Medical Biases and Misconceptions in Diagnosing Male RTT

Research study background

Rett syndrome (RTT), a rare neurodevelopmental disorder, is caused by loss-of-function variants in a transcriptional regulator gene called methyl-CPG binding protein-2, or MECP2. There is a clear clinical care pathway for female patients with RTT, but historically, the condition was believed to be incompatible with life for male children, resulting in early death.

However, as genetic testing has become more accessible allowing for more broad genetic characterizations of RTT, studies have shown more male RTT cases than expected. In fact, researchers have classified four categories of male RTT (classic, atypical, neonatal encephalopathy and X-linked intellectual disability). Despite the availability of whole-genome sequencing as a clear diagnostic tool, most males with symptoms of RTT are diagnosed based on clinical observation. This has resulted in many misdiagnoses and delayed diagnoses for males with RTT.

Until now, no one had investigated the diagnostic experience of families faced with male RTT. This study aimed to not only understand prominent symptoms and timing of diagnosis, but also provide rich descriptions of how diagnoses were ultimately made and the impact of an RTT diagnosis on children and caregivers. In doing so, the Children’s Hospital Colorado research team hoped to foster more timely diagnoses, evidence-based counseling and clinical recommendations tailored to the needs of male RTT.

Study methodology

The study sample included 47 boys with MECP2 variations, with 36 living and 11 deceased. All of the study’s participants were diagnosed between 2000 and 2023 and were between 3 months and 16 years old at the time of diagnosis. Current ages ranged from 7 months to 31.5 years, demonstrating that some patients with male RTT can live well passed the common life expectancy for the condition.

Using both qualitative and quantitative methods, researchers determined that most of the participants showed milestone delay before their first birthdays, and experienced common RTT diagnostic features such as regression of hand use and language, gross motor delays, repetitive hand movements, seizures, and breathing and feeding difficulties.

In trying to better understand the diagnostic experience of families, researchers defined three phases:

• Difficult, demanding and diverse journeys to diagnoses
• Uninformed delivery of the diagnosis, with either providers showing total unawareness of male RTT or characterized by misinformation
• Mixed reactions to the diagnosis, including anticipatory grief, but also relief and resolve

The delays in diagnosis and irregular use of genetic testing delayed proper treatment, provided false hope and in some cases, led to counterproductive interventions. Providers were at risk of ignoring or missing clear signs of RTT because of the misconception that males cannot have it.

When families eventually did receive diagnoses, they were often met with more misinformation that led them to believe that in all cases, male RTT was a death sentence. This took an extreme emotional toll on families surveyed.

Clinical implications

The study’s findings indicate that a lack of awareness and medical biases serve as primary barriers to timely diagnosis. Parents and caregivers noted that their providers did not suspect RTT and hesitated to order genetic tests, whereas in female patients, providers often suspect RTT and quickly verify via genetic testing.

Researchers also highlighted a need for male-specific anticipatory guidance and updated clinical care recommendations based on the four categories of male RTT. Additionally, they recommend that providers guide families toward trustworthy resources and communities and prepare them for potential misinformation.

“The old knowledge was that males with certain MECP2 mutations do not survive infancy,” says Tim Benke, MD, PhD, one of the study’s authors. “This inaccuracy negatively impacted families. We provide new knowledge that there is a spectrum of disease to allow clinicians to better counsel families, improve access to interventional clinical trials and recognize our knowledge gaps in rare diseases.”