Covering Letter for Bohring-Opitz Syndrome Case Report
[Your Name, Credentials]
[Your Institution/Department]
[Address]
[Email]
[Date]
Editor-in-Chief
[Target Journal Name]
[Journal Address]
Dear Editor,
We submit for your consideration a case report documenting a patient with Bohring-Opitz syndrome (BOS), a rare and life-limiting genetic disorder caused by pathogenic variants in the ASXL1 gene. This case contributes meaningfully to the limited published literature on BOS, particularly regarding multidisciplinary management strategies that may improve survival and quality of life in this devastating condition.
Clinical Significance and Rationale for Publication
BOS remains critically underreported, with fewer than 50 molecularly confirmed cases in the literature, despite an estimated 40% mortality rate in early childhood from unexplained bradycardia, obstructive apnea, or pulmonary infections 1. Our patient demonstrates the cardinal diagnostic features established for BOS: characteristic facial dysmorphism (trigonocephaly, retrognathia, prominent eyes with underdeveloped supraorbital ridges, upslanting palpebral fissures, depressed nasal bridge, anteverted nares, low-set posteriorly-rotated ears, glabellar nevus flammeus), severe feeding difficulties requiring gastrostomy, growth retardation, profound neurodevelopmental delay, microcephaly, flexion anomalies of the upper limbs with the pathognomonic "BOS posture" (radial head dislocation and ulnar deviation of fingers), structural brain anomalies, and seizures 1, 2, 3.
Molecular confirmation via whole exome sequencing identified a de novo pathogenic ASXL1 variant, consistent with the loss-of-function mechanism underlying nearly 50% of clinically diagnosed BOS cases 2, 3. The ASXL1 gene functions as a tumor suppressor with transforming capacity when mutated, conferring an approximately 7% risk of Wilms tumor (WT) development in BOS patients 1. Our case emphasizes the critical need for WT surveillance using renal ultrasound protocols adapted from Beckwith-Wiedemann syndrome guidelines, as recommended by the AACR Workshop Committee 1.
Novel Contributions to the Literature
This case report provides several unique contributions:
Detailed documentation of seizure management with levetiracetam (30 mg/kg/day), addressing a manifestation present in the majority of BOS patients but with limited published treatment protocols 1, 3.
Comprehensive description of our structured feeding program and nutritional support strategies, which are essential given that severe feeding difficulties represent one of the three main diagnostic criteria for BOS and contribute significantly to failure to thrive 2, 4.
Longitudinal developmental assessment data, which is particularly valuable given that most published BOS cases focus on early childhood presentation, whereas our patient's age provides insight into the natural history beyond the high-risk early mortality period 3, 4, 5.
Multidisciplinary care coordination protocols that may serve as a template for other centers managing this complex syndrome, potentially improving the 60% survival rate to age 20 years currently reported in the literature 1.
Relevance to Clinical Practice
Early recognition of BOS is paramount because distinctive facial features may fade over time in survivors past infancy, potentially delaying diagnosis 1. Our case illustrates the importance of maintaining clinical suspicion for BOS in any child presenting with the triad of severe feeding difficulties, characteristic facial appearance, and fixed flexion contractures of the upper limbs, even when molecular testing is not immediately available 2, 4.
Furthermore, the female predominance in BOS (approximately 3:1 ratio) without evidence of differential viability between sexes remains unexplained 1, and our patient's demographic characteristics contribute to the phenotypic database necessary for understanding this sex bias.
Genetic Counseling Implications
This case underscores the importance of accurate recurrence risk counseling, as germline mosaicism has been documented in BOS, with at least one reported case of maternal germline mosaicism resulting in transmission of a pathogenic ASXL1 variant to an affected child 6. While most BOS cases result from de novo mutations, trio exome sequencing should be considered to exclude low-level parental mosaicism, which would elevate recurrence risk above the baseline de novo mutation rate 6.
Tumor Surveillance Recommendations
Given the 7% incidence of renal neoplasms (WT and nephroblastomatosis) in BOS patients with confirmed ASXL1 mutations, with documented cases diagnosed between ages 2 and 6 years, we have implemented the WT screening protocol recommended by the AACR Workshop Committee, consisting of abdominal/renal ultrasound surveillance 1. This represents a critical but underemphasized aspect of BOS management that warrants broader dissemination through case report publication.
Conclusion
This case report fills important gaps in the BOS literature by providing detailed management protocols, longitudinal outcome data, and reinforcement of tumor surveillance guidelines. We believe this manuscript will serve as a valuable resource for clinicians encountering this rare syndrome and will contribute to improved recognition, diagnosis, and comprehensive care of affected patients.
We confirm that this case report has not been published elsewhere and is not under consideration by another journal. All authors have approved the manuscript and agree with its submission to your journal. Informed consent for publication was obtained from the patient's legal guardians.
Thank you for considering our manuscript. We look forward to your response.
Sincerely,
[Your Name, Credentials]
[Title/Position]
[Institution]
Enclosures: Manuscript, figures, supplementary materials, signed consent forms