Medical Biases and Misconceptions Impact Rett Syndrome Diagnoses in Males
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Rett syndrome (RTT) is a rare neurodevelopmental disorder typically caused by loss-of-function variants in the transcriptional regulator methyl-CpG binding protein-2 (MECP2) gene. As an X-linked condition, RTT was historically believed to be incompatible with life in males. However, recent advances in genetic testing have revealed more males with MECP2 variants than previously known, and significant clinical heterogeneity. A broadly distributed phenotype within a rare disorder makes phenotypic recognition difficult. Therefore, male RTT is at high risk for non-diagnosis, diagnostic delays, and inaccurate estimates of incidence. The current mixed methods study aimed to improve our understanding of diagnostic experiences for males with RTT.
Methods:
An international sample of caregivers of males with confirmed pathogenic alteration of MECP2 (all ages, alive, deceased) completed a survey of clinical characteristics and diagnostic experiences, followed by in-depth, semi-structured interviews. Descriptive statistics were used to characterize the sample, and linear regression was used to assess associations with age at diagnosis. Results are presented as median [IQR] (range) with significance set at p<0.05. Qualitative data were analyzed using a descriptive phenomenological approach.
Results:
The sample included parent caregivers to 47 boys with RTT , including 36 living and 11 deceased. Median age of living boys was 8.1 [3.9-15.9] (7-months to 31.5-years) and median age of death for boys who had passed was 6.0 [2.0-13.0] (1 to 16-years). Concerns for developmental delay were observed early; the vast majority (94.9%) showed delayed milestones before 12-months of age. Developmental regression was observed in over 70% of boys. Median age of diagnosis was 3-years [1.08, 6.75] (3-months to 16-years). Diagnosis was most often made by a geneticist and less frequently by a neurologist. The median length of time between onset of symptoms and receiving the RTT diagnosis was 2-years [0.94, 6.00] (2-months to 17-years).
Univariate associations showed age of diagnosis was negatively correlated with child’s year of birth (p<0.001) and positively correlated with age of symptom onset (p=0.002). Age of diagnosis was not associated with the type of provider who diagnosed, clinical features characteristic of Rett (e.g., regression, hand stereotypies), or socio-demographic variables (e.g., geographic location, socioeconomic status). Multivariate analysis showed that for every year increase in year of birth, the age of diagnosis (in years) decreased by 0.61 after adjusting for age of symptom onset.
Qualitative findings demonstrate that medical biases and widespread misconceptions contribute to delays in accurate diagnosis of RTT in males, which negatively impacts child health and family functioning. The diagnostic experience can be conceptualized as a three-phase phenomenon beginning with a difficult and demanding journey to the diagnosis, including long diagnostic odysseys for many boys and some sudden diagnoses in younger children. The diagnosis is typically delivered by an uninformed provider working within an unaware medical community, sometimes providing harmful misinformation about male RTT (e.g., all boys die before age 3). The diagnostic experience results in mixed emotional reactions from parents about the RTT diagnosis that may include grief, despair, relief, and/or a renewed focus. Illustrative quotes will be shared to support our interpretation of the data.
Conclusion:
As genomic sequencing is rapidly becoming more widely available, age of male RTT diagnosis is decreasing, resulting in more providers and families with unexpected results and a notable lack of male-specific anticipatory guidance and clinical recommendations. Diagnostic providers must increase their awareness of RTT in males and be prepared to deliver the diagnosis with empathy and accurate, up-to-date information on prognosis and treatment options in order to facilitate more positive caregiver adaptation to this life altering diagnosis.
Rett syndrome (RTT) is a rare neurodevelopmental disorder typically caused by loss-of-function variants in the transcriptional regulator methyl-CpG binding protein-2 (MECP2) gene. As an X-linked condition, RTT was historically believed to be incompatible with life in males. However, recent advances in genetic testing have revealed more males with MECP2 variants than previously known, and significant clinical heterogeneity. A broadly distributed phenotype within a rare disorder makes phenotypic recognition difficult. Therefore, male RTT is at high risk for non-diagnosis, diagnostic delays, and inaccurate estimates of incidence. The current mixed methods study aimed to improve our understanding of diagnostic experiences for males with RTT.
Methods:
An international sample of caregivers of males with confirmed pathogenic alteration of MECP2 (all ages, alive, deceased) completed a survey of clinical characteristics and diagnostic experiences, followed by in-depth, semi-structured interviews. Descriptive statistics were used to characterize the sample, and linear regression was used to assess associations with age at diagnosis. Results are presented as median [IQR] (range) with significance set at p<0.05. Qualitative data were analyzed using a descriptive phenomenological approach.
Results:
The sample included parent caregivers to 47 boys with RTT , including 36 living and 11 deceased. Median age of living boys was 8.1 [3.9-15.9] (7-months to 31.5-years) and median age of death for boys who had passed was 6.0 [2.0-13.0] (1 to 16-years). Concerns for developmental delay were observed early; the vast majority (94.9%) showed delayed milestones before 12-months of age. Developmental regression was observed in over 70% of boys. Median age of diagnosis was 3-years [1.08, 6.75] (3-months to 16-years). Diagnosis was most often made by a geneticist and less frequently by a neurologist. The median length of time between onset of symptoms and receiving the RTT diagnosis was 2-years [0.94, 6.00] (2-months to 17-years).
Univariate associations showed age of diagnosis was negatively correlated with child’s year of birth (p<0.001) and positively correlated with age of symptom onset (p=0.002). Age of diagnosis was not associated with the type of provider who diagnosed, clinical features characteristic of Rett (e.g., regression, hand stereotypies), or socio-demographic variables (e.g., geographic location, socioeconomic status). Multivariate analysis showed that for every year increase in year of birth, the age of diagnosis (in years) decreased by 0.61 after adjusting for age of symptom onset.
Qualitative findings demonstrate that medical biases and widespread misconceptions contribute to delays in accurate diagnosis of RTT in males, which negatively impacts child health and family functioning. The diagnostic experience can be conceptualized as a three-phase phenomenon beginning with a difficult and demanding journey to the diagnosis, including long diagnostic odysseys for many boys and some sudden diagnoses in younger children. The diagnosis is typically delivered by an uninformed provider working within an unaware medical community, sometimes providing harmful misinformation about male RTT (e.g., all boys die before age 3). The diagnostic experience results in mixed emotional reactions from parents about the RTT diagnosis that may include grief, despair, relief, and/or a renewed focus. Illustrative quotes will be shared to support our interpretation of the data.
Conclusion:
As genomic sequencing is rapidly becoming more widely available, age of male RTT diagnosis is decreasing, resulting in more providers and families with unexpected results and a notable lack of male-specific anticipatory guidance and clinical recommendations. Diagnostic providers must increase their awareness of RTT in males and be prepared to deliver the diagnosis with empathy and accurate, up-to-date information on prognosis and treatment options in order to facilitate more positive caregiver adaptation to this life altering diagnosis.