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Diagnosing Rare But Deadly Skin Diseases

July 8, 2025

Your skin is the body’s largest organ and provides many unique functions to protect itself. For starters, it keeps out common causes of skin disease like bacteria or viruses. Plus, it plays a major role in retaining fluids to prevent dehydration and to help stabilize body temperature. In fact, your skin even creates vitamin D after exposure to UVB sunlight by converting it to vitamin D3, which is the active form absorbed into the bloodstream. That means it is important to get some sun but it is also critical to protect your skin from overexposure that could potentially lead to dangerous skin damage.

“Diagnosing those rarely seen but potentially deadly skin diseases requires a multi-faceted approach that goes beyond visual inspection,” says Michael Steppie, Orlando Mohs surgeon and medical director of Associates in Dermatology. “It incorporates dermatopathology that focuses on examining tissue samples affecting the skin, hair and nails as well as the broader field of histopathology for identifying changes in tissues associated with organs, the brain, and connective tissues like tendons. To pinpoint the exact condition for an accurate diagnosis, it may require a skin biopsy analysis, specialized immunofluorescence or genetic testing to determine the most appropriate treatment plan.”

Early diagnosis is crucial for the effective management of potentially deadly skin diseases as it identifies treatment options and protocols that can help manage severe complications and extend life expectancy. A thorough physical examination is the first step, which includes assessing the appearance, distribution, and extent of skin lesions, as well as any associated symptoms like fever, pain, tissue swelling, or systemic illness. Skin biopsies usually rule out conditions but a high index of suspicion may lead to specialized testing like immunofluorescence or precision imaging to identify organ involvement.

How routine skin disease starts...

Skin pores are the tiny openings in your skin that serve as an important pathway for sebum, the body’s oil that keeps it soft and supple. Sweat is normally released through pores to help regulate body temperature, especially when the temperature is hot or during physical activity. While some pores are visible to the naked eye, most are not. But, except for the palms of the hands and soles of the feet, millions of pores are distributed over the entire body. These follicle openings can easily become blocked by a mix of sebum, dead skin cells and hair that may cause clogging of the pores. In addition to infections and UV exposure, conditions that impact key organs, touching another person’s skin, or your own immune system and environmental triggers are common causes of skin disease.

Complex & Potentially Deadly Skin Conditions

Several rare but complex skin conditions can be very dangerous to a patient’s long-term health due to the lack of an early diagnosis. A combination of clinical evaluation, histopathological analysis, and specialized or genetic testing may be necessary to accurately diagnose complex, deadly skin disorders. Such conditions often require collaboration with other specialists, such as a rheumatologist, but it depends on the suspected cause or systemic conditions. Internal organs, autoimmune diseases, certain cancers, and even allergic responses can trigger skin problems, such as:

Merkel Cell Carcinoma (MCC) – This is a rare and aggressive skin cancer that originates from specialized cells in the skin's outer layer, known as Merkel cells. Recent research suggests MCC may arise from other mutated cells that mimic Merkel cells. This cancer is characterized by its rapid growth and high likelihood of spreading to lymph nodes or other parts of the body, making early detection critical. It usually appears as a painless, firm nodule on sun-exposed areas of the body, such as the head, neck, arms, or legs. Although uncommon, incidences may be growing due to aging population. It was the fatal cancer that killed Margaritaville billionaire Jimmy Buffet.
Acral Lentiginous Melanoma (ALM) – ALM is a rare yet serious subtype of melanoma that develops on the non-hair-bearing areas of the body, notably the palms, soles and under the nails. Reggae pioneer Bob Marley had a specific form of the subungual melanoma that originates under the fingernails or toenails and presents as a dark streak running vertically along the nail. Marley had confused this sign as a result of a previous soccer injury. Unique among melanomas, ALM is not caused by UV radiation and unrelated to sun exposure. This skin disease is difficult to detect and more common in individuals with darker skin tones or those of Asian descent.
Toxic Epidermal Necrolysis (TEN) – This is a rare but life-threatening condition that is often caused by a severe reaction to certain medications. It is characterized by widespread blistering and peeling of the skin, similar to severe burns, and can affect more than 30% of the body. Flu-like symptoms such as fever, cough, and malaise often appear before the skin damage and it has the potential to involve the mucous membranes of the mouth, eyes, and genital or urinary tract that can cause significant pain, difficulty swallowing, and other complications. Due to its severity, TEN is a medical emergency that usually requires hospitalization in a burn center or intensive care unit.
Pemphigus – Pemphigus is a group of rare autoimmune disorders in which the body's immune system mistakenly attacks the proteins that bind skin cells together. This leads to fragile blisters and painful sores that cause life-threatening skin rashes and affects mucous membranes, including the mouth, nose, throat, genitals, or eyes. Pemphigus foliaceus is limited to the skin, often causing itchy or painful blisters on the scalp, face, chest, or upper back. Though not contagious, pemphigus is a serious condition that requires early diagnosis and treatment to prevent complications and potential fatality. With proper care, patients can improve their quality of life.
Necrotizing Fasciitis – Necrotizing fasciitis, often referred to as flesh-eating disease, is a rare but life-threatening bacterial infection that rapidly destroys soft tissues, including skin, muscles, and connective tissues. The bacteria typically enters the body through cuts, scrapes, burns, or insect bites, causing an infection that can progress rapidly, sometimes leading to tissue death (necrosis) within hours. Early symptoms include severe pain that feels disproportionate to the size or severity of the wound, along with redness and swelling. Individuals with chronic health conditions, such as diabetes, are at a higher risk of developing necrotizing fasciitis.
Nodular Melanoma – Nodular melanoma is the most aggressive form of melanoma and the second most common subtype. Originating in melanocytes, it grows rapidly in thickness rather than expanding outward in diameter. Unlike many skin cancers, it does not develop from pre-existing moles. This type of melanoma is particularly dangerous due to its rapid vertical growth, quickly penetrating deeper layers of skin and metastasizing to lymph nodes or distant organs if not detected early. The primary risk factor for nodular melanoma is prolonged overexposure to ultraviolet (UV) light, often through sunburns. Prompt medical attention is vital.
Undifferentiated Pleomorphic Sarcoma (UPS) – Undifferentiated refers to the cancer cells not maturing into a specific type, making it difficult to pinpoint their origin under a microscope. The pleomorphic descriptor signifies the varied shapes and sizes of the tumor cells. Linked to UV exposure or radiation therapy, UPS is now recognized as a distinct type of high-grade sarcoma, known for its rapid growth and ability to spread aggressively, primarily to the lungs. It is an aggressive form of soft tissue sarcoma that primarily affects adults over 50 and develops in connective tissues including limbs, trunk and the area behind the abdominal organs.
Scleroderma – Scleroderma is a complex autoimmune condition that primarily affects the skin but can also impact connective tissues and internal organs. The name translates to “hard skin,” which refers to the hallmark symptom of thickened and tightened skin caused by excess collagen production. Systemic sclerosis is a type that extends beyond skin to include blood vessels, connective tissues, and major organs like the lungs, heart and kidneys. Scleroderma symptoms can vary greatly from person to person and there are currently no cures but lifestyle adjustments, occupational therapy and medications help manage symptoms and slow progression.
Kaposi’s Sarcoma – This is a type of cancer that can manifest as a skin disease. It originates in the cells lining blood or lymph vessels. The first visible signs of the disease commonly appears as purplish, reddish, or brownish patches or bumps on the skin. These lesions can range in size and may be flat patches, slightly raised plaques, or form nodules. While skin lesions are most typical, KS can also affect the mucous membranes, lymph nodes, lungs, and digestive tract, especially in patients living with HIV/AIDS or those taking immunosuppressive drugs after organ transplants. Fortunately, KS is now highly treatable with a five-year survival rate of 72%.
Cerebrotendinous Xanthomatosis (CTX) – CTX is a rare genetic disorder that disrupts the body’s ability to metabolize certain fats, particularly cholesterol. This condition is caused by mutations in the CYP27A1 gene, which is responsible for producing an enzyme required to convert cholesterol into bile acids. Without enough of this enzyme, its byproduct accumulates abnormally in tissues such as the brain and tendons, resulting in progressive damage. If left untreated, CTX leads to worsening symptoms and substantially reduces life expectancy, with cases of death reported as early as infancy.

Diagnosis of a Rare Metabolic Skin Disorder

CTX is a rare genetic disorder that disrupts the body's ability to convert cholesterol into bile acids. As a result, cholesterol and related substances build up in various parts of the body including yellowish skin deposits as well as in the brain, tendons and eyes. This accumulation can lead to symptoms such as neurological issues, cataracts, and fatty deposits known as tendon xanthomas. Caused by mutations in the CYP27A1 gene, it is extremely rare and often found in specific populations. Although there's no cure for CTX, early diagnosis and treatment can slow disease progression and manage symptoms, such as:

Early Symptoms: Chronic diarrhea, especially in infancy, and a much earlier onset of clouding of the eye lens or childhood cataracts are common.
Cholestatic Jaundice: Yellowing of the skin or whites of the eyes caused by impaired bile flow, but this is not a universal symptom for everyone.
Tendon Xanthomas: Fatty deposits in tendons (e.g., Achilles tendon) are hallmark signs appearing in adolescence or young adulthood.
Neurological Issues: Cognitive impairment, loss of coordination, seizures, movement disorders, and neurological problems can develop over time.

Visible signs of CTX includes xanthomas, which are fatty growths most often found on the Achilles tendons, elbows or hands. Neurological complications, such as seizures, movement disorders and even progressively worsening symptoms, may also develop over time. Eye issues, like childhood cataracts, are another hallmark of the condition. However, the range of symptoms can vary significantly from person to person and even within the same family. While CTX is incredibly rare, early diagnosis and proper treatment can make a world of difference by greatly improving the quality of life for those living with the disease.

So how rare is CTX...

Classified as a rare disease, its true prevalence is likely underestimated due to significant underdiagnosis. Older studies once estimated a prevalence of 3 to 5 per 100,000 in European-descended populations in the United States. However, newer figures suggest a range of 1 in 72,000 to 1 in 150,000 Americans, meaning as many as 8,400 individuals might be affected. Unfortunately, less than a hundred cases were originally documented in the United States, underscoring just how often CTX goes misdiagnosed or undiagnosed altogether. Variance in symptoms, potential misdiagnoses, and delayed detection contribute significantly to the disparity between observed and actual cases.

Discovery Channel "Mystery Diagnosis" CTX Video - Michael Steppie, M.D.

“The Girl Who Was Covered in Bumps”

During his residency at a New Orleans Dermatology Clinic, Dr. Michael Steppie’s work with a 27-year old patient named Tina Ancar, her sister, and her cousin led to an amazing family diagnosis of CTX that was later shown as a documentary on The Discovery Channel’s Mystery Diagnosis show. At that time, there were only around a hundred diagnosed cases worldwide of the baffling genetic disease called Cerebrotendinous Xanthomatosis. Even though Tina was indeed a sufferer of the rare disease, the young mother was most concerned as to whether this baffling CTX disorder might affect her 6-year old daughter.

Tina and her family members had presented the nodular cyst-like formations on their ankles and elbows to area doctors, but no one had been able to diagnose this very rare disease. After Dr. Steppie contacted several universities, CTX symptoms appeared on his radar. According to Chromatography Today, the latest urine gas chromatography techniques were used on the samples submitted for testing, which confirmed the diagnosis of CTX. Working with Dr. Gerald Salen, a New Jersey clinician whose cholesterol studies included CTX, Dr. Steppie was able to help the Ancar family qualify for an experimental drug trial using Chenodeoxycholic Acid.

Twenty years ago, the drug was not even available in the U.S. but thanks to Dr. Galen trial dosages were obtained from a German pharmaceutical company. Three months after everyone were in their treatment program, Dr. Steppie repeated EEGs and MRIs and saw significant improvement in brain functions. In addition, the skin nodules had stopped growing. Unfortunately after leaving residency to continue his medical education, Hurricane Katrina changed everything in New Orleans and medications stopped. Although still out of state, Dr. Steppie tracked down his former patients, re-examined and helped them continue their CTX drug trial.

Today, others can still have the disease and not even know it. An estimated 10,000 to 20,000 people may have CTX but are undiagnosed or misdiagnosed. Fortunately this year on February 21, 2025, the FDA approved the brand name Ctexil (chenodiol) specifically for the treatment of CTX in adults. Making it the first FDA-approved medication for treating the rare lipid-storage disease. Although chenodiol was earlier approved for treatment of gallstones, more recent clinical trial data demonstrated that the drug significantly reduced plasma cholesterol levels associated with CTX.

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At Associates in Dermatology, our professional staff can accurately diagnose your skin condition and will recommend the most appropriate treatment plan to ensure optimal skin health. Call 800-827-7546 today or schedule your appointment online at one of our sixteen Central Florida offices in Orlando, Altamonte Springs, Apopka, Celebration, Clermont, Davenport, Dr. Philips, Hunter's Creek, Kissimmee, Mount Dora, Ocoee, Poinciana, Sanford, or St. Cloud for effective treatment options.

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