RAD51Related Fanconi Anemia is Commonly Associated with VACTERL: Expanding the Phenotypic Spectrum with a Fifth Reported Case<
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Fanconi anemia (FA) is a multiorgan disease caused by pathogenic variants in DNA repair genes involved in the FA/BRCA pathway. Most patients with FA present with congenital anomalies, later develop bone marrow failure, and display increased risk of leukemia and solid tumors. Approximately 90% of FA patients carry pathogenic variants in FANCA, FANCC and FANCG. RAD51/FANCR is an ultra-rare disorder, reported only in 4 patients to date. Due to the rarity of this genotype, its characterization remains limited.
Case Presentation
The proband is now a 10-year-old female who was born at 37 weeks of gestation. Pregnancy was complicated by placenta accreta. She was born small for gestational age with birth weight at Z-score -2.16, length at Z-score -1.51, and head circumference at Z-score -3.97. At birth, she was noted to have hypotelorism, bilateral epicanthal folds and short palpebral fissures, wide nasal bridge and broad nasal tip, overriding lambdoid sutures, and imperforate anus with rectovaginal fistula. She was suspected to have VACTERL association; echocardiogram revealed patent ductus arteriosus (PDA) and patent foramen ovale and abdominal ultrasound showed horseshoe kidneys. Hand radiographs showed bilateral hypoplastic thumbs, bilateral clinodactyly of index fingers, and right 5th finger. Head computed tomography confirmed left coronal craniosynostosis. Brain and spine magnetic resonance imaging studies were unremarkable. Spinal radiographs showed fusion of S4-S5 vertebrae. Audiology evaluation showed moderate bilateral conductive hearing loss at age 3 years, likely related to recurrent ear infections and middle ear effusion. Her endocrine evaluation for short stature and low body weight at age 7 years was unremarkable. The proband exhibited speech/language delay and learning difficulties, and was diagnosed with attention-deficit/hyperactivity disorder.
Diagnostic Workup
A chromosomal SNP microarray was normal. Because of the proband’s physical findings and the suspected VACTERL association, a chromosomal breakage test (CBT) on blood lymphoblasts was ordered and showed slightly increased breaks and radial forms but was insufficient to confirm the diagnosis of FA. Subsequently, CBT was performed on skin fibroblasts which also showed inconclusive results. FA gene panel uncovered a de novo RAD51 c.884A>G; p.(His295Arg) variant. Based on ACMG/AMP criteria, this variant was interpreted as likely pathogenic based on PS2, PM2, PM6, PP3 and PP4 scores, establishing the RAD1-related FA diagnosis.
Treatment and Management
The proband underwent imperforate anus repair with diversion colostomy during the neonatal period, PDA ligation at age 2 ½ months, posterior sagittal anorectoplasty at age 11 months, and loop colostomy take-down and closure at age 19 months. For recurrent ear infections, underwent bilateral myringotomy and pressure equalization tube placement at age 19 months. She now attends third grade with an individualized education plan and continues receiving speech therapy for pronunciation difficulties.
Outcome and Follow-Up
The proband is followed through the Cancer Predisposition Clinic with annual complete blood counts, and so far, she has no macrocytosis, cytopenia or other evidence of bone marrow failure.
Discussion
We describe a fifth patient with RAD51/FANCR caused by a novel RAD51 variant. This case highlights VACTERL as a significant feature of RAD51-related FA. In fact, 4 of 5 reported patients with RAD51-related FA (including our proband) showed VACTERL association. Similarly, 4/5 had developmental delays/behavioral manifestations that are not as prevalent in more common FA complementation groups. This is the second case where cardiac manifestation is described, and where borderline blood and fibroblast CBT results are reported, underscoring the importance of molecular testing in the appropriate clinical context.
Conclusion
This report expands our understanding of the phenotypic spectrum seen in RAD51-related FA and its relation with VACTERL association. Our findings raise intriguing questions about FA pathophysiology and somatic mosaicism. As we continue to unravel the complexities of RAD51-related FA, larger cohorts of patients are needed to determine potential genotype-phenotype correlations and improve personalized tumor surveillance and management.
Fanconi anemia (FA) is a multiorgan disease caused by pathogenic variants in DNA repair genes involved in the FA/BRCA pathway. Most patients with FA present with congenital anomalies, later develop bone marrow failure, and display increased risk of leukemia and solid tumors. Approximately 90% of FA patients carry pathogenic variants in FANCA, FANCC and FANCG. RAD51/FANCR is an ultra-rare disorder, reported only in 4 patients to date. Due to the rarity of this genotype, its characterization remains limited.
Case Presentation
The proband is now a 10-year-old female who was born at 37 weeks of gestation. Pregnancy was complicated by placenta accreta. She was born small for gestational age with birth weight at Z-score -2.16, length at Z-score -1.51, and head circumference at Z-score -3.97. At birth, she was noted to have hypotelorism, bilateral epicanthal folds and short palpebral fissures, wide nasal bridge and broad nasal tip, overriding lambdoid sutures, and imperforate anus with rectovaginal fistula. She was suspected to have VACTERL association; echocardiogram revealed patent ductus arteriosus (PDA) and patent foramen ovale and abdominal ultrasound showed horseshoe kidneys. Hand radiographs showed bilateral hypoplastic thumbs, bilateral clinodactyly of index fingers, and right 5th finger. Head computed tomography confirmed left coronal craniosynostosis. Brain and spine magnetic resonance imaging studies were unremarkable. Spinal radiographs showed fusion of S4-S5 vertebrae. Audiology evaluation showed moderate bilateral conductive hearing loss at age 3 years, likely related to recurrent ear infections and middle ear effusion. Her endocrine evaluation for short stature and low body weight at age 7 years was unremarkable. The proband exhibited speech/language delay and learning difficulties, and was diagnosed with attention-deficit/hyperactivity disorder.
Diagnostic Workup
A chromosomal SNP microarray was normal. Because of the proband’s physical findings and the suspected VACTERL association, a chromosomal breakage test (CBT) on blood lymphoblasts was ordered and showed slightly increased breaks and radial forms but was insufficient to confirm the diagnosis of FA. Subsequently, CBT was performed on skin fibroblasts which also showed inconclusive results. FA gene panel uncovered a de novo RAD51 c.884A>G; p.(His295Arg) variant. Based on ACMG/AMP criteria, this variant was interpreted as likely pathogenic based on PS2, PM2, PM6, PP3 and PP4 scores, establishing the RAD1-related FA diagnosis.
Treatment and Management
The proband underwent imperforate anus repair with diversion colostomy during the neonatal period, PDA ligation at age 2 ½ months, posterior sagittal anorectoplasty at age 11 months, and loop colostomy take-down and closure at age 19 months. For recurrent ear infections, underwent bilateral myringotomy and pressure equalization tube placement at age 19 months. She now attends third grade with an individualized education plan and continues receiving speech therapy for pronunciation difficulties.
Outcome and Follow-Up
The proband is followed through the Cancer Predisposition Clinic with annual complete blood counts, and so far, she has no macrocytosis, cytopenia or other evidence of bone marrow failure.
Discussion
We describe a fifth patient with RAD51/FANCR caused by a novel RAD51 variant. This case highlights VACTERL as a significant feature of RAD51-related FA. In fact, 4 of 5 reported patients with RAD51-related FA (including our proband) showed VACTERL association. Similarly, 4/5 had developmental delays/behavioral manifestations that are not as prevalent in more common FA complementation groups. This is the second case where cardiac manifestation is described, and where borderline blood and fibroblast CBT results are reported, underscoring the importance of molecular testing in the appropriate clinical context.
Conclusion
This report expands our understanding of the phenotypic spectrum seen in RAD51-related FA and its relation with VACTERL association. Our findings raise intriguing questions about FA pathophysiology and somatic mosaicism. As we continue to unravel the complexities of RAD51-related FA, larger cohorts of patients are needed to determine potential genotype-phenotype correlations and improve personalized tumor surveillance and management.
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