
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
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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pwCF (BGpwCF) [author unpublished data].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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