Complete DiGeorge Syndrome with congenital athymia
This is the story of Daniel, who was born in Romania, with the rare disorder Complete DiGeorge Syndrome with congenital athymia (the lack of a thymus at birth). His mum Stela, who quickly became an expert in this condition, tells his story. It tracks Daniel’s journey from diagnosis to a successful thymus transplant at Great Ormond Street Hospital.
Daniel’s first days of life
Daniel was born 10 years ago after a perfect pregnancy, and he was considered a perfectly healthy baby boy at birth. Although Daniel had experienced a few breathing difficulties, the doctor felt that they were due to the hard birth labour my son had been through.
He had the BCG vaccine on his first day of life (tuberculosis vaccine is a live vaccine and it is part of the national vaccination schedule in Romania) and afterwards we were discharged from the maternity department.
In the first 3–4 months we had a perfectly normal family life: we had guests, we went shopping, we went to the park, and we had no idea that Daniel was supposed to be kept in strict isolation. We were so happy as parents. Things just couldn’t have been better.
Things got complicated after 4 months
When Daniel was 4 months old, he suddenly became very ill. He had a high temperature; he developed a generalized rash; he had reflux and aspiration pneumonia, flu-like symptoms, difficulties in breathing and swallowing and he picked up rotavirus from the hospital waiting rooms.
He was immediately admitted to the hospital and things went from bad to worse.
- He started having low-calcium seizures due to very low levels of parathyroid hormone (PTH), which is the hormone that regulates calcium levels in the body.
- He didn’t respond to treatment.
- He developed severe infections leading to sepsis, an infection of the bloodstream, with multiple causes: Klebsiella, Enterococcus, Staphylococcus and fungus.
- He had otitis (inflammation of the ear canal) and needed 3 surgical procedures to remove diseased cells, the last procedure leaving him with permanent facial paralysis on the left side.
The ear infections affected his hearing.
We stayed in the hospital for months without having answers for all of this.
He was given no chance of survival and we had a huge decision to make
Daniel’s health deteriorated rapidly, he lost 2kg and he couldn’t eat. We were in shock because from a healthy baby, he had become a severely ill child who was struggling to survive. He was given no chance of survival.
We found an article about a doctor from Timisoara (a city in Romania) who specialized in primary immunodeficiencies. We took Daniel from the hospital in Bucharest and drove 700km to Timisoara to get some answers.
At Timisoara, Daniel was immediately suspected of having Complete DiGeorge Syndrome with total absence of T-cells (congenital athymia). In Romania, doctors could only offer us bone marrow transplantation from an unrelated donor, but this is high risk with low probability of success for congenital athymia patients.
We had a huge decision to make! I felt so hopeless and this huge burden of making a life-or-death decision for my child was incredibly painful.
The thymus is a gland located on top of the heart. It acts like a schoolhouse where T-cells get educated.
How to determine that there is no thymus (athymia)
Stem cells in the bone marrow make all the cells in the blood. However, T-cells play a very important role in the immune system and they need to be “highly educated” in order to fulfill their role. The thymus is the “schoolhouse” where T-cells get “educated”. Pre-T-cells “educated” in the thymus emerge into the blood afterwards as naïve T-cells. Children like Daniel are born without the “schoolhouse” for the T-cells. Without T-cells, the immune system cannot work, thus babies are born without a defence system. The life span of a child born without a thymus may be significantly impaired.
Determination that there is no thymus (athymia) is predominantly based on blood tests. Imaging (x-rays, scans, etc.) is not usually helpful.
T-cell numbers may be:
- very low or absent
- moderately low, normal or high and associated with skin rashes, enlarged lymph glands and sometimes diarrhoea.
Naïve T-cell numbers are always absent or very low. These findings may be associated with other non-immunological problems, including:
- low calcium due to under-functioning of the parathyroid glands
- congenital heart disease
- features of DiGeorge Syndrome with a chromosome 22q deletion
- features of CHARGE Syndrome
- absence of hair and poorly formed nails in so-called Nude-SCID due to mutations in the FOXN1 gene.
Athymia may be due to:
- DiGeorge Syndrome with a 22q deletion on chromosomal testing
- CHARGE Syndrome with CHD7 mutation on genetic testing
- rare single-gene disorders, e.g. single TBX1 (a gene which is part of 22q11), PAX1 or FOXN1
- maternal diabetes with poorly controlled blood sugar levels in early pregnancy.
Getting in touch with Great Ormond Street Hospital in London, UK
I started doing research on the internet and soon found Dr Louise Markert’s articles on thymus transplantation. I contacted Dr Markert and she put me in touch with Dr Graham Davies at Great Ormond Street Hospital in London, UK.
Thymus transplantation is only performed in 2 hospitals: Duke University, North Carolina, USA and Great Ormond Street Hospital, London, UK
Initially our Health Authority in Romania refused to pay for this procedure. We had no other choice but to fundraise to save Daniel.
Daniel had a gastrostomy tube inserted in Austria
During this time Daniel’s health deteriorated and he urgently needed a feeding tube. We were denied this in every hospital in Bucharest because doctors considered the surgery too risky, plus they didn’t believe that surgery was necessary as he was already too ill to make it.
We took the little money we had fundraised and left for Austria to have the feeding tube and reflux surgery there. Things got complicated and we ended up being stuck there, as Daniel’s health wasn’t good enough for him to fly back home. Eventually we returned.
Daniel got to have his life-saving thymus transplantation at Great Ormond Street Hospital in London. He was the 9th thymus transplant patient at GOSH.
Daniel got to have his life-saving thymus transplantation when he was 1 year and 5 months old in Great Ormond Street Hospital in London, but complications did arise due to his late diagnosis and pre-transplant infections:
- chronic cough needing intermittent oxygen treatment
- chronic respiratory syncytial virus (RSV) infection
- chronic BCG lymphadenopathy, which caused swelling of his lymph nodes and required 3 years of anti-tuberculosis treatment
- chronic diarrhoea with persistent rotavirus and Clostridium difficile infection
- late immune system reconstitution (3 years after transplantation)
- autoimmune issues
- facial paralysis due to surgery
- hearing loss.
What late diagnosis means for the patient and the importance of SCID newborn screening
Late diagnosis means: more infections, an increased number of hospital admission days, more treatments and therapies, lower than expected outcomes and a high mortality rate (vs. early diagnosis).
During Daniel’s diagnosis Odyssey he had:
- several episodes of sepsis
- 10 surgeries
- 2 years of hospital admissions
- BCG-related infection, 3 years of strong TBC drugs, severe swelling of the lymph nodes
- 3 years of tube feeding
- 3 surgeries to deal with ear infections, which caused a permanent facial paralysis and hearing loss
- 6 central lines inserted during 2 years of hospital admissions (PICC lines, port-a-cath, femoral line, jugular line).
Late diagnosis also means so much suffering from the patient’s perspective!
All this may have been avoided with SCID newborn screening! Why? Because SCID newborn screening picks up babies who have low or no T-cells.
Today Daniel is a smart, brave and kind 10-year-old boy and he has a perfectly normal, happy life. He is a very wise boy, he enjoys school, learning, reading, practising sports and making new friends. He has a great attitude towards everything he does, pushing his limits and wanting to try new things all the time. He wants to enjoy everything life has to offer. As one of his teachers said: “He has shown great wisdom in all aspects of his learning. He shows a huge amount of aspiration and resilience daily and he is a role model to his classmates and to all adults who were lucky enough to meet and work with him.”
He still has lower T-cells than expected and he deals with issues related to DiGeorge Syndrome, such as making too little parathyroid hormone, which can be hard to manage sometimes.
I don’t have words to express how thankful I am to the Thymus Transplantation team at Great Ormond Street Hospital! Their work and dedication to save children like Daniel has made it possible for many more children to receive life-saving thymus transplantation. Daniel was the 9th thymus transplant patient in 2013.
In 2021, Great Ormond Street Hospital reached an important milestone of 50 thymus transplantations; that is, 50 children who were given the chance to benefit from this pioneering technique and to live a relatively normal life.