholar.org/paper/91906bd71b0ad9d6cb9c99178bf916f54239354d
DOI: 10.3389/fped.2018.00409
PMID: 30619800
PMCID: 6305704
Citations: 1
Summary: This study presents a probabilistic procedure to characterize the immune checkpoints of the central nervous system and shows clear signs of rejection in children aged between the ages of 13 and 18.
Evidence snippets:
Snippet 1 (score: 0.343) > A manuscript of this research topic summarizes the molecular mechanisms and the genetic basis resulting in Nephronophthisis (Srivastava et al.). Two additional manuscripts describe current collaborative research consortia that aim to link the findings of genetics and cellular biology with a deep clinical phenotyping and biobanking in order to set the basis for evidence-based clinical recommendations and future translational research approaches for cystic kidney diseases (König et al.; Renkema et al.). > Likewise, an array of defective genes has been identified to date to cause renal tubular dysfunction, leading to diverse phenotypes in human such as Bartter syndrome (Yang et al.) Cystinosis (Bäumner and Weber), magnesium transport defects (Giménez-Mascarell et al.) or inherited disorders with kidney stone formation (Halbritter et al.). Genetic diagnosis has not only provided opportunities of highly specialized clinical care and genetic counseling of at-risk and carrier individuals but also offers for the first time causative treatment options such as for cystinosis where cysteamine therapy has now been implemented. > Inherited renal diseases with childhood onset can be manifestations of syndromal disease patterns with multiple organ systems involved such as in case of ciliopathies like BBS or MKS. Other examples include rare conditions affecting the skin and the kidneys (Reimer et al.), resulting from basal membrane defects or defects involving the heart and the kidneys (Gabriel et al.) The latter often but not always result from cilia dysfunction, however the precise underlying molecular mechanisms, e.g., cell signaling pathways defective, have not been understood. Last but not least, patients with congenital anomalies of the kidney and urinary tract (CAKUT) can present with complex syndromal appearances as described for individuals harboring PBX1 mutations (Riedhammer et al.) and kidney function seems to be regulated by programming events very early in life that likely result in long-term modulation of gene function in the kidney (Nüsken et al.). > This research topic provides a concise overview about current state-of-knowledge and outlook on future developments with respects to the diverse landscape of inherited childhood onset renal diseases.

[17] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Citations: 2
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.340) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[18] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

Authors: K. Lourida, G. Louridas
Year: 2022
Venue: Cardiogenetics
URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
DOI: 10.3390/cardiogenetics12020015
Citations: 4
Influential citations: 1
Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
Evidence snippets:
Snippet 1 (score: 0.340) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[19] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

Authors: Kyung-Yil Lee
Year: 2022
Venue: Cell & Bioscience
URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
DOI: 10.1186/s13578-022-00920-5
PMID: 36384812
PMCID: 9668226
Citations: 11
Influential citations: 1
Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
Evidence snippets:
Snippet 1 (score: 0.340) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[20] Use of Frogs as a Model to Study the Etiology of HLHS

Authors: Shuyi Nie
Year: 2023
Venue: Journal of Cardiovascular Development and Disease
URL: https://www.semanticscholar.org/paper/e0aa4e33e25327796109e84685e6f0ab37503ce8
DOI: 10.3390/jcdd10020051
PMID: 36826547
PMCID: 9965361
Citations: 1
Summary: It is concluded that a frog model offers its unique advantage in uncovering the cellular mechanisms of hypoplastic left heart syndrome; however, combining multiple model organisms, including frogs, is needed to gain a comprehensive understanding of the disease.
Evidence snippets:
Snippet 1 (score: 0.339) > Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart diseases and accounts for nearly 25% of cardiac deaths in the first year of life [57]. This is because the left ventricle that pumps blood to the systemic circulation including coronary circulation is malformed and largely non-functional in HLHS. Besides the underdevelopment of the left ventricle, additional characteristics of HLHS include defects in the mitral valve and aortic valve (mitral/aortic stenosis or atresia). Babies born with HLHS require multiple palliative surgeries to redirect the right ventricle for systemic circulation and ultimately require a cardiac transplant for survival. Despite the severity of the disease, we still do not have a clear understanding of the cause of HLHS. Two major challenges in elucidating the mechanisms of HLHS are the multifactorial nature of the syndrome and the lack of relevant animal models that faithfully describe the disease. Multiple genes have been reported in association with HLHS, including Nkx2. 5 [58,59], Notch1 [60][61][62], Hand1 [59,63], rbFOX2 [64], and Ets1 [65]. However, specific genetic causes are only known in a small subset of patients [66]. Moreover, significant anatomical variability is observed among different HLHS patients, suggesting that multiple animal models may be necessary to represent different anatomical subtypes of HLHS. This phenotypic variability makes the elucidation of the molecular and cellular mechanisms underlying the syndrome even more difficult. For a comprehensive review of HLHS, see [67,68].

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Congenital Rubella Syndrome. Core disease mechanisms, molecular and cellul...

Relevant Papers

[1] Susceptibility to Rubella Infection and Incidence of Congenital Rubella Infection: 6 Years Retrospective Study

[2] Alterations in Cell Mechanics by Actin Cytoskeletal Changes Correlate with Strain-Specific Rubella Virus Phenotypes for Cell Migration and Induction of Apoptosis

[3] Skin Development and Disease: A Molecular Perspective

[4] New therapeutic targets in rare genetic skeletal diseases

[5] Immunolocalization and Distribution of Rubella Antigen in Fatal Congenital Rubella Syndrome

[6] Relationship between HLA Polymorphisms and Gamma Interferon and Interleukin-10 Cytokine Production in Healthy Individuals after Rubella Vaccination

[7] Next-Generation Sequencing Technologies and Neurogenetic Diseases

[8] Assembly, maturation and three-dimensional helical structure of the teratogenic rubella virus

[9] Congenital Rubella Syndrome - A Major Review and Update

[10] Discovering cell types underlying rare disease phenotypes using scRNA-seq data from non-diseased tissues

[11] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

[12] Cardiac Phenotype and Gene Mutations in RASopathies

[13] Psychoneurological Disorders in Children with Congenital Aniridia and PAX6-Associated Syndromes

[14] Targeted drug development in fragile X syndrome: Molecular medicine as a key tool in clinical pharmacology

[15] Are there environmental forms of systemic autoimmune diseases?

[16] Editorial: Genetic Kidney Diseases of Childhood

[17] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

[18] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

[19] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

[20] Use of Frogs as a Model to Study the Etiology of HLHS

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