The following are a few pictures of public figures who have port-wine stain birthmarks!
References for pictures:
The following are a few pictures of public figures who have port-wine stain birthmarks!
References for pictures:
What do you visualize when you hear the word silver? If you are a chemist, you might instantly picture silver as a chemical element; a soft, white transition metal with a high thermal conductivity and an atomic number of 47. If you are an athlete, silver probably represents second place; a disappointing triumph just shy of the prestigious gold medal. For the majority of citizens living in Western society, silver is considered to be a practical material for everyday living because of its contributions to jewellery, silverware, and even coin production. While all of the above responses are quite common, I bet there is one effect of silver you did not consider: the development of silver skin. Although this is an unfamiliar condition for many of us, it has become a disappointing reality for Rosemary Jacobs. The colour silver has become a unique, defining characteristic of Jacobs and causes many people to recognize her as the “face no one can forget”. Her silver discolouration has impacted how she is perceived by others, how she forms personal relationships, and how she lives her day to day life. For Jacobs, silver is a devastating compound that, for almost sixty years, has prevented her from blending in with the crowd.
Argyria is a medical condition that causes a bluish-grey discolouration of the skin due to an accumulation of silver-containing compounds within the body. By looking at Figure 1, you can see an example of normal skin colour compared to a change in the tissue colour that results from the development of argyria. Argyria is an irreversible condition, which means that there is no current treatment to reduce the colour; however, it has been shown that the silver discolouration can intensify due to the prolonged exposure of sunlight on an unprotected region of skin. Silver can be exposed to the body by ingestion during the consumption of medicinal or dietary products, or by inhalation in an occupational setting. Argyria can be classified as either localized or generalized. Localized argyria is when there is direct, external contact of silver and generalized argyria is when there is a widespread pigmentation of the skin, eyes, and nails. In 1956, Rosemary Jacobs was diagnosed with generalized argyria because her entire face was described as slate-grey. Before we examine the factors contributing to the production of argyria, let’s begin by looking at Jacobs’ story and the main factors that resulted in her skin discolouration.
In 1953, when Jacobs was 11 years old, a doctor prescribed her nose drops that contained silver to help improve her allergies. The only instructions she was given was to use the medication periodically whenever they were required. At this time, soluble silver salts were often distributed to patients suffering from mental illnesses, infectious diseases, and epilepsy. The growing popularity of prescription drugs containing silver was due to the suggested positive impact that silver has on the body. However, the potential negative, toxic effects that a high abundance of this metal could have on an individual was never considered when determining the specific doses to be administered to patients. Three years after being prescribed the silver containing nose drops, Jacobs was volunteering at a local hospital in New York when the slate-grey discolouration of her face became apparent. By simply taking one look at her, a dermatologist was able to diagnose generalized argyria. Even though dermatologists were able to properly diagnose Jacobs, the chemical transformation of silver in the body after inhalation was not fully understood until 2012 when Jingyu Liu et al. from the Institute for Molecular and Nanoscale Innovation at Brown University studied the toxicity and risks of silver nanoparticles in a biological environment. The interest in this research resulted from an increased use of silver in consumer products, such as dietary supplements, and medicinal products. By referring to Jacobs’ story, let’s take a look at the mechanism that has been proposed by Liu et al. to cause her argyria.
When Jacobs began to use the nose drops that had been prescribed by her doctor, the silver nanoparticles that were present within the drops were inhaled and transferred to the lungs. By referring to Figure 2, it can be observed that the silver nanoparticles were next transferred from the lungs to the gastrointestinal (G.I.) tract by macrophage clearance. These alveolar macrophages are phagocytes present in the pulmonary alveolus that play an important role in host defense and response to foreign substances. The low pH in the gastric fluid will quickly dissolve the silver nanoparticles within the stomach into silver cations (Ag+). Ag+ will then be transported from the G.I. tract through an active transport route denoted for a sodium ion and into the bloodstream. Once in the bloodstream, Ag+ will bind to serum albumin, an extremely abundant plasma protein that is necessary for the transportation of other ions throughout the systemic circulation. Finally, this will result in the distribution of Ag+ in a variety of tissues and organs throughout the body. Specifically, Ag+ can accumulate in the basement membrane of the skin resulting in the generalized argyria that Rosemary Jacobs was diagnosed with in 1956.
Once diagnosed with argyria, Jacobs immediately stopped using the prescribed nose drops; however, her skin gradually became a darker tint of grey with the passing years. Referring back to the research performed by Liu et al., we see that there has been a proposed mechanism relating to the intensification of the bluish-grey colour of affected skin that is exposed to sunlight. Looking again at Figure 2, we see that the Ag+ that have accumulated in the basement membrane of the skin can be photoreduced to metallic silver nanoparticles in the presence of sunlight. The formation of these metallic nanoparticles results in the immobilization of the silver and a deepening of the grey discolouration of the skin.
The numerous medicinal applications of silver suggest that it must have some positive health effects, but the risks related to prolonged consumption of these silver products have been shown to greatly outweigh its advantages. With the current research concluding that irreversible argyria can result from silver exposure, it would be expected that the occurrences of this disease are significantly decreasing; however, this is not the case. An important factor preventing a decrease in argyria patients is that colloidal silver proteins, which are microscopic silver particles suspended within a base, have become increasingly popular in dietary supplements over the past two decades. It is hoped that current research studies, which have identified colloidal silver as an ineffective and unsafe product, will help to significantly decrease the number of cases of individuals affected by this devastating condition.
After being diagnosed with argyria, Rosemary Jacobs realized the importance of beginning each day with a positive attitude, while being grateful that she was a healthy, grey individual. She learned to defy the odds by accepting how others perceived her and by focusing on the relationships with her friends and family who were able to see past her grey appearance. Remarkably, it is safe to say that Rosemary Jacobs was able to find her silver lining.
Refer to the Cited Publications page to find a list of journal articles relating to argyria.
When parents hold their newborn baby for the first time, all they see, and all they will continue to see, is perfection. Nevertheless, the presence of tiny white bumps, irregular brown patches, or reddish-purple splotches can trouble the parents of an otherwise healthy child. Fortunately, as time passes these distinct characteristics become isolated from being labelled as an imperfection and are instead classified as a miraculous feature; an exquisite detail that distinguishes the marked individuals from the ordinary.
When I was born, it was not difficult for my parents to discover my unique signature. I have a port-wine stain birthmark that consists of varying sizes of red splotches that migrate from my right shoulder down to my wrist (Figure 1). Since my family and I effortlessly became accustomed to the appearance of my arm, I naively expected other people to do the same. However, after years of enduring the stares and questions from bystanders, I realized that they were not investigating to be rude or insensitive; they were simply curious. Unfortunately, reaching this point of acceptance does not happen immediately because it is acquired with time and encouragement. After twenty-two years of living with a birthmark, I have been fortunate to have the support I needed to embrace my mark and understand the true meaning of inner beauty. However, this acceptance has not provided me with the answers for the questions I began pondering as a young child. Even after numerous visits with my dermatologist, I could never be given a proper response that explained my distinct physical difference. It was not until now, as a biochemistry student, that I was introduced with an opportunity and the knowledge to learn what actually causes the formation of port-wine stain birthmarks.
While I have always been interested in uncovering the truth about birthmarks for my disposition, I believe that this science can benefit the lives of others beyond myself. Although I was able to naturally embrace my birthmark, there are many children who struggle to understand why this happened to them. If we hope to improve the confidence and lives of children suffering from the consequences of having a port-wine stain, the first step is to forget about the superficial appearance of these marks and to take a glimpse skin deep. By uncovering the layered factors contributing to the formation of these reddish-purple marks, I am optimistic that children will no longer waste the valuable moments of their childhood pondering the perpetual question, “Why?”
Nevus flammeus, or the port-wine stain, is a cutaneous capillary malformation that affects 0.3% of newborns and is characterized by abnormally dilated capillary vessels within the skin that produce a reddish discolouration (Figure 2). In newborns, port-wine stains tend to be flat and pink, but if left untreated, the birthmark will become a dark reddish-purple as the child develops. Although physicians can easily diagnosis port-wine stains based solely on their appearance, an understanding of the causes of capillary malformation leading to port-wine stains was not discovered until recently. In 1987, Rudolf Happle was the first to propose that port-wine stains could be caused by a somatic mosaic mutation occurring after conception. Somatic mosaicism is defined as groups of somatic cells within an individual that possess different genotypes. In other words, the genomic content between the somatic cells is not identical. For the next thirty years, this was the most accepted and persistent prediction related to port-wine stain development; however, it was not until May 2013 that this hypothesis was confirmed.
To determine the underlying cause of port-wine stain birthmarks, Shirley et al. (2013) at the Johns Hopkins School of Medicine performed whole-genome sequencing on samples of skin with port-wine stains and samples of normal, unaffected human tissue. Skin biopsies were performed to obtain tissue samples from healthy subjects and all samples were collected from the legs, shoulders, face, or lips. The sequencing resulted in the identification of one somatic, single-nucleotide variant that was present in 92% of the affected tissue samples. The mutation was identified as a single nucleotide transition from a guanine to an adenine at position 548 of the GNAQ gene. The gene encoded a subunit of a heterotrimeric guanine nucleotide binding (G) protein, but specifically the alpha (α) subunit (polypeptide q) (G(q)α). These G proteins couple specific receptors to their downstream signal transduction pathways. The G(q)α subunit is associated with the mitogen-activated protein kinase (MAPK) signalling pathway, an important regulator of cell proliferation. Of course, to understand the consequences of a mutation in the GNAQ gene during embryonic development, we have to understand its role in regulating the MAPK pathway.
The wild-type G(q)α protein is conserved within the guanine triphosphate (GTP) binding site of the G(q)α subunit. In general, G proteins function as molecular switches. When a G protein that is bound to guanine diphosphate (GDP) interacts with a G protein-coupled receptor it is considered to be in an inactive state (Figure 3). After an external signal activates the G protein-coupled receptor, a conformational change in this seven-transmembrane domain will induce the G protein-coupled receptor to function as a guanine nucleotide exchange factor (GEF). This will result in the exchange of GDP for GTP and the activation of the Gα protein subunit for further cellular signalling. For the Gα protein to return to an inactive state, GTPase-activating proteins will hydrolyze GTP and terminate the activation signal.
Conservation of the amino acid sequence of the G(q)α protein is extremely important for these molecular switches. Specifically, G(q)α contributes to the hydrolysis of GTP and is required for the inactivation of the G protein subunits. However, a single point mutation in the G(q)α protein sequence will cause a change in an encoded amino acid resulting in the elimination of GTPase activity during the vulnerable periods of embryonic development (weeks three through eight). The mutated GNAQ gene will prevent the hydrolysis of GTP; therefore, this will cause GTP to continuously bind and activate the G(q)α subunit (Figure 3). This hyperactivity of the G(q)α subunit can result in malformed, dilated blood vessels by increasing the constitutive downstream signalling activity of the MAPK pathway. Specifically, a signalling cascade will result in the phosphorylation of Raf kinase, followed by the phosphorylation of MEK kinase. MEK kinase will lead to the activation of the extracellular signal-regulated kinase (ERK) which will cause the cellular proliferation of capillary vessels and the development of port-wine stains. Increasing the activity of G(q)α has also been identified as a prominent factor in the induction of oncogenic proliferation. However, it has been hypothesized that the somatic mutation causing port-wine stains has a weaker effect than other single point mutations and this results in the non-oncogenic proliferation that is observed in these birthmarks.
The identification of a somatic mutation in the GNAQ gene of the MAPK signalling pathway is a compelling breakthrough in the field of dermatology. After having previously learned about the involvement of G proteins in various cellular pathways, it was astonishing to understand and relate their function to the formation of port-wine stain birthmarks. Before beginning this research, I naively thought that I understood the impact that a mutation could have on an affected individual; however, it was not until I was aware of the connection between port-wine stains and G protein-coupled receptors that I understood the consequences these mutations can afflict on someone’s life. Most importantly, this research allowed me to answer one of the most recurring questions from my childhood while giving me an opportunity to speculate on my own perception of my birthmark. Throughout this process, the appearance of my birthmark became even less significant as I developed my understanding that a physical mark does not define you. Instead, I realized that what actually defines you is the mark you leave behind!
Refer to the Cited Publications page to find a list of journal articles relating to port-wine stain development.
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