Featured rare disease

On this page, we highlight one of the many rare diseases. We feature a new rare disease periodically; in this way we can raise awareness and understanding of rare diseases one disease at a time, raising people’s awareness not only that the disease exists but what it is and how to recognise it. If you have been diagnosed with one of the diseases highlighted and would like to share a story about your journey please contact us at enquiries@nzord.org.nz and we can arrange to put it up on our website.

Dyskeratosis Congenita

Picture of chromosome replicationOur Rare Disease Day poster child Gabrielle has a rare genetic disorder called dyskeratosis congenita (DC). DC is a telomere biology disorder where mutations in specific genes lead to abnormally short telomeres. These shortened telomeres create a cellular vulnerability with a higher risk of error during cell replication and cause an array of serious health consequences. DC is estimated to occur in one in a million people.

What are Telomeres?

Telomere (tel-uh-meer) from the Greek telos (end) and meros (part)

Telomeres are distinctive structures found at the ends of chromosomes which consist of repeating short DNA patterns, that can repeat 3000 times in healthy individuals. Telomeres help to organise the 46 chromosomes in the nucleus of our cells. They protect the ends of our chromosomes by forming a protective cap (much like the one at the end of shoelaces) which then allows the chromosomes to replicate properly and prevents important DNA from being lost when a cell divides.

Telomeres have been named as the ‘biological clock’ that determine our lifespan and the ability for our cells to regenerate.Everyone has a gradual shortening of telomeres throughout their lifetime; once a critical threshold is reached the cell is unable to divide and it dies. From birth the telomere length is 11 kilobases (kb) and it reduces each time the cell divides so that by the time a person is one hundred years old the length will be approx. 4 kb. A child with DC can have the same length telomeres as that of a 100-year-old!

DC is caused by a mutation in one of nine genes important in telomere biology. There may be other unidentified genes involved, and there is ongoing research to discover more gene mutations and learn about the wider picture of how telomere genes contribute to cancer development and ageing.

How do telomeres cause disease?

Cell division occurs constantly in our bodies at varying rates in different organs. As telomeres are required for safe and effective cell replication, when something goes wrong with them the process of division is affected and can lead to that cell reaching its "use-by date" much earlier than normal. This means that some organs will have an insufficient number of cells and the organ can eventual fail completely. As bone marrow divides prolifically, DC patients may first present with bone marrow failure (aplastic anaemia) and an increased risk of cancer due to the vulnerability of unprotected chromosome ends during replication.

Two different people, both with DC, who have the same genotype (genetic sequence) will have different disease progression, due to the complexity and influence of environmental and lifestyle factors. This provides many important avenues for research such as: What are the modifying effects of other genes? What are optimal environmental factors? What precautions can be taken and what treatments are most effective?

Telomeres on chromosome drifting offDC can be inherited in one of three ways: autosomal dominant, where only one faulty copy of the gene is needed to cause the disease; autosomal recessive, where two faulty copies from each parent are requiredto cause the disease; or the most common form, X-linked recessive where the gene responsible for DC is carried on the X-chromosome. As men have only one copy of the X chromosome they are more likely to express the disease than women. If there is awareness of a family history children may be tested before or after birth, and this early diagnosis allows a patient to harvest his own bone marrow for storage for potential use in the future. Prenatal testing diagnosis can inform the decision to store cord blood, but not bone marrow.

What are the symptoms of dyskeratosis congenita?

Features can overlap with Fanconi anaemia, idiopathic aplastic anaemia and myelodysplasia.

The symptoms are broad and cause daily challenges along with an increased risk of serious illness and organ failures. Up to 15–20% of people with DC face digestive issues due to cell lining of the gastro-intestinal tract having a higher rate of turnover, which can cause daily problems of nausea, abdominal pain and feeling full after eating small amounts of food. Up to 40% of patients have eye complications including eyelashes irritating the eye, obliteration of the lacrimal (tear duct) system and inflammation of the eyelids. The disease also affects the skin and nails and can cause liver disease. When bone marrow doesn't make enough blood cells or the liver becomes very damaged, it can be life-threatening. Lung complications including ‘pulmonary arteriovenous malformations’, which cause shortness of breath and dizziness, are a leading cause of mortality. Lung fibrosis can occur due to DNA damage causing the triggering of detrimental cellular processes.

Some other symptoms include:

  • Nail abnormalities. It often causes the fingernails and toenails to grow poorly and fall off. They may also have ridges or a thin spoon-like shape.
  • Skin abnormalities. The condition causes unusual changes in skin colour. It also causes a distinct lace-like pattern on the chest and neck.
  • Patches in the mouth. Called oral leukoplakia, these thick, white patches often form inside the mouth and can be precancerous tissue.
  • Progressive bone marrow failure. In approximately 90% of the cases.

Treatment and management

Not everyone with DC will get all these complications, but it is important that the range of symptoms are known by clinicians and that the possibilities are shared with new patients. This knowledge can also guide the formation of a potential treatment plan which would be tailored to each specific individual case and could include the benefits and risks of starting specific treatments (such as those involving the use of potential hepatic, pulmonary or haematopoietic drugs) so informed decisions can be made.

Treatment is complex and is tailored specifically to each patient’s disease and needs. More detailed information on how to diagnose, manage and treat DC is provided in a summary article by Sharon A Savage, MD can be found at this link: https://www.ncbi.nlm.nih.gov/books/NBK22301/ (Gene Reviews Nov 12, 2009; Last update: May 26, 2016)

What support is available?

There is a strong DC community connected through an international DC Outreach group (DCO) which offers great resources for patients, families and medical professionals. DCO has a guideline document which has combined the knowledge of 35 clinicians and researchers to produce a resource on managing and treating the most devastating symptoms.

DCO hosts monthly family chats and invites a medical doctor or researcher to attend to answer questions. The website also provides detail on a 2016 clinical trial looking at alternative and less toxic ways to complete bone marrow transplants for people with DC.

The issue that is often highlighted with rare disease is the power of the patient’s perspective, their combined stories and how this can influence, enable and build momentum for targeted research. Gathering international patient data into a directory that enables researchers to piece together the causes, and thus eventual treatment of the disease is absolutely vital.

Genetic Alliance have provided patients access to a data registering tool known as PEER (Platform for Engaging Everyone Responsibly) which gives the power of sharing to the patient and provides a platform for a DC patient research registry. Patients can choose to make their own health information available and limit permissions with the ability to change their mind at any point. By learning how the condition affects each individual and finding trends, this data helps accelerate the quest to develop better therapies in the future through a more in-depth understanding of DC patient outcomes.

What about the patient perspective?

NZORD posed some key questions to those who know more about DC than anyone else: the patients themselves.  We were truly inspired by how their inner strength, support for one another and general positivity in the face of adversity shone through.  We hope that their thoughts and feedback help patients, clinicians and researchers to understand the formidable journey for those with DC:

  • The most challenging aspects was detailed by one parent of child with DC as “having to explain to every new medical specialist details about DC and learning that this was just the way it was going to be.”
  • The advice that people wished they had been given at the start of their journey included the emotional aspects of “enjoying the good days, being patient with the bad and not being discouraged by bad test results nor blaming themselves in any way.” Plus “allowing emotions to be felt and acknowledged and sharing all the small details with the clinicians”. Another comment made was “educating yourself with small chunks at a time, prioritising and building a solid multi-disciplinary team which may include GP, specialists, social workers, school officials, etc. Asking for what you need not being afraid to change providers – be persistent!”
  • The most helpful aspect during their journey that was highlighted by patients and carers was having a GP willing to learn about the condition as highlighted in this quote: “The amazing determination of my son's doctors to learn as much as they could to treat my son they best way they could and being as informative and learning with me along the way. New things we learned we shared.”

Also having the DC community through DC Outreach to form relationships, family support and in America access to doctors who specialise in DC. The ability to locate a good haematologist who can liaise and collaborate with the multi-disciplinary team involved was also mentioned as a major plus.

  • Future wishes included improved treatments for the whole range of symptoms, “enrolling in registry and studies so that disease processes and progressions get to the right people (researchers) who need the data. Creating consistent protocols and recommendations in clear treatment plans so that consistency of care can be provided and improve long term outcomes.”

Resources

http://www.bloodjournal.org/content/110/5/1439?sso-checked=true

Dyskeratosis Congenita and Telomere Biology Disorders: Diagnosis and Management Guidelines (First Edition, 2015 Editors: Sharon A. Savage, MD, and Elizabeth F. Cook, MD) located https://www.dcoutreach.org/sites/default/files/DC%20%26%20TBD%20Diagnosis%20And%20Management%20Guidelines.pdf

Dyskeratosis congenita and other short telomere syndromes official reprint from UpToDate www.uptodate.com 2017 located at https://www.uptodate.com/contents/dyskeratosis-congenita-and-other-short-telomere-syndromes?search=dyskeratosis-congenita-and-o&source=search_result&selectedTitle=1~86&usage_type=default&display_rank=1

Accessed 6.11.2017.