August 2014 CME/CE
August 2014 CME/CE
By Christopher Chu and Adam Rees, MD
A 45-year-old male presented for evaluation with a complaint of scaly skin since childhood. Physical exam revealed superficial scaling of his trunk and extremities that had spared the antecubital and popliteal fossae.
His palms and soles were mildly scaly. In the winter months, the man develops eczema and is significantly itchy. When the man was a child, he received a diagnosis of atopic dermatitis from a dermatologist. Two of the man’s 4 sisters and 1 of his 3 brothers have the same condition, as do his father and paternal grandmother.
A 10-year-old boy presenting with his mother had a complaint of scaly skin that had been present since he was an infant. One of the boy’s brothers as well as his maternal grandfather and his maternal uncle have the same condition.
At school the child was being teased and called “dirty” because the scale on the skin of his neck made him appear unwashed. His medical history was unremarkable. His birth history was significant for a delivery complicated by failure of labor to progress, requiring his mother to undergo a Cesarean section.
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Ichthyosis vulgaris (IV) is a common inherited autosomal-dominant disorder of the skin characterized by xerosis (dry skin), with an estimated prevalence of 1 in 250.1,2IV is caused by a loss-of-function mutation in the filaggrin gene.3
Due to incomplete penetrance in heterozygotes, patients within the same family with heterozygous and homozygous filaggrin mutations can present with mild ichthyosis and severe ichthyosis, respectively.1,2Epidemiologically, filaggrin mutations are observed in approximately 7.7% of Europeans and 3.0% of Asians, but are rare in darker-skinned populations.3
The pathogenesis of IV is linked to a decrease in the size and number or a complete absence of epidermal keratohyaline granules found in the granular layer of the epidermis.4The mutated filaggrin gene in IV normally codes for profilaggrin, the protein found in the keratohyalin granules.1
During keratinocyte differentiation, profilaggrin is cleaved into filaggrin, which facilitates aggregation of keratin intermediate filaments. The intermediate filament-filaggrin complexes are cross-linked with the cells of the stratum corneum, resulting in the formation of compact squamous cells.1,4
Because filaggrin is used in the formation of the stratum corneum, deficiency leads to impaired squamous cell formation and an increased propensity toward inflammatory responses upon exposure to allergens and haptens. This propensity may explain the association between IV and atopic dermatitis.1,2
Filaggrin is eventually degraded into water-retaining amino acids that serve as a natural moisturizer. Decreased filaggrin, therefore, leads to decreased skin hydration and increased transepidermal water loss, which in turn results in the xerotic skin seen in IV.3,5
IV is not evident at birth. Typically, the dry skin and mild-to-moderate scaling appear during infancy, between ages 3 months and 12 months.2,3The dry skin progresses during childhood but eventually improves with age.1
Clinically, IV is characterized by xerosis, hyperkeratosis (thickening of the stratum corneum), excess scaling, keratosis pilaris, palmar and plantar hyperlinearity (exaggerated skin markings), and a strong association with atopic disorders.6
Fine, white, flaky scales appear “pasted on” over the entire body.2,3The axillary folds, gluteal folds, inguinal folds, and other flexural areas such as the antecubital and popliteal fossae are spared because of increased hydration in those regions.2However, atopic dermatitis associated with IV may present with confounding lesions within flexural areas.2,3
The lower extremities, especially the extensor surfaces, present with the coarsest and largest scales, with an adherent center with detached, outward-turning edges.2The scalp is usually involved, with only light scaling. In more severe cases, however, scaling can occur anywhere, including the trunk, scalp, forehead, and cheeks.2
Mild hyperkeratosis of the palms and soles lead to palmar and plantar hyperlinearity.2More severe palmoplantar involvement may also result in painful fissures of the hands, fingers, and heels (chapping). In one study, chapping was found in 76% of British schoolchildren with IV.3
The presence of pruritus is dependent on the season and climate; pruritus improves during the summer due to the higher humidity, and worsens in dry and cold environments.1
IV is associated with atopic disorders and keratosis pilaris. Atopic associations manifest as hay fever, eczema, asthma, or urticarial lesions.1Atopic dermatitis, found in 25% to 50% of patients with IV, can involve the flexural areas and therefore confound the diagnosis of IV.2
Keratosis pilaris, defined by keratotic elevations around hair follicle orifices, is also often present in patients with IV.3
On histology, persons with IV have mild eosinophilic orthokeratotic hyperkeratosis (thickening of the stratum corneum with non-nucleated cells present)2Many patients have diminished granular layers, and up to 50% have no detectable granular layer.4
On electron microscopy, keratohyalin granules in the granular layer appear spongy or fragmented, or may be completely absent.2,4Perinuclear keratin retractions are visible in granular cells under electron microscopy, most likely because filaggrin mutations result in aberrant keratin intermediate filament organization, which leads to cytoskeletal abnormalities.5
The spinous layer is of normal thickness. Immunohistochemistry shows reduced or absent filaggrin staining in involved epidermis.3
The differential diagnosis of IV changes depending on the severity of the disease. Xerosis and mild IV may be difficult to distinguish, and both can be associated with atopic dermatitis.1X-linked ichthyosis can be differentiated from IV both by the clinical presentation and the history:
Patients with X-linked ichthyosis present with larger, darker scales, and unlike in IV, there is involvement of the neck and other flexural areas.7,8In X-linked ichthyosis, the patient will have a maternal history of delayed or prolonged labor and an estimated 20% of children will have associated cryptorchidism.1,2Molecular tests such as fluorescence in situ hybridization (FISH) can exclude the steroid sulfatase deficiency seen in X-linked ichthyosis.4
Another condition in the differential diagnosis of IV is that of acquired ichthyosis, which can be distinguished from IV by its development later in life and its associated conditions. Patients with acquired ichthyosis often have concomitant conditions, such as malnutrition, infections (leprosy), neoplasms (lymphoma), and inflammatory disorders (sarcoidosis).1-9
The primary therapeutic goal in IV is to reduce scaling and treat xerosis without causing irritation.3Recommendations currently include repeated daily application of emollients and humectants containing either lactic or glycolic acid (5%-15%), propylene glycol (10%-25%) and/or urea.3,9
Preparations that contain urea or keratolytics such as α-hydroxy, lactic, and salicylic acids are beneficial. In salicylic acids, care must be taken to prevent salicylate toxicity.9
However, for the majority of individuals with IV, application of emollients with high-lipid content but without skin sensitizers should suffice. Emollient therapy showed a promising effect in reducing atopic dermatitis in predisposed individuals.3
Topical retinoids may decrease scaling but may irritate the skin. Vitamin D analogues are ineffective. Systemic treatment with acitretin or isotretinoin is helpful but rarely necessary.1,2The use of moisturizing cleansers and humidifiers may also be helpful.1Occupational advice about avoidance of professions involving wet work or excessive metal and contact-irritant exposure should be considered. Cats in the household as well as tobacco smoking should be discouraged because they may aggravate the atopic aspects of the disease.9This patient was treated with various over-the-counter moisturizing creams and lotions and had moderate improvement in xerosis.
X-linked ichthyosis (XLI), also known as steroid sulfatase deficiency, is a skin condition caused by a hereditary deficiency of the enzyme steroid sulfatase that results in dry, scaly skin.1,2,8
The pattern of inheritance of XLI is X-linked recessive. The X-linked recessive trait that results in XLI is transmitted exclusively to males by an asymptomatic heterozygous mother.1,2The worldwide incidence is between 1 in 2,000 and 1 in 9,500 male births.1
The pathogenesis of XLI is explained by the deletion of the entire steroid sulfatase (microsomal), isozyme S (STS) gene on chromosome 22 and the resulting deficiency of the enzyme steroid sulfatase.1,2
The steroid sulfatase enzyme is responsible for hydrolysis of cholesterol sulfate and dehydroepiandrosterone sulfate (DHEAS), and loss of function of the enzyme results in accumulation of the metabolite cholesterol 3-sulfate in the epidermis.1
The subsequent accumulation of cholesterol 3-sulfate in the epidermis results in inhibition of transglutaminase-1, an enzyme important in the formation of the most superficial layer of the skin, the stratum corneum.1Malformation of the stratum corneum results in the symptoms of dry, scaly skin seen in XLI.
Onset of XLI is usually before age 3 months and 90% of affected boys present during the neonatal period with mild erythroderma and generalized peeling, often with exfoliation of large, translucent scales.1,2,8
The typical polygonal, dark-brown, adherent scales develop later during infancy and are distributed symmetrically on the extensor surfaces of the extremities, trunk, and neck.1,2Scales on the lower extremity tend to be larger, and can occasionally be grayish or white.1
The sides of the neck are always involved, producing an unwashed appearance that is often described as the “dirty neck disease.”1,2The antecubital and popliteal fossae are usually spared, as are the face, scalp, palms, and soles.2
Fine scaling of the scalp is seen during early childhood but diminishes over time.1The preauricular area is only sometimes involved, but involvement of this area is often considered pathognomonic for XLI.1XLI improves in the summer, but does not subside with age.1
Patients with XLI should be screened for associated extracutaneous manifestations. Corneal opacities that do not affect vision can be seen by slit-lamp examination on the posterior capsule in 10% to 50% of male patients and in some female carriers.1,2
Other reported associated ocular abnormalities such as deuteranopia (green color-blindness) are rarer but should be asked about during the history.1Male patients also have a 20-times increased incidence of cryptorchidism.1,2Independent of the cryptorchidism, there is a higher risk of developing testicular cancer and hypogonadism.1
XLI affects pregnancy due to the inadequate deconjugation of DHEAS by steroid sulfatase, a process necessary for estrogen synthesis.1The estrogen deficiency results in insufficient dilation of the cervix, and as a result, labor fails to initiate spontaneously or to progress.1
Because of failure to progress, even with oxytocin administration, obstetric history will usually be complicated by a Cesarean section.1,2Also, because of the infant’s appearance at birth, a common story obtained from mothers is that the child “peeled all over” shortly after birth, and the diagnosis of “collodion baby” is often mistakenly made.8
XLI may be confused with ichthyosis vulgaris (IV), an autosomal-dominant disorder also characterized by xerosis. However, the two can be distinguished by subtle clinical findings. Patients with XLI typically have darker scales, and the condition clears dramatically during the summer months.2,8
In XLI, unlike in IV, the abdomen is more involved than the back and the ichthyosis extends down the entire dorsum of the leg.2IV also spares the flexural areas, including the neck, whereas XLI invariably affects the neck, producing the “unwashed” look in children.1,8
IV is commonly associated with keratosis pilaris and atopic disorders, whereas XLI is associated with extracutaneous manifestations such as cryptorchidism and corneal opacities.2,8Finally, unlike IV, XLI does not improve with age but gradually worsens in both extent and severity.2
Histopathologically, XLI presents with hyperkeratosis (thickening of the stratum corneum) or parakeratosis (thickening of the stratum corneum with retention of nuclei) overlying a normal or slightly thickened granular layer.1
On electron microscopy, an increased size and number of keratohyalin granules are present.1This is in contrast with IV, in which the granular layer and keratohyalin granules are diminished or completely absent1,8In the stratum corneum of XLI, desmosomes are retained and cells contain a large number of melanosomes.1
A multitude of tests exist to diagnose XLI. Array comparative genomic hybridization (CGH), FISH, Southern blot, and polymerase chain reaction (PCR)-based analysis are useful for detecting the underlying steroid sulfatase gene defect.1
These same tests can be performed on chorionic villi or amniotic fluid samples of female carriers, and amniocytes will show decreased activity of steroid sulfatase.1,2However, noninvasive prenatal diagnosis in pregnancy can be performed by detecting decreased or absent estrogen levels and the presence of nonhydrolyzed sulfated steroids in maternal urine and amniotic fluid.1
Lipoprotein electrophoresis can confirm the diagnosis of XLI. The increase in cholesterol sulfate in the serum makes serum low-density lipoproteins migrate much more rapidly.1,2
Cholesterol sulfate can also be measured directly by chromatography or spectrophotometry using epidermal scale, placental tissue, or amniotic fluid.1,2A biochemical assay to measure steroid sulfatase enzymatic activity in fibroblast, keratinocytes, and leukocytes is also available.1,2
XLI can be treated with topical humectants such as propylene glycol, keratolytics, and retinoids as monotherapy or in combination.1Vitamin D analogs are disappointing and cause significant irritation.1Systemic retinoids are rarely necessary.1
In this case, the patient was treated with a variety of topical agents including urea cream and ammonium lactate, with mild improvement in the scaliness of his skin.
Christopher Chu is a medical student at Baylor College of Medicine in Houston.
Adam Rees, MD, a graduate of the David Geffen School of Medicine at UCLA, practices dermatology in Los Angeles.