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X-linked ichthyosis

X-linked ichthyosis
Literature review current through: Aug 2023.
This topic last updated: Aug 02, 2023.

INTRODUCTION — X-linked ichthyosis (XLI; MIM #308100), also called steroid sulfatase (STS) deficiency, is caused by deletions or pathogenic variants in the STS gene (encoding the STS enzyme) and is generally considered nonsyndromic [1].

The disease presents at birth or in early infancy with dry skin and a tendency to form scales on the extremities and trunk. Along with ichthyosis vulgaris, the skin phenotype of XLI tends to be milder than most other hereditary forms of ichthyosis.

This topic will review the clinical features, diagnosis, and management of XLI. An overview of syndromic and nonsyndromic ichthyoses (table 1) and selected subtypes of inherited ichthyoses are presented separately.

(See "Overview and classification of the inherited ichthyoses".)

(See "Ichthyosis vulgaris".)

(See "Autosomal recessive congenital ichthyoses".)

(See "Keratinopathic ichthyoses".)

EPIDEMIOLOGY — Recessive XLI is the second most frequent ichthyosis after ichthyosis vulgaris. It is reported worldwide in all ethnic groups and almost exclusively affects males. XLI prevalence ranges from 1 in 1300 to 1 in 9000 male births [2-5].

Since the prevalence of steroid sulfatase (STS) deficiency detected by routine prenatal biochemical screening is approximately 1 in 1500 males and the rate detected by clinical diagnosis is significantly lower (1 in 3000 to 1 in 6000), STS deficiency may not cause clinically identifiable disease in a significant number of cases [6].

PATHOGENESIS

Genetics — The majority of cases of XLI are caused by complete deletion of the steroid sulfatase gene (STS) on chromosome Xp22.31 [7,8]. Other cases result from partial deletion or point mutations of STS [9,10]. These pathogenic variants of the STS gene cause complete loss of STS enzyme activity.

In a Dutch cohort of 109 males with suspected XLI, 71 (65 percent) had a molecularly confirmed pathogenic variant of STS [11]. Of these, 57 (80 percent) had a contiguous hemizygous deletion of the entire STS gene and at least part of the flanking PUDP sequence. The rest were point mutations or smaller copy number errors (deletions, duplications) that disrupted only the STS gene.

Due to the location of the STS gene within a small region on the distal half of the short arm of the X chromosome that escapes X-inactivation (lyonization), recessive XLI almost exclusively affects males, and females do not show mosaic skin lesions [12,13]. Affected males usually inherit the X chromosome bearing a deleted or mutated gene from their carrier mother, who is clinically unaffected. Rare de novo cases have been reported [14,15]. In 5 to 8 percent of cases, a larger deletion includes additional genes adjacent to STS, resulting in a number of contiguous gene syndromes depending on the size of the deletion [16,17]. (See 'Contiguous gene syndromes' below.)

Of note, some patients with XLI also carry concomitant variants in the filaggrin gene (FLG), which result in a more severe phenotype as well as in associated findings of atopic dermatitis [11,18].

Protein function — STS is a 65 kDa microsomal enzyme that localizes to the endoplasmic reticulum, Golgi apparatus, and endosomal membranes, including coated pits of placenta and several other tissues. STS hydrolyzes alkyl steroid sulfates (eg, dehydroepiandrosterone sulfate [DHEAS], aryl steroid sulfates) to their unconjugated (unsulfated) forms [19,20]. In the epidermis, STS activity is high in the granular layer and persists in the stratum corneum, where it contributes to the production of cholesterol available to form the extracellular lamellar bilayers and participates in the regulation of permeability barrier function and desquamation. Deficient STS activity leads to accumulation of cholesterol sulfate in the stratum corneum, which inhibits proteases that normally degrade corneodesmosomes [21]. Impaired desquamation is associated with increased corneocyte cohesion, retention hyperkeratosis, and impaired skin permeability [19,22-24].

Effects of fetal STS deficiency on maternal estriol levels during pregnancy — In women pregnant with an affected fetus, placental STS deficiency causes low maternal urinary and blood unconjugated estriol levels due to inadequate deconjugation of DHEAS, which is necessary for estrogen synthesis [19]. Normally, the STS enzyme synthesizes estriol in the placenta, which circulates in maternal blood. When a fetus is affected with XLI (STS deficiency), the mother, correspondingly, has abnormally low levels of unconjugated serum estriol (uE3) during pregnancy. If a mother carrying an XLI-affected fetus is offered and pursues a second-trimester screening test for Down syndrome, which relies on levels of serum analytes including uE3, the screen will be abnormal and not useful for detection of Down syndrome. (See "Maternal serum marker screening for Down syndrome: Levels and laboratory issues".)

Effects of STS deficiency on brain development — STS is expressed in the brain both during development and normal function [6]. Several studies support that impaired STS function may affect neurodevelopment and brain function [6,21,25]. Neurocognitive differences present in affected males, who carry pathogenic point mutations and small deletions, as well as in those with deletions of the entire STS gene and a small number of surrounding genes, which supports that behavioral changes are caused by reduced STS activity itself (rather than deletion of adjacent genes as previously suspected) [21]. Affected males have an increased tendency toward behaviors such as inattention, impulsivity, mood disorders, and autism-related traits [6]. Data suggest that female carriers also have an increased risk of attention deficit hyperactivity disorder (ADHD)-related behaviors, similar to that of affected males, due to reduced STS activity and expression [6].

Atrial fibrillation is reported at an increased rate in adult males with XLI [26]. The mechanism is not known with certainty, though a relationship with circulating DHEAS levels is suspected.

PERINATAL MANIFESTATIONS OF STS DEFICIENCY — Steroid sulfatase (STS) is a key enzyme in the biosynthesis of estriol in the human placenta. A placental STS deficiency, which occurs in pregnancies of XLI fetuses, causes abnormally low levels of serum estriol in mothers during pregnancy. Recessive XLI may be diagnosed prenatally as an incidental finding in pregnant women undergoing a screening blood test for Down syndrome, which includes alpha-fetoprotein (AFP), unconjugated estriol, human chorionic gonadotropin, and inhibin A. (See "Down syndrome: Overview of prenatal screening".)

The impact of STS deficiency on pregnancy and delivery is unclear. Some authors report a delayed or prolonged labor (>20 hours) and reduced response to oxytocin, especially in primiparous females [27,28]. However, no special interventions are recommended unless there are specific obstetric indications [28,29].

CLINICAL MANIFESTATIONS — In addition to ichthyosis, steroid sulfatase (STS) deficiency may be associated with several extracutaneous manifestations, including corneal opacities; cryptorchidism; and less commonly, neurologic, cognitive, and developmental abnormalities [1,30,31]. Increased risk of atrial fibrillation/flutter has been reported in affected adult males [26].

Cutaneous features — The age at presentation is variable. The cutaneous features of XLI may appear at birth [32] or in the first few weeks of life with mild, diffuse scaling (picture 1A-D) and gradually develop over the following months. A presentation with a collodion membrane at birth ("collodion baby") is unusual in XLI, and most parents/caregivers do not describe noticeable skin scale or dryness at birth.

Over time, the mild desquamation may be replaced by larger, polygonal, translucent scales (picture 2A-B) [27]. The scales may become plate like and adherent with a brownish color and particularly involve the anterior aspect of the lower extremities. The lack of involvement in flexural areas, such as the popliteal (picture 3) and antecubital (picture 4) fossae, has traditionally been considered a distinctive feature of XLI. However, in a series of 30 patients with XLI, one-third had flexural involvement [21]. Palms, soles, and the central face are often spared. During childhood, the scalp, preauricular areas, and neck may be involved ("dirty neck" appearance) [33].

The scales tend to increase throughout childhood and then stabilize after adolescence with little subsequent change. In some patients, a concurrent ichthyosis vulgaris and/or atopic dermatitis may exacerbate the symptoms [34-36]. (See 'Differential diagnosis' below.)

Pruritus is generally less severe than in other forms of ichthyosis [21,37]. The desquamation improves during the summer months and is worsened by dry and cold weather [33,38]. Correspondingly, pruritus is more likely in a cold environment compared with a hot environment [37].

Hypohidrosis is associated with many forms of ichthyosis and has been reported in 19 percent of patients with XLI [21].

Clinically affected individuals with XLI have an increased risk of having associated atopic dermatitis. A Spanish study identified atopic dermatitis as a comorbidity in 23 percent of individuals affected by XLI [25]. Individuals who also have mutations in the filaggrin gene, a risk factor for atopic dermatitis, may have a more severe presentation of XLI and more skin infections [21].

Extracutaneous features

Ocular — Harmless "punctate corneal opacities" are the most characteristic eye finding, present in up to 50 percent of affected males and 25 percent of carrier females [39]. The appearance is described as fine, hazy or "flour-like," comma-shaped dots in the cornea, anterior to Descemet's membrane and best visualized using a slit lamp (picture 5) [34]. Increasingly, multimodal high-resolution techniques (eg, in vivo confocal microscopy, optical coherence tomography) are used to visualize the anterior segment and have been reported to be useful as early as childhood [40,41]. These punctate corneal opacities are usually asymptomatic and can only rarely cause recurrent corneal erosions [1,39].

Genitourinary — Cryptorchidism is described in up to 20 percent of affected male children [1]. A Spanish study of 30 patients found that 10 percent of affected male children required orchiopexy. Despite cryptorchidism, affected males have normal sexual development, testosterone levels, and fertility [1]. Of particular concern to patients and families is a possible association of recessive XLI with testicular germ cell cancer independent of cryptorchidism. However, the data to support this association are weak, with only a few cases reported in the literature [42,43]. (See "Undescended testes (cryptorchidism) in children: Management".)

There are a few case reports of nephrotic syndrome associated with recessive XLI [44-47]. However, a true association has not been proven.

Cardiac — In a large UK Biobank study of males aged 40 to 69 years, atrial fibrillation or flutter was reported in 10.5 percent of individuals with the STS deletion versus 2.7 percent in male controls [26].

Cognitive and behavioral — Male children with recessive XLI have a higher rate of cognitive and behavioral disorders, especially attention deficit hyperactivity disorder (ADHD), compared with nonaffected children in the same age range [21,32,48]. Mood disorders, anxiety, and depression are also more prevalent in affected males and carrier females compared with the general population. In a study of 25 male children with recessive XLI, 10 fulfilled the criteria for ADHD (especially the inattentive subtype), and five fulfilled the criteria for an autistic spectrum disorder or related language/communication difficulty [30]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features' and "Autism spectrum disorder in children and adolescents: Clinical features".)

In another study of patients from 25 families, 30 percent were affected with ADHD. Despite this well-supported association of XLI and ADHD, a study revealed no difference in highest academic level achieved between STS deletion carriers aged 40 to 69 years (male or female) and controls [26].

Neurologic — Epilepsy was overrepresented (13 percent) in a group of 30 clinically diagnosed male children in Spain [21]. Increased seizure risk in XLI is further supported in a report of three affected male children with self-limited focal epilepsy of childhood and an Xp22.31 STS deletion that includes STS, PUDP, and MIR4767 [49]. These findings suggest that STS pathogenic variants may be an independent risk factor for seizures [49].

CLINICAL FINDINGS IN FEMALE CARRIERS — Corneal opacities and increased risk of attention deficit hyperactivity disorder (ADHD)-related behaviors have been described in female carriers of STS variants [6,26,39].

CONTIGUOUS GENE SYNDROMES — Abnormal recombination of homologous sequences in the STS chromosomal region may cause terminal or interstitial deletions that include adjacent genes, resulting in complicated clinical phenotypes [50]. In addition to ichthyosis, abnormalities reported in male patients with recessive XLI and contiguous gene syndromes include:

Cognitive disability [51,52]

Hypogonadotropic hypogonadism and anosmia (Kallmann syndrome, MIM #308700), caused by a large deletion of the short arm of the X chromosome proximal to and including the STS gene [53] (see "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)")

Chondrodysplasia punctata, nasal hypoplasia, and developmental delay [54-56]

Developmental delay and short stature [57]

Anosmia, hypogonadotropic hypogonadism, nystagmus, and decreased visual acuity [58]

EVALUATION AND DIAGNOSIS

Clinical suspicion — The diagnosis of recessive XLI is suspected in an infant based upon one or more of the following [1]:

Presence of unusually dry skin in the first weeks of life that evolves to polygonal, brownish scales

Birth history characterized by a prolonged labor (>20 hours) and/or nonelective cesarean section

Maternal finding of low serum estriol in the second trimester of pregnancy

Family history of scaly skin affecting the male relatives of the mother

Diagnosis confirmation — The diagnosis of recessive XLI can be confirmed by biochemical techniques demonstrating absent steroid sulfatase (STS) enzyme activity or by molecular techniques demonstrating a deletion or mutation of the STS gene. Some authors advocate for a multispecialty approach in assessment of children with XLI to include assessment for the presence of neuropsychiatric signs [32].

Biochemical diagnosis — The demonstration of reduced STS activity in cultured fibroblasts has the highest sensitivity because it detects cases caused by gene deletions as well as those caused by mutations. Fibroblasts can be cultured from skin biopsy using a standard technique. Typically, a 4 mm punch biopsy from a convenient area of the skin (eg, under the upper arm) is placed in a sterile container with standard culture media (not formalin) and sent to a laboratory that performs fibroblast culture. A request for STS enzyme activity testing should accompany the specimen.

Molecular diagnosis — The diagnosis of recessive XLI can be confirmed by a chromosomal microarray (CMA) test of peripheral blood. Using CMA, the STS region of the X chromosome (Xp22.3) can be examined for a microdeletion. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)

CMA is a powerful genetic test that interrogates the entire genome for small deletions and copy number variants. CMA is used in obstetrics for certain situations, such as fetal congenital anomalies, and in the postnatal setting in children with multiple congenital anomalies not explained by a specific syndrome. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray".)

CMA may detect recessive XLI prenatally and is also useful for excluding an associated contiguous gene syndrome. Similarly, in patients who present with suspected XLI and congenital anomalies, CMA and genetic consultation may be helpful for an accurate diagnosis.

However, CMA cannot detect the minority of XLI cases caused by point mutations in STS or very small deletions. In suspected cases in which CMA is negative for an STS deletion, deoxyribonucleic acid (DNA) sequencing for point mutations in STS and small deletions can be performed.

Histopathology — A skin biopsy is generally not helpful for the diagnosis of XLI because the histologic features of XLI may be nonspecific, with a wide range of changes in the stratum corneum and granular layer reported. For example, the stratum corneum may appear normal or have thick hyperkeratosis (picture 6) [1]. The granular layer may appear normal (picture 7) [59], diminished [19], or absent (picture 8) [59]. In contrast with early reports of a normal to slightly thickened granular layer in XLI, a review of slides from eight patients found that the granular layer was generally normal or thinned [60].

PRENATAL DIAGNOSIS — Since the mothers of XLI-affected fetuses have abnormally low levels of serum estriol during pregnancy, the diagnosis is sometimes made prenatally in women who undergo a screening blood test for Down syndrome in the second trimester of pregnancy, which includes the measurement of unconjugated estriol. (See 'Perinatal manifestations of STS deficiency' above.)

When the diagnosis of STS deficiency is made prenatally, further evaluation to exclude a contiguous gene syndrome using chromosomal microarray (CMA) is recommended [16]. (See 'Molecular diagnosis' above.)

CARRIER DETECTION — Measurement of steroid sulfatase (STS) enzyme activity in fibroblast culture is not useful to detect carrier females. Biochemical assay of cultured fibroblasts detects complete absence or extremely low STS activity and considers a broad range of STS activity to be normal. Since female carriers have residual activity from their normal X chromosome, an assay result from a carrier female is typically not different enough from normal to distinguish carrier status.

If an affected male is identified using chromosomal microarray (CMA), then less expensive and more specific DNA sequencing or fluorescence in situ hybridization (FISH) testing are useful to test the carrier status of female family members and male relatives. (See 'Molecular diagnosis' above.)

Genetic consultation is useful for families to understand the testing strategy and implications of the findings. (See 'Genetic counseling' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of XLI includes:

Ichthyosis vulgaris – In contrast to XLI, the skin in ichthyosis vulgaris is likely to lack the translucent, polygonal scale. Palmar hyperlinearity is characteristic of ichthyosis vulgaris but is usually absent in XLI (picture 9) [21]. On histology, the granular layer is absent in ichthyosis vulgaris but is usually normal or thinned in XLI. (See "Overview and classification of the inherited ichthyoses", section on 'Ichthyosis vulgaris'.)

Lamellar ichthyosis and congenital ichthyosiform erythroderma – Lamellar ichthyosis is more severe than XLI and typically presents at birth with a collodion membrane (picture 10) and later with large, plate-like scales that are most prominent on the trunk and lower extremities (picture 11). (See "Overview and classification of the inherited ichthyoses", section on 'Lamellar ichthyosis and congenital ichthyosiform erythroderma'.)

Atopic dermatitis – In infants and young children, atopic dermatitis typically presents with dry skin; pruritus; and red, scaly, or weeping lesions on the extensor surfaces and cheeks or scalp (picture 12A-C). Histology shows spongiosis (epidermal edema) and a lymphohistiocytic infiltrate in the dermis. In contrast to atopic dermatitis, XLI is not associated with inflammation, vesiculation, or pruritus. However, atopic dermatitis may rarely be present concurrently with XLI. Individuals with XLI have a heightened risk of atopic dermatitis, and the two conditions may occur together. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

MANAGEMENT

General considerations — There is no definitive cure for recessive XLI. Many authors report mild forms diagnosed prenatally or incidentally that may not come to clinical attention based on skin features. The disease rarely interferes with the activities of daily living, and mild forms may not require treatment [1]. However, some patients with XLI experience a significantly reduced quality of life due to self-consciousness and social embarrassment [61-63]. These patients may need lifelong treatment to control scaling and skin dryness and improve their skin appearance.

Educating parents, caregivers, and patients about the importance of daily bathing and regular, frequent application of emollients is an essential part of the management of XLI. (See 'Control of scaling and dryness' below.)

It is also essential to guide the patient in the choice of cosmetically acceptable creams and lotions to improve adherence to treatment [64]. An excellent resource for patients, parents, and caregivers with information on skin care can be found on the website of the Foundation for Ichthyosis and Related Skin Types (FIRST).

Overheating — In some individuals, the skin is dry and thick enough to impede normal function of the sweat glands by mechanically blocking them. These patients may have a tendency to become overheated, especially in direct sunlight [1]. One of the first signs of overheating is increased redness of the skin. Ready access to a cool environment or water (including sprays or cooling vests), if needed, is recommended.

Affected individuals usually learn over time what they can or cannot tolerate, and overheating rarely causes medical problems.

Control of scaling and dryness — Treatment of recessive XLI is directed at removing scales, reducing skin dryness, and improving skin appearance without causing excessive irritation. It involves regular bathing and use of emollients and keratolytics.

Bathing and moisturizing — Daily bathtub soaks in water or long showers with gentle removal of scale using a roughly textured sponge are helpful. The addition of baking soda or lubricating bath oils to bath water may be helpful [65]. Moisturizing creams or ointments should be applied immediately after bathing, while the skin is still damp. Useful moisturizers typically contain oils alone (eg, petroleum jelly) or in combination with humectants (eg, sodium lactate, low-concentration urea, propylene glycol).

In infants and young children, daily baths followed by the application of emollients is usually sufficient to remove scales. Increasing the environmental humidity is also helpful.

Keratolytics — Topical keratolytic agents are first-line treatment for reducing scale in older children and adults with XLI. Potential irritation and stinging in children, especially prior to school age, limits use and requires monitoring and dose adjustment when needed. (See "Inherited ichthyosis: Overview of management", section on 'Topical keratolytic agents'.)

Topical keratolytic preparations available on the market usually contain:

5% to 12% lactic acid

2% to 10% urea

5% to 15% glycolic acid

10% to 25% propylene glycol

3% to 6% salicylic acid

Topical keratolytics should not be used in infants and young children because of the high risk of toxicity due to systemic absorption [66-68].

Administration – Keratolytic preparations should be applied up to once or twice daily in a thin layer to the affected skin. An excessive concentration of keratolytic agents may cause skin irritation, pain, and excess peeling. As a general rule, concentration of keratolytic creams may be increased in a "start low, go slow," stepwise fashion, such as starting once per week in a small area to avoid burning and irritation. Patients with an unsatisfactory response to single keratolytics may benefit from using ointments containing a combination of keratolytics, such as 5% lactic acid with 10% urea or 2% salicylic acid with 20% urea.

Efficacy – The evidence on the efficacy of keratolytics for the treatment of ichthyosis is limited to a few low-quality, randomized trials and observational studies, and their use is mainly based upon clinical experience and patient preference. In one study, 60 children with mild to moderate types of ichthyosis treated one side of the most severely affected extremity with a 10% urea cream and the contralateral side with vehicle for eight weeks [69]. A very good or good investigator-assessed improvement was noted in more areas treated with 10% urea lotion than those treated with vehicle (79 versus 62 percent).

Topical and systemic retinoids — Patients with more severe forms of XLI may benefit from intermittent courses of topical retinoids (eg, tazarotene) or oral retinoids (eg, isotretinoin, acitretin) [70]. Retinoids have antikeratinizing properties and modulate keratinocyte proliferation and differentiation. In children, treatment with topical retinoids is useful and typically individualized according to severity and body surface area involvement. For example, they can be applied to areas of thickest scale, starting once weekly and increasing frequency as tolerated.

The dosing and administration of topical and systemic retinoids in patients with severe ichthyosis are discussed in detail separately. (See "Inherited ichthyosis: Overview of management", section on 'Topical retinoids' and "Inherited ichthyosis: Overview of management", section on 'Systemic retinoids'.)

Retinoic acid metabolism-blocking agents, such as liarozole and rambazole, are an alternative to topical or systemic retinoids. Liarozole has received the orphan drug status by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of congenital ichthyosis, but it is not yet available.

Evidence on the efficacy of topical or systemic retinoids or retinoic acid metabolism blockers in XLI is limited to a few small, uncontrolled studies; single case reports; and one randomized trial [71-74]:

In one right-left comparison study, 12 patients with congenital ichthyosis (4 with XLI) applied tazarotene 0.05% gel on one side of the body (≤10 percent of the body surface area) and an ointment containing 10% urea on the contralateral area twice daily for two weeks and then twice weekly for two additional weeks [71]. In the four patients with recessive XLI, a marked clinical improvement was noted only on the side treated with tazarotene after 14 to 20 days, and the beneficial effect persisted for up to two months after discontinuing tazarotene. Adverse effects of tazarotene were mild irritation and discomfort that did not require the interruption of treatment.

In a small, right-left comparison trial, liarozole 5% cream was more effective than vehicle in reducing scaling and roughness in 12 patients with recessive XLI, epidermolytic ichthyosis, or lamellar ichthyosis [73].

In a randomized trial including 32 patients (21 with XLI), oral liarozole 150 mg per day was as effective as oral acitretin 35 mg per day in inducing a marked improvement in scaling and erythema as assessed by clinician evaluation and patient self-evaluation [74]. Adverse events were moderate and less frequent in the liarozole group.

Adverse effects of systemic retinoids include mucosal dryness, photosensitivity, hyperlipidemia, transaminase elevation, and skeletal hyperostosis. As XLI only affects males, the risk of teratogenicity associated with systemic retinoids is not a concern.

Management of extracutaneous manifestations — Patients with extracutaneous manifestations and patients with contiguous gene syndromes may require a specialized or multidisciplinary approach:

Corneal opacities – The corneal punctate opacities in XLI are asymptomatic and generally do not cause harm. A baseline ophthalmology examination using a slit lamp to examine the cornea can be considered to document the presence or absence of corneal changes associated with XLI.

Cryptorchidism – The management of cryptorchidism is discussed elsewhere. (See "Undescended testes (cryptorchidism) in children: Clinical features and evaluation".)

Of particular concern to patients and families is a possible association of XLI with testicular germ cell cancer [42,75]. The data to support a true connection are weak [19]. Because the evidence for a true association of XLI with testicular cancer is weak outside the setting of cryptorchidism, no additional screening measures are recommended for patients without a history of cryptorchidism. (See "Epidemiology of and risk factors for testicular germ cell tumors".)

Cognitive/behavioral issues – The management of attention deficit hyperactivity disorder (ADHD) in children and adolescents is discussed elsewhere. (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis".)

Contiguous gene syndromes – The management of children with contiguous gene syndromes who present with developmental, endocrine, or neurologic abnormalities and/or intellectual disability requires a multidisciplinary team, including a pediatrician, pediatric neurologist, geneticist, and occupational and physical therapists.

GENETIC COUNSELING — Patients diagnosed with recessive XLI may benefit from genetics consultation to better understand the inheritance pattern and impact on relatives.

Mothers who are carriers of steroid sulfatase (STS) deficiency will pass the X chromosome bearing the STS deletion or mutation to 50 percent of offspring. Therefore, 50 percent of male children will be affected by recessive XLI, and 50 percent of female children will be carriers (figure 1).

Affected fathers will never transmit the disease to their male children, but all female children will be carriers. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Sex-linked patterns'.)

Rare affected females usually have homozygous mutations on both X chromosomes due to consanguinity [38,76].

PROGNOSIS AND FOLLOW-UP — In the absence of a contiguous gene syndrome, the prognosis for patients with recessive XLI is excellent. There is no known reduction in life expectancy associated with XLI [1].

Scheduled dermatologic follow-up (eg, every six weeks) is initially recommended in patients with XLI to monitor improvement in skin dryness and scaling. Once optimal management is established, "as needed" periodic follow-up is usually sufficient.

ONLINE RESOURCES — Information and support for patients and families with recessive XLI can be found on the website of the Foundation for Ichthyosis and Related Skin Types (FIRST).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ichthyosis".)

SUMMARY AND RECOMMENDATIONS

Definition and pathogenesis – Recessive X-linked ichthyosis (XLI; MIM #308100), also called steroid sulfatase (STS) deficiency, is an X-linked recessive, nonsyndromic ichthyosis caused by deletions or mutations in the STS gene, encoding the STS enzyme. (See 'Introduction' above and 'Pathogenesis' above.)

Cutaneous features – The cutaneous features of recessive XLI may appear in the first few weeks of life with mild, diffuse scaling (picture 1A-D) and gradually develop over the following months. Over time, the mild desquamation may be replaced by large, polygonal, brownish scales that particularly involve the anterior aspect of the lower extremities (picture 2A-B). The flexural areas tend to be spared. (See 'Cutaneous features' above.)

Extracutaneous features – Extracutaneous features include asymptomatic punctate corneal opacities, cryptorchidism, and cognitive/behavioral disorders, especially attention deficit hyperactivity disorder (ADHD). Deletions of the STS gene and adjacent genes result in complicated clinical phenotypes called contiguous gene syndromes. (See 'Extracutaneous features' above and 'Contiguous gene syndromes' above.)

Diagnosis – The diagnosis of recessive XLI can be confirmed by biochemical techniques demonstrating absent STS enzyme activity in cultured fibroblasts or by molecular techniques demonstrating a deletion or point mutation of the STS gene. Chromosomal microarray (CMA) may be used to exclude an associated contiguous gene syndrome. (See 'Evaluation and diagnosis' above.)

Management – There is no definitive cure for recessive XLI. Symptomatic treatment is directed at removing scales, reducing skin dryness, and improving skin appearance without causing excessive irritation. For most patients with mild to moderate XLI, we suggest regular bathing and use of emollients and keratolytics rather than topical or systemic retinoids (Grade 2C). Topical keratolytics should not be used in infants and young children because of the high risk of toxicity due to systemic absorption. Patients with severe disease may benefit from intermittent use of topical or systemic retinoids. The management of extracutaneous manifestations may require a specialized or multidisciplinary approach. (See 'Management' above.)

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Topic 15472 Version 17.0

References

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