Phrynoderma

Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients may describe a prolonged history of poor dietary intake, or medical or surgical causes of poor nutrition, such as pancreatic insufficiency, previous small-bowel bypass surgery, and inflammatory bowel disease. Phrynoderma classically presents after a period of poor nutrition, such as following bariatric surgery, pancreatic insufficiency, or a strict diet avoiding vegetables, fruits, and fats. The initial presentation is hyperkeratotic follicular papules, first appearing as patches over the elbows and knees.

Characteristic findings on physical examination

On physical examination, patients frequently have patches on the knees and elbows measuring 5 cm or more in diameter, with dome-shapes papules consisting of slightly distended follicles with keratin plugs. Typically, lesions are non-tender but mildly pruritic. Lesional morphology may range from the classical presentation to flatter papules with very mild erythema at the base.

The disease preferentially affects extensor surfaces, but with time it can spread to the thighs, buttocks, trunk, and upper extremities, while sparing the face (Figure 1). Initial patches on the knees and elbows may be hypopigmented, but hypopigmentation is generally not present once the lesions have become generalized and extended proximally to the trunk.

Figure 1.

In the setting of an isolated vitamin A deficiency, patients may also have generalized xerosis of the skin and hair. The hyperkeratotic follicular papules rarely occur on the hands, feet, face or ears, which is often helpful in distinguishing this entity from other processes that present with hyperkeratotic papules.

Expected results of diagnostic studies

No pathognomonic histological feature of phrynoderma exists, and histological findings may vary with the age of the lesion. In general, hyperkeratosis is present with dilated hair follicles featuring keratin plugs (Figure 2, Figure 3). A sparse dermal inflammatory infiltrate may be present. No foreign bodies or microbial organisms have been reported to be associated with phrynoderma.

Work-up

In patients with suspected phrynoderma, start with a complete history and physical examination followed by laboratory investigations for vitamin and essential fatty acid deficiencies.

Patients may present at any age, and will typically have a poor nutritional appearance. Populations with an increased risk of phrynoderma include children living in poverty, patients with a history of alcoholism, and chronically ill patients.

The history should focus on surgical history, history or symptoms of diabetes, chronic pancreatitis, liver, and/or gallbladder disease, and overall diet and calorie intake over the past 1 to 2 years. For institutionalized or mentally handicapped patients, an investigation into eating habits as well as possible abuse should be considered.

Incisional or deep punch biopsies can be taken and submitted for hematoxylin and eosin staining as well as for bacterial and fungal cultures, although biopsy is not necessary for diagnosis.

Labs

Vitamin A and other vitamin levels may range from low to near-normal. In severe nutritional deficiency states, hypoalbuminemia may also be present. A complete blood count with differential may indicate a microcytic, normocytic, or macrocytic anemia depending on whether B12, iron, or other nutritional deficiencies are present. Because vitamin A stores may last for up to a year in adults, blood levels may not reflect the clinically apparent deficiency evidenced by complaints of night blindness and the appearance of classic skin lesions.

Imaging

No imaging is recommended.

Other

A multidisciplinary approach may be indicated in cases of severe malnutrition. Physicians should tailor referrals according to each patient’s indications, as the presentation of phrynoderma can range from primarily only skin symptoms to multi-system involvement.

Ophthalmologic examination is valuable in determining the extent of conjunctival (xerosis conjunctiva and Bitot’s spots) and corneal (xerosis corneae and keratomalacia) involvement, which can lead to permanent scarring if not treated.

For patients with no known cause of vitamin A deficiency, appropriate referrals for a malnutrition work-up may include an internist, a gastroenterologist, an endocrinologist, and, in the case of inadequate diet, a nutritionist or dietician.

Diagnosis confirmation

Clinically, phrynoderma can resemble a number of conditions presenting as hyperkeratotic papules, including (1) keratosis pilaris and (2) keratosis spinulosa (differentiated by history of onset, sites of involvement, and nutritional status); (3) keratosis follicularis (Darier-White disease) (differentiated clinically by history of onset, hand involvement, location on seborrheic areas such as forehead, scalp, nasolabial folds, ears, chest, and back, and histologically by the characteristic presence of epidermal suprabasalar clefts and focal acantholytic dyskeratosis); and (4) pityriasis rubra pilaris (PRP) (differentiated by physical exam findings, with PRP characteristically involving the face, palms, and soles [palmoplantar keratoderma]).

The diagnosis of phrynoderma is confirmed by the characteristic clinical morphology and histopathologic findings, a positive history of nutritional deficiency, and resolution of symptoms with nutritional supplementation.

Who is at Risk for Developing this Disease?

Although the prevalence of phrynoderma is unknown, it is rare in developed countries. One study on malnutrition in Singapore found no individuals with deficient vitamin A levels, but 0.1% of the randomly sampled individuals had vitamin E deficiency and low vitamin C levels.

Risk factors for the development of phrynoderma include causes of vitamin A deficiency and causes of general malnutrition that may lead to other nutritional deficiencies. Individuals on a diet devoid of vegetables, fruits, and fats are at risk for vitamin A deficiency. Susceptible populations in the United States include children living in poverty, the elderly, alcoholics, and the chronically ill. Epidemiological data does not support a gender predilection for phrynoderma.

What is the Cause of the Disease?

Etiology

Phrynoderma is generally accepted as a consequence of malnutrition, but the exact nutritional deficiency is debated. It has been difficult to prove an exclusive causal relationship between vitamin A deficiency and phrynoderma because patients often present with general malnutrition and their skin symptoms resolve with overall nutritional supplementation.

Pathophysiology

Vitamin A exists in three main forms: retinolds, beta carotenes, and carotenoids. Retinol is the most active form, and is found in animal sources of food, particularly liver. Beta carotene is the plant source of retinol. Carotenoids are the most abundant form of vitamin A, which are almost exclusively found in fruits and vegetables.

Vitamin A deficiency may be caused by increased body requirements, altered metabolism, decreased ingestion, and defective absorption. Malabsorptive conditions that can lead to hypovitaminosis A include pancreatic insufficiency, celiac sprue, cholestasis, inflammatory bowel disease, and bariatric surgery. Biological processes that require vitamin A: vision, bone growth, reproduction, maintenance of the surface linings of the eyes, immune response, and epithelial cell growth and repair.

Transfer of vitamin A from liver stores to other parts of the body requires a binding protein, which relies on adequate levels of zinc for production. Therefore, zinc deficiency can lead to a vitamin A deficient state. In addition, alcoholism can lead to vitamin A deficiency, because ethanol impedes the liver’s metabolism of vitamin A. In adults, liver stores of vitamin A may last up to one year. In children, vitamin A stores may only last a few weeks.

History

Historically, phrynoderma was most common among groups of laborers in Southeast Asia and sub-Saharan Africa who were kept on strict maize diets. The term phrynoderma means toad skin, and was coined in an article published in 1933 by Nicholls. Nicholls described laborers in East Africa who arrived in good health, but after a period of time become emaciated, with “toad-like” skin, and complaining of poor eyesight in the dark. Upon receiving nutritional supplementation, the workers’ skin cleared and their eyesight improved.

Loewenthal, also writing in 1933, documented patients in Uganda who presented with similar findings. Complete resolution of skin and ocular symptoms occurred with daily consumption of cod oil, which contains a substantial amount of vitamin A. Both Nicholls’ and Loewenthal’s early reports are likely the reason phrynoderma’s etiology was believed to be solely vitamin A deficiency. However, during the late 1960s and 1970s, researchers linked deficiencies in B complex vitamins, vitamin E, vitamin C, and essential fatty acids to phrynoderma.

In the past 20 years, all cases of phrynoderma reported from around the world had been associated with a malabsorptive state or malnutrition. The major evidence in favor of a direct link between vitamin A deficiency and phrynoderma are anecdotal case reports citing deficient levels of vitamin A in patients with phrynoderma and poor vision in the dark, with complete resolution of symptoms after 1-4 months of daily vitamin A supplementation.

Systemic Implications and Complications

Ophthalmologic involvement poses the greatest threat to phrynoderma patients who are deficient in vitamin A. Referring patients for an ophthalmologic examination before and after treatment is recommended to determine if there are signs of permanent conjunctiva or corneal scarring. In addition, for patients with malnutrition caused by a specific diet (ie, vegan or weight-loss dieting), an intervention by a nutritionist or dietician may be valuable.

Treatment Options

Treatment options are summarized in Table I.