乌鸦传媒

Incidental detection of a genetic abnormality in a fetus at 29 weeks' gestation was the conundrum facing Ido Didi Fabian, MD, of The Goldschleger Eye Institute at Sheba Medical Center in Tel Aviv, Israel, and colleagues.

As described in their case report in , it all began when routine fetal ultrasound raised suspicions of a potential polycystic kidney, prompting the 37-year-old primigravid mother to undergo amniocentesis for further investigation.

While whole-exome sequencing did not identify any genetic abnormality to indicate polycystic kidney, an incidental finding of a heterozygous c.501-2 A<G sequence variant in the RB1 gene was identified. Although the specific RB1 variant had not been previously reported in any genetic databases, the commercial laboratory considered it pathogenic under the American College of Medical Genetics for interpreting sequence variants.

Inherited retinoblastoma arises from biallelic pathogenic variants in that gene, with high penetrance such that most carriers develop intraocular tumors.

However, fetal ultrasound did not detect any intraocular tumors in this case. Nor was there any evidence of retinoblastoma or ocular disorders in the family history. Both parents underwent complete ophthalmic examinations, with normal findings and no suspected retinomas.

In the absence of a family history or sonographic features to suggest a retinoblastoma, clinicians diagnosed the 29-week-old fetus with RB1 pathogenic sequence variant. They advised the parents that they, and their child in utero, should undergo further genetic assessment.

Both parents received whole-exome sequencing, which confirmed that the father, who had no history of cancer, carried the same genetic variant as the fetus. This finding reduced concerns that the variant was pathogenic, authors noted. "RNA sequencing demonstrated disruption of the splice site, resulting in shortened protein product; however, the reading frame remained intact," they explained.

In light of these features, the sequence variant's status was lowered to be considered a variant of undetermined significance and termination of the pregnancy was not recommended.

Similarly, premature delivery for early diagnosis and treatment was not advised after a multidisciplinary evaluation of the fetus, the team said. They pointed to the risks associated with early fetal delivery, the absence of any radiological findings suggestive of intraocular tumors, and downgraded pathogenicity of the incidental variant based on additional further genetic evaluation.

Retinoblastoma cannot be ruled out based solely on routine prenatal examinations, Fabian and co-authors noted. Hence, they collaborated with clinical geneticists and used multimodal fetal imaging for additional investigations for any potential intraocular pathologies. At 38 weeks' gestation, they followed up with fetal MRI and did not detect any intraocular tumors or intracranial abnormalities suggestive of trilateral retinoblastoma.

The parents decided to continue the pregnancy. The child was born at 39 weeks and 6 days with no complications. Clinicians examined the infant without anesthesia at the parents' request. They found no evidence of intraocular tumors. The child was age 10 months at the time of publication and had no pathogenic ocular abnormalities. The child continues to have regular examinations to ensure that retinoblastoma does not develop, Fabian and co-authors reported.

Discussion

Retinoblastoma affects one in 17,000 live births and is generally diagnosed in the first few years of life. With timely diagnosis and treatment, the survival rate is nearly 100%. However, children with retinoblastoma that is not identified and treated early in the disease course have a poor prognosis.

Inherited retinoblastoma occurs due to biallelic pathogenic sequence variants (PSVs) in the RB1 gene in a precursor retinal cell. It tends to differ from disease with in being more likely to affect both eyes, the group noted. "An inherited mutated allele (i.e., germline PSV) predisposes to tumorigenesis in utero or after birth in 40% of retinoblastoma cases, with high penetrance of the disease."

According to a recent systematic , newborns at risk due to a family history of retinoblastoma should be screened regularly until they reach age 4, although a recommended screening at-risk children until age 7.

Fabian and co-authors noted that performing genetic testing prenatally facilitates earlier detection, which in turn offers an opportunity to inform family planning, access genetic counseling, and employ interventions sooner. "For example, planned delivery for prenatally confirmed carriers of RB1 mutations can lead to earlier diagnosis, reduced treatment-associated morbidity, and favorable visual outcomes," they noted.

The group cautioned that the process requires careful multidisciplinary evaluation, given the possible risks associated with preterm delivery, such as developmental delays. And although there is no established threshold for planned , success is possible with active intervention after 26 weeks' gestation, they added.

"Inactivating RB1 germline PSVs have been associated with high penetrance, with most PSV carriers developing intraocular tumors by early childhood," authors noted. Yet individual phenotype presentation may vary, even among identical PSV carriers. Fabian's group cited one report of "a substantial prevalence of asymptomatic mutated RB1 PSV carriers among parents of retinoblastoma patients with more children inheriting a defective RB1 gene from the father." Fabian and colleagues observed that this finding suggested that the penetrance of retinoblastoma may be influenced by parental origin. Other found that bilateral retinoblastoma had a later onset in individuals with low-penetrance RB1 PSVs (e.g., splice-site and missense SVs) compared with patients with null PSVs.

RNA sequencing of amniotic fluid cells and other methods of genetic screening have helped clinicians assess the that a specific RB1 SV may be associated with any phenotypic manifestations.

"However, there currently are no clinically acceptable predictive parameters to better define the phenotypic expression of RB1 PSV carriers," they concluded. And this case of an incidental finding of RB1 PSV highlights the "clinical and ethical dilemma to both clinician and family."

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