Genetic diagnosis of inherited disease, including many X-linked diseases, has increased dramatically in recent years with more advanced genetic testing options. After a genetic diagnosis is made, family member testing may be warranted. Family member testing can identify those who are carriers of disease, those who may be affected by disease, and add insight and guidance regarding the risk of future offspring being born with the disease. While this has fostered an improved understanding of genetic drivers behind these diseases, most of the medical community has considered the carrier population as simply the messengers of the genetic information, clinically unaffected by an abnormal gene; but we’re learning this isn’t always the case.
Increasingly, research has found that there are many X-linked diseases in which carriers show signs and symptoms of the disorder, in varying degrees of severity. Historically, these symptoms have gone largely unaddressed by the medical community. Studies show that the often-overlooked symptoms in X-linked carriers may negatively impact their physical and mental health if not properly addressed. A more holistic care approach for X-linked carriers of genetic diseases requires that we look at the carrier population as potential patients, too.
Chronic Granulomatous Disease (CGD) is a good example of this. CGD is a rare, genetic immunodeficiency that increases susceptibility to severe, recurrent and life-threatening bacterial and fungal infections and can produce abscesses in internal organs like the lungs, brain and liver.1 Sophisticated diagnostic tools employed today, like the Dihydrorhodamine (DHR) assay, can accurately determine if someone has X-linked CGD, autosomal recessive CGD, or is an X-linked carrier of CGD, and also provides a prognosis for the severity of the disease. X-linked carriers of CGD can also present with recurrent skin infections and abscesses and may have DHR test values in the same range as patients with X-linked CGD.
In an essence, they phenotypically can have CGD and the providers who care for them may need to think of them like patients. We now know that DHR values of X-linked CGD carriers may change over time with age, and as a result the risk of serious infections may increase as carriers age.2 The evolving clinical state of the X-linked CGD carriers demands that they be closely followed by medical providers, so that if and when their disease declares itself, they can be treated appropriately.
Follow-up and close monitoring are particularly important among this population, as case reports and large case series have shown that carriers of X-linked CGD may develop more symptoms as they age. Symptoms can include recurrent infections and abscesses, skin abnormalities (e.g. photosensitive rashes and discoid lupus), autoimmune thyroid disease, abdominal pain and diarrhea, and lupus-like symptoms (e.g. chronic fatigue and joint pain).
The impact of being a carrier isn’t just physical – it’s psychological, as well, and can greatly impact quality of life (QoL). In a survey of 75 X-linked CGD carriers, more than 40 percent reported experiencing moderate or higher levels of anxiety, which correlated to depression, lower self-esteem, presence of joint or bowel complications, and fatigue.3 Like in many other diseases, it is well documented that these types of QoL indicators can carry a significant impact of health and quality of life, warranting closer monitoring and care for the carrier populations.
This phenomenon is assuredly not unique to CGD, but likely a consideration across many genetic diseases. It requires a fundamental shift in thinking among not only clinicians, but the entire healthcare team, including nurses, genetic counselors and other allied professionals. Holistic care for inherited genetic disease should involve family testing, identification and proactive monitoring; and disease management guidelines for X-linked genetic diseases should clearly reflect this to improve the care we provide for both diagnosed patient populations as well as the genetic messengers, the carrier patients.
Kelli Williams, MD, MPH, is a pediatric allergist-immunologist at the Medical University of South Carolina in Charleston, South Carolina, USA. She has cared for many patients and carriers with Chronic Granulomatous Disease (CGD) – a rare primary immunodeficiency that can cause serious, recurrent and potentially life-threatening infections, among other symptoms.
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1. Chronic Granulomatous Disease. AAAAI. 2021. Available at: https://www.aaaai.org/conditions-treatments/primary-immunodeficiency-disease/chronic-granulomatous-disease
2. Marciano B, et al. X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability. Journal of Allergy and Clinical Immunology. 2018 Jan;141(1):365-371. https://pubmed.ncbi.nlm.nih.gov/28528201/
3. Battersby A, et al. Health-Related Quality of Life and Emotional Health in X-Linked Carriers of Chronic Granulomatous Disease in the United Kingdom. Journal of Clinical Immunology (2019) 39:195–199. https://doi.org/10.1007/s10875-019-00607-6