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Mikhael Krotov has advanced pulmonary fibrosis and bone marrow failure due to telomere-mediated disease, with a pathogenic gene variant in the TINF2 gene, known to cause dyskeratosis congenita syndrome.

A rare disease, congenital dyskeratosis

Dyskeratosis Congenita (CD), or Zinsser-Cole-Engman syndrome, is an inherited, often fatal disease, first described dermatologically by Zinsser in 1906. The clinical symptoms of DC are highly variable, some may appear late, and its mode of genetic transmission is very complex and still poorly understood. For this reason it is often difficult to diagnose.

The root cause of Dyskeratosis Congenita is the presence of shortened telomeres. Telomeres are the endings of chromosomes, non-coding DNA sequences that function to protect the encoding DNA. With each cell division, the telomeres get shorter, and when they get too short the cells stop dividing and therefore stop renewing themselves properly. This is part of the aging phenomenon.

People with DC carry a dysfunctional gene that reduces their ability to maintain telomeres. Their cells stop dividing too soon, leading to very rapid degradation of their organs.

Patients with DC can develop bone marrow failure, lung disease, cancer, or liver disease, which are often fatal.

A medical innovation makes a treatment possible

Mikhael Krotov is followed at the Nice University Hospital for lung fibrosis and has long been followed at St-Louis Hospital in Paris, and it has been confirmed that no treatment is available in France and in Europe.After research, it appeared that in the context of Dyskeratosis Congenita (DC) the only possible treatment route, although risky, is a double transplant: transplant of both lungs followed by a bone marrow transplant from the same donor. This operation was performed by Prof. Szabolcs and Prof. McDyer at UPMC   (Pittsburgh, United States) 5 times, and by Prof. Szabolcs previously for the first time, i.e. 6 times in all, on patients suffering from DC and other patients with Primary Immune Deficiency. Out of all 6 cases, significant success was recorded.

“Madeline was 10 when she was diagnosed with secondary combined immune deficiency. Within a year, her health had deteriorated to the point that her parents were told they could take her home on palliative care, or contact Szabolcs and the pediatric lung transplant team at Children’s to explore whether she could enroll in their clinical trial. She was 11 when she was added to the transplant waiting list. She received her new lungs in September 2015; a month later she celebrated her 14th birthday at the Ronald McDonald House in Pittsburgh. Her new bone marrow was transplanted in January 2016. Today, she’s applying to college. ”

Sharon tregaskis for Pittmed, Summer 2019. Read more about the success story of double transplantation

On the combined lung and bone marrow transplant

This innovative double transplant procedure from the same donor, developed at UPMC, aims to treat end-stage lung disease when combined with bone marrow failure.

The premise of this protocol is that it corrects bone marrow failure and improves tolerance to lung transplants from the same donor. At the same time, it eliminates the need for immunosuppressive therapy which is standard in traditional procedures, not only preventing the death of the patient, but leading to a significant improvement in their quality of life.

The procedure is carried out in two stages: the team first performs the lung transplant, then a few weeks later, once the patient has recovered from the first operation, the bone marrow transplant is performed.

This clinical trial has been approved by the US Food and Drug Administration (FDA) and has already delivered significant successes (Szabolcs et al. 2015, McDyer et al. 2020). 

Both professors Dr. Szabolcs and Dr. John F. McDyer in UPMC believe Mikhael is a good candidate to pursue combined lung transplantation and bone marrow transplant (Lung/BMT). Without this therapy, he will certainly die of his pulmonary fibrosis, most likely in the next few months, as there is no highly effective alternative therapy. 

UPMC stand ready to rapidly accept Mikhael Krotov for tandem lung transplant followed by bone marrow transplant as soon he has sufficient funds for the operation. Mikhael’s official contact at UPMC is Kathy Iurlano. Her full contact details can be found on our contact page.

Some supporting links:

Description of Dyskeratosis Congenita: https://www.childrenshospital.org/conditions-and-treatments/conditions/d/dyskeratosis-congenita/symptoms-and-causes

Description of the procedure by the UPMC: https://www.chp.edu/research/clinical-studies/blood-marrow-transplant/tandem-lung-marrow-transplant

Publication about the procedure by the UPMC: https://www.upmcphysicianresources.com/news/031819-crohns-sclerosis-sickle-tandem-lung-bmt-transplant

Clinical trial in the US: https://clinicaltrials.gov/ct2/show/NCT03500731

A webpage of Dr Szabolcs

Article by Szabolcs et al. in the Journal of Allergy and Clinical Immunology (2015, 135(2): 567-570) describing successful the first successful double transplants. doi: 10.1016/j.jaci.2014.07.058

Conference Abstract by McDyer et al. in the American Journal of Respiratory and Critical Care Medicine (2020, 201: A1021) describing more cases: https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A1021

A success story of double transplantation

Acceptance letters at UPMC:

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