Picture Hyperlink : https://en.wikipedia.org/wiki/Harlequin-type_ichthyosis Dear prospective medical students, Today, let's explore a rare medical condition that will leave you on the edge of your seat in intrigue. In this series of: The Curious Case Files, I’m going to explore the cases that made me want to pursue medicine in the first place, due to their unnatural, terrifying, curious nature. Let me know if this has sparked a lifelong intrigue in you, too. It's time to scrub in... Overview & Background [ Cleveland Clinic ] Harlequin Ichthyosis is an autosomal recessive disorder affecting the ABCA12 gene (essential for lipid transport to the skin), leading to an incomplete formation of the skin barrier. Can you comprehend taking your first breath and movements, riddled with pain, due to the cracking of hardened, armour-like plates of skin? The first case was reported in 1750 by Reverend Oliver Hart, and the overall incidence is 1 in 300,000 births [ PubMed ]. The disorder belongs to the group of ‘congenital ichthyosis’. Congenital ichthyosis is characterised by dry, thickened, scaly, or flaky skin, resembling fish scales (from the Greek word ichthys meaning fish) [ GOSH ].  Of this group, HI is considered the most severe as this rare form burdens its poor patients with armour-like plates of skin, outlined by deep red fissures that can lead to life-threatening complications [ MedicalNewsToday ]. Causation The disorder is caused by another pesky mutation that causes the ABCA12 gene to be non-functioning or completely absent. ‘This gene provides instructions for making a protein known as an ATP-binding cassette (ABC) transporter.’. This protein transports lipids to the stratum corneum (outer surface of the epidermis) into the lamellar granules inside keratinocytes (skin cells). [ MedlinePlus ] Without it, the skin barrier remains lacking essential lipids.  Context through dermatology: To truly understand the detrimental effect of this disease, let us take a short whistle stop tour into the world of dermatology in order to explore the importance of lipids, and the implications of their absence. Cells called keratinocytes, in the basal layer (stratum basale) of the epidermis, mature to gain lamellar granules. These granules haul ceramides, cholesterol and fatty acids, basically all necessary goods that need to be transported up to the stratum corneum (outermost layer of epidermis). These lipids are transported by the ABCA12 protein. The stratum corneum resembles a brick house, the bricks being corneocytes (dead skin cells packed with keratin) and the mortar being the lipid matrix between the cells (received from the ABCA12 protein), as shown in the figure. [ NIH Figure 1 ]. The lipids support the skin barrier by forming a protective, waterproofing layer, allowing the skin to block out infections and retain necessary moisture.   If the protein is absent or non functioning, then the lipids will not be delivered, and the lamellar granules will be defective. The stratum corneum cannot be formed fully. In unaffected bodies, the corneocytes are regularly shed due to the lipids ensuring hydration and regular exfoliation. Exfoliation is ensured due to the lipids containing enzymes that break the protein bonds holding corneocytes together. If the patient lacks the ABCA12 gene, lipids are not delivered from the lamellar granules therefore the body cannot shed the layers of corneocytes, causing a build up. The lack of lipids prevents retention of moisture so the corneocytes become dry and packed, creating the characteristic feature of dry, cracked scales or plates. Additionally, as previously mentioned, corneocytes are packed with keratin, a tough protein, and so their building thickens the stratum corneum making the plates truly hardened and armor-like. Any simple movement stretches this hard, dry skin over joints, causing the skin to crack and form  deep, red fissures. [ Italian Journal of Paediatrics ] Causation for facial abnormalities Eclabium This is where the lips are pulled outwards due to extreme tautness of the skin around the lips, flipping them inside out. This often makes it difficult for babies to close their lips, leading to feeding complications and further dehydration. Nasal Constriction The skin is extremely thick and mercilessly presses down on the nose, pushing it flat. These constricted nasal openings mean it can be difficult for the baby to breathe. Ectropion This is where the eyelid turns outward. This leaves the inner eyelid surface exposed and prone to irritation. The tight armor like plates pull the delicate eyelids away from the eyes causing it to puff outwards. [ MayoClinic ] Symptoms & Diagnosis As many of the symptoms and tell-tale signs have features in the introduction, I will keep this section brief. Characteristic symptoms: Limited movement Cracked skin with deep red fissures. Armour like skin tissue Facial Abnormalities Ectropion Eclabium  Flattened nose/absent nasal openings Breathing difficulties due to constricted skin around chest area Temperature regulation problems: Fissures allow heat to escape Sweat glands can be blocked and compressed so sweat cannot be secreted to prevent overheating Rapid dehydration can affect temperature control as water cannot be retained due to missing lipid layer [ FirstSkinFoundation ] Management & Treatment Children may need intensive support soon after birth as the scaly sore patches of skin can lead to rapid heat loss and infection. [ GOSH ] The broken skin means there is no protective barrier to pathogens entering the body so we have to manage opportunistic infection. They need to: Be admitted to Neonatal Intensive Care Unit (NICU) to ensure: Sterile environments  to avoid infections Temperature-controlled incubators  (since they can’t regulate their own temperature) Careful fluid and electrolyte management  to prevent dehydration Need to be given antibiotics and wound care to prevent bacteria entering through cracks ‘Oral retinoids such as acitretin have been instrumental in the treatment of severe inherited ichthyoses like Harlequin ichthyosis’. [ PubMed ] These retinoids can promote normal skin shedding and reduce thickness of the skin plates. Keratolytic creams can aid with gentle exfoliation. Regular bathing can help improve hydration. Manual removal of plates under strict medical and professional supervision can be extremely helpful for patients as well. Management requires a multidisciplinary approach including neonatologists, dermatologists, nutritionists, geneticists, ophthalmologists etc.  [ Cleveland Clinic  ]

Med Connection Dear Prospective Medical Students, it's time to scrub in. Let us dissect the incredibly rare and intriguing case that is Fibrodysplasia Ossificans Progressiva. Overview & Cause FOP is an extremely rare, autosomal dominant, genetic disorder estimated to affect only 1 out of 2 million people worldwide. Tendons, muscles, and connective tissue eventually metamorphose into bone, forming a second skeleton ( NORD ). The disorder restricts movement due to the bone taking the place of soft tissue and will progressively worsen, possibly even leading to total immobility. The disease is caused by a mutation in the ACVR1 gene. This gene, when healthy, ‘provides instructions for making the activin receptor type-1 (ACVR1) protein, which is a member of a protein family called bone morphogenetic protein (BMP) type I receptors’ ( Medline ). The BMP pathway regulates osteoblast (bone-forming) activity. When the BMPs bind to ACVR1 receptors, it trigger new bone formation and regulate the metamorphosis of existing cartilage into bone. In normal cells, the ACVR1 is activated in the development of children, where bone must grow or when there is physical trauma that requires bone repair. In FOP, this receptor is overactive, and cells receive constant signals for stem cells to form osteoblasts, therefore forming new bone. Minor injuries can trigger bone formation, causing the disorder to progress, eventually leading to complete immobility where the body’s tissues and ligaments have been overtaken by bones. Symptoms A hallmark feature is malformed big toes in the early years Painful bumps under the skin (will develop into bone over time) Loss of mobility due to “locked” areas like the jaw, neck, limbs, etc. Shortened lifespan, typically due to respiratory problems caused by abnormal bone growth around the ribs/thoracic region ( ifopa ) Diagnosis Look out for… Clinical features  Malformed toes Painful bumps (nodules) under the skin Genetic testing ACVR1 gene sequencing, where a blood or saliva sample is taken and the DNA is extracted to identify any mutations within the ACVR1 gene Imaging (X-rays, MRIs or CTs) May show the abnormal bone growth within an area of soft tissue  BUT BE AWARE: FOP can be misdiagnosed as cancer, and so biopsies can be taken, which will further worsen the disorder and trigger heterotopic ossification (formation of bones outside the skeleton) Management & Treatment Unfortunately, FOP has no definitive cure and can only be managed to help prevent complications. Maybe one of us, future doctors, will solve this problem in the future. For now, this is all we can do… Prevent Flare-ups Physical Injury and inflammation are seen to trigger abnormal heterotopic ossification, and so any and all invasive procedures and physical trauma should be prevented. Therapy  Physiotherapy will be provided to maintain flexibility and manage the development of muscle weakness as ossification limits movement and use of these muscles. Physiotherapy will allow gentle exercises; however, they must be done very carefully to prevent inflammation Occupational therapy should be provided to reduce day to day strain that could trigger inflammation Medical Management Corticosteroids reduce inflammation and, therefore, can limit progression into ossification Palovarotene, a retinoid (Vitamin A derivative), has shown promise to slow ossification by reducing BMP signalling ( PubMed 1)( ifopa ) Genetic Counselling If a parent is diagnosed with FOP, then genetic counselling and prenatal genetic testing can help identify the risks of a fetus inheriting the ACVR1 gene, as the disease is autosomal dominant. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) ‘The CRISPR/Cas9 system has been developed as a genome-editing tool that can correct DNA mutations underlying human diseases.’ ( PubMed 2).  CRISPR could potentially cut out the mutated DNA and replace it with the normal, correct sequence for a fully functioning ACVR1.  It could even be used in IVF or gene editing embryos to prevent passing on the mutation to future generations For the treatment of FOP, it is still within the realm of research due to various ethical issues around the idea of “designer babies” and the difficulties around delivering the Cas9 protein to the correct target cells. ( PubMed 3)

Dear Prospective Medical Students, it's time to scrub in. Let us dissect the controversial debate that is still so prevalent: Is smoking or vaping more detrimental to the body physically, mentally, and to the environment? History To begin, join me for a historical adventure through both. Smoking is the act of inhaling the smoke of burning plants for dopamine and adrenaline, which helps relieve stress and induce a feeling of pleasure and euphoria. The idea was first introduced as far back as the Aztecs, where they would smoke tobacco through a hollow reed or cane tube. When Christopher Columbus travelled across South America he discovered the tradition of smoking tobacco wrapped in corn husks or other leaves. These cigars were introduced to Spain in the 1600s, showing a sign of wealth, and eventually, their popularity spread as a common product for all. ( Britannica ). For as long as we know, cigarettes (or even the act of smoking) have been the poster child for health damage. It has been long associated with various lung diseases, heart diseases, cancers, and strokes. Warnings ‘not to smoke’ play before movies. Horrifying pictures of bloody, gory wounds are displayed on cigarette packets to deter people, at the sight of what could happen to them if they continued smoking. ‘Tobacco Duty is included in the price you pay for cigarettes, cigars and other tobacco products’, atop the standard 20% VAT. ( GOV.UK ) This tax aims to reduce smokers by increasing the number of people who are no longer willing to pay or can’t afford to pay for them. It is a decent strategy to build up a negative media image to reduce new smokers, agree? ( ONS ). This graph shows a gradual decline in smoking among different age groups in the UK. This proves that the negative media exposure to smoking and the taxes are effective in repelling smokers. However, we could also assume that the smoking rates have gone down due to another preferable alternative, ‘vaping’. Vapes are a much more recent invention. ‘The first documented reference to vapes was a patent for them in the 1930s, but they only hit the market as we know them today in the early 2000s.’ ( Business Insider ) They were mainly introduced to the UK in 2005 and have since been associated with several different health issues, despite being marketed as a cessation tool for smoking, and a “safer option”. In spite of all the health complications as a result of vaping, vaping rarely holds a negative image. The packaging is bright and colourful; fruity scents and flavourings are added, blowing ‘smoke rings’ and other vaping tricks had a massive spike in popularity during 2018-2020 in social media and TikTok, making vaping a trend. This shift successfully draws people towards vaping and away from smoking, but not only has it attracted smokers, but it has also caught the eye of the younger demographic. This, unfortunately, results in nicotine addiction from very young ages, serious health risks, and threatens the well-being of our future generations. Let’s explore how vaping, much like smoking, can pose just as dangerous a threat. Health Impacts: Physical Ruin Since the exploration of modern medicine, extensive research has been conducted on smoking to reveal its negative health impacts. Cigarettes contain many destructive chemicals, like carbon monoxide, nicotine, tar, formaldehyde, arsenic, benzene, ammonia, and more. It is important to discuss the harmful qualities of each of these to recognise exactly how cruel they are to the body.  We learn, as early as GCSEs, that carbon monoxide binds irreversibly to haemoglobin in the blood. This means that the ability to carry blood around the body is significantly reduced; smoking slowly poisons its victims bit by bit, reducing their ability to breathe, and that is not all. According to the ATSDR, long-term exposure to benzene can cause anaemia, significant changes to the immune system, and even leukaemia ( CDC ). The risks are well-established and deadly. According to the Southhampton Data Observatory, ‘Every year around 78,000 people in the UK die from smoking, with many more living with debilitating smoking-related illnesses’. ( Southampton Data Observatory ).  However, at least we are aware of the symptoms and the consequences of smoking. Fear the unknown, we say, so why do we not fear vapes? Vaping appears to be a healthier alternative and is advertised as one, however, this can be seen as false advertising as there is actually no conclusive, long-term evidence confirming its nature. From the few chemicals and effects we do know of, several are just as toxic as smoking. Since June, 2019, more than 1000 new cases of e-cigarette, or vaping, product use-associated lung injury (EVALI) have been reported in the USA. ( PubMed ) The vapes contain several harmful substances like acrolein, propylene glycol, diacetyl and formaldehyde. Diacetyl is used to ‘deepen e-cigarette flavours’ strengthening its addictiveness and drawing in more and more of the youth. Inhalation of diacetyl and formaldehydes lead to inflammation and scarring of the bronchioles, resulting in popcorn lung, bronchiolitis obliterans (BO), causing chest pain, wheezing, and shortness of breath ( John Hopkins ). Acrolein is generally used in weed killers. Why are we voluntarily inhaling products we use to tackle our garden weeds? Its long-term exposure can lead to chronic diseases like asthma and COPD (Chronic Obstructive Pulmonary Disease) ( PubMed ). Acrolein is present in both e-cigarettes and traditional smoking cigarettes. However, in vapes and e-cigarettes, acrolein has a much more significant impact.  When the e-liquid, or coil overheats (due to low e-liquid or increased wattage), greater amounts of acrolein can be released into the inhaled vapour. Vapes often contain propylene glycol or vegetable glycerin that can break down to form harmful byproducts like acrolein, when the liquid is vaporised, and so increased overheating will increase the release of acrolein. The problem is intensified by the fact that ‘users can buy extra-strength cartridges, which have a higher concentration of nicotine, or increase the e-cigarette voltage to get a greater hit of the substance.’ ( John Hopkins ). This ability to increase voltage means it increases the overall heating of the device which increases the likelihood of these harmful products from being formed. Additionally, increasing the voltage of an electrochemical reaction means that the products produced are less predictable. Under higher voltages, the activation energy required for various unforeseen reactions is overcome, leading to the release of products that we would not have originally intended to make. Another dangerous element is the voltage running through the vape itself. The Lithium-ion battery can actually overheat and explode leading to multiple-degree burns, and even loss of limbs. According to The New York Times, in 2018, in Florida, US, a man had suffered shrapnel entering his brain and burns on about 80% of his body. It appeared that the explosion projected into his head and had also started a fire in the bedroom where he was found. ( The New York Times ) This unfortunate disaster helps demonstrate exactly the type of danger that comes with vaping, and we are allowing this weapon around mere children. The list continues growing in the proof as to why vapes should be considered just as dangerous as smoking. Now you can see that, although vaping in its innate composition may not be that much different to smoking cigarettes, the heating, vaporisation, and voltage control aspects increase the intake of harmful substances (sometimes entirely unknown substances) significantly.  The Mental Meltdown Vaping and smoking take a terrible toll on the brain, cultivating vicious addiction and withdrawal symptoms, however, in adolescents and perpetual smokers, the chemicals taken in corrode mental ability over time. The Royal Children’s Hospital of Melbourne informs that ‘Nicotine exposure during the teenage years can harm brain development, which continues until about age 25. It can impact learning, memory and attention, and increases the risk for future addiction to other drugs’ ( The Royal Children's Hospital Melbourne ). Let’s explore some of the ways in which smoking, vaping and most importantly, the nicotine within them, cause reduced brain development.  Nicotine, as mentioned, is what causes addiction in the brain. To explain the science behind the addiction to nicotine in simple terms: nicotine is an agonist. Agonists are molecules that can activate receptors by mimicking the shape of the receptor’s natural neurotransmitter. Nicotine has a shape similar to that of the neurotransmitter ‘Acetylcholine’ and therefore binds to nicotinic receptors. When activated, these receptors act like a gate allowing Sodium and Calcium ions to flow into the neuron. Calcium stimulates ‘the release of numerous neurotransmitters, including dopamine, serotonin, and glutamate.’ ( Khan Academy ). Dopamine and serotonin create a sense of ‘pleasure’, ‘happiness’ and ‘reward’. Our brains crave this feeling and become addicted to it. Preliminary research suggests similar effects of nicotine from cigarettes and vapes, without much difference apart from the previously mentioned fact that nicotine can be controlled and increased within many vapes. To explain withdrawal symptoms: the release of ‘feel-good’ hormones due to nicotine, causes a short-term burst of positive emotions, once this wears off, the body and mind are left in a state of withdrawal, craving more dopamine. This causes a vicious cycle of addiction where withdrawal causes a need for further consumption which only magnifies the psychological impact as this cycle runs. Additionally, nicotine stimulates the release of adrenaline, which increases heart rate and alertness, eventually, as this becomes a bodily norm, the body will remain in this state of constant stimulation and develop chronic anxiety. This also adds to the cycle, as short-term happiness relieves the anxiety momentarily.  This nicotine over-stimulates the limbic system, composed of your hippocampus and amygdala which controls and regulates emotions. So we can easily assume that overstimulating this system can lead to various mood-related disorders, like depression, anger issues, etc.  Damage done in growing, adolescent brains can be much more destructive. The prefrontal cortex is ‘responsible for higher-order cognitive functions, including decision making, reasoning, and social behaviour.’ ( PubMed ) In adolescents, this part of the brain is still maturing and a process called synaptic pruning occurs, prevalently through these years, which helps the brain function more efficiently by ridding the brain of unnecessary synapses. Nicotine disrupts this process therefore reducing brain development. Let’s delve into the details of how. Nicotine binds to nicotinic acetylcholine receptors (nAChRs) and the activation of this receptor stimulates other neurotransmitters to be released, which signal for which synapses are useful and which are used less, therefore should be marked for pruning. When nicotine over-stimulates these receptors, regardless of whether they need to be activated or not, these other transmitters are released and prune synapses regardless of whether they are useful or useless. This causes inaccurate pruning, possibly leading to decreasing useful synapses and remaining useless synapses, resulting in weaker neural connections. Indirect Impacts Here, I’d like to highlight the ways in which smoking and vaping can affect not only those who take part but also their surroundings. For example, how this affects the environment, the government and the economy, and babies conceived by frequent ‘vapers’ and ‘smokers’ (who continue this practice through their term). Let us start by analysing the effect of smoking on babies and second-hand smokers, to follow through with the physical impacts from before.  The affinity of carbon monoxide (CO) for haemoglobin is more than 200 times that of oxygen. ( ScienceDirect ) This reduces the amount of oxygen the baby receives, causing fetal hypoxia (oxygen deprivation in babies), which can significantly stunt growth and brain development by disrupting critical cellular processes during placental growth and organ development. It can also cause placental impairments where nutrients necessary to the baby are reduced as nicotine causes vasoconstriction of placental blood vessels. This limits blood supply, further depleting the amount of oxygen and reducing the amount of vital glucose and amino acids supplied. The reduced growth and development may lead to low birth weight, which can be dangerous as it will be hard for the baby to maintain body temperature or fight against infections and many more. Furthermore, smoking and vaping can lead to preterm birth, fetal hypoxia triggers stress hormones and this can sometimes induce labour early. Nicotine and other chemicals can also interfere with progesterone levels, reducing them, and this can be dangerous as progesterone prevents uterine contractions and so without it, contracts and labour can be induced early.  Let us move on to the effects on the environment and economy. As well as affecting the individual, smoking and vaping also take an incredible toll on the country and NHS due to the number of health problems that come about because of this deadly addiction. The National Health Service is government-funded and contributed to by public taxes. The severity of the consequences (like cancers, tumours, COPD) requires intensive treatments like chemotherapy, surgery and much more expensive treatments, which inevitably rip a huge hole out of the budget. ‘In 2023, 20.5% of children had tried vaping, up from 15.8% in 2022 and 13.9% in 2020 before the first COVID lockdown’ ( ASH ), and this graph from Statista demonstrates an upward curve stating that more children are becoming addicted to vaping, meaning that more funds need to be put towards rehabilitation for a larger demographic ( Statista ). Smoking has consistently been a larger financial burden, however, recently, the costs of tackling vape-related health issues are climbing rapidly. More money would be saved in the long run if these funds were placed towards preventative measures. Unfortunately, spending is not only on primary smokers who need help but also on newborns whose mothers continue to smoke and vape well into their pregnancy. Funds have to go towards victims of secondary smoking, where smoke is taken in when passing by another smoker. On top of this, smoking and vaping can affect the environment in many ways which can add to the financial burden. The chemicals released from the smoke can pollute the air, releasing toxic fumes and harming air quality, like carbon monoxide and formaldehyde. This is another instance in which the chemical products at the end of unknown reactions of vapes could be fatally destructive to the earth. Cigarette butts also contribute massively towards litter as they are so commonly left around and can take up to a decade to decompose due to plastic, cellulose acetate, that takes years to degrade. So here we have assessed some other factors to counter our little debate as to whether vapes or cigarettes are more detrimental to our society. Which is the better villain? In the end, it is hard to say exactly which of the two is worse for our environment, health and growth, as they both release toxic, disastrous chemicals. However, I feel it is fair to say that vapes may recently be becoming the unexpected mass murderer. The new technological additions of nicotine level adjustments, the positive, bright, fun media portrayal, and mechanical malfunction possibilities push me to consider that smoking may not be the most vindictive villain roaming about.  With the unfortunate case of the mechanical failure previously mentioned, it appeared that the explosion projected into his head and had also started a fire in the bedroom where he was found. This unfortunate disaster helps demonstrate exactly the type of danger that comes with vaping, and we are allowing this weapon around mere children. This is a danger that doesn’t accompany the use of smoking cigarettes which is one of the main reasons why vapes should be considered more dangerous than vapes. However, it is important to realise that, although one may be more calamitous than the other, both vapes and cigarettes are undeniably harmful to the body and should be avoided entirely.