Broadening molecular and phenotype spectrum including thrombocytopenia in KAT6A-associated condition
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Arboleda-Tham Syndrome is caused by pathogenic mutations in the KAT6A gene. This condition is characterized by intellectual disability, speech delay, hypotonia, eye malformations, and distinctive facial features. Known for its wide phenotypic spectrum, our study presents three cases that expand the understanding of the phenotype and mutation spectrum.
Case Presentation
First case is a 7-year-old female with a history of thrombocytopenia since birth with platelet count averaging 40-60K (ranges 27K to 91K), mildly decreased white count (3-5K) and normal haemoglobin and hematocrit. Bone marrow evaluation at 7 revealed hypocellularity (30%). She had a history of spontaneously resolved atrial septal defect (ASD), horseshoe kidney, tethered spinal cord, and expressive language delay. Her growth has been normal and there is minimum dysmorphology.
The second case involves a 2-month-old near full-term baby boy who presented with a hoarse cry, dysmorphic features, borderline hypotonia, and feeding failure requiring G-tube placement, and hydronephrosis. Significant developmental delay was noted.
The third case is a boy who presented at 4 months of age with sagittal and metopic craniosynostosis. He had significant hypotonia, PDA and ASD, global developmental delays, feeding difficulties, tracheomalacia with obstructive sleep apnea, and bilateral undescended testes.
Diagnostic Workup
Whole exome sequencing was performed in all three cases, revealing novel variants in KAT6A: a heterozygous frameshift deletion in exon 2 (c.270delA, p.K90fs) in case 1; a heterozygous insertion/deletion c.3124_3125insT; 3129delA, p.Thr1042IlefsTer2 in case 2; and a heterozygous nonsense mutation in exon 17 (c.G3661T, p.E1221X) in case 3. Subsequent parental testing confirmed that these variants were all de novo.
Treatment and Management
Current treatment options primarily focus on symptom management, such as physical therapy, speech therapy and occupational therapy. Understanding the pathophysiology of the condition may lead to more targeted therapy in the future.
Outcome and Follow-Up
Case 1 and 2 are yet to return for follow up in genetics. Case 3 has been followed regularly and had cranioplasty and orchiopexy, PDA and ASD resolved spontaneously, and he sleeps with CPAP. He continues to have significant hypotonia, global developmental delays with feeding difficulties. At 8 years of age, his growth parameters are all below the 1%. He is mostly fed via G-tube but is able to take puree PO and can drink water through a straw independently. He is able to walk with minimum assistance, can express thirst, hunger, and pain via eye gaze on iPad.
Discussion
Our three patients have a broad spectrum of clinical findings from mild developmental delay with thrombocytopenia and bone marrow hypocellularity to severe growth and developmental delays. The KAT6A gene consists of 17 exons. Based on the literature, loss-of-function early truncating mutations in exons 1-15 tend to result in milder phenotypes with microcephaly, hypotonia, gastrointestinal problems, congenital heart defects, and developmental delay, while late truncating mutations in exons 16 or 17 cause a more severe phenotype especially with significant cognitive delays. Late truncating mutations have been associated with one case of persistent thrombocytopenia and another case of pancytopenia with bone marrow failure. Our case 1 adds to this literature although our patient has an early truncating mutation in exon 2. This patient has normal growth and mild speech delay. Both our cases 2 and 3 have late truncating mutations with case 3 presenting with severe growth and developmental delays. Case 2 has a complex insertion-deletion that resulted in a frame shift that was not been reported previously.
Conclusion
Our report broadens the phenotype-genotype map of Arboleda-Tham syndrome and expands the known spectrum of mutations in the KAT6A gene. Our case of thrombocytopenia supports a function of KAT6A in hematopoietic cell regulation.
Arboleda-Tham Syndrome is caused by pathogenic mutations in the KAT6A gene. This condition is characterized by intellectual disability, speech delay, hypotonia, eye malformations, and distinctive facial features. Known for its wide phenotypic spectrum, our study presents three cases that expand the understanding of the phenotype and mutation spectrum.
Case Presentation
First case is a 7-year-old female with a history of thrombocytopenia since birth with platelet count averaging 40-60K (ranges 27K to 91K), mildly decreased white count (3-5K) and normal haemoglobin and hematocrit. Bone marrow evaluation at 7 revealed hypocellularity (30%). She had a history of spontaneously resolved atrial septal defect (ASD), horseshoe kidney, tethered spinal cord, and expressive language delay. Her growth has been normal and there is minimum dysmorphology.
The second case involves a 2-month-old near full-term baby boy who presented with a hoarse cry, dysmorphic features, borderline hypotonia, and feeding failure requiring G-tube placement, and hydronephrosis. Significant developmental delay was noted.
The third case is a boy who presented at 4 months of age with sagittal and metopic craniosynostosis. He had significant hypotonia, PDA and ASD, global developmental delays, feeding difficulties, tracheomalacia with obstructive sleep apnea, and bilateral undescended testes.
Diagnostic Workup
Whole exome sequencing was performed in all three cases, revealing novel variants in KAT6A: a heterozygous frameshift deletion in exon 2 (c.270delA, p.K90fs) in case 1; a heterozygous insertion/deletion c.3124_3125insT; 3129delA, p.Thr1042IlefsTer2 in case 2; and a heterozygous nonsense mutation in exon 17 (c.G3661T, p.E1221X) in case 3. Subsequent parental testing confirmed that these variants were all de novo.
Treatment and Management
Current treatment options primarily focus on symptom management, such as physical therapy, speech therapy and occupational therapy. Understanding the pathophysiology of the condition may lead to more targeted therapy in the future.
Outcome and Follow-Up
Case 1 and 2 are yet to return for follow up in genetics. Case 3 has been followed regularly and had cranioplasty and orchiopexy, PDA and ASD resolved spontaneously, and he sleeps with CPAP. He continues to have significant hypotonia, global developmental delays with feeding difficulties. At 8 years of age, his growth parameters are all below the 1%. He is mostly fed via G-tube but is able to take puree PO and can drink water through a straw independently. He is able to walk with minimum assistance, can express thirst, hunger, and pain via eye gaze on iPad.
Discussion
Our three patients have a broad spectrum of clinical findings from mild developmental delay with thrombocytopenia and bone marrow hypocellularity to severe growth and developmental delays. The KAT6A gene consists of 17 exons. Based on the literature, loss-of-function early truncating mutations in exons 1-15 tend to result in milder phenotypes with microcephaly, hypotonia, gastrointestinal problems, congenital heart defects, and developmental delay, while late truncating mutations in exons 16 or 17 cause a more severe phenotype especially with significant cognitive delays. Late truncating mutations have been associated with one case of persistent thrombocytopenia and another case of pancytopenia with bone marrow failure. Our case 1 adds to this literature although our patient has an early truncating mutation in exon 2. This patient has normal growth and mild speech delay. Both our cases 2 and 3 have late truncating mutations with case 3 presenting with severe growth and developmental delays. Case 2 has a complex insertion-deletion that resulted in a frame shift that was not been reported previously.
Conclusion
Our report broadens the phenotype-genotype map of Arboleda-Tham syndrome and expands the known spectrum of mutations in the KAT6A gene. Our case of thrombocytopenia supports a function of KAT6A in hematopoietic cell regulation.