Thirty-Year Odyssey to Dual Diagnoses: Value of Longitudinal Genetics Follow-Up
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Widespread use of whole exome sequencing (WES) significantly improves diagnostic rates in previously undiagnosed individuals. Atypical presentations of monogenic conditions are often attributed to phenotypic variability. However, newer testing strategies increasingly identify more than one genetic condition in some patients. Pediatric patients that received a genetic diagnosis may forgo genetics follow-up in later years. We present a patient who returned to our clinic 20 years after initial genetic evaluation because several symptoms were not explained by his first diagnosis. Updated genetic testing identified a second condition which explained his health issues not related to the initial diagnosis and facilitated appropriate medical management and genetic counseling. This case demonstrates the need for longitudinal follow-up for individuals with genetic conditions, especially in the setting of an atypical phenotype.
Case Presentation
A 16-month-old male presented in 1997 for evaluation of bilateral aniridia, microcephaly, external ear malformations, and developmental delays attributed to vision loss. By age 9, absent speech, intellectual disability, and autistic features were present. Oral aversion and limited jaw opening caused failure to thrive. Gastrostomy tube placement incidentally revealed intestinal malrotation. Skeletal abnormalities included shortened forearms and toes, and femoral anteversion. At age 21, he returned to clinic at which time he demonstrated profound vision loss and glaucoma after multiple retinal surgeries, severe pes cavus requiring multiple tendon releases, continued G-tube dependency, and confirmed autism. At age 29, he presented to clinic with onset of progressive spasticity.
Diagnostic Workup
Initial workup included normal biochemical testing, EEG, and brain MRI. WAGR syndrome was suspected, which at that time was exclusively attributed to 11p13/PAX6 deletions. Microarray was normal. PAX6 sequencing revealed a novel missense variant (p.(Ile87Arg)), explaining his aniridia. His other anomalies and delays were tentatively attributed to PAX6, with limited gene-phenotype data at that time. By his return to clinic in 2022, PAX6 missense variant phenotypes were further delineated to include neurological abnormalities like cerebellar ataxia and cortical atrophy, in additional to ophthalmic abnormalities. Nevertheless, with multiple features remaining unexplained, further genetic testing was indicated. WES revealed a likely pathogenic variant in DYRK1A, establishing his second diagnosis: DYRK1A-related neurodevelopment disorder, characterized by gastrointestinal, skeletal, and neurological features.
Treatment and Management
Targeted medical management was implemented based on symptoms. He underwent Wilms tumor screening, diligent ophthalmologic management (monitoring, medications, and several retinal surgeries), and orthopedic care for severely progressive pes cavus. The Foundation for the Blind provided critical early education and support throughout school. He currently benefits from occupational, speech, and equine therapies.
Outcome and Follow-Up
After most symptoms remained unexplained for nearly 30 years, the second diagnosis provided his family with valuable psychosocial benefits including accurate genetic counseling for his unaffected siblings. Now age 31, the patient is thriving in a group home, receiving low vision mobility training and new ophthalmic medications to improve his quality of life.
Discussion
The possibility of multiple diagnoses should always be considered during genetic evaluation. Atypical presentations of known conditions and incompletely characterized phenotypes of emerging conditions complicate the diagnostic process. Broad testing should be considered when a known diagnosis does not completely explain a patient’s phenotype. Our timeline demonstrates the striking advances of testing technologies and gene-phenotype characterization. For undiagnosed patients, we cannot underestimate the value of longitudinal follow-up to mitigate delays in diagnosis and care.
Conclusion
This case exemplifies opportunities to improve care both for diagnosed patients with an atypical phenotype and for those without a diagnosis. Although the impact of experiencing a diagnostic odyssey has been studied, the utility of and barriers to long term follow up with genetics providers has not been explored. Understanding the barriers to accessing long-term genetics follow-up is a critical component to addressing these gaps in access and delays in diagnosis.
Widespread use of whole exome sequencing (WES) significantly improves diagnostic rates in previously undiagnosed individuals. Atypical presentations of monogenic conditions are often attributed to phenotypic variability. However, newer testing strategies increasingly identify more than one genetic condition in some patients. Pediatric patients that received a genetic diagnosis may forgo genetics follow-up in later years. We present a patient who returned to our clinic 20 years after initial genetic evaluation because several symptoms were not explained by his first diagnosis. Updated genetic testing identified a second condition which explained his health issues not related to the initial diagnosis and facilitated appropriate medical management and genetic counseling. This case demonstrates the need for longitudinal follow-up for individuals with genetic conditions, especially in the setting of an atypical phenotype.
Case Presentation
A 16-month-old male presented in 1997 for evaluation of bilateral aniridia, microcephaly, external ear malformations, and developmental delays attributed to vision loss. By age 9, absent speech, intellectual disability, and autistic features were present. Oral aversion and limited jaw opening caused failure to thrive. Gastrostomy tube placement incidentally revealed intestinal malrotation. Skeletal abnormalities included shortened forearms and toes, and femoral anteversion. At age 21, he returned to clinic at which time he demonstrated profound vision loss and glaucoma after multiple retinal surgeries, severe pes cavus requiring multiple tendon releases, continued G-tube dependency, and confirmed autism. At age 29, he presented to clinic with onset of progressive spasticity.
Diagnostic Workup
Initial workup included normal biochemical testing, EEG, and brain MRI. WAGR syndrome was suspected, which at that time was exclusively attributed to 11p13/PAX6 deletions. Microarray was normal. PAX6 sequencing revealed a novel missense variant (p.(Ile87Arg)), explaining his aniridia. His other anomalies and delays were tentatively attributed to PAX6, with limited gene-phenotype data at that time. By his return to clinic in 2022, PAX6 missense variant phenotypes were further delineated to include neurological abnormalities like cerebellar ataxia and cortical atrophy, in additional to ophthalmic abnormalities. Nevertheless, with multiple features remaining unexplained, further genetic testing was indicated. WES revealed a likely pathogenic variant in DYRK1A, establishing his second diagnosis: DYRK1A-related neurodevelopment disorder, characterized by gastrointestinal, skeletal, and neurological features.
Treatment and Management
Targeted medical management was implemented based on symptoms. He underwent Wilms tumor screening, diligent ophthalmologic management (monitoring, medications, and several retinal surgeries), and orthopedic care for severely progressive pes cavus. The Foundation for the Blind provided critical early education and support throughout school. He currently benefits from occupational, speech, and equine therapies.
Outcome and Follow-Up
After most symptoms remained unexplained for nearly 30 years, the second diagnosis provided his family with valuable psychosocial benefits including accurate genetic counseling for his unaffected siblings. Now age 31, the patient is thriving in a group home, receiving low vision mobility training and new ophthalmic medications to improve his quality of life.
Discussion
The possibility of multiple diagnoses should always be considered during genetic evaluation. Atypical presentations of known conditions and incompletely characterized phenotypes of emerging conditions complicate the diagnostic process. Broad testing should be considered when a known diagnosis does not completely explain a patient’s phenotype. Our timeline demonstrates the striking advances of testing technologies and gene-phenotype characterization. For undiagnosed patients, we cannot underestimate the value of longitudinal follow-up to mitigate delays in diagnosis and care.
Conclusion
This case exemplifies opportunities to improve care both for diagnosed patients with an atypical phenotype and for those without a diagnosis. Although the impact of experiencing a diagnostic odyssey has been studied, the utility of and barriers to long term follow up with genetics providers has not been explored. Understanding the barriers to accessing long-term genetics follow-up is a critical component to addressing these gaps in access and delays in diagnosis.