Lack of awareness spurs diagnostic delays for Rett syndrome in males
Study urges providers to be up to date on disorder in boys, men
A lack of awareness or misconceptions in the medical community about Rett syndrome occurring in boys and men commonly leads to misdiagnoses or diagnostic delays, according to a new study.
“Diagnostic providers must increase their awareness of males with [Rett] and be prepared to deliver the diagnosis with empathy and accurate, up-to-date information on prognosis and treatment options,” researchers wrote in the study “Medical Biases and Misconceptions Impact Diagnoses in Males With Loss of Function MECP2 Variants.” It was published in the American Journal of Medical Genetics Part A.
Disorder affects girls almost exclusively
Most cases of Rett syndrome are caused by mutations in the MECP2 gene, which disrupt the function of a protein of the same name that plays a critical role in brain development and function.
The neurodevelopmental disorder almost exclusively affects girls because the MECP2 gene is located on the X chromosome. Females have two X chromosomes, so they still have one healthy copy of MECP2, even if the other is mutated. Since males have one X chromosome, they usually don’t survive early infancy with an MECP2 mutation.
However, recent advances in genetic testing have revealed more males with rarer MECP2 mutations than previously known. Male Rett is characterized by severe symptoms, such as developmental delays, intellectual disability, dependence on breathing and feeding support, and early death.
Because Rett is rare in boys and men and has nonspecific symptoms, genetic testing for MECP2 mutations in boys may be delayed or overlooked, making diagnosis more challenging.
“To date, there have been no studies investigating important diagnostic experiences in male [Rett],” wrote researchers who investigated the diagnostic experiences of male Rett patients with a MECP2 mutation to understand the timing of diagnoses and potential associations with clinical and social factors.
Family caregivers for 47 Rett males, including 36 living and 11 deceased, completed a survey of diagnostic experiences. Living patients ranged in age from 7 months to 31.5 years, while the age of those who died ranged from 1 to 16 years.
Nearly all showed developmental delays before the age of 1, with most exhibiting at least two out of four Rett diagnostic features: regression of hand use and language, gross motor delays, and repetitive hand movements. Most experienced seizures and/or needed feeding support, while nearly half required breathing support.
The median age at diagnosis was 3 years, while the range was 3 months to 16 years. Most cases received one or more clinical diagnoses before the Rett diagnosis, with the most common being autism spectrum disorder, followed by cerebral palsy, epilepsy, abnormal muscle tone, and intellectual disability/global developmental delay.
In an adjusted statistical analysis, for every year increase in the year of birth, the age of diagnosis decreased by 0.31 years, meaning more recent diagnoses occurred at a younger age.
Diagnosis of Rett syndrome in males a long odyssey for some families
Parents were asked about the diagnostic experience, with nearly half saying it was negative, one-third saying it was positive, and about one in five deeming it neutral. Still, no relationships were found between parent rating of the diagnosis and year of birth, age at diagnosis, U.S. versus non-U.S. residence, or the provider delivering the diagnosis.
The researchers also interviewed 32 caregivers, who said their diagnostic stories fell into two categories: longer diagnostic odysseys and sudden diagnoses.
Most participants described an extended journey to a male Rett diagnosis, with the time between first symptoms and diagnosis varying widely — from eight months to over a decade. Parents of older children, especially those born before routine genetic testing became common or who lived in countries with limited testing access, faced longer delays. Early genetic tests were inconclusive in some cases due to a failure to detect a MECP2 mutation.
Parents often felt dismissed by providers, who attributed delays to parental inexperience or gave an incorrect diagnosis like autism, cerebral palsy, or intellectual disability. Clinicians familiar with female Rett were among this group. Such misdiagnoses delayed proper treatment, caused emotional harm, and sometimes led to inappropriate interventions, according to parents.
Providers were often reluctant to order genetic testing without clear symptom patterns, mainly due to the misconception that males cannot have Rett, parents said.
Earlier diagnosis of male [Rett] is critical for enabling targeted care plans and expanding families’ social support networks. However, medical biases, misconceptions, and low incidence have historically delayed diagnosis.
In some cases, however, a diagnosis of male Rett came suddenly and unexpectedly, more commonly among younger boys. Still, the diagnosis often arrived during high-stress situations, such as hospitalizations due to the severity of the child’s symptoms. While the diagnostic journey was shorter, parents said the emotional impact was still profound.
Despite varied paths to a male Rett diagnosis, nearly all participants shared the common experience of an uninformed medical community. They said many providers lacked knowledge about male Rett and often gave alarming or inaccurate information. While families later benefited from Rett specialists and support from the male Rett parent community, the initial lack of provider awareness was a significant source of stress and confusion.
Online misinformation was also tricky to navigate, with sources frequently claiming that Rett boys would not survive past early childhood, which was echoed by some medical professionals. Looking back, many parents wished they had been better informed about the broader range of outcomes for male Rett patients.
Lastly, many parents initially saw the diagnosis as a death sentence, triggering intense grief. Receiving an accurate diagnosis brought relief and a sense of clarity, offering families a new direction after long periods of uncertainty.
“Earlier diagnosis of male [Rett] is critical for enabling targeted care plans and expanding families’ social support networks,” the researchers concluded. “However, medical biases, misconceptions, and low incidence have historically delayed diagnosis.”
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