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Chromosomal Rearrangements Resulting in Beckwith-Wiedemann Syndrome and Beyond 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
The majority of identifiable pathogenic alterations that cause Beckwith-Wiedemann syndrome (BWS) are methylation abnormalities. Less than 1% of cases of BWS are caused by duplication, inversion, or translocation of 11p15.5. Such chromosomal changes often lead to imbalance of genetic material, opening the possibility for concurring diagnoses. We report on two patients with an unbalanced rearrangement resulting in BWS and a second chromosomal condition.





 

Case Presentation
Patient one was prenatally noted to have hepatomegaly, enlarged gallbladder, and possibly a congenital heart defect. Patient two presented at 14 months of age to the local children’s hospital due to concern for seizure activity.
 



Diagnostic Workup
For patient one, amniocentesis, including karyotype and chromosomal microarray, demonstrated a 4 Mb terminal gain of 11p15.5p15.4 and a 12 Mb terminal loss of 11q24.1q25. This was suggestive of an unbalanced, recombinant derivative chromosome 11 secondary to a balanced parental pericentric inversion. Parental karyotypes demonstrated that the patient’s father had a pericentric inversion of chromosome 11. For our patient, this established a dual diagnosis of BWS and Jacobsen syndrome (JBS).



Patient two’s physical evaluation was notable for large head, epicanthal folds, upslanting palpebral folds, tongue protrusion, hypotonia, and global developmental delay. Chromosomal microarray [DA1] demonstrated a 4 Mb terminal loss of 4p16.3 and a 3.2 Mb terminal gain of 11p15.5p15.4. Parental karyotypes demonstrated that the patient’s father had a balanced rearrangement between chromosomes 4 and 11. For our patient, this establishes a dual diagnosis of BWS and Wolf-Hirschhorn (WHS).  



 

Treatment and Management
Given the concurring diagnosis for patient one, an abdominal ultrasound was obtained during his NICU stay which was unremarkable. For the BWS diagnosis, the patient was monitored for hypoglycemia, feeding difficulties, and placed on surveillance screening for embryonal tumors associated with the condition. For the diagnosis of JBS, specific screening bloodwork and imaging were recommended. Of note, an echocardiogram was obtained during the NICU stay which demonstrated a persistent left superior vena cava, bicuspid aortic valve, and[DA1]  small patent ductus arteriosus. In addition, a CBC was obtained, was consistent with thrombocytopenia, and the patient was subsequently referred to hematology for routine surveillance. Finally, the patient was referred to early interventional services given the increased risk for developmental delay.



Patient two was previously established with neurology, physical medicine and rehabilitation, and early interventional services, but the diagnosis of BWS prompted initiation of surveillance screening for associated embryonal tumors.

Outcome and Follow-Up
Both patients continue to follow with several specialties, including hematology given the thrombocytopenia diagnosis for patient one and neurology given the epilepsy diagnosis for patient two. Both patients received early interventional therapies, and have made significant developmental progress. Both patients also remain on the BWS surveillance protocol.

Discussion
Given the rarity of inversions and translocations causing BWS in addition to another diagnosis, it makes our patients noteworthy to report on their unique cytogenetic findings. In addition, early identification of the dual diagnoses has proven advantageous for both patients, as it directly led to alterations in their medical management, such as allowing for condition specific management recommendations to be placed (BWS embryonal tumors surveillance screening, monitoring for thrombocytopenia, and enrolling in early interventional services). This also was beneficial to their families, as identification was able to clarify their recurrence risk and reproductive options.  

Conclusion
Dual diagnoses may be unexpected in some cases, but allow for tailored medical management recommendations that can better the patient’s long-term outcomes.

 

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