PREVENTABLE HAZARDS FROM IN VITRO FERTILIZATION – A CASE SERIES OF CF PATIENTS FROM BULGARIA
Yaneva N, Baycheva M, Kostova P, Papochieva V, Mileva S, Miteva D, Savov A, Petrova G
*Corresponding Author: Guergana Petrova, MD, PhD, University Hospital Alexandrovska, Pediatric clinic, Medical University of Sofia; Sofia, Bulgaria, 1 G. Sofiiski bld tel: +3598877570386, e-mail: gal_ps@yahoo.co.uk
page: 83

MATERIALS, METHODS AND RESULTS

In Bulgaria there are currently 248 living confirmed pwCF (BGpwCF) [author unpublished data]. All patients have genetic confirmation of the disease, with more than 95% carrying two disease causing mutations. Genetic tests include evaluating the most common CF causing mutations using “in house” methods. The methodology for mutation detection includes single-strand conformation polymorphism (SSCP), Sanger sequencing, multiplex ligation dependent probe amplification (MLPA) analysis and next-generation sequencing (NGS) of the entire CFTR coding region and splice site junctions (Applied Biosystems, USA) if none or only one mutation was found [6]. Since newborn screening (NBS) for CF is not yet performed in our country, the diagnosis depends solely on clinical presentation. The median age at diagnosis in Bulgaria is currently 1.2 years (minimum 0 years – maximum 64 years) In the group of 248 BGpwCF, 5 were conceived by IVF and born in a family not previously affected by CF. In 4 families, donor oocytes had to be used, while in the last case the parent’s own gametes were used. Two IVF pregnancies involved twins – in both cases the sibling is a healthy CF carrier. All five children were diagnosed within the last 5 years. The age of diagnosis ranged from 0 (for two children with meconium ileus) to 9 years (Table 1). There was a significant delay in diagnosis in one of the patients (9 years), despite classical failure to thrive and severe nasal polyposis. The case was peculiar as the parents didn’t want to accept the diagnosis for almost 4 years and only recently agreed to proper therapy for CF. Due to severe polyposis the parents were aiming for biological therapy, but after appropriate explanation of the disease agreed for surgery. The turning point for accepting diagnosis in this family was the approval of CFTR modulator therapies in Bulgaria. All patients but one are carriers of at least one c.1521_1523 delCTT, the most common mutation described in 80.65% of BGpwCF. One female patient is homozygous for the same mutation, and this combination occurs in 35.58% of BGpwCF. After birth, she suffered from diarrhea and failure to thrive. She also contracted COVID19 at three months of age. The infection resulted in severe respiratory insufficiency and CF was confirmed by sweat test and genetic analysis. It took three months in the hospital and 4 more months on home oxygen before the patient reached the current, stable condition. She also had positive sputum cultures for Pseudomonas aeruginosa and is on an inhaled antibiotic. The second girl in the group also has a healthy twin carrier of c.1521_1523 delCTT. The mutation is inherited from the father, while the donor oocyte carried the c.828C>A mutation. The patient suffered recurrent airway obstructions, but due to good weight gain, the diagnosis was confirmed when she was 11 months old. At the time of diagnosis, positive sputum cultures for Pseudomonas aeruginosa led to aggressive therapy with intravenous and inhaled antibiotic. However, eradication of the bacterium was not achieved. Currently, her condition is stable and expecting to begin CFTR modulator therapy next month. The c.828C>A mutation is found in approximately 1.6% of BGpwCF. There is another patient with this mutation in our group (the only case where donor gametes were not used). He had inherited c.828C>A from his father, while his mother’s oocyte carried c.3909C>G. The boy was born with meconium ileus, and had survived two surgeries (an initial one, at diagnosis, and later a reconstructive surgery). He is currently in a stable condition with no infectious bacteria from respiratory samples. He has a good weight/height curve. The c.3909C>G is the second most common allele in BGpwCF found in 5.6% and is also confirmed in another child in this study. The patient had c.1739_1740insT and underwent surgery for meconium ileus at birth and is currently in a stable overall condition. (Table 1)



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