There are more than 100 genetic syndromes with cutaneous manifestations that are referred to as genodermatoses. There are disorders of: pigmentation (e.g., albinism), cornification (e.g., the ichthyoses and Darier disease), vascularization (e.g., Sturge-Weber syndrome), connective tissue (e.g., Ehlers-Danlos syndrome), metabolism (e.g., phenylketonuria), immune system (e.g., Wiskott-Aldrich syndrome), and DNA repair (e.g., xeroderma pigmentosa). Some textbooks are dedicated to the topic of genodermatoses alone.¹ This chapter introduces the topic and illustrates several genodermatoses. We will focus our discussion on Darier disease and pachyonychia congenita as an introduction to the genodermatoses.

Patient Story

A 12-year-old girl presents to her pediatrician with a scaling rash around her neck. A family history reveals that her mother, maternal grandmother, maternal aunt, and uncle all have Darier’s disease. Because this genodermatosis is inherited as an autosomal dominant trait, the pediatrician states that this is likely to be the onset of her Darier disease. The pediatrician prescribes a low potency steroid cream to help the occasional itching that occurs with this new rash. She suggests that the patient also see a local dermatologist. Years later, the young woman returns and her rash is much worse. Upon examination she had red greasy scale around the neck and over the anterior chest (Figures 169-1 to 169-3). The patient states that she was given the diagnosis of Darier disease by the dermatologist but was unable to get an appointment during this acute flare-up. She asked the pediatrician if she could prescribe some 0.1 percent triamcinolone cream because that is what has helped her in the past and she ran out of it 1 month ago. The pediatrician agrees to give her a prescription but encourages her to make an appointment with her dermatologist to see what else can be done. She also notes that the nails have the distinctive red-and-white striping seen in Darier disease (Figure 169-4).

Epidemiology

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  Darier disease, also known as keratosis follicularis, has been reported in approximately 1:30,000 to 1:100,000 people.

  
  
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  Males and females are equally affected as this occurs through autosomal dominant inheritance.

  
  
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  Clinically it becomes apparent near puberty.

Etiology and Pathophysiology

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  In Darier disease, a gene mutation in the ATP2A2 gene in chromosome 12q23-24.1 results in production of an abnormal calcium pump in the sarcoendoplasmic reticulum, SERCA2. How this mutation affects the way the cells interact together is still unknown, but it results in abnormal epidermal differentiation.² It is inherited in an autosomal-dominant fashion.

Diagnosis

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  Clinical features—Greasy, hyperkeratotic, yellowish-brown papules and plaques with scale in a seborrheic distribution (Figures 169-1 to 169-3). The feet can be covered with hyperkeratotic plaques. The palms may have pits or keratotic papules, and the nails can have V-shaped nicking and alternating longitudinal red and white bands (Figures 169-4 and 169-5). The keratotic papules can be intensely malodorous such that it can interfere with normal social situations (Figure 169-6).

  
  
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  Typical distribution—The clinical lesions involve skin in the seborrheic distribution (face, ears, scalp, upper chest, upper back, and groin; Figures 169-1 to 169-3 and 169-6). The axilla and inframammary areas may be involved (Figure 169-3). In early, mild, or partially treated disease, only the skin behind the ears may be affected.³ The nails are characteristically involved (Figures 169-4 and 169-5).

  
  
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  Laboratories—Skin biopsy reveals the characteristic histopathology. A test for the ATP2A2 gene mutation can be performed.

Differential Diagnosis

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  Hailey-Hailey disease (aka benign familial pemphigus)—Another genodermatosis with crusted erosions and flaccid vesicles distributed in the intertriginous areas as opposed to the greasy keratotic papules in the seborrheic distribution. A 4-mm punch biopsy is adequate to make this diagnosis.

  
  
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  Seborrheic dermatitis—Erythematous patches and thin plaques with yellow greasy scale on the scalp, central face, and chest. This is rarely as severe as Darier disease (see Chapter 135, Seborrheic Dermatitis).

Management

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  Darier disease is so rare that there are no randomized controlled trials to guide treatment.

  
  
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  Mild-to-moderate disease can be treated by avoiding exacerbating factors (sunlight, heat, and occlusion) and with topical medications, SOR C but severe disease is best treated with oral retinoids. SOR C

  
  
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  Frequent application of emollients, humectants, and keratolytics are the mainstay of therapy. SOR C There are many effective nonprescription and prescription products that contain propylene glycol, urea, or lactic acid. Ammonium lactate can be obtained in a 6 percent lotion OTC and can be prescribed in a 12 percent lotion.

  
  
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  Topical retinoids (adapalene, tretinoin, or tazarotene) are effective in some patients, but their main limitation is irritation. Adapalene use may be effective in localized variants.⁴ SOR C All retinoids are contraindicated in pregnancy.

  
  
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  Topical corticosteroids may be of some help. Lower-potency topical corticosteroids should be used on the face, groin, and axillae to minimize side effects in these areas. SOR C

  
  
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  Topical calcineurin inhibitors (pimecrolimus and tacrolimus) may also be helpful as noted in some case reports.^5,6 SOR C These do not have a risk of skin atrophy like steroids, but are generally more expensive and have the controversial black box warning related to the rare risk of skin malignancy and lymphoma.

  
  
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  Systemic retinoids (acitretin initial 10 to 20 mg/day or isotretinoin 0.5 to 1mg/kg/day) are the most potent treatment and treatment of choice for severe disease.² SOR C They should only be prescribed by physicians who have experience with these medications. Patients on systemic retinoids require close monitoring and careful selection, as they are teratogenic (category X) and can cause hyperlipidemia, hypertriglyceridemia, mucous membrane dryness, alopecia, hepatotoxicity, and possible mood disturbances. Females must not get pregnant for at least 1 month after stopping isotretinoin and at least 3 years after stopping acitretin.

  
  
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  Topical or oral antibiotics may be necessary for flares as they often are secondarily infected with bacteria. SOR C

  
  
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  Laser, radiation, photodynamic, and gene therapy are newer treatment modalities that are being investigated.

  
  
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  Refer to an urologist or ophthalmologist if testicular abnormality or corneal opacities are detected. SOR C

  
  
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  Gene therapy has also been studied but has not yet become a viable treatment option.

  
  
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  The malodor that accompanies the disease, as well as the facial involvement, often adversely affects the patient’s quality of life; thus, treatment is often warranted.