Phrynoderma [other manifestations of vitamin A deficiency]
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 (
Multiple follicular papules with keratotic plugging on the forearm. Archives of Dermatology, 144 (11):1509-1514. Copyright © (2008) American Medical Association. All rights reserved.
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 (
Distention of the upper follicular ostia with prominent keratotic plugging (H&E, X4).
Distended follicle with keratotic plugging and overlying parakeratosis (H&E, X10).
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.
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.
No imaging is recommended.
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.
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?
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.
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.
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 are summarized in
Treatment options for phyrnoderma
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Systemic||Not indicated||Not indicated|
|50,000-150,000IU oral vitamin A daily until skin resolution, then 5,000 IU daily-monitor vitamin A level|
|Supplemental protein and calorie intake|
|Topical (keratolytic agents)|
|2-5%sulfur and 2-5% salicylic acid in an emulsifying base applied twice daily|
|Topical application of 0.1% tretinoin in a gel or cream base applied to the affected area daily|
|Urea 10-30% applied to the affected sites daily|
Optimal Therapeutic Approach for this Disease
For cases of isolated vitamin A deficiency, treat with daily high-dose oral vitamin A, consisting of between 50,000-150,000 international units, until resolution of ocular and skin symptoms. Ocular disturbances typically resolve within days of starting therapy, although corneal scarring is permanent. Skin lesions can take 1 to 4 months to resolve.Once all symptoms have resolved, patients should be kept on 5000 units of daily vitamin A supplementation. Vitamin A levels should be assessed periodically to monitor for vitamin A deficiency and excess.
Patients with generalized malnourishment require overall nutritional supplementation. This should be tailored for each patient by a nutritionist or dietician.
Temporary relief of the papules has been reported with topical keratolytics, such as a combination of 2-5% sulfur and 2-5% salicylic acid in an emulsifying base, applied twice daily to the affected areas. In addition, topical application of 0.1% tretinoin in a gel or cream base and/or urea 10-30% may yield good results. It is important to note that while these palliative treatments provide some symptomatic relief, definitive treatment requires restoration of nutrition.
In patients who have a very mild presentation of hyperkeratotic papules on the knees and/or elbows and no eyesight disturbances, increased dietary consumption of vitamin A rich foods, such as liver, carrot, egg yolk, and spinach, may alleviate skin involvement. These patients must be encouraged to supplement with oral vitamin A if symptoms are not resolved with dietary changes alone.
At this time there is no role for surgical or physical approaches to the treatment of phrynoderma.
Explain to patients the importance of compliance with vitamin A supplementation before beginning therapy. Prolonged supplementation may be necessary to ensure nutritional status is maintained and vitamin A stores are replenished. Complete resolution of skin lesions may take up to four months, while night vision is usually restored within days of beginning therapy. Patients with a history of poor dietary intake will likely benefit from an educational intervention by a nutritionist or dietician.
Encourage patients to persist with treatment. Mentally handicapped patients may require more frequent follow-up and may warrant treatment with directly observed therapy (DOT) if there is any concern for noncompliance or abuse.
While some cases have been reported as refractory to nutritional supplementation, complete recovery is most common when nutritional deficiencies were identified and corrected. Inadequately treated disease may result in relapse of lesions or persistent hyperkeratotic papules and/or complications secondary to ophthalmologic involvement. The prognosis of phrynoderma is excellent with appropriate treatment.
Unusual Clinical Scenarios to Consider in Patient Management
In patients with no history of an identifiable etiology for nutritional deficiency; ie. no history of dieting and no medical or surgical causes, it is suggested that patients be referred for evaluation by an internist or gastroenterologist. Appropriate screening may require checking pancreatic enzymes, stool fat content, gallbladder studies, and hepatic function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], conjugated and unconjugated bilirubin, albumin, total protein, gamma glutamyl transpeptidase [GGT], prothrombin time [PT], lactate dehydrogenase [LDH], Hepatitis A, B, and C). If these tests are all within normal limits, and there is no surgical history, a more detailed assessment of the patient’s diet may reveal the cause.
What is the Evidence?
Armstrong, AW, Setvadi, HG, Liu, V, Strasswimmer, J. "Follicular eruption on arms and legs. Phrynoderma". Arch Dermatol. vol. 144. 2008. pp. 1509-14.(This case report offers the classic clinical picture of phrynoderma appearing in the setting of decreased vitamin A consumption. The patient was treated with daily vitamin A supplementation for two months and achieved complete resolution of skin and ocular symptoms.)
Bleasel, NR, Stapleton, KM, Lee, MS, Sullivan, J. "Vitamin A deficiency phrynoderma: due to malabsorption and inadequate diet". J Am Acad Dermatol. vol. 41. 1999. pp. 322-4.(This is an excellent case report and discussion of the clinical presentation and management of phrynoderma.)
Chia, MW, Tay, YK, Liu, TT. "Phrynoderma: a forgotten entity in a developed country". Singapore Med J. vol. 49. 2008. pp. e160-2.(This article describes a nursing home resident who developed phrynoderma secondary to inadequate caloric intake. The authors emphasize at-risk populations in developed countries and the importance of including phrynoderma in the differential diagnosis in the setting of follicular keratosis and malnourishment.)
Di Stefani, A, Orlandi, A, Chimenit, S, Bianchi, L. "Phrynoderma: a cutaneous sign of an inadequate diet". CMAJ. vol. 177. 2007. pp. 855-6.(This article describes a case involving extreme dieting as the cause of nutritional deficiency leading to phrynoderma.)
Maronn, M, Allen, DM, Esterly, NB. "Phrynoderma: a manifestation of vitamin A deficiency?...The rest of the story". Pediatr Dermatol. vol. 22. 2005. pp. 60-3.(In this excellent case report, Maronn et al describe a malnourished 14-month old with phrynoderma who had no identifiable vitamin or essential fatty acid deficiency. The authors detail the evidence in favor of a combination of phrynoderma etiologies including vitamin E, B complex vitamins, and essential fatty acids. They emphasize that clinicians should assess a complete profile of cell markers of nutritional status, in addition to vitamin A, in patients presenting with symptoms consistent with phrynoderma in the setting of malnourishment.)
Nakjang, Y, Yuttanavivat, T. "Phrynoderma: a review of 105 cases". J Dermatol. vol. 15. 1988. pp. 531-4.(This is the largest case series review published in the English language to date. It describes the histological findings of more than 100 cases of suspected phrynoderma, and offers evidence for histological differentiation from other follicular keratoses.)
Pettit, J. H. "“Phrynoderma.”". Int J Dermatol. vol. 22. 1983. pp. 117-9.(This manuscript is one of the most complete descriptions of phrynoderma published in English. It includes sections on the historical context, clinical variation, differential diagnosis, and etiologic debate that had taken place in the literature up to the year 1983.)
Copyright © 2017, 2012 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
Sign Up for Free e-newsletters
Regimen and Drug Listings
GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION
|Head and Neck Cancer||Regimens||Drugs|
|Renal Cell Carcinoma||Regimens||Drugs|
Cancer Therapy Advisor Articles
- Pancreatitis and the Risk of Cancer
- RAMIE May Improve Post-operative Outcomes Among Patients With Esophageal Cancer
- Hyperthermic Intraperitoneal Chemotherapy With Cytoreductive Surgery Prolongs OS in Gastric Cancer
- Renal Cell Carcinoma: Cost of Treatment May Negate Impact of Treatment Advances
- Pembrolizumab May Be Effective for Previously Treated Hepatocellular Carcinoma
- CTC Screening May Be Effective Method for Preventing Colorectal Cancer
- Physical Activity Intervention May Improve Functional Well-being Among CRC Survivors
- Atezolizumab With Cobimetinib Yields Partial Response in Small Number of Patients With CRC
- Nivolumab May Improve Long-term Complete Response Rate in Subset of Patients With mCRC
- Alcohol Consumption and Cancer