(Reuters Health) – Fragile X syndrome may be underdiagnosed, particularly among women, a U.S. study suggests.

Researchers examined electronic health record data for 1.7 million patients seen over approximately 40 years at the Marshfield Clinic Health System and 2.1 million patients seen over approximately 33 years at the University of Wisconsin Health System. The main goal was to compare the rate of clinically diagnosed cases of Fragile X syndrome within these health systems to the expected number of cases in the general population, which researchers identified as 1.4 per 10,000 in males and 0.9 per 10,000 in females.

During the study period, researchers identified a total of 87 clinically diagnosed cases of Fragile X syndrome at UW Health and 55 cases at Marshfield Clinic. These figures were far below the expected number of cases during the study period: 239 at UW Health and 196 at Marshfield Clinic, the authors report in JAMA Network Open.

“Previous studies have shown that only a small fraction of potential individuals who in fact have Fragile X syndrome are tested, so we expected to see a gap between the prevalence estimate and the number of individuals who actually received a clinical diagnosis,” said lead study author Marsha Mailick of the University of Wisconsin-Madison.

“However, the high rate of underdiagnosis was surprising to us,” Mailick said by email.

The underdiagnosis rate was more pronounced among females than males at both UW Health (71.9% vs 58.0%) and the Marshfield Clinic (86.8% vs 61.1%).

When researchers looked at the subset of patients with complete data on race and ethnicity, they also found that the vast majority of clinically diagnosed cases of Fragile X syndrome (84.6%) occurred among people who self-identified as white.

Guidelines may play a role in underdiagnosis because testing for Fragile X syndrome is currently only recommended for individuals who have autism and/or an intellectual disability of unknown cause, Mailick said. Some cases may also go undiagnosed because Fragile X syndrome isn’t covered by mandatory newborn screenings and because the condition doesn’t have any recognizable physical characteristic at birth, Mailick added.

Beyond this, the characteristics that usually prompt consideration for testing such as speech delay and developmental delay are not unique to Fragile X syndrome, Mailick said.

“Therefore, the similarity of characteristics could lead to misdiagnosis or add delay to Fragile X syndrome testing,” Mailick said. “Lack of access to testing and genetic counseling, lack of awareness about the condition and also practices such as watchful waiting are other possible reasons that not all individuals who in fact have Fragile X syndrome are clinically diagnosed.”

Limitations of the study include the predominantly white patient population at both UW Health and the Marshfield Clinic, which may limit generalizability of the findings, the study team notes. More research in larger, more diverse populations is needed.

SOURCE: https://bit.ly/33zy6pt JAMA Network Open, online December 30, 2021.

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