A Case of TBR-1 Gene Deletion Associated with Keratoconus: Cause or Coincidence?
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
TBR-1-related disorders are due to mutations of the TBR-1 gene. The TBR-1 gene is a neuron-specific transcription factor involved in cortical neurogenesis. Only about 40 cases have been reported worldwide. These patients demonstrate neurodevelopmental delay, including learning disability, autism, and behavioral disorders. Common features include hypotonia and fine motor delay. Others may have feeding difficulties, constipation, and seizures.
TBR-1 plays a role in retinal ganglion cell (RGC) development. Patients with keratoconus (KC) have also been associated with abnormal RGC development. TBR-1 is also involved in corneal homeostasis and interacts with collagen-modifying proteins.
We present a young adult who was diagnosed with TBR1 gene deletion and also found to have KC.
Case Presentation
A 26-year-old Hispanic male with autism, speech impairment, and learning disability (LD) presented with 3 possible seizures.
Patient’s pregnancy and delivery were uneventful. He weighed 6 lbs. 5 oz. at birth. Patient walked normally and started talking at age 6.
He was diagnosed with autism and intellectual disability as a child.
There was no history of behavioral problems. He enjoyed building Legos, bowling, basketball, and golf. Family history was significant for intellectual disability and autism.
Exam revealed a young man who was sitting with his hands folded, smiling, and not disruptive. His speech was a little explosive. He followed commands. There was mild facial asymmetry; his right face was flatter than the left. He had a bifid tongue and clinodactyly on both hands. Calf bulk was normal. There were no features associated with Fragile X or Down Syndrome.
Diagnostic Workup
Patient’s EEG was normal. Brain MRI showed a reduced anterior commissure.
Munson’s sign was present on gross exam. Slit-lamp examination showed paracentral thinning and bulging of the cornea, Fleischer’s ring, Vogt’s striae, and corneal hydrops. Corneal topography revealed inferior steepening consistent with keratoconus. Thus he was diagnosed with keratoconus at age 25.
Chromosome microarray revealed a 247 kb interstitial deletion of 2Q24.2->2Q24.2, which was pathogenic, resulting in deletion of 2 OMIM genes (PSMD14, TBR1). FISH confirmed 2Q24.2 deletion in the proband. His mom tested negative for this deletion. His father’s genetic testing results are pending.
Treatment and Management
He was started empirically on lamotrigine 50mg twice daily for presumed seizures, which resulted in resolution of the previous episodes. No medications for behavior were required.
He was referred to Genetics for further assessment and counseling.
Outcome and Follow-Up
He is now speaking more clearly and won a medal in basketball. He enjoys playing sports with his friends.
Discussion
TBR-1 related disorders are extremely rare and to date no cases associated with keratoconus have been reported. There have been reports of mutations in the TBR-1 gene leading to abnormal development of RGCs. Patients with KC may exhibit similar RGC abnormalities. Given that RGCs are among the first cells to develop in the embryonic eye, these findings suggest that disruptions in the RGC complex may lead to irregular eye development.
In TBR-1/Smad4 double-knockout mice, Smad4 played a pivotal role in TBR1-dependent ECM synthesis and TBR-1 independent ECM degradation for maintaining corneal homeostasis.
TBR-1 also interacts with collagen-modifying proteins, which may also suggest a plausible mechanism for keratoconus in this condition.
Neither PSMD14 and AHCTF1P1 are associated with human disease, however in theory these may explain his keratoconus as well.
Conclusion
This case may serve as human evidence that TBR1 mutations may cause KC. More cases of TBR-1 related disorders need to be collected and analyzed to prove whether TBR-1 gene mutations are truly a cause of KC or not.
TBR-1-related disorders are due to mutations of the TBR-1 gene. The TBR-1 gene is a neuron-specific transcription factor involved in cortical neurogenesis. Only about 40 cases have been reported worldwide. These patients demonstrate neurodevelopmental delay, including learning disability, autism, and behavioral disorders. Common features include hypotonia and fine motor delay. Others may have feeding difficulties, constipation, and seizures.
TBR-1 plays a role in retinal ganglion cell (RGC) development. Patients with keratoconus (KC) have also been associated with abnormal RGC development. TBR-1 is also involved in corneal homeostasis and interacts with collagen-modifying proteins.
We present a young adult who was diagnosed with TBR1 gene deletion and also found to have KC.
Case Presentation
A 26-year-old Hispanic male with autism, speech impairment, and learning disability (LD) presented with 3 possible seizures.
Patient’s pregnancy and delivery were uneventful. He weighed 6 lbs. 5 oz. at birth. Patient walked normally and started talking at age 6.
He was diagnosed with autism and intellectual disability as a child.
There was no history of behavioral problems. He enjoyed building Legos, bowling, basketball, and golf. Family history was significant for intellectual disability and autism.
Exam revealed a young man who was sitting with his hands folded, smiling, and not disruptive. His speech was a little explosive. He followed commands. There was mild facial asymmetry; his right face was flatter than the left. He had a bifid tongue and clinodactyly on both hands. Calf bulk was normal. There were no features associated with Fragile X or Down Syndrome.
Diagnostic Workup
Patient’s EEG was normal. Brain MRI showed a reduced anterior commissure.
Munson’s sign was present on gross exam. Slit-lamp examination showed paracentral thinning and bulging of the cornea, Fleischer’s ring, Vogt’s striae, and corneal hydrops. Corneal topography revealed inferior steepening consistent with keratoconus. Thus he was diagnosed with keratoconus at age 25.
Chromosome microarray revealed a 247 kb interstitial deletion of 2Q24.2->2Q24.2, which was pathogenic, resulting in deletion of 2 OMIM genes (PSMD14, TBR1). FISH confirmed 2Q24.2 deletion in the proband. His mom tested negative for this deletion. His father’s genetic testing results are pending.
Treatment and Management
He was started empirically on lamotrigine 50mg twice daily for presumed seizures, which resulted in resolution of the previous episodes. No medications for behavior were required.
He was referred to Genetics for further assessment and counseling.
Outcome and Follow-Up
He is now speaking more clearly and won a medal in basketball. He enjoys playing sports with his friends.
Discussion
TBR-1 related disorders are extremely rare and to date no cases associated with keratoconus have been reported. There have been reports of mutations in the TBR-1 gene leading to abnormal development of RGCs. Patients with KC may exhibit similar RGC abnormalities. Given that RGCs are among the first cells to develop in the embryonic eye, these findings suggest that disruptions in the RGC complex may lead to irregular eye development.
In TBR-1/Smad4 double-knockout mice, Smad4 played a pivotal role in TBR1-dependent ECM synthesis and TBR-1 independent ECM degradation for maintaining corneal homeostasis.
TBR-1 also interacts with collagen-modifying proteins, which may also suggest a plausible mechanism for keratoconus in this condition.
Neither PSMD14 and AHCTF1P1 are associated with human disease, however in theory these may explain his keratoconus as well.
Conclusion
This case may serve as human evidence that TBR1 mutations may cause KC. More cases of TBR-1 related disorders need to be collected and analyzed to prove whether TBR-1 gene mutations are truly a cause of KC or not.