Congenital rubella syndrome (CRS) is a general term for organ malformations caused by primary maternal rubella virus infection in early pregnancy, with transplacental (hematogenous) transmission to the fetus. Its three main features are cataracts, congenital heart disease, and sensorineural hearing loss.
The earlier the infection occurs in pregnancy (within the first 3 months), the higher the incidence and severity. In the first 2 months of pregnancy, 65–85% of fetuses are affected, leading to multiple congenital anomalies or miscarriage1). After 20 weeks of gestation, it is rarely seen.
Worldwide, an estimated 100,000 children with CRS are born each year3). As of 2022, 175 of 194 countries had introduced rubella-containing vaccine (RCV), and 93 countries had verified rubella elimination4). In the same year, global reported cases were 17,407 rubella cases and 1,527 CRS cases4).
In Japan, rubella vaccination is routinely administered. However, CRS remains prevalent in regions where vaccine introduction was delayed, and in India, it is estimated that approximately 25% of children who become blind due to congenital cataracts have CRS. In China, only 16 confirmed CRS cases were identified over the 10-year period from 2014 to 2023, indicating significant underreporting due to inadequate surveillance systems2).
During the global rubella epidemic of 1963–1965, 30% of children born to infected mothers developed congenital anomalies, and more than 13,000 fetal and early infant deaths were reported.
CRS can develop with infection during early pregnancy (1–5 months). The risk is highest with infection within the first 3 months of pregnancy, and CRS rarely occurs with infection after 20 weeks of gestation. For details, see the “Causes and Risk Factors” section.
Ocular symptoms of CRS are often present from birth, and the following are findings that parents may first notice.
Ocular symptoms are the most frequent abnormalities in CRS, with one study reporting cataracts in 93.1%, microphthalmia in 85.1%, iris abnormalities in 58.6%, pigmentary retinopathy in 37.9%, nystagmus in 50%, strabismus in 26%, and glaucoma in 6%1).
Pigmentary Retinopathy
Salt-and-pepper fundus: A characteristic finding with diffuse mixture of fine depigmented spots and pigment spots from the posterior pole to the equator.
Optic nerve and retinal vessels: Usually normal.
Course: Most cases are stationary with minimal impact on visual function, but electroretinography may show abnormalities. Very rarely, it progresses to subfoveal choroidal neovascularization.
Cataract
Pearl-white nuclear cataract: Rubella virus delays proliferation of lens epithelial cells, causing degeneration and opacification of lens fibers.
Bilateral involvement is common: 89% of cases are reported to be bilateral. Onset occurs in 50–85% of patients by age 20.
Spontaneous absorption: Spontaneous absorption of cataracts has been rarely reported.
Glaucoma
Congenital glaucoma: Accompanied by corneal opacity and buphthalmos. It is caused by incomplete resorption of mesodermal tissue in the angle and poor differentiation of Schlemm’s canal.
Secondary glaucoma: May occur after the teenage years as a result of cataracts or microphthalmia. Secondary glaucoma has been reported in 43% of cases after cataract extraction.
Frequency: Reported in 2–25% of cases.
Microphthalmia
More than half of CRS patients have congenital heart disease. Chinese data showed cardiac defects in 62.50%, hearing impairment in 31.25%, and thrombocytopenia in 31.25%2).
Rubella retinopathy (salt-and-pepper fundus) is mostly stationary, and if there are no other complications, vision is usually maintained at 0.3 or better. However, in extremely rare cases, it may progress to subfoveal choroidal neovascularization, causing sudden vision loss. Regular retinal examinations are recommended.
CRS is caused by maternal infection with the rubella virus, which belongs to the Togaviridae family. The rubella virus only infects humans and is transmitted through droplet infection. Infected individuals shed the virus from the nose, throat, urine, blood, and cerebrospinal fluid for up to 10 days after the onset of rash.
The virus is vertically transmitted to the fetus through the maternal placenta, inhibiting normal cell proliferation during organogenesis.
Children with CRS are particularly contagious and continue to shed the virus through secretions and urine for months to years 4). Unless two cultures taken one month apart are negative, they are considered contagious until at least 1 year of age.
The most important preventive measure is rubella vaccination and antibody titer check before pregnancy. In Japan, the measles-rubella (MR) vaccine is introduced as a routine vaccination. Since vaccination cannot be given during pregnancy, pre-pregnancy measures are essential.
According to WHO criteria, a clinical definitive case is confirmed when a skilled physician identifies two items from Group A, or one item from Group A plus one item from Group B2).
| Group | Findings |
|---|---|
| Group A | Cataract, congenital glaucoma, congenital heart disease, hearing loss, retinitis pigmentosa |
| Group B | Purpura, splenomegaly, microcephaly, intellectual disability, meningoencephalitis, translucent bone disease, jaundice within 24 hours after birth |
A complete ophthalmic examination is necessary for all patients with suspected or confirmed CRS. The characteristic salt-and-pepper fundus appearance of rubella retinopathy has high diagnostic value. Even if no ocular complications are found, children with congenital rubella syndrome require ophthalmologic follow-up for at least one year after birth, with attention to late-onset ocular complications that can cause visual impairment.
Evaluation of pediatric glaucoma includes intraocular pressure measurement with a handheld tonometer, corneal diameter measurement, and gonioscopy. In infants, a cup-to-disc ratio of 0.3 or more suggests glaucoma.
Important diseases for differential diagnosis of CRS are listed below.
| Category | Differential Diagnosis |
|---|---|
| Infectious diseases | Congenital CMV infection, congenital syphilis, congenital toxoplasmosis, congenital varicella, congenital HSV infection |
| Genetic disorders | Retinitis pigmentosa, X-linked ocular albinism |
Congenital syphilis also presents with “salt-and-pepper” retinal findings, so serological testing is important for differentiation.
There is no curative treatment for CRS. Symptomatic treatment for each organ disorder is the mainstay.
| Target | Treatment | Notes |
|---|---|---|
| Refractive error | Eyeglass correction, tinted glasses | Tinted contact lenses are also effective for photophobia |
| Cataract | Cataract surgery (early) | Zinn zonule fragility → IOL with caution |
| Glaucoma | Trabeculectomy | Angle surgery is not indicated |
| Corneal opacity | Penetrating keratoplasty | Difficulty improving vision, high rejection rate |
| Amblyopia | Occlusion therapy, refractive correction | Early intervention is important |
Nuclear cataracts often progress to total cataracts after birth, so early surgery is necessary from the perspective of visual development. However, special attention must be paid to the following points.
Intraocular pressure control with eye drops is often difficult. Due to angle dysgenesis, trabeculotomy and goniotomy are not indicated, and trabeculectomy is selected considering the patient’s age.
Full-thickness corneal transplantation for corneal opacity often does not lead to visual improvement, and caution is required due to a high rate of rejection.
For the combination of PDA and branch pulmonary artery stenosis, the most common cardiac anomaly in CRS, catheter intervention (device closure + stent placement) has been reported 5).
Children with CRS are considered contagious until at least 1 year of age, requiring isolation and appropriate hand hygiene 4).
To support visual development, many patients can attend regular classes but require aids such as enlarged textbooks. Partial attendance in classes for visually impaired students or educational consultation at schools for the blind or special needs schools for visual impairment is also recommended.
The zonules of Zinn are fragile, requiring careful judgment for intraocular lens implantation. Poor pupillary dilation due to iris developmental abnormalities makes surgery difficult. Additionally, secondary glaucoma has been reported in 43% of cases after cataract extraction, making long-term intraocular pressure management essential. For details, refer to the “Standard Treatment” section.
The pathophysiology of CRS is multifactorial and not fully understood. The following mechanisms have been proposed for how the rubella virus inhibits normal cell proliferation during organogenesis.
Rubella virus is thought to have an affinity for structures derived from the sixth branchial arch during the embryonic period, which is speculated to be the reason why the combination of PDA and branch pulmonary artery stenosis is the most common cardiac malformation in CRS5).
In autopsy reports, characteristic neuropathological findings of CRS include perivascular calcification of the basal ganglia and microglial nodules 3). Cystic infarction may also be present.
Gong et al. (2024) reported only 16 confirmed CRS cases in China from 2014 to 2023, pointing out significant underreporting due to deficiencies in the CRS surveillance system. In China, RCV has been included in routine vaccination since 2008, but women of childbearing age born before that generally have not received RCV. The study concludes that prenatal rubella susceptibility screening and RCV vaccination for non-immune women are key to preventing CRS 2).
Loeve et al. (2025) reported a case of a CRS infant born to a Somali refugee mother in the Netherlands. As of 2022, rubella elimination has been achieved in 93 of 194 countries worldwide, but vaccination rates remain low in the African and Eastern Mediterranean regions (36% and 42%, respectively), highlighting the urgent need to strengthen vaccination campaigns for refugee and migrant populations4).
Gupta et al. (2023) reported the first case of lens coloboma combined with high axial myopia in a CRS patient. It was inferred that rubella virus-induced developmental abnormalities of the zonules caused the lens coloboma. Additionally, the combination with high myopia may increase the risk of rhegmatogenous retinal detachment1).
Kumar et al. (2022) reported perivascular calcification of the basal ganglia and microglial nodules in autopsies of children with CRS. These are considered characteristic neuropathological findings of CRS. They also emphasized that persistent severe thrombocytopenia (4,000/μL) should be recognized as an initial symptom of CRS and highlighted the importance of screening for TORCH infections 3).
Roy et al. (2022) reported the results of catheter-based device closure and stent placement in three cases of CRS-associated PDA combined with left pulmonary artery stenosis. Good long-term outcomes were achieved in two cases, but one case required emergency open-heart surgery due to main pulmonary artery occlusion caused by the device. The importance of case selection is emphasized 5).
