Category Archive Skin & Beauty Care

Polycystic kidney disease (ADPKD) is an autosomal dominant disorder. It’s a multisystem and progressive disease with cysts formation and kidney enlargement along with other organ involvement (e.g., liver, pancreas, spleen).

Causes of Polycystic Kidney Disease

ADPKD is an autosomal dominant disease, so it is found in males and females equally, and each offspring has a 50% chance of inheriting the disease.

ADPKD involves at least two genes. PKD1 accounts for most ADPKD cases and is located on 16p13.3. PKD2 accounts for 15% of ADPKD cases.

PKD1 codes for polycystin 1, a 4304 amino acid protein. Polycystin 1 interacts with polycystin 2 and is involved in cell cycle regulation and intracellular calcium transport. PKD2 codes for polycystin two, which is structurally similar to polycystin 1. It is a member of the family of voltage-activated calcium channels.

Polycystin 1 and two are located in the epithelial cells of the renal tubules and other areas of the renal cell epithelium. Both form heteromeric complexes and are found in the primary cilium of epithelial cells in kidneys. The primary cilium is considered a mechanical receptor that can sense changes in tubular fluid flow, and that can transduce them into intracellular calcium signaling. ADPKD1 is more severe than ADPKD2.

Mutations in the PKD1, PKD2, and PKHD1 genes cause polycystic kidney disease.

Mutations in either the PKD1 or PKD2 gene can cause autosomal dominant polycystic kidney disease; PKD1 gene mutations cause ADPKD type 1, and PKD2 gene mutations cause ADPKD type 2. These genes provide instructions for making proteins whose functions are not fully understood. Researchers believe that they are involved in transmitting chemical signals from outside the cell to the cell’s nucleus. The two proteins work together to promote normal kidney development, organization, and function. Mutations in the PKD1 or PKD2 gene lead to the formation of thousands of cysts, which disrupt the normal functions of the kidneys and other organs. People with mutations in the PKD2 gene, particularly women, typically have a less severe form of the disease than people with PKD1 mutations. The signs and symptoms, including a decline in kidney function, tend to appear later in adulthood in people with a PKD2 mutation.

Mutations in the PKHD1 gene cause autosomal recessive polycystic kidney disease. This gene provides instructions for making a protein whose exact function is unknown; however, the protein likely transmits chemical signals from outside the cell to the cell nucleus. Researchers have not determined how mutations in the PKHD1 gene lead to the formation of numerous cysts characteristic of polycystic kidney disease.

Although polycystic kidney disease is usually a genetic disorder, a small percentage of cases are not caused by gene mutations. These cases are called acquired polycystic kidney disease. This form of the disorder occurs most often in people with other types of kidney disease who have been treated for several years with hemodialysis (a procedure that filters waste products from the blood).

Polycystin-1 (PKD1 protein) and polycystin-2 (PKD2 protein) belong to a subfamily of transient receptor potential (TRP) channels[rx]. PKD2 is found in the endoplasmic reticulum and also in the plasma membrane in spindles in cell division and primary cilium. PKD1 inactivation determines the rate of development of the cystic disease. PC1 interacts with PC2 and helps in the maturation of PC2, and vice versa. PC1 and PC2 also interact with additional calcium channel proteins.

A common finding in animal models of PKD has increased levels of cyclic adenosine monophosphate (cAMP), not only in the kidney but also in the liver and vascular smooth muscle. cAMP exerts effects on cell proliferation in different cell types. cAMP and PKA signaling enhances several pro-proliferative pathways in cells derived from polycystic kidneys while inhibiting proliferation in cells derived from the normal human kidney cortex.

Liver cysts arise by excessive proliferation and dilation of biliary ductules and peribiliary glands.

Endothelial vasodilation and constitutive nitric oxide synthase activity are reduced in subcutaneous resistance vessels from patients with ADPKD and normal glomerular filtration rate (GFR), thus causing hypertension.

Symptoms of Polycystic Kidney Disease

Polycystic kidney disease symptoms can include:

• High blood pressure
• Back or side pain
• Blood in your urine
• A feeling of fullness in your abdomen
• Increased size of your abdomen due to enlarged kidneys
• Headaches
• Kidney stones
• Kidney failure
• Urinary tract or kidney infections

Diagnosis of Polycystic Kidney Disease

History and Physical

Renal size increases with age, and renal enlargement eventually occurs in 100% of patients with ADPKD. The severity of the structural abnormality correlates with the manifestations of ADPKD, such as pain, hematuria, hypertension, and renal impairment. Most clinical manifestations are directly related to the enlargement of renal cysts. [rx]

Episodes of acute renal pain are seen quite often due to cyst hemorrhage, infection, stone, and, rarely, tumors. Visible hematuria may be the initial presenting symptom[rx]. Cyst hemorrhage is a frequent complication causing gross hematuria when the cyst communicates with the collecting system. It can manifest with fever, raising the possibility of cyst infection. Occasionally a hemorrhagic cyst will rupture, resulting in a retroperitoneal bleed.

Urinary tract infection (UTI) is common in ADPKD. UTI presents as cystitis, acute pyelonephritis, cyst infection, and perinephric abscesses. Most infections are caused by Escherichia coli, Klebsiella and Proteus species, and other Enterobacteriaceae.

Both CT and MRI are sensitive to detect complicated cysts.

Renal stone disease occurs in about 20% of patients with ADPKD. Most stones are composed of uric acid, calcium oxalate, or both. Stones can be difficult to diagnose on imaging in ADPKD because of cyst wall and parenchymal calcification. CT urography is helpful.

Hypertension is the most common manifestation of ADPKD. Microalbuminuria, proteinuria, and hematuria are more common in hypertensive patients with ADPKD.

In a majority of patients, renal function is within the normal range. By the time renal function starts worsening, the kidneys usually are greatly enlarged. ESRD is not inevitable in ADPKD. Up to 77% of patients are alive with preserved renal function at age 50 years, and 52% at age 73. Kidney and cyst volumes are the strongest predictors of renal functional decline.

Most simple hepatic cysts are solitary, and PLD should be suspected when four or more cysts are present in the hepatic parenchyma.

Lab Test and Imaging

Ultrasound criteria for the diagnosis of ADPKD:

Original Ravine’s PKD1 Diagnostic Criteria

• Age 15-29 years – two or more cysts unilateral or bilateral
• Age 30-39 years – two or more cysts in each kidney
• Age 40-49 years – two or more cysts in each kidney
• Age 60 years or above – four or more cysts in each kidney

Genetic testing is done when a precise diagnosis is not confirmed enlargement along, and the results of imaging are indeterminate.[rx]

Treatment of Polycystic Kidney Disease

• Flank Pain – Causes of flank pain that may require intervention, such as infection, stone, and tumor, should be excluded. Opioid analgesics should be reserved for the management of acute pain. Reassurance, lifestyle modification, and avoidance of aggravating activities may be helpful. Tricyclic antidepressants are helpful as in other chronic pain syndromes, as they are well tolerated. Cyst aspiration, under ultrasound or CT guidance, can be done if distortion of the kidney by a large cyst is considered the cause of the pain. If multiple cysts are contributing to pain, laparoscopic or surgical cyst fenestration may be of benefit.
• Cyst hemorrhage – Cyst hemorrhage episodes are self-limited, and patients respond well to conservative management with bed rest, analgesics, and increased fluid intake to prevent obstructing clots. Rarely, bleeding is more severe, leading to hemodynamic instability; this requires hospitalization and transfusions.
• Cyst and urinary tract infection – Immediate treatment of symptomatic cystitis and asymptomatic bacteriuria is indicated to prevent retrograde seeding of the renal parenchyma[rx]. Agents of choice include trimethoprim-sulfamethoxazole and fluoroquinolones. If fever persists after 1 to 2 weeks of appropriate antimicrobial therapy, infected cysts should be drained percutaneously or surgically. In the case of end-stage polycystic kidneys, nephrectomy should be considered.
• Nephrolithiasis – Potassium citrate is the treatment of choice in stone-forming conditions associated with it, which are uric acid stones, hypo-citraturic calcium oxalate stones[rx], and distal acidification disorders.
• Hypertension – Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)[rx] increase renal blood flow in ADPKD and are antihypertensives of choice.

Treating polycystic kidney disease involves dealing with the following signs, symptoms, and complications in their early stages:

• Kidney cyst growth – Tolvaptan therapy may be recommended for adults at risk of rapidly progressive ADPKD. Tolvaptan (Jynarque, Samsca) is a pill that you take by mouth that works to slow the rate of kidney cyst growth and the decline in how well your kidneys work. There’s a risk of serious liver injury when taking tolvaptan, and it can interact with other medicines you take. It’s best to see a doctor who specializes in kidney health (nephrologist) when taking tolvaptan so that you can be monitored for side effects and possible complications.
• High blood pressure – Controlling high blood pressure can delay the progression of the disease and slow further kidney damage. Combining a low-sodium, low-fat diet that’s moderate in protein and calorie content with not smoking, increasing exercise, and reducing stress may help control high blood pressure. However, medications are usually needed to control high blood pressure. Medications called angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are often used to control high blood pressure.
• Declining kidney function. To help your kidneys stay as healthy as possible for as long as possible, experts recommend maintaining a normal body weight (body mass index). Drinking water and fluids throughout the day may help slow the growth of kidney cysts, which in turn could slow down a decline in kidney function. Following a low-salt diet and eating less protein might allow kidney cysts to respond better to the increase in fluids.
• Pain. You might be able to control the pain of polycystic kidney disease with over-the-counter medications containing acetaminophen. For some people, however, the pain is more severe and constant. Your doctor might recommend a procedure using a needle to draw out cyst fluid and inject a medication (sclerosing agent) to shrink kidney cysts. Or you may need surgery to remove cysts if they’re large enough to cause pressure and pain.
• Bladder or kidney infections. Prompt treatment of infections with antibiotics is necessary to prevent kidney damage. Your doctor may investigate whether you have a simple bladder infection or a more complicated cyst or a kidney infection. For more complicated infections, you may need to take a longer course of antibiotics.
• Blood in the urine. You’ll need to drink lots of fluids, preferably plain water, as soon as you notice blood in your urine to dilute the urine. Dilution might help prevent obstructive clots from forming in your urinary tract. In most cases, the bleeding will stop on its own. If it doesn’t, it’s important to contact your doctor.
• Kidney failure. If your kidneys lose their ability to remove waste products and extra fluids from your blood, you’ll eventually need either dialysis or a kidney transplant. Seeing your doctor regularly for monitoring of PKD allows for the best timing of a kidney transplant. You may be able to have a preemptive kidney transplant, which means you wouldn’t need to start dialysis but would have the transplant instead.
• Aneurysms. If you have polycystic kidney disease and a family history of ruptured brain (intracranial) aneurysms, your doctor may recommend regular screening for intracranial aneurysms.

If an aneurysm is discovered, surgical clipping of the aneurysm to reduce the risk of bleeding may be an option, depending on its size. Nonsurgical treatment of small aneurysms may involve controlling high blood pressure and high blood cholesterol, as well as quitting smoking.

Should people with PKD take a special diet?

• At present, no specific diet is known to prevent cysts from developing in patients with PKD. Reducing salt intake helps control blood pressure in PKD patients who have high blood pressure. A diet low in fat and moderate in calories is recommended to maintain a healthy weight. Speak to your doctor or a dietitian about other changes to your diet, such as avoiding caffeine.

Is exercise recommended for people with PKD?

• Absolutely. However, exercises that are potentially harmful to the kidney, such as contact sports, should be avoided. It is important not to become too dehydrated during any physical activity.

Who is at risk for developing PKD?

PKD runs in families. It is an inherited disorder that is passed from parents to children through genes. Genes are the basic elements of heredity. At conception, children receive a set of genes from each parent. They determine many characteristics such as hair color and eye color. Genes can also determine the likelihood of developing a disease.

A genetic disease can happen if one or both parents pass abnormal genes to a child. This happens through something called dominant inheritance or recessive inheritance.

• Dominant inheritance – If one parent has the disease and passes an abnormal gene to the child, it is called dominant inheritance. Each child has a 50% chance of getting the disease. The risk is the same for every child, regardless of how many children develop the disease.

• Recessive inheritance – If both parents carry the abnormal gene, and both parents pass an abnormal gene to the child, it is called recessive inheritance. In this situation, every child has a 25% chance of getting the disease.

Are there different types of PKD?

Yes. The three main types of PKD are

• • Autosomal Dominant PKD – (also called PKD or ADPKD)This form of the disease is passed from parent to child by dominant inheritance. In other words, only one copy of the abnormal gene is needed to cause the disease. Symptoms usually begin between the ages of 30 and 40, but they can begin earlier, even in childhood. ADPKD is the most common form of PKD. In fact, about 90 percent of all PKD cases are ADPKD.
  • Infantile or Autosomal Recessive PKD(also called ARPKD) – This form of the disease is passed from parent to child by recessive inheritance. Symptoms can begin in the earliest months of life, even in the womb. It tends to be very serious, progresses rapidly, and is often fatal in the first few months of life. This form of ARPKD is extremely rare. It occurs in 1 out of 25,000 people.
  • Acquired Cystic Kidney Disease (also called ACKD) – ACKD can happen in kidneys with long-term damage and severe scarring, so it is often associated with kidney failure and dialysis. About 90 percent of people on dialysis for 5 years develop ACKD. People with ACKD usually seek help because they notice blood in their urine. This is because the cysts bleed into the urinary system, which discolors urine.

• https://www.ncbi.nlm.nih.gov/books/NBK279385/
• https://www.ncbi.nlm.nih.gov/books/NBK535404/
• https://www.ncbi.nlm.nih.gov/books/NBK482385/
• https://www.ncbi.nlm.nih.gov/books/NBK499861/
• https://www.ncbi.nlm.nih.gov/books/NBK441896/
• https://www.ncbi.nlm.nih.gov/books/NBK554544/
• https://www.ncbi.nlm.nih.gov/books/NBK544228/
• https://www.ncbi.nlm.nih.gov/books/NBK441859/
• https://www.ncbi.nlm.nih.gov/books/NBK532934/
• https://www.ncbi.nlm.nih.gov/books/NBK499952/
• https://www.ncbi.nlm.nih.gov/books/NBK507815/
• https://www.ncbi.nlm.nih.gov/books/NBK431105/
• https://www.ncbi.nlm.nih.gov/books/NBK459218/
• https://www.ncbi.nlm.nih.gov/books/NBK470390/
• https://www.ncbi.nlm.nih.gov/books/NBK536971/
• https://www.sciencedirect.com/book/9781437709872/
• https://medlineplus.gov/ency/article/000500.htm
• https://www.nice.org.uk/guidance/ng148
• https://www.nhs.uk/conditions/acute-kidney-injury/
• https://www.mayoclinic.org/diseases-conditions/kidney-failure/diagnosis-treatment/drc-20369053
• https://en.wikipedia.org/wiki/Acute_kidney_injury
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198510/
• https://www.aafp.org/afp/2012/1001/p631.html
• https://www.kidney.org/atoz/content/what-creatinine
• https://www.nuh.nhs.uk/creatinine-clearance-calculator
• https://www.sciencedirect.com/topics/medicine-and-dentistry/uremia
• https://en.wikipedia.org/wiki/Uremia
• https://www.mayoclinic.org/diseases-conditions/polycystic-kidney-disease/symptoms-causes/syc-20352820
• https://medlineplus.gov/genetics/condition/polycystic-kidney-disease/#synonyms

Angioedema is non-pitting edema that involves subcutaneous and/or submucosal layers of tissue that affect the face, lips, neck, and extremities, oral cavity, larynx, and/or gut. It becomes life-threatening when it involves the larynx. This activity examines the differential diagnosis of this condition and how to properly evaluate a patient presenting with it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Angioedema is characterized by one or more areas of well-demarcated, non-pitting edema of deep subcutaneous tissues. It is primarily known to involve the face, lips, tongue, and oropharynx, but also, can also involve the genitals, distal extremities, and gastrointestinal mucosa. Immediate identification of angioedema is of the utmost importance due to the potential for rapid development and progression of life-threatening airway compromise. This activity reviews the evaluation and treatment of angioedema and highlights the importance of a cohesive interprofessional team in providing optimal care to patients with angioedema.

Angioedema is a skin reaction similar to urticaria. It is most often characterized by an abrupt and short-lived swelling of the skin and mucous membranes. All parts of the body may be affected but swelling most often occurs around the eyes and lips. In severe cases, the internal lining of the upper respiratory tract and intestines may also be affected.

Angioedema is defined as ” subcutaneous tissues and/or submucosal tissues circumscribed non-pitting edema affecting lips, face, neck, and extremities oral cavity, larynx, and gut.” It becomes life-threatening when it involves the larynx, while intestinal angioedema is painful and mimics the acute abdomen.[rx][rx]

Classification of angioedema

Acquired

• Allergic (histaminergic angioedema) associated with anaphylaxis
• Non-allergic (non-histaminergic angioedema), presenting isolated or in combination with urticaria
• Drug-induced, e.g., angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs
• Complement-mediated secondary to acquired deficiency of C1-inhibitor
• Idiopathic which is subdivided into histaminergic and non-histaminergic

Hereditary forms

• C1-Inhibitor deficiency divided into type 1 (lack of C1-inhibitor molecule) and typed 2 (dysfunctional C1-inhibitor molecule) with normal C1 inhibitor.

Causes of Angioedema

• Inherited (hereditary angioedema) – Mutations in the gene encoding for C1-inhibitor cause hereditary angioedema and it is an autosomal dominant condition.
• Acquired –  lymphoproliferative disorders, autoimmune, neoplastic, infection and drug-induced.[1]
• Histamine-mediated angioedema –  is the most common and is secondary to mast-cells and basophil activation.
• Bradykinin-mediated angioedema – (hereditary angioedema, acquired C1-inhibitor deficiency and angiotensin-converting enzyme inhibitor-associated angioedema). Allergic reactions and hives do not trigger this condition. C1-inhibitor is a regulator of complement and the contact system; if deficient or dysfunctional it causes activation of the contact system resulting in uncontrolled production of kallikrein leading to proteolysis of high-molecular-weight kininogen and bradykinin, leading to edema by increasing in vascular permeability.
• C1 inhibitor deficiency – Excessive production of bradykinin
• Angiotensin-converting enzyme inhibitor-associated angioedema – Decreased degradation of bradykinin[rx][rx]
• Histamine and bradykinin – increase localized microvascular permeability.[rx]
• NSAID induced – cyclooxygenase 1 inhibitor affects arachnoid acid metabolism, leukotriene/prostaglandin binding to the receptor or may be IgE mediated[rx][rx]
• Genetics – Hereditary angioedema can be secondary to the F12 gene, angiopoietin-1, and plasminogen or some unknown gene mutation.[rx][rx] C1 inhibitor is a serine protease inhibitor (SERPIN) [rx] C1 inhibitor deficiency is associated with  SERPING 1 mutation or mutated genes which encode for metabolizing and functioning enzymes of bradykinin.[rx] Abnormal accumulation of C1 inhibitor in dominant harmful disease affects plasma levels of hereditary angioedema type 1.[rx]
• There are several etiologies of angioedema – most notably angiotensin-converting enzyme inhibitor (ACEI) use. With tens of millions of people taking ACEIs, the incidence of ACEI angioedema is rising[rx]. African Americans are at a much higher risk for ACEI angioedema, possibly due to lower endogenous bradykinin and increased sensitivity to ACEI-mediated increases in bradykinin.
• Other etiologies include IgE-mediated allergic reactions – (such as to food, drug, or environmental triggers), nonsteroidal anti-inflammatory drug (NSAID) use (including aspirin), and chemically-induced histamine release (most commonly opiates, highly cationic antibiotics, and muscle relaxants)[rx]. A less common cause is hereditary angioedema (HAE) and acquired angioedema (AAE), both caused by a C1-inhibitor (C1-INH) deficiency.
• HAE and AAE are rare. AAE – is due to an acquired deficiency of (C1-INH), caused by either consumption (type 1) or inactivation (type 2)[rx]. This increased catabolism can be related to an autoimmune disorder (e.g., systemic lupus erythematosus) or a malignant tumor (e.g., lymphoma)[rx]. Angioedema recurs unpredictably, lasting from two to five days. It not only presents with edema of the areas mentioned above, but it can also cause severe abdominal pain due to gastrointestinal mucosa edema.

The causes of angioedema depend on the type of angioedema a patient has. Angioedema can be classified into at least four types, acute allergic angioedema, non-allergic drug reactions, idiopathic angioedema, hereditary angioedema (HAE) and acquired C1 inhibitor deficiency.

AAE recurrence is associated with various conditions such as different forms of lymphoproliferative disorders[rx].

• Acute contact dermatitis
• Drug rash with eosinophilia and systemic symptoms
• Dermatomyositis
• Morbus Morbihan
• Superior vena cava syndrome
• Hypothyroidism
• Subcutaneous emphysema
• Orofacial granulomatosis
• Hypocomplementemic urticarial vasculitis syndrome
• Clarkson’s disease
• Gleich’s syndrome
• A cluster headache
• Idiopathic edema [rx]

Angioedema is one of the differential diagnoses in sudden onset of diffuse isolated edema.[rx] C1 inhibitor hereditary angioedema can be misdiagnosed as familial Mediterranean fever.[rx]

Symptoms of Angioedema

Symptoms and signs of angioedema may vary slightly between the different types of angioedema but in general, some or all of the following occur.

• Marked swelling, usually around the eyes and mouth
• Throat, tongue, hands, feet and/or genitals may be affected too
• The skin may appear normal, i.e. no hives or another rash
• Swellings may or may not be itchy
• Swellings may be painful, tender or burning
• In severe angioedema swelling of the throat and/or tongue may make it difficult to breath
• Swelling of the lining of the intestinal tracts may cause gastrointestinal pain and cramps

Some features specific to the different types of angioedema are listed below.

Diagnosis of Angioedema

History and Physical

The presentation can be acute or chronic. Vital signs, level of consciousness, as well as a thorough ski, head, neck, respiratory, and abdomen evaluation should be completed.[rx] General monitoring of angioedema in the Emergency room includes Oxygen saturation and Cardiac status.

Histaminergic angioedema

Symptoms can involve different systems including skin (Urticaria, flushing, pruritus), Respiratory (bronchospasm), GI symptoms (abdominal pain and vomiting).[rx]  Onset is within 60 minutes of allergen exposure and may last for one to two days.[rx]

Etiologies: Drugs, foods, latex, and insect stings.[rx]

While comparing the bradykinin-mediated angioedema with histaminergic angioedema, the former has the following characteristics:

• It is not associated with urticaria
• More severe and longer duration
• Has associated abdominal symptoms [rx]

Lab Test

• Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor – It clinically presents as angioedema without urticaria or itching[rx] It is common in African-Americans.[rx] It can develop anytime but common in the first week of exposure.[rx]
• Nonsteroidal anti-inflammatory disease-induced angioedema – NSAID-induced drug reactions include angioedema presenting with urticaria and facial swelling.[rx]
• Hereditary angioedema – begins in childhood or young adulthood, gets worse at puberty and presents as recurrent episodes of swelling or abdominal pain.[rx][rx][rx][rx] Patients can develop prominent prodromal symptoms like erythema marginatum (erythematous, serpentine,non-pruritic rash).[rx] An acute attack takes one day to peak and resolves in two to three days.[rx]
• Acquired angioedema with C1 inhibitor deficiency – Acquired C1 inhibitor deficiency presents similarly to hereditary angioedema. However, the low C1 inhibitor in many cases is from an underlying lymphoproliferative disorder which increases protein consumption and an antibody against C1-INH causing overproduction of bradykinin.[rx]
• The initial evaluation in the Emergency room – A specific drug and family history is needed along with screening blood work for C4 for hereditary angioedema and tryptase for angioedema with anaphylaxis. These labs when drawn during acute attacks are useful during follow-ups. In the case of anaphylaxis, (tryptase is normal in hereditary angioedema one and two but will be elevated in cases of anaphylaxis and other mast cell disorders associated with angioedema)[rx]. Flexible fiberoptic laryngoscopy may be done to evaluate the involvement of the tongue and larynx in patients with head, neck and upper airway symptoms.[rx] Clear differentiation between histamine-induced vs. bradykinin-induced angioedema can be life-saving.[rx]
• Hereditary angioedema type 1 – C1 inhibitor function low, C1-Inhibitor level low, and C4 level low
• Hereditary angioedema type 2 – C1 inhibitor function and C4 level will be low, but the C1 inhibitor level will be normal or high.[rx] Confirm them by repeating the blood test.
• Acquired C1-inhibitor deficiency – Low C1-inhibitor antigen and function and low C1q.[rx]

Treatment of Angioedema

Initially, the cause of angioedema is likely to be unknown, the mainstays of initial medical management include supplemental oxygen, a parenteral H-blocker, a parenteral steroid, and intramuscular epinephrine. Unfortunately, in AAE standard regimens of epinephrine, corticosteroids and antihistamines do not have much effect and are not recommended for AAE. Administration of plasma-derived or recombinant C1-INH can resolve acute attacks, but some patients will become non-responsive[rx].

• Icatibant, a bradykinin B2 receptor antagonist –  has been shown to provide symptoms relief in AAE and was well tolerated[rx]. Icatibant is an effective home-based, on-demand treatment.[rx] Before any high-risk procedure in high-risk patients, it is essential to give short-term prophylaxis.[rx] Anesthetists must be aware of the guidelines for HANE and AANE.[rx] C1 esterase inhibitor is the first-line long-term prophylaxis and androgens are used as second-line prophylaxis.[rx] The majority of AANE cases are asymptomatic and respond to immunochemotherapy.[rx]
• Ecallantide, a potent bradykinin pathway inhibitor – has also shown promise in the treatment of AAE, providing another alternative in the treatment of patients with resistance to C1-INH replacement[rx].
• Fresh frozen plasma (FFP) – may be used. Although effective (at least in HAE), it at times will lack efficacy or even cause a sudden worsening of the patient’s symptoms. There is also the risk of viral transmission to consider[rx].
• Rituximab  – efficacy has been shown to be inconstant in AAE[rx]. It is also important to consider that treatment of an underlying causative condition can result in improvement of AAE[rx].
• Antihistamine, corticosteroids, and epinephrine – are treatments of histaminergic angioedema.[rx][rx] Treatment of Bradykinin-mediated angioedema is often resistant to standard therapies such as epinephrine, glucocorticoids, or antihistamines.[rx]
• Hereditary angioedema (On-demand treatment) – Treat airway via intubation or surgical airway intervention. Treatment should be as early as possible. Hereditary angioedema attacks should be treated with C1 Inhibitor concentrate, [rx] ecallantide (Kallikrein inhibitor), or icatibant (bradykinin-receptor antagonist).[rx] Icatibant is an effective home-based, on-demand treatment.[rx]
• Pre-procedural (short-term) prophylaxis – Short-term prophylaxis before high-risk procedures in high-risk individuals. [rx] Anesthesiologists must be aware of guideline-based treatment for hereditary and acquired angioedema. [rx]
• Long-term prophylaxis – C1 Inhibitor is the first-line long-term prophylaxis, while the androgens are used as second-line agents.[rx]
• Hereditary angioedema with mutations in the F12 gene is treated as follows – Discontinuing trigger factors (estrogen-containing oral contraceptives, hormonal replacement therapy, angiotensin-converting enzyme inhibitors). Treating with plasma-derived C1 inhibitor for acute attacks.  Preventing attacks with progestins, tranexamic acid, and danazol.[rx]
• Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor – Treatment is with antihistamines, epinephrine, and glucocorticoids.[rx] Care should be taken to stop the offending ACE inhibitor, and the patient should be not rechallenged with any of the ACE inhibitors in the future.
• Acquired C1 inhibitor deficiency angioedema  – The majority of cases are asymptomatic and respond to immunochemotherapy[rx] Treatment of acute attacks with icatibant and plasma-derived C1 inhibitor concentrate, and prophylaxis is with rituximab with or without chemotherapy and splenectomy.[rx]
• Antifibrinolytics and androgens – Two other therapies, which have recently fallen out of favor, include antifibrinolytics and androgens. Androgens induce the production of C1-inhibitor and are very effective in preventing attacks, but have no benefit in treating an attack. Short-term prophylaxis is tolerated well and is effective for pre-procedure of other short-term events; however, the toxicity of androgens limits their use for long-term prophylaxis. Most experts recommend not exceeding 200 mg of Danocrine a day. Adverse effects include hyperlipidemia, obesity, androgenic effects in females, and disposition problems.[rx][rx]
• Antifibrinolytics – include tranexamic acid and aminocaproic acid, and both have minimal effectiveness in the prevention and treatment of attacks. Presently, multiple other therapies are in the investigation including an oral kallikrein inhibitor and a monoclonal antibody that inhibits kallikrein. Table one includes the drugs that are currently available, and that may be available in the next few years.

Special considerations

• In pregnancy, the recommended therapy is plasma-derived nano-filtered C1-inhibitor,[rx] however, in acute episodes, bradykinin receptor antagonist Icatibant can be used as it is safe with no maternal and fetal adverse effects.[rx]
• In the pediatric population, the doses include 500 units (10-25 kg weighed patients), 1000 units, and 1500 Units in patients weighing more than 25kg.[rx]
• Plasma-derived C1 esterase inhibitor is safe and efficacious in pediatric patients below 12 years.[rx]
• Icatibant is a well-tolerated medication in the pediatric group and might have a role in treating angiotensin II receptor blocker-induced angioedema.[rx]
• Recombinant human C1 esterase inhibitor for acute hereditary angioedema treatment has a persistent response for three days.[rx]
• C1 inhibitor is used in the acute management of hereditary angioedema-associated pancreatitis.[rx]
• Patients with life-threatening orolingual angioedema who are treated with recombinant tissue plasminogen activator infusion, have a rapid response after using icatibant treatment.[rx]
• Concurrent use of angiotensin-converting enzyme inhibitors with, dipeptidyl peptidase-4 inhibitors should be monitored closely as dipeptidyl peptidase-4 is also a major enzyme in the degradation pathway of bradykinin like an angiotensin-converting enzyme.[rx]
• Use of liquid steroids in patients with severe urticaria-associated angioedema in a setting of severe dysphagia secondary to anaphylaxis.[rx]
• Use of omalizumab (Anti-immunoglobulin-E antibody) in Idiopathic non-histaminergic acquired angioedema, which is a rare disease resistant to antihistamines.[rx][rx]

Complications

• Critical airway occlusion resulting in death
• Acute laryngeal, pharynx, and tongue swelling[rx]
• Death from asphyxiation[rx]
• Hereditary angioedema associated pancreatitis[rx]
• Physicians should be mindful of cardiovascular instability including bradycardia after recombinant tissue plasminogen inhibitor in patients who take angiotensin-converting enzyme inhibitors[rx]

References

Kraurosis vulva is a cutaneous condition characterized by atrophy and shrinkage of the skin of the vagina and vulva often accompanied by a chronic inflammatory reaction in the deeper tissues.^[rx]

Lichen Sclerosis (LS) is a chronic inflammatory disease. It was first described by Hallopeau in 1881.  In 1976, the International Society for the Study of Vulvovaginal Disease adopted the term lichen sclerosis. LS is a mucocutaneous autoimmune disorder characterized by hypopigmentation and skin atrophy. It involves most commonly the genital skin, less often the extragenital sites. LS is more common in women than in men. It may cause phimosis or scarring of the vaginal introitus. The diagnosis is based on the clinical features, but it is often confirmed by biopsy. The lesions can evolve towards the destruction of anatomic structures, functional impairment, and a potential risk for malignant evolution. Thus, treatment and long term follow-up are mandatory.

Another Name

Causes of Lichen Sclerosis

• LS is considered to be an autoimmune condition; however, its etiology remains unclear. Given its association with other autoimmune diseases such as alopecia areata, vitiligo, autoimmune thyroiditis, and pernicious anemia, its etiology is probably multifactorial. Further etiologic factors have been implicated such as genetic susceptibility, infectious agents such as spirochetes, sex hormone, and the Koebner phenomenon. Furthermore, recent data demonstrated a high prevalence of lichen sclerosis associated with morphea. [rx]
• The underlying pathogenesis of LS includes an infiltrate of activated T cells releasing interleukin 4 (IL 4) and transforming growth factor β (TGF β). So, these cytokines activate fibroblasts producing significantly altered collagen leading to fibrosis. Besides, the pathogenesis includes vascular damage by the decrease in the number of capillaries.
• Interleukin 1 (IL 1) and interleukin one receptor antagonist (IL 1ra) may also be included in the pathogenesis of lichen sclerosis as well as an increased number of monoclonal T lymphocyte CD4 +, lymphocyte T dendritic CD1a + cells, macrophages, mast cells, and decreased number of T lymphocyte CD3 +. [rx]
• Another hypothesis has been suggested such as an increased number of circulating IgG autoantibodies targeting extracellular matrix 1 (ECM 1) protein leading to widespread deposition of hyaline material in the dermis. [rx]

Symptoms of Lichen Sclerosis

• The reduction in structural complexity of vulvar tissue commonly occurs with advancing age, which is manifest externally by drying, shriveling and white patches. Formally known as kraurosis vulvae.
• Often asymptomatic; less commonly, itching, dyspareunia, dysuria and tenderness.
• LSA may present at any age, from pediatric to geriatric age groups.
• The condition is more common in women.
• The anogenital region alone is affected in about 50% of cases, the anogenital and extragenital disease is present in about 25% of cases, and only extragenital areas are affected in about 25% of cases.
• Extragenital LSA is common on the neck, wrists, and inframammary areas.
• Anogenital LSA in girls and women often demonstrates an hourglass-like or figure-eight configuration that surrounds the genitalia and anal region.
• Early LSA may be pruritic or asymptomatic.
• Primary lesions quickly evolve into white atrophic areas, with variable telangiectasias.
• Some cases demonstrate the surrounding brown hyperpigmentation.
• Variable features include hyperkeratosis and follicular plugging, fissures, blister formation hemorrhage, and ulceration.
• Phimosis is a complication in uncircumcised men, and urethral stricture may also occur.
• Squamous cell carcinoma is a rare complication with chronic genital LSA.

Diagnosis of Lichen Sclerosis

LS has a specific histologic pattern characterized by a band-like lymphocytic infiltrate below a zone of dermal edema and orthokeratotic hyperkeratosis. Histopathology findings vary depending on disease duration. In earlier stages, it shows vacuolar degeneration of the basal layer, hyalinization of subepithelial collagen, decreased elastic fibers in the upper dermis, and dilated blood vessels under the basement membrane. In older lesions, histology shows a reduced number of mononuclear cells and dispersed patchy islands of mononuclear cells within the hyalinized dermis. [rx][rx]

History and Physical

LS affects most commonly the genital site and less often the extragenital area. Typical lesions begin as a sharply demarcated erythema that becomes thin, hypopigmented, ivory-white, porcelain-like, and sclerotic plaques. Plaques may become later thickened due to repeated excoriations. Itch is the main symptom and is often worse at night. Other lesions may include telangiectasias, purpura, fissures, ulcerations, and edema. Typical complaints commonly include significant pruritus, local burning sensation, pain, painful defecation. Constipation is frequent in children but rarely seen in adults. However, lesions can be asymptomatic. Genital lesions begin around the periclitoral hood. The affected area varies from a small and single area to a large area involving the entire region of the vulva, perineum, and perianus assuming a typical aspect of ‘keyhole sign.’

However, LS usually spares the vagina and cervix. In girls, LS presents commonly with irritation and soreness although it can mimic sexual abuse. However, LS and sexual abuse can coexist. Visual lichen sclerosis exhibits the Koebner phenomenon at sites of trauma; sexual abuse can aggravate lesions of LS. [5] Male genital LS (boys and men) occurs in the foreskin, glans penis, and the coronal sulcus penis. Extragenital lesions occur on any part of the skin and usually asymptomatic. The most commonly involved areas are inframammary areas, neck, wrists, thighs, upper back, and shoulders. The involvement of the oral mucosa appears clinically as bluish-white papules on the buccal mucosa or under the tongue.

Evaluation

The diagnosis is based on taking a careful history including the autoimmune diseases in the patient and family, the examination of the mucosas, extragenital skin, and completed by a gynecological exam. Thus, the diagnosis of LS is usually clinical. But in some cases, a biopsy can be performed. However, atypical histology does not rule out the diagnosis.

Biopsies should be performed in case of:

• Atypical clinical presentation
• Suspected malignancy
• Nonresponse, after an appropriate duration, to recommended first-line treatment

The workup of the condition should include investigation of thyroid function, and according to symptoms investigation of the other autoimmune diseases.

Treatment of Lichen Sclerosis

The aims of the treatment are relief of the symptoms, stopping the atrophy, prevention of scar formation, and anatomical distortion, as well as malignant transformation. The therapy includes general care, topical treatments, systemic treatments, and surgical procedures. It is fundamental to inform the patient to avoid the use of irritating products such as soap and to prefer emollients to break the itch-stretch cycle.

For genital LS, the gold standard treatment is three months application of high potency topical steroids (clobetasol propionate). Second-line therapies include topical calcineurin inhibitors and imiquimod. In men, early circumcision may be recommended. Surgery is indicated only for the treatment of complications associated with lichen sclerosus. For extragenital LS, therapeutic modalities are limited and include phototherapy, ultrapotent topical steroids, tacrolimus ointment 0, 1%, and systemic steroids or methotrexate. Follow-up examinations must be kept indefinitely. [rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479569/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483306/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK557803/
• https://www.ncbi.nlm.nih.gov/books/NBK532271/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK538246/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC475719/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1969198/
• https://en.wikipedia.org/wiki/Bartholin%27s_cyst
• https://en.wikipedia.org/wiki/Kraurosis_vulvae
• https://www.health.harvard.edu/a_to_z/bartholins-gland-cyst-a-to-z
• https://www.sciencedirect.com/topics/medicine-and-dentistry/vulva-kraurosis

Lichen Sclerosis Atrophicus (LSA) or, simply, lichen sclerosis, is a disorder characterized by an atrophic epidermis, altered collagen in the superficial dermis, and an overlying white or white-blue appearance to the skin. The terms balanitis xerotica obliterans and kraurosis vulvae have been applied to genital lesions of LSA in men and women, respectively. The pathogenesis of LSA is poorly understood, but the increased incidence of LSA with other autoimmune diseases (e.g., morphea) and the presence of autoantibodies directed against extracellular matrix protein 1 suggest LSA is an autoimmune disorder.

Kraurosis vulva is a cutaneous condition characterized by atrophy and shrinkage of the skin of the vagina and vulva often accompanied by a chronic inflammatory reaction in the deeper tissues.^[rx]

Lichen Sclerosis (LS) is a chronic inflammatory disease. It was first described by Hallopeau in 1881.  In 1976, the International Society for the Study of Vulvovaginal Disease adopted the term lichen sclerosis. LS is a mucocutaneous autoimmune disorder characterized by hypopigmentation and skin atrophy. It involves most commonly the genital skin, less often the extragenital sites. LS is more common in women than in men. It may cause phimosis or scarring of the vaginal introitus. The diagnosis is based on the clinical features, but it is often confirmed by biopsy. The lesions can evolve towards the destruction of anatomic structures, functional impairment, and a potential risk for malignant evolution. Thus, treatment and long term follow-up are mandatory.

Another Name

Causes of Lichen Sclerosis Atrophicus

• LS is considered to be an autoimmune condition; however, its etiology remains unclear. Given its association with other autoimmune diseases such as alopecia areata, vitiligo, autoimmune thyroiditis, and pernicious anemia, its etiology is probably multifactorial. Further etiologic factors have been implicated such as genetic susceptibility, infectious agents such as spirochetes, sex hormone, and the Koebner phenomenon. Furthermore, recent data demonstrated a high prevalence of lichen sclerosis associated with morphea. [rx]
• The underlying pathogenesis of LS includes an infiltrate of activated T cells releasing interleukin 4 (IL 4) and transforming growth factor β (TGF β). So, these cytokines activate fibroblasts producing significantly altered collagen leading to fibrosis. Besides, the pathogenesis includes vascular damage by the decrease in the number of capillaries.
• Interleukin 1 (IL 1) and interleukin one receptor antagonist (IL 1ra) may also be included in the pathogenesis of lichen sclerosis as well as an increased number of monoclonal T lymphocyte CD4 +, lymphocyte T dendritic CD1a + cells, macrophages, mast cells, and decreased number of T lymphocyte CD3 +. [rx]
• Another hypothesis has been suggested such as an increased number of circulating IgG autoantibodies targeting extracellular matrix 1 (ECM 1) protein leading to widespread deposition of hyaline material in the dermis. [rx]

Symptoms of Lichen Sclerosis Atrophicus

• The reduction in structural complexity of vulvar tissue commonly occurs with advancing age, which is manifest externally by drying, shriveling and white patches. Formally known as kraurosis vulvae.
• Often asymptomatic; less commonly, itching, dyspareunia, dysuria and tenderness.
• LSA may present at any age, from pediatric to geriatric age groups.
• The condition is more common in women.
• The anogenital region alone is affected in about 50% of cases, the anogenital and extragenital disease is present in about 25% of cases, and only extragenital areas are affected in about 25% of cases.
• Extragenital LSA is common on the neck, wrists, and inframammary areas.
• Anogenital LSA in girls and women often demonstrates an hourglass-like or figure-eight configuration that surrounds the genitalia and anal region.
• Early LSA may be pruritic or asymptomatic.
• Primary lesions quickly evolve into white atrophic areas, with variable telangiectasias.
• Some cases demonstrate the surrounding brown hyperpigmentation.
• Variable features include hyperkeratosis and follicular plugging, fissures, blister formation hemorrhage, and ulceration.
• Phimosis is a complication in uncircumcised men, and urethral stricture may also occur.
• Squamous cell carcinoma is a rare complication with chronic genital LSA.

Diagnosis of Lichen Sclerosis Atrophicus

LS has a specific histologic pattern characterized by a band-like lymphocytic infiltrate below a zone of dermal edema and orthokeratotic hyperkeratosis. Histopathology findings vary depending on disease duration. In earlier stages, it shows vacuolar degeneration of the basal layer, hyalinization of subepithelial collagen, decreased elastic fibers in the upper dermis, and dilated blood vessels under the basement membrane. In older lesions, histology shows a reduced number of mononuclear cells and dispersed patchy islands of mononuclear cells within the hyalinized dermis. [rx][rx]

History and Physical

LS affects most commonly the genital site and less often the extragenital area. Typical lesions begin as a sharply demarcated erythema that becomes thin, hypopigmented, ivory-white, porcelain-like, and sclerotic plaques. Plaques may become later thickened due to repeated excoriations. Itch is the main symptom and is often worse at night. Other lesions may include telangiectasias, purpura, fissures, ulcerations, and edema. Typical complaints commonly include significant pruritus, local burning sensation, pain, painful defecation. Constipation is frequent in children but rarely seen in adults. However, lesions can be asymptomatic. Genital lesions begin around the periclitoral hood. The affected area varies from a small and single area to a large area involving the entire region of the vulva, perineum, and perianus assuming a typical aspect of ‘keyhole sign.’

However, LS usually spares the vagina and cervix. In girls, LS presents commonly with irritation and soreness although it can mimic sexual abuse. However, LS and sexual abuse can coexist. Visual lichen sclerosis exhibits the Koebner phenomenon at sites of trauma; sexual abuse can aggravate lesions of LS. [rx] Male genital LS (boys and men) occurs in the foreskin, glans penis, and the coronal sulcus penis. Extragenital lesions occur on any part of the skin and usually asymptomatic. The most commonly involved areas are inframammary areas, neck, wrists, thighs, upper back, and shoulders. The involvement of the oral mucosa appears clinically as bluish-white papules on the buccal mucosa or under the tongue.

Evaluation

The diagnosis is based on taking a careful history including the autoimmune diseases in the patient and family, the examination of the mucosas, extragenital skin, and completed by a gynecological exam. Thus, the diagnosis of LS is usually clinical. But in some cases, a biopsy can be performed. However, atypical histology does not rule out the diagnosis.

Biopsies should be performed in case of:

• Atypical clinical presentation
• Suspected malignancy
• Nonresponse, after an appropriate duration, to recommended first-line treatment

The workup of the condition should include investigation of thyroid function, and according to symptoms investigation of the other autoimmune diseases.

Treatment of Lichen Sclerosis Atrophicus

The aims of the treatment are relief of the symptoms, stopping the atrophy, prevention of scar formation, and anatomical distortion, as well as malignant transformation. The therapy includes general care, topical treatments, systemic treatments, and surgical procedures. It is fundamental to inform the patient to avoid the use of irritating products such as soap and to prefer emollients to break the itch-stretch cycle.

For genital LS, the gold standard treatment is three months application of high potency topical steroids (clobetasol propionate). Second-line therapies include topical calcineurin inhibitors and imiquimod. In men, early circumcision may be recommended. Surgery is indicated only for the treatment of complications associated with lichen sclerosus. For extragenital LS, therapeutic modalities are limited and include phototherapy, ultrapotent topical steroids, tacrolimus ointment 0, 1%, and systemic steroids or methotrexate. Follow-up examinations must be kept indefinitely. [rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479569/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483306/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK557803/
• https://www.ncbi.nlm.nih.gov/books/NBK532271/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK538246/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC475719/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1969198/
• https://en.wikipedia.org/wiki/Bartholin%27s_cyst
• https://en.wikipedia.org/wiki/Kraurosis_vulvae
• https://www.health.harvard.edu/a_to_z/bartholins-gland-cyst-a-to-z
• https://www.sciencedirect.com/topics/medicine-and-dentistry/vulva-kraurosis

Leukoplakia/Lichen Sclerosis atrophicus (LSA) or, simply, lichen sclerosis, is a disorder characterized by an atrophic epidermis, altered collagen in the superficial dermis, and an overlying white or white-blue appearance to the skin. The terms balanitis xerotica obliterans and kraurosis vulvae have been applied to genital lesions of LSA in men and women, respectively. The pathogenesis of LSA is poorly understood, but the increased incidence of LSA with other autoimmune diseases (e.g., morphea) and the presence of autoantibodies directed against extracellular matrix protein 1 suggest LSA is an autoimmune disorder.

Kraurosis vulva is a cutaneous condition characterized by atrophy and shrinkage of the skin of the vagina and vulva often accompanied by a chronic inflammatory reaction in the deeper tissues.^[rx]

Lichen Sclerosis (LS) is a chronic inflammatory disease. It was first described by Hallopeau in 1881.  In 1976, the International Society for the Study of Vulvovaginal Disease adopted the term lichen sclerosis. LS is a mucocutaneous autoimmune disorder characterized by hypopigmentation and skin atrophy. It involves most commonly the genital skin, less often the extragenital sites. LS is more common in women than in men. It may cause phimosis or scarring of the vaginal introitus. The diagnosis is based on the clinical features, but it is often confirmed by biopsy. The lesions can evolve towards the destruction of anatomic structures, functional impairment, and a potential risk for malignant evolution. Thus, treatment and long term follow-up are mandatory.

Another Name

Causes of Leukoplakia

• LS is considered to be an autoimmune condition; however, its etiology remains unclear. Given its association with other autoimmune diseases such as alopecia areata, vitiligo, autoimmune thyroiditis, and pernicious anemia, its etiology is probably multifactorial. Further etiologic factors have been implicated such as genetic susceptibility, infectious agents such as spirochetes, sex hormone, and the Koebner phenomenon. Furthermore, recent data demonstrated a high prevalence of lichen sclerosis associated with morphea. [rx]
• The underlying pathogenesis of LS includes an infiltrate of activated T cells releasing interleukin 4 (IL 4) and transforming growth factor β (TGF β). So, these cytokines activate fibroblasts producing significantly altered collagen leading to fibrosis. Besides, the pathogenesis includes vascular damage by the decrease in the number of capillaries.
• Interleukin 1 (IL 1) and interleukin one receptor antagonist (IL 1ra) may also be included in the pathogenesis of lichen sclerosis as well as an increased number of monoclonal T lymphocyte CD4 +, lymphocyte T dendritic CD1a + cells, macrophages, mast cells, and decreased number of T lymphocyte CD3 +. [rx]
• Another hypothesis has been suggested such as an increased number of circulating IgG autoantibodies targeting extracellular matrix 1 (ECM 1) protein leading to widespread deposition of hyaline material in the dermis. [rx]

Symptoms of Leukoplakia

• The reduction in structural complexity of vulvar tissue commonly occurs with advancing age, which is manifest externally by drying, shriveling and white patches. Formally known as kraurosis vulvae.
• Often asymptomatic; less commonly, itching, dyspareunia, dysuria and tenderness.
• LSA may present at any age, from pediatric to geriatric age groups.
• The condition is more common in women.
• The anogenital region alone is affected in about 50% of cases, the anogenital and extragenital disease is present in about 25% of cases, and only extragenital areas are affected in about 25% of cases.
• Extragenital LSA is common on the neck, wrists, and inframammary areas.
• Anogenital LSA in girls and women often demonstrates an hourglass-like or figure-eight configuration that surrounds the genitalia and anal region.
• Early LSA may be pruritic or asymptomatic.
• Primary lesions quickly evolve into white atrophic areas, with variable telangiectasias.
• Some cases demonstrate the surrounding brown hyperpigmentation.
• Variable features include hyperkeratosis and follicular plugging, fissures, blister formation hemorrhage, and ulceration.
• Phimosis is a complication in uncircumcised men, and urethral stricture may also occur.
• Squamous cell carcinoma is a rare complication with chronic genital LSA.

Diagnosis of Leukoplakia

LS has a specific histologic pattern characterized by a band-like lymphocytic infiltrate below a zone of dermal edema and orthokeratotic hyperkeratosis. Histopathology findings vary depending on disease duration. In earlier stages, it shows vacuolar degeneration of the basal layer, hyalinization of subepithelial collagen, decreased elastic fibers in the upper dermis, and dilated blood vessels under the basement membrane. In older lesions, histology shows a reduced number of mononuclear cells and dispersed patchy islands of mononuclear cells within the hyalinized dermis. [rx][rx]

History and Physical

LS affects most commonly the genital site and less often the extragenital area. Typical lesions begin as a sharply demarcated erythema that becomes thin, hypopigmented, ivory-white, porcelain-like, and sclerotic plaques. Plaques may become later thickened due to repeated excoriations. Itch is the main symptom and is often worse at night. Other lesions may include telangiectasias, purpura, fissures, ulcerations, and edema. Typical complaints commonly include significant pruritus, local burning sensation, pain, painful defecation. Constipation is frequent in children but rarely seen in adults. However, lesions can be asymptomatic. Genital lesions begin around the periclitoral hood. The affected area varies from a small and single area to a large area involving the entire region of the vulva, perineum, and perianus assuming a typical aspect of ‘keyhole sign.’

However, LS usually spares the vagina and cervix. In girls, LS presents commonly with irritation and soreness although it can mimic sexual abuse. However, LS and sexual abuse can coexist. Visual lichen sclerosis exhibits the Koebner phenomenon at sites of trauma; sexual abuse can aggravate lesions of LS. [5] Male genital LS (boys and men) occurs in the foreskin, glans penis, and the coronal sulcus penis. Extragenital lesions occur on any part of the skin and usually asymptomatic. The most commonly involved areas are inframammary areas, neck, wrists, thighs, upper back, and shoulders. The involvement of the oral mucosa appears clinically as bluish-white papules on the buccal mucosa or under the tongue.

Evaluation

The diagnosis is based on taking a careful history including the autoimmune diseases in the patient and family, the examination of the mucosas, extragenital skin, and completed by a gynecological exam. Thus, the diagnosis of LS is usually clinical. But in some cases, a biopsy can be performed. However, atypical histology does not rule out the diagnosis.

Biopsies should be performed in case of:

• Atypical clinical presentation
• Suspected malignancy
• Nonresponse, after an appropriate duration, to recommended first-line treatment

The workup of the condition should include investigation of thyroid function, and according to symptoms investigation of the other autoimmune diseases.

Treatment of Leukoplakia

The aims of the treatment are relief of the symptoms, stopping the atrophy, prevention of scar formation, and anatomical distortion, as well as malignant transformation. The therapy includes general care, topical treatments, systemic treatments, and surgical procedures. It is fundamental to inform the patient to avoid the use of irritating products such as soap and to prefer emollients to break the itch-stretch cycle.

For genital LS, the gold standard treatment is three months application of high potency topical steroids (clobetasol propionate). Second-line therapies include topical calcineurin inhibitors and imiquimod. In men, early circumcision may be recommended. Surgery is indicated only for the treatment of complications associated with lichen sclerosus. For extragenital LS, therapeutic modalities are limited and include phototherapy, ultrapotent topical steroids, tacrolimus ointment 0, 1%, and systemic steroids or methotrexate. Follow-up examinations must be kept indefinitely. [rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479569/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483306/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK557803/
• https://www.ncbi.nlm.nih.gov/books/NBK532271/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK538246/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC475719/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1969198/
• https://en.wikipedia.org/wiki/Bartholin%27s_cyst
• https://en.wikipedia.org/wiki/Kraurosis_vulvae
• https://www.health.harvard.edu/a_to_z/bartholins-gland-cyst-a-to-z
• https://www.sciencedirect.com/topics/medicine-and-dentistry/vulva-kraurosis

Balanitis Xerotica Obliterans/Lichen Sclerosis atrophicus (LSA) or, simply, lichen sclerosis, is a disorder characterized by an atrophic epidermis, altered collagen in the superficial dermis, and an overlying white or white-blue appearance to the skin. The terms balanitis xerotica obliterans and kraurosis vulvae have been applied to genital lesions of LSA in men and women, respectively. The pathogenesis of LSA is poorly understood, but the increased incidence of LSA with other autoimmune diseases (e.g., morphea) and the presence of autoantibodies directed against extracellular matrix protein 1 suggest LSA is an autoimmune disorder.

Kraurosis vulva is a cutaneous condition characterized by atrophy and shrinkage of the skin of the vagina and vulva often accompanied by a chronic inflammatory reaction in the deeper tissues.^[rx]

Lichen Sclerosis (LS) is a chronic inflammatory disease. It was first described by Hallopeau in 1881.  In 1976, the International Society for the Study of Vulvovaginal Disease adopted the term lichen sclerosis. LS is a mucocutaneous autoimmune disorder characterized by hypopigmentation and skin atrophy. It involves most commonly the genital skin, less often the extragenital sites. LS is more common in women than in men. It may cause phimosis or scarring of the vaginal introitus. The diagnosis is based on the clinical features, but it is often confirmed by biopsy. The lesions can evolve towards the destruction of anatomic structures, functional impairment, and a potential risk for malignant evolution. Thus, treatment and long term follow-up are mandatory.

Another Name

Causes of Balanitis Xerotica Obliterans

• LS is considered to be an autoimmune condition; however, its etiology remains unclear. Given its association with other autoimmune diseases such as alopecia areata, vitiligo, autoimmune thyroiditis, and pernicious anemia, its etiology is probably multifactorial. Further etiologic factors have been implicated such as genetic susceptibility, infectious agents such as spirochetes, sex hormone, and the Koebner phenomenon. Furthermore, recent data demonstrated a high prevalence of lichen sclerosis associated with morphea. [rx]
• The underlying pathogenesis of LS includes an infiltrate of activated T cells releasing interleukin 4 (IL 4) and transforming growth factor β (TGF β). So, these cytokines activate fibroblasts producing significantly altered collagen leading to fibrosis. Besides, the pathogenesis includes vascular damage by the decrease in the number of capillaries.
• Interleukin 1 (IL 1) and interleukin one receptor antagonist (IL 1ra) may also be included in the pathogenesis of lichen sclerosis as well as an increased number of monoclonal T lymphocyte CD4 +, lymphocyte T dendritic CD1a + cells, macrophages, mast cells, and decreased number of T lymphocyte CD3 +. [rx]
• Another hypothesis has been suggested such as an increased number of circulating IgG autoantibodies targeting extracellular matrix 1 (ECM 1) protein leading to widespread deposition of hyaline material in the dermis. [rx]

Symptoms of Balanitis Xerotica Obliterans

• The reduction in structural complexity of vulvar tissue commonly occurs with advancing age, which is manifest externally by drying, shriveling and white patches. Formally known as kraurosis vulvae.
• Often asymptomatic; less commonly, itching, dyspareunia, dysuria and tenderness.
• LSA may present at any age, from pediatric to geriatric age groups.
• The condition is more common in women.
• The anogenital region alone is affected in about 50% of cases, the anogenital and extragenital disease is present in about 25% of cases, and only extragenital areas are affected in about 25% of cases.
• Extragenital LSA is common on the neck, wrists, and inframammary areas.
• Anogenital LSA in girls and women often demonstrates an hourglass-like or figure-eight configuration that surrounds the genitalia and anal region.
• Early LSA may be pruritic or asymptomatic.
• Primary lesions quickly evolve into white atrophic areas, with variable telangiectasias.
• Some cases demonstrate the surrounding brown hyperpigmentation.
• Variable features include hyperkeratosis and follicular plugging, fissures, blister formation hemorrhage, and ulceration.
• Phimosis is a complication in uncircumcised men, and urethral stricture may also occur.
• Squamous cell carcinoma is a rare complication with chronic genital LSA.

Diagnosis of Balanitis Xerotica Obliterans

LS has a specific histologic pattern characterized by a band-like lymphocytic infiltrate below a zone of dermal edema and orthokeratotic hyperkeratosis. Histopathology findings vary depending on disease duration. In earlier stages, it shows vacuolar degeneration of the basal layer, hyalinization of subepithelial collagen, decreased elastic fibers in the upper dermis, and dilated blood vessels under the basement membrane. In older lesions, histology shows a reduced number of mononuclear cells and dispersed patchy islands of mononuclear cells within the hyalinized dermis. [rx][rx]

History and Physical

LS affects most commonly the genital site and less often the extragenital area. Typical lesions begin as a sharply demarcated erythema that becomes thin, hypopigmented, ivory-white, porcelain-like, and sclerotic plaques. Plaques may become later thickened due to repeated excoriations. Itch is the main symptom and is often worse at night. Other lesions may include telangiectasias, purpura, fissures, ulcerations, and edema. Typical complaints commonly include significant pruritus, local burning sensation, pain, painful defecation. Constipation is frequent in children but rarely seen in adults. However, lesions can be asymptomatic. Genital lesions begin around the periclitoral hood. The affected area varies from a small and single area to a large area involving the entire region of the vulva, perineum, and perianus assuming a typical aspect of ‘keyhole sign.’

However, LS usually spares the vagina and cervix. In girls, LS presents commonly with irritation and soreness although it can mimic sexual abuse. However, LS and sexual abuse can coexist. Visual lichen sclerosis exhibits the Koebner phenomenon at sites of trauma; sexual abuse can aggravate lesions of LS. [5] Male genital LS (boys and men) occurs in the foreskin, glans penis, and the coronal sulcus penis. Extragenital lesions occur on any part of the skin and usually asymptomatic. The most commonly involved areas are inframammary areas, neck, wrists, thighs, upper back, and shoulders. The involvement of the oral mucosa appears clinically as bluish-white papules on the buccal mucosa or under the tongue.

Evaluation

The diagnosis is based on taking a careful history including the autoimmune diseases in the patient and family, the examination of the mucosas, extragenital skin, and completed by a gynecological exam. Thus, the diagnosis of LS is usually clinical. But in some cases, a biopsy can be performed. However, atypical histology does not rule out the diagnosis.

Biopsies should be performed in case of:

• Atypical clinical presentation
• Suspected malignancy
• Nonresponse, after an appropriate duration, to recommended first-line treatment

The workup of the condition should include investigation of thyroid function, and according to symptoms investigation of the other autoimmune diseases.

Treatment of Balanitis Xerotica Obliterans

The aims of the treatment are relief of the symptoms, stopping the atrophy, prevention of scar formation, and anatomical distortion, as well as malignant transformation. The therapy includes general care, topical treatments, systemic treatments, and surgical procedures. It is fundamental to inform the patient to avoid the use of irritating products such as soap and to prefer emollients to break the itch-stretch cycle.

For genital LS, the gold standard treatment is three months application of high potency topical steroids (clobetasol propionate). Second-line therapies include topical calcineurin inhibitors and imiquimod. In men, early circumcision may be recommended. Surgery is indicated only for the treatment of complications associated with lichen sclerosus. For extragenital LS, therapeutic modalities are limited and include phototherapy, ultrapotent topical steroids, tacrolimus ointment 0, 1%, and systemic steroids or methotrexate. Follow-up examinations must be kept indefinitely. [rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479569/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483306/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK557803/
• https://www.ncbi.nlm.nih.gov/books/NBK532271/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK538246/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC475719/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1969198/
• https://en.wikipedia.org/wiki/Bartholin%27s_cyst
• https://en.wikipedia.org/wiki/Kraurosis_vulvae
• https://www.health.harvard.edu/a_to_z/bartholins-gland-cyst-a-to-z
• https://www.sciencedirect.com/topics/medicine-and-dentistry/vulva-kraurosis

Hypopigmentation Skin Atrophy/Lichen Sclerosis atrophicus (LSA) or, simply, lichen sclerosis, is a disorder characterized by an atrophic epidermis, altered collagen in the superficial dermis, and an overlying white or white-blue appearance to the skin. The terms balanitis xerotica obliterans and kraurosis vulvae have been applied to genital lesions of LSA in men and women, respectively. The pathogenesis of LSA is poorly understood, but the increased incidence of LSA with other autoimmune diseases (e.g., morphea) and the presence of autoantibodies directed against extracellular matrix protein 1 suggest LSA is an autoimmune disorder.

Kraurosis vulva is a cutaneous condition characterized by atrophy and shrinkage of the skin of the vagina and vulva often accompanied by a chronic inflammatory reaction in the deeper tissues.^[rx]

Lichen Sclerosis (LS) is a chronic inflammatory disease. It was first described by Hallopeau in 1881.  In 1976, the International Society for the Study of Vulvovaginal Disease adopted the term lichen sclerosis. LS is a mucocutaneous autoimmune disorder characterized by hypopigmentation and skin atrophy. It involves most commonly the genital skin, less often the extragenital sites. LS is more common in women than in men. It may cause phimosis or scarring of the vaginal introitus. The diagnosis is based on the clinical features, but it is often confirmed by biopsy. The lesions can evolve towards the destruction of anatomic structures, functional impairment, and a potential risk for malignant evolution. Thus, treatment and long term follow-up are mandatory.

Another Name

Causes of Hypopigmentation Skin Atrophy

• LS is considered to be an autoimmune condition; however, its etiology remains unclear. Given its association with other autoimmune diseases such as alopecia areata, vitiligo, autoimmune thyroiditis, and pernicious anemia, its etiology is probably multifactorial. Further etiologic factors have been implicated such as genetic susceptibility, infectious agents such as spirochetes, sex hormone, and the Koebner phenomenon. Furthermore, recent data demonstrated a high prevalence of lichen sclerosis associated with morphea. [rx]
• The underlying pathogenesis of LS includes an infiltrate of activated T cells releasing interleukin 4 (IL 4) and transforming growth factor β (TGF β). So, these cytokines activate fibroblasts producing significantly altered collagen leading to fibrosis. Besides, the pathogenesis includes vascular damage by the decrease in the number of capillaries.
• Interleukin 1 (IL 1) and interleukin one receptor antagonist (IL 1ra) may also be included in the pathogenesis of lichen sclerosis as well as an increased number of monoclonal T lymphocyte CD4 +, lymphocyte T dendritic CD1a + cells, macrophages, mast cells, and decreased number of T lymphocyte CD3 +. [rx]
• Another hypothesis has been suggested such as an increased number of circulating IgG autoantibodies targeting extracellular matrix 1 (ECM 1) protein leading to widespread deposition of hyaline material in the dermis. [rx]

Symptoms of Hypopigmentation Skin Atrophy

• The reduction in structural complexity of vulvar tissue commonly occurs with advancing age, which is manifest externally by drying, shriveling and white patches. Formally known as kraurosis vulvae.
• Often asymptomatic; less commonly, itching, dyspareunia, dysuria and tenderness.
• LSA may present at any age, from pediatric to geriatric age groups.
• The condition is more common in women.
• The anogenital region alone is affected in about 50% of cases, the anogenital and extragenital disease is present in about 25% of cases, and only extragenital areas are affected in about 25% of cases.
• Extragenital LSA is common on the neck, wrists, and inframammary areas.
• Anogenital LSA in girls and women often demonstrates an hourglass-like or figure-eight configuration that surrounds the genitalia and anal region.
• Early LSA may be pruritic or asymptomatic.
• Primary lesions quickly evolve into white atrophic areas, with variable telangiectasias.
• Some cases demonstrate the surrounding brown hyperpigmentation.
• Variable features include hyperkeratosis and follicular plugging, fissures, blister formation hemorrhage, and ulceration.
• Phimosis is a complication in uncircumcised men, and urethral stricture may also occur.
• Squamous cell carcinoma is a rare complication with chronic genital LSA.

Diagnosis of Hypopigmentation Skin Atrophy

LS has a specific histologic pattern characterized by a band-like lymphocytic infiltrate below a zone of dermal edema and orthokeratotic hyperkeratosis. Histopathology findings vary depending on disease duration. In earlier stages, it shows vacuolar degeneration of the basal layer, hyalinization of subepithelial collagen, decreased elastic fibers in the upper dermis, and dilated blood vessels under the basement membrane. In older lesions, histology shows a reduced number of mononuclear cells and dispersed patchy islands of mononuclear cells within the hyalinized dermis. [rx][rx]

History and Physical

LS affects most commonly the genital site and less often the extragenital area. Typical lesions begin as a sharply demarcated erythema that becomes thin, hypopigmented, ivory-white, porcelain-like, and sclerotic plaques. Plaques may become later thickened due to repeated excoriations. Itch is the main symptom and is often worse at night. Other lesions may include telangiectasias, purpura, fissures, ulcerations, and edema. Typical complaints commonly include significant pruritus, local burning sensation, pain, painful defecation. Constipation is frequent in children but rarely seen in adults. However, lesions can be asymptomatic. Genital lesions begin around the periclitoral hood. The affected area varies from a small and single area to a large area involving the entire region of the vulva, perineum, and perianus assuming a typical aspect of ‘keyhole sign.’

However, LS usually spares the vagina and cervix. In girls, LS presents commonly with irritation and soreness although it can mimic sexual abuse. However, LS and sexual abuse can coexist. Visual lichen sclerosis exhibits the Koebner phenomenon at sites of trauma; sexual abuse can aggravate lesions of LS. [5] Male genital LS (boys and men) occurs in the foreskin, glans penis, and the coronal sulcus penis. Extragenital lesions occur on any part of the skin and usually asymptomatic. The most commonly involved areas are inframammary areas, neck, wrists, thighs, upper back, and shoulders. The involvement of the oral mucosa appears clinically as bluish-white papules on the buccal mucosa or under the tongue.

Evaluation

The diagnosis is based on taking a careful history including the autoimmune diseases in the patient and family, the examination of the mucosas, extragenital skin, and completed by a gynecological exam. Thus, the diagnosis of LS is usually clinical. But in some cases, a biopsy can be performed. However, atypical histology does not rule out the diagnosis.

Biopsies should be performed in case of:

• Atypical clinical presentation
• Suspected malignancy
• Nonresponse, after an appropriate duration, to recommended first-line treatment

The workup of the condition should include investigation of thyroid function, and according to symptoms investigation of the other autoimmune diseases.

Treatment of Hypopigmentation Skin Atrophy

The aims of the treatment are relief of the symptoms, stopping the atrophy, prevention of scar formation, and anatomical distortion, as well as malignant transformation. The therapy includes general care, topical treatments, systemic treatments, and surgical procedures. It is fundamental to inform the patient to avoid the use of irritating products such as soap and to prefer emollients to break the itch-stretch cycle.

For genital LS, the gold standard treatment is three months application of high potency topical steroids (clobetasol propionate). Second-line therapies include topical calcineurin inhibitors and imiquimod. In men, early circumcision may be recommended. Surgery is indicated only for the treatment of complications associated with lichen sclerosus. For extragenital LS, therapeutic modalities are limited and include phototherapy, ultrapotent topical steroids, tacrolimus ointment 0, 1%, and systemic steroids or methotrexate. Follow-up examinations must be kept indefinitely. [rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479569/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483306/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK557803/
• https://www.ncbi.nlm.nih.gov/books/NBK532271/
• https://www.ncbi.nlm.nih.gov/books/NBK76813/
• https://www.ncbi.nlm.nih.gov/books/NBK538246/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC475719/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1969198/
• https://en.wikipedia.org/wiki/Bartholin%27s_cyst
• https://en.wikipedia.org/wiki/Kraurosis_vulvae
• https://www.health.harvard.edu/a_to_z/bartholins-gland-cyst-a-to-z
• https://www.sciencedirect.com/topics/medicine-and-dentistry/vulva-kraurosis

Pathophysiology

The pathogenesis of Wells syndrome is obscure. Many triggering factors have been reported including insect bites, viral infections (parvovirus B19, herpes simplex virus, varicella zoster virus, mumps virus), parasitic infections[rx] (Ascaris, Toxocara canis, Giardia), bacterial or fungal infections, drugs (antibiotics, non-steroidal anti-inflammatory drugs, thiazide diuretics, anti-TNF, biomedicines) and vaccines. Association of Wells syndrome with other diseases has also been described such as hematologic malignancies (chronic myeloid leukemia,[rx] chronic lymphocytic leukemia, polycythemia vera, non-Hodgkin lymphoma), malignant tumors, ulcerative colitis,[rx] eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome),[rx] hypereosinophilic syndrome[rx]). Wells syndrome may be prior, revealing, or concomitant to these diseases. The fortuitous nature of some of these situations cannot be ruled out, but one must remain vigilant in case of prolonged evolution beyond 6 months, persistent eosinophilia and/or systemic manifestations associated with Wells syndrome.[rx]

The most interesting associations from a pathogenic point of view are certainly those belonging to the spectrum of eosinophilic diseases,[rx] such as Shulman syndrome, Churg-Strauss syndrome, and hypereosinophilic syndrome. Wells syndrome could be the first clinical manifestation of these diseases.[rx][rx][rx]

The physiopathogenic links between the triggering factors and the associations mentioned above are not clearly established. Inappropriate activation of a Th2-like T lymphocyte clone, synthesizing IL-5, and other eosinophil-stimulating cytokines in response to various, often unidentified, antigenic stimuli is the commonly accepted assumption.

Causes of Wells Syndrome

The pathogenesis of Wells syndrome is unknown. It may be explained as an inappropriate eosinophilic reaction to a wide variety of stimuli due to an abnormal function of eosinophil regulatory systems. Many triggering factors have been proposed: insect bites, drugs, allergic contact dermatitis, an underlying myeloproliferative disorder, and infections (e.g., dermatophytes, viruses, Toxocara canis).

Symptoms of Wells Syndrome

• Plaque type
• Annular granuloma-like
• Urticaria-like
• Papulovesicular
• Bullous
• Papulonodular
• Fixed drug eruption-like.

Diagnosis of Wells Syndrome

Histopathology

The histological images vary according to the progressive stage of the lesions. Initially, significant edema and a dermal infiltrate of eosinophils are seen. Some of the eosinophils are degranulated. The sub-acute stage is characterized by images called “flame-figures,” located in the mid to deep dermis. The flame-figures are composed of a central part consisting of collagen fibers and eosinophilic granules, surrounded by a histiocytic and eosinophilic infiltrate.[rx] Subsequently, eosinophils tend to disappear and are replaced by phagocytic granulomas, consisting of histiocytes and sometimes giant cells, around the flame figures. The absence of vasculitis is an important negative sign.

The flame-figures are not specific to Wells syndrome and can be observed in many other skin conditions in which degranulation of eosinophils occurs including prurigo, eczema, arthropod bite, scabies, bullous pemphigoid, pemphigus vegetans, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

The study in electron microscopy shows many eosinophils in degranulation, expressing signs of membrane cytolysis. Intact or fragmented free granules are seen in the dermis around the collagen fibers, thus forming the flame figures.[rx]

The diversity of clinical aspects of Wells syndrome is probably explained by the level of eosinophilic infiltrate, which may be dermic (superficial or deep), hypodermic thus giving an image of eosinophilic panniculitis,[rx] or even subcutaneous.[rx]

History and Physical

Wells described the first patient in 1971 as “recurrent granulomatous dermatitis with eosinophilia.” He later renamed the disease “eosinophilic cellulitis.”[rx] In 1979, Spiegel and Winkelmann proposed the eponym “Wells syndrome.”

Wells syndrome has a sudden onset. In the classic form, symptomatology is marked by large well limited inflammatory erythematous and edematous patches that are often covered with vesicles or bullae. The lesions are located preferentially on the trunk and the extremities. The eruption is preceded by sensations of itching or burning. General signs are rare. A low fever can be associated with the cutaneous symptoms. The evolution in the following days is marked by an extension of the patches, which take an annular configuration, with the center healing while the border becomes purple. Inflammatory signs regress within approximately 10 days while the plaques become indurated. Restitutio ad integrum usually occurs in 4 to 6 weeks. Recurrence is the rule, with variable locations. The period between recurrences varies from a few months to several years; however, the prognosis remains good with long-term recovery.

Evaluation

Biologically, the main element is peripheral blood eosinophilia which is found in about 50% of cases during the acute phase.

• Diagnosis is by complete blood count (CBC) – However, in some cases, a more accurate absolute eosinophil count may be needed.^[rx][rx]
• Specific test – for causative conditions are performed, often including chest x-ray, urinalysis, liver and kidney function tests, and serologic tests for parasitic and connective tissue diseases.
• The stool – is often examined for traces of parasites (i.e. eggs, larvae, etc.) though a negative test does not rule out parasitic infection; for example, trichinosis requires a muscle biopsy.^[rx]
• Elevated serum B₁₂ or low white blood cell  – alkaline phosphatase, or leukocytic abnormalities in a peripheral smear indicates a disorder of myeloproliferation.^[rx] In cases of idiopathic eosinophilia, the patient is followed for complications. A brief trial of corticosteroids can be diagnostic for allergic causes, as the eosinophilia should resolve with suppression of the immune over-response.^[rx]
• Marrow aspiration and biopsy – Neoplastic disorders are diagnosed through the usual methods, such as bone marrow aspiration and biopsy for the leukemias, MRI/CT to look for solid tumors, and tests for serum LDH and other tumor markers.^[rx]
• The evaluation for primary eosinophilia – should begin with screening peripheral blood for FIP1L1- PDGFRA gene fusion. Diagnostic testing should start with a peripheral smear. Cytogenetic testing and FISH analysis can be performed on peripheral blood as well.[rx][rx]
• Concurrent cytophilic or cytopenias – if present, can help for diagnosis. In that case, bone marrow biopsy, along with karyotype and genetic screen of chromosomes, may be required.[rx][rx]
• B12 level and tryptase level – along with cytogenetic/immunophenotypic testing and marrow findings, help diagnose chronic mastocytosis, acute/chronic myeloid leukemia, myelodysplastic syndrome, MDS/MPN overlap. When skin rashes are present, skin biopsy helps to diagnose cutaneous disorders like pemphigoid, eczema, mycosis fungoides, Sezary syndrome. Imaging of the chest helps diagnose aspergillosis, Loeffler syndrome, Churg Strauss syndrome. An ultrasound abdomen helps to evaluate for splenomegaly. Stool testing helps to assess for parasitic infections.

Treatment of Wells Syndrome

The treatment of Wells syndrome is not codified. Apart from the etiological treatment of a triggering or associated disease, corticosteroids and dapsone are the two main treatments for Wells syndrome.

[stextbox id=’custom’]

[/stextbox]

Therapeutic Agents

• Corticosteroids – It is the reference treatment for all reactional dermatoses whether neutrophilic or eosinophilic. General corticotherapy reduces the duration and importance of relapses in 10% of cases.[rx] Initial doses range from 0.5 to 1 mg/kg/day, with rapid tapering. During the decrease of the treatment, it is not uncommon to observe a relapse of the lesions, which can lead, in certain cases, to a real corticosteroid dependence. Local corticosteroids represent an interesting alternative to general corticosteroids, especially in superficial forms, with inconsistent results of the order of 50%.[rx] However, it should not be used in deep hypodermic or extended forms.
• Dapsone – Dapsone is an interesting therapeutic alternative to corticosteroids, with doses ranging from 50 to 200 mg daily. It would reduce the duration of relapses. The optimal duration of treatment is not clearly defined but can be several months in the absence of adverse effects requiring discontinuation of treatment. It can be used alone or in combination with other treatments, including corticosteroids. It can also serve as a relay for general corticosteroids, especially in cases of corticosteroid dependence.
• Antihistamines – Antihistamines, especially hydroxyzine if pruritus, is important and maybe tried as a first intention, because of their excellent tolerance even if their effectiveness does not seem to exceed 25% of the cases.[rx] They sometimes allow the practitioner to avoid the use of general steroid treatment. The dosage varies from 50 to 100 mg/day. Hydroxyzine can be combined with other antihistamines.
• Methotrexate and other treatments – These are all anecdotal, with their interest being reported in only a few clinical cases.[rx] Colchicine, PUVA (psoralen and ultraviolet A) therapy, interferon-alpha, cyclins [rx], synthetic antimalarials, ciclosporin, and anti-TNF agents can be mentioned.[rx]
• Typically treated – with oral or topical corticosteroids such as Prednisone. Other medications that may be used to treat this condition include antifungal drugs, antibiotics, immunosuppressants, and/or antihistamines (H1 receptor antagonists).^[rx][rx]
• Phototherapy – narrow band ultraviolet (UV) B preferred to broadband UVB, as well as psoralen plus UVA (PUVA), is often used as an adjuvant to the above therapeutic modalities.

Therapeutic Strategy

In most cases, general corticosteroids (10 to 80 mg daily) allow rapid healing. Tapering the dose over one month is generally well tolerated. Continued low-dose therapy with corticosteroids allows preventing recurrences. Dapsone may be prescribed as first-line treatment in low inflammatory forms. It also seems to give good results in case of corticosteroids resistance [rx]. IFN-alpha and IFN-beta could represent interesting alternatives.[rx][rx] For mild cases, topical corticosteroids may be sufficient. Finally, the treatment of an associated disease, when it is found, is essential. It must be prescribed as a first-line treatment and can cure Wells syndrome.[rx]

In aggressive forms of the disease, second-line cytotoxic agents and stem cell transplants have proven some benefit. Antibody use against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), and CD52 (alemtuzumab), as well as other targets on eosinophils, continues to be an active area of investigation.[rx][rx] Timely intervention is vital to reduce morbidity and mortality.

Treatment is directed toward the underlying cause.^[rx] However, in primary eosinophilia, or if the eosinophil count must be lowered, corticosteroids such as prednisone may be used. However, immune suppression, the mechanism of action of corticosteroids, can be fatal in patients with parasitosis.^[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK537169/
• https://www.ncbi.nlm.nih.gov/books/NBK470600/
• https://www.ncbi.nlm.nih.gov/books/NBK547729/
• https://www.ncbi.nlm.nih.gov/books/NBK560929/
• https://www.ncbi.nlm.nih.gov/books/NBK532294/
• https://www.ncbi.nlm.nih.gov/books/NBK459297/
• https://www.ncbi.nlm.nih.gov/books/NBK557524/
• https://www.ncbi.nlm.nih.gov/books/NBK557618/
• https://www.ncbi.nlm.nih.gov/books/NBK513313/
• https://www.ncbi.nlm.nih.gov/books/NBK534850/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746377/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095570/
• https://en.wikipedia.org/wiki/Eosinophilic_gastroenteritis
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708180/
• https://en.wikipedia.org/wiki/Tropical_eosinophilia
• https://rarediseases.info.nih.gov/diseases/329/wells-syndrome

Grazes/ Scrapes/An abrasion is a partial thickness wound caused by damage to the skin and can be superficial involving only the epidermis to deep, involving the deep dermis. Abrasions usually involve minimal bleeding.^[rx] Mild abrasions, also known as grazes or scrapes, do not scar or bleed because the dermis is left intact, but deep abrasions that disrupt the normal dermal structures may lead to the formation of scar tissue. A more traumatic abrasion that removes all layers of skin is called an avulsion.

Types of Abrasions

Abrasions are classified into three types:

• Linear or scratch abrasions – Linear abrasions are caused by tangential forces resulting in denuding of the epidermis. Linear abrasions are the simplest of injuries and tend to heal by primary intention, without any sequelae. Linear abrasions have significant medicolegal importance, especially when seen over the neck, inner thighs, and genitalia. Linear or semicircular injuries are classically seen as a result of nail scratches, and their presence on the inner aspect of thighs and around female genitalia may indicate resistance in cases of sexual assault. Likewise, nail scratch abrasions on the neck may be suggestive of throttling.
• Grazed or brush abrasions – Grazed abrasions are usually multiple in presentation and result from friction against a broad, rough surface. These are most commonly seen in cases of road traffic accidents as well as in sports falls. Grazed abrasions are caused by the dragging of the body against a rough surface, resulting in the scrapping of the epidermis. The depth of grazed injuries varies depending on the irregularity of the surface, as well as the speed tugging the body. Extensive, grazed abrasions are sometimes referred to as “brush burns.”
• Patterned abrasion – Patterned abrasions are a result of perpendicular force on the epidermis, resulting in an impression of the offending item. Patterned abrasions can be further sub-classified as pressure abrasion and impact abrasion, depending on the duration of contact with the offending object.
  • Pressure abrasions result from prolonged compression of the epidermis. The force required to produce pressure abrasion is, however, minimal. E.g., the use of rough material for hanging produces a ligature mark that is an imprint of the material used.[rx]
  • Impact abrasions result from a swift blow and require considerable force. Patterned abrasions resulting from blows, collisions, and run-over, etc. are examples of impact abrasions.

By degree

• A first-degree abrasion involves only epidermal injury.
• A second-degree abrasion involves the epidermis as well as the dermis and may bleed slightly.
• A third-degree abrasion involves damage to the subcutaneous layer and the skin and is often called an avulsion.

Pathophysiology

Abrasions range from a break in the epithelial lining to damage to the deeper structures, including nerves, blood vessels, muscles, tendons, organs, and even bone.[rx][rx]

Forensic investigations are necessary to determine the extent of the injury and the antemortem or postmortem nature of the wound. The presence of vital reactions, including hemorrhage, cell infiltration, granulation tissue, etc. are indicative of the antemortem quality of an abrasion.[rx]

Diagnosis of Grazes/ Scrapes

Hostory and Physical exam

Relevant history should be documented, including the time of injury, cause, and mechanism of injury, as well as other relevant details pertaining to the causation as well as management of the injury.

Abrasions are commonly associated with physical trauma; this could result from falls and impact against hard and uneven surfaces, as well as the pressure of impending objects. They are commonly seen along with other forms of blunt force trauma, such as contusions and lacerations.

While the physical examination of abrasions is important for treatment, the medicolegal examination of abrasions is considerably more significant. Abrasions could be present over any part of the body, frequently seen over the exposed parts of the body, especially the head and neck, as well as the extremities. When found over the neck or genitalia, they tend to have a particular significance that could be precarious, if wrongly interpreted.

The physical examination should include the type, size, shape, color, location, size, depth, association with other injuries as well as the presence of extraneous material. The scientific collection and evaluation of these extraneous materials can provide valuable information regarding the scene of a crime, and in linking the suspect to the crime.

The systematic management of the injury for medical and medicolegal purposes will ensure not just treatment of the injury but also help in providing justice to the victim. The medicolegal examination is especially important in injuries over the head and neck and around the genitalia. Injuries around the genitalia could be vital in identifying sexual violence, while minor injuries over the head and neck could be an indication of more serious underlying injuries.

Evaluation

Abrasions are usually simple in nature and frequently small in size. These abrasions usually heal by the first intention and do not leave any scarring. However, the involvement of large surface area can lead to healing by second intentions, resulting in scar formation. This is particularly seen in individuals susceptible to keloid hyperplasia and should be started on steroid therapy to prevent keloid formation.

The medicolegal investigation may require a biopsy of the abrasion for histological examination. The histological examination investigates the stage of wound healing to provide an estimate of time of injury. Wound healing involves a series of coordinated cellular changes that include bleeding and coagulation, inflammatory response, regeneration, and remodeling. The regeneration process further involves migration and proliferation, while remodeling involves extracellular matrix protein and collagen synthesis, as well as the formation of new parenchymal and connective tissue. These processes are four time-dependent phases:

• (i) bleeding and coagulation, begins immediately
• (ii) inflammation, also begins without delay;
• (iii) regeneration, begins in days and lasts for the primary part of the acute healing phase; and
• (iv) remodeling, begins weeks after the injury and can last for longer than a year.[rx][rx][rx]

The information may be further augmented by histochemical analysis of inflammatory cells and cell mediators. This may assist in informing the law enforcement about the time of occurrence of injury. A skin biopsy is relatively painless and can even be performed in the living if required. Histopathology of an injury can provide vital information for the investigation.[rx][rx][rx]

Infection of the injury is another concern and should be managed judiciously. At the same time, the emergence of antibiotic resistance in many organisms should ensure strict follow-up to evaluate compliance and adherence to the full protocol. Injuries should also be swabbed and sent for culture and sensitivity.

Treatment of Grazes/ Scrapes

Abrasions are usually simple, minor injuries that do not require much medical intervention. A sponsored study showed that wet healing, using polyurethane and hydrocolloid plasters, are found to be more efficient and effective in wound healing.[rx]

First aid for abrasions

An abrasion means that the surface layers of the skin (epidermis) has been broken. Thin-skinned bony areas (like knees, ankles and elbows) are more prone to abrasions than thicker, more padded areas. The scraped skin of abrasion can contain particles of dirt.

First aid treatment includes:

• Clean the wound with a non-fiber shedding material or sterile gauze, and use an antiseptic such as Betadine. If there is embedded dirt, Savlon may be used as it contains an antiseptic and a surfactant to help remove debris. Rinse the wound after five minutes with sterile saline or flowing tap water.
• Don’t scrub at embedded dirt, as this can traumatize the site even more.
• Cover the cleaned wound with an appropriate non-stick sterile dressing.
• Change the dressing according to the manufacturer’s instructions (some may be left in place for several days to a week). If you reapply antiseptic, wash it off after five minutes and then redress the wound.

The abrasion should be cleaned and any debris removed. A topical antibiotic (such as neomycin or bacitracin) should be applied to prevent infection and to keep the wound moist.^[rx] Dressing the wound is beneficial because it helps keep the wound from drying out, providing a moist environment conducive for healing.^[rx] If the abrasion is painful, a topical analgesic (such as lidocaine or benzocaine) can be applied, but for large abrasions. a systemic analgesic may be necessary.^[rx] Avoid exposing abraded skin to the sun as permanent hyperpigmentation can develop.

Due to the loss of the epidermis, the outermost layer of protection of the body, abrasions are particularly susceptible to Clostridium tetani and Staphylococcus aureus, particularly in sports injuries. Tetanus toxoid status should always be checked. Abrasions should be cleansed and dressed, protecting the area from reinjury. Debridement may be required, especially if dirt or other contaminants are found embedded. Prevention of infection is the primary objective of any medical intervention. Antibiotic ointments may be applied; after confirming the allergy history, a dressing may be necessary, depending on the area and depth of the injury. Systemic antibiotics may be indicated and should be judiciously prescribed.

Facial abrasions and considered more serious as these have a higher risk of cicatrization and should be cleaned, debrided, and dressed daily. Dressings may require skin adhesives like the combination of gum mastic, styrax, alcohol, and methyl salicylate or tincture of benzoin.[rx]

Cuts that require medical attention include the following signs:

• They are deep (doctors usually are more concerned with how deep a cut is rather than how long it is, because of the concern that deeper tissues like blood vessels, nerves, or tendons may be damaged)
• They expose any muscle tissue (red) or fat tissue (yellowish)
• They stay open if you let go of the sides of the cut
• They are on a joint or in an area where healing might be difficult (stitching might be needed to keep it closed)
• They remain visibly dirty after being cleaned.
• They continue to bleed longer than 10 minutes.

If no medical attention is needed, treat the cut in the following way:

• Cleanse the cut with tap water. You can also use a mild soap. This process helps remove any debris and bacteria from the cut. Avoid using cotton or wool to clean the cut because fibres may get into the wound and cause infection.
• You can use astringents, alcohol, and antiseptics (e.g., hydrogen peroxide) on the area surrounding the cut, but it is best to avoid using them directly on or in the cut, as they can disrupt the natural healing process.
• Dress the wound with an over-the-counter topical antibiotic to help prevent infection, if necessary.
• Cover the wound with a dressing (cloth bandage) that can help keep the cut moist. If you are not sure what type of dressing to use, ask your pharmacist for a recommendation.

Factors influencing wound repair

Traumatized skin heals at different rates, depending on individual and environmental factors, which include:

• the person’s general state of health
• age – older skin repairs itself at a slower rate than younger skin
• the functioning of the immune system
• dietary factors – skin needs proper nutrition
• external temperature and weather conditions
• stress on the injury site, such as friction
• whether or not the wound becomes infected
• smoking and some drugs (discuss with doctor or chemist)
• pre-existing medical conditions, such as some types of vascular disease.

References

Hirsutoid Papillomas/Pearly Penile Papules, also known as papillomatosis corona penis, corona capillitii, hirsuties coronae glandis, papillae coronis glands, and hirsutoid papillomas, are benign lesions of the penis.[rx][rx][rx]

Pearly penile papules (PPP) are painless and benign lesions that present in rows around the corona of the glans penis in late adolescence or early adulthood. Although asymptomatic, they are often mistaken for sexually transmitted infections such as condyloma acuminata

Hirsuties coronae glandis (also known as hirsutoid papillomas^[rx] and pearly penile papules; PPP)^[rx] are small protuberances that may form on the ridge of the glans of the human penis. They are a form of acral angiofibromas.^[rx] They are a normal anatomical variation in humans and are sometimes described as vestigial remnants of penile spines, sensitive features found in the same location in other primates. In species in which penile spines are expressed, as well as in humans who have them, the spines are thought to contribute to sexual pleasure and quicker orgasms.^[rx][rx] It has been theorized that pearly penile papules stimulate the female vagina during sexual intercourse.^[rx] In addition, pearly penile papules secrete oil that moistens the glans of the penis.^[rx]

Causes of Hirsutoid Papillomas

Pearly penile papules are considered normal anatomical variant.[rx][rx]

Penile papules are a normal anatomic variant. They are not due to sexual activity or lack of hygiene. They are not infectious or contagious, unlike genital warts. They are not malignant or pre-malignant.

The exact role of pearly penile papules is not clear to date. They might be vestigial of penile snipes, which are seen in primates and other mammals and may promote sexual pleasure.

Symptoms of Hirsutoid Papillomas

Pearly penile papules do not cause any other symptoms to develop with them.

Once a man has developed pearly penile papules, they typically remain for life. The growths can fade with age, but they do not tend to change shape, color, or spread further over time. Given the similarity in their appearance to some other conditions, such as genital warts, any men that experiencing other symptoms alongside the growths should seek medical attention.

Other conditions that resemble pearly penile papules include:

• genital warts
• Fordyce spots
• molluscum contagious

For example, growths that begin to itch or cause any discomfort may indicate the presence of an underlying condition that a doctor should examine.

Diagnosis of Hirsutoid Papillomas

History and Physical

Although pearly penile papules are usually asymptomatic, they are often mistaken by males who carry them for genital warts, thus causing concerns of having a sexually transmitted infection. This fear of infection may cause tense couple relationships, as it raises questions about fidelity within the couple. One study from Singapore showed that approximately one in seven men, who were examined in a sexually transmitted infection clinic, had only pearly penile papules and no infection.

The level of patient concern appears to be related to the size of the papules. According to a study, two-thirds of males with moderate-to-large pearly penile papules have concerns about their lesions, while one-third of those with less-noticeable papules are worried.

Evaluation

Penile pearly papules are flesh-colored or white, dome-shaped or filiform papules. Their size ranges from 1 mm to 4 mm. Pearly penile papules are arranged in rows around the corona of the glans penis, mainly on its dorsal aspect. There can be one row or many rows. The papules may encircle the entire glans and even have ectopic locations on the penile shaft.

The differential diagnosis includes genital warts, molluscum contagiosum, lichen nitidus, and sebaceous hyperplasia of the penis.

Genital warts are viral tumors induced by human papillomavirus. However, no viral particles are found in pearly penile papules. Nevertheless, the coexistence of both conditions may be observed, and genital warts might be seen in about 1% of males with pearly penile papules.

Molluscum contagiosum may be located on the penis as a sexually transmitted infection. However, these lesions have a larger size and are umbilicated in their center. They rarely have an exclusive location on the corona of the glans.

Lichen nitidus may be limited to the genital area. It manifests as small translucent papules that may involve the glans. However, lichen nitidus lesions are smaller and are usually not limited to the corona of the glans.

Sebaceous hyperplasia is usually seen on the face, but rare cases of the penile location were reported. Lesions usually occur on the ventral aspect of the penile shaft and are white to yellow papules.

In the case of diagnostic difficulty, dermoscopy and histopathology are helpful tools.

On dermoscopic examination, penile pearly papules are arranged according to a grape-like or a cobblestone pattern. They exhibit a white or pink color, with central comma-like, hairpin, or dotted vessels. Such a vascular pattern is not specific, as it may be observed in genital warts. However, pearly penile papules, unlike genital warts, do not show desquamation which manifests as an irregular reflection.

Histopathologically, pearly penile papules share the same features as angiofibroma. Microscopic examination shows an acanthotic epidermis, with elongated rete ridges, overlying dilated vessels located in the papillary dermis. There is usually a dermal proliferation of stellate fibroblasts and marked concentric fibrosis.

Treatment of Hirsutoid Papillomas

Because of the benign nature of pearly penile papules, as well as their possible resolution with age, treatment is not indicated. However, some patients feel distressed or have important cosmetic concerns. Furthermore, about half of males who are reassured of the benign nature of their pearly penile papules want to remove them. Some of them may use inappropriately over-the-counter topicals for common warts, which may cause injuries and scarring.

Pearly penile papules removal is based on physical treatments, namely, cryotherapy and laser therapy.

Studies having assessed cryotherapy are scarce. Two sessions of liquid nitrogen induced good cosmetic results with no pigmentation in a few patients.

• Ablative lasers and Carbon dioxide laser vaporization – leads to the complete removal of pearly penile papules. This procedure is painful and requires local anesthesia. The vascularization of the penis may cause bleeding during laser sessions but also makes the reepithelialization faster, so that wound healing is achieved within a week. Post-procedure wound management may be inconvenient for patients. Furthermore, there is a risk of scarring and/or pigmentary changes.
• Unlike continuous-wave and pulsed modes – fractionated carbon dioxide laser causes less tissue damage with fewer adverse effects, but it may require more than one treatment to achieve acceptable cosmetic results.
• One to six sessions of ablative 2940 nm erbium YAG laser – cleared pearly penile papules in 45 males. Wounds healed within two weeks. No recurrence, no scarring, and no residual pigmentation were noted at the one-year follow-up.
• Fractional nonablative 1550 nm erbium laser – is less painful than ablative devices and produces only microscopic skin damage which heals rapidly. Up to five treatment sessions were reported to be necessary to obtain a good cosmetic result. Pulsed dye laser may be indicated in pearly penile papules treatment, as it is reported to give good aesthetic results, with a few side effects after one to three sessions.
• CO₂ laser ablation – The high vascularity of penile tissue allows for rapid healing after laser-induced thermal injury, but this also predisposes the patient to bleed during the procedure. The continuous wave mode of the CO₂ laser provides better hemostasis and operative field visualization than the short pulse mode [rx]. Using the fractionated CO₂ laser, one group reported more than 90% resolution after a single treatment. Another group concluded that two to three treatments were sufficient to completely resolve lesions without adverse effects in both light and dark skin types. While the CO₂ laser exposes the underlying tissue, reepithelialization generally occurs within 5 to 7 days. Nevertheless, the procedure requires anesthesia and increases the risk of scarring and infection. Additionally, postoperative management, including home dressing changes, can be inconvenient to patients. The CO₂ laser can also lead to postinflammatory pigmentation changes in dark skin types. Despite this fact, two groups reported complete lesion resolution with no adverse pigmentary events.
• Using the ablative 2940-nm Er – YAG laser, Baumgartner treated 45 patients for one to six sessions. All lesions were successfully cleared with no adverse effects and no recurrence after 1 year. Notably, many of the patients in this study had prior failed treatment attempts with agents such as podophyllin, cryotherapy, and topical fluorouracil plus salicylic acid. Ablated areas healed within 2 weeks after treatment. Despite sustaining up to six laser sessions, no scarring or pigmentation changes were noted.
• Fractional resurfacing with the 1550-nm erbium laser – has shown complete clearance in one patient after five treatment sessions. Unlike ablative approaches, this laser was relatively painless and did not produce open wounds in the skin. Additionally, there was no lesion recurrence after 1 year

• https://www.ncbi.nlm.nih.gov/books/NBK482236/
• https://www.ncbi.nlm.nih.gov/books/NBK441886/
• https://www.ncbi.nlm.nih.gov/books/NBK499930/
• https://www.ncbi.nlm.nih.gov/books/NBK442028/
• https://www.ncbi.nlm.nih.gov/books/NBK535389/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602825/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445897/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458986/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987947/
• https://pubmed.ncbi.nlm.nih.gov/1574815/
• https://pubmed.ncbi.nlm.nih.gov/16763399/
• https://www.nhs.uk/conditions/penile-cancer/
• https://en.wikipedia.org/wiki/Penile_cancer
• https://en.wikipedia.org/wiki/Hirsuties_coronae_glandis
• https://www.cancer.org/cancer/penile-cancer/detection-diagnosis-staging/signs-symptoms.html