X-Linked Ichthyosis
X-linked ichthyosis is a relatively common genetic disorder of keratinization. It is the second most common type of ichthyosis after vulgaris. The incidence is estimated to be between 1 in 2000 and 1 in 6000 male live births.
GENETICS/BASIC DEFECTS
1. Inheritance
a. X-linked recessive b. Usually affects males only
c. Transmitted by carrier females (about 1 in 2000 women are carriers of steroid sulfatase (STS) enzyme deficiency)
d. Most apparently sporadic cases appear to be inherited based on biochemical analysis (as their mothers showed low values of STS enzyme activity)
e. Reports of a few affected female patients.
2. Etiology
a. Caused by a deficiency of STS enzyme b. The STS gene
i. Mapped on the distal part of the short arm of the X chromosome (Xp22.3)
ii. Close to the pseudoautosomal region
iii. Unlike most X-chromosome genes, the STS gene escapes the X-inactivation process.
3. Molecular defects
a. Deletion of the entire steroid sulfatase (STS) gene: the most common molecular defect in X-linked ichthyosis (XLI) patients (observed in 90% of patients)
b. Partial deletion or point mutation (observed in 10% of patients)
c. The deletion of STS gene may occasionally extend to involve neighboring genes (interstitial and termi- nal deletions of Xp22.3), resulting in a contiguous gene defect and may be associated with the follow- ing conditions. Depending on the length of the deletion, these disorders occur independently from each other or in combination as a contiguous gene syndrome.
i. Kallmann syndrome (hypogonadotropic hypog- onadism and anosmia)
ii. X-linked chondrodysplasia punctata iii. Short stature
iv. Mental retardation v. Ocular albinism vi. Ichthyosis
CLINICAL FEATURES
1. Cutaneous manifestation
a. Generalized scaling of the skin (ichthyosiform hyper- keratosis)
i. Early onset: usually at birth or within 4 months of life
ii. Large, dark-brown polygonal scales a) Usually symmetrically distributed
b) More prominent on the trunk and the exten- sor aspects of the limbs
c) Usually the flexures less affected
iii. Face usually free from scales, except in the preauricular areas, giving the classic “unwashed appearance,” which is considered by many to be pathognomonic
iv. Sparing palms and soles in most cases b. Normal nails and hair
c. Seasonal influence
i. Improve during the summer ii. Worsen during dry, cold weather 2. Extracutaneous manifestations
a. Corneal opacities
i. The most common extracutaneus features ii. Secondary to deposits of cholesterol sulfate crys-
tals
iii. Asymptomatic (not affecting the visual acuity) iv. Occurring in the posterior capsule of Descemet’s
membrane or the corneal stroma
v. More frequent during the second and third decades of life
vi. Observed in 10–50% of affected males and car- rier females
b. Cryptorchidism
i. Occurring in 10–20% of patients (vs the incidence of cryptorchidism in the normal population of 1%) ii. Possible mechanisms
a) A deficit in the STS enzyme
b) A genetic disturbance located on the short arm of chromosome X close to the STS gene c. Patients at an increased risk of testicular cancer
development d. CNS manifestations
i. Epileptic seizures
ii. Reactive psychological disorders
e. Clinical manifestations as a part of the contiguous gene syndrome expression
i. Kallmann syndrome ii. Short stature iii. Mental retardation
iv. X-linked chondrodysplasia punctata f. Other rare manifestations
i. Pyloric hypertrophy
ii. Congenital abdominal wall defect iii. Acute lymphoblastic leukemia
3. Steroid sulfatase deficiency during pregnancy in carrier females
a. Leads to an overall decrease in the levels of estrogen b. Causes poor cervical dilatation and prolonged labor c. Frequently necessitates a Caesarean section 1057
1058 X-LINKED ICHTHYOSIS
DIAGNOSTIC INVESTIGATIONS
1. Direct biochemical demonstration of STS deficiency (undetectable levels of STS activity) from the following tissue:
a. Placenta b. Skin fibroblasts c. Leukocytes d. Keratinocytes
2. Demonstration of an increase in substrates of STS a. Dihydroepiandrosterone sulfate (DHEAS) b. Cholesterol sulfate
3. Electrophoresis: rapid migration of serum cholesterol sul- fate (negatively charged and carried by low-density lipoprotein [LDL] particles) towards the positive pole during electrophoresis
4. Molecular genetic diagnosis yielding reliable results in most affected patients
a. Detection of complete deletion of the STS gene in most patients
i. Fluorescence in situ hybridization (FISH) ii. Southern blotting
iii. Multiplex polymerase chain reaction (PCR) b. Partial deletion by FISH: may provide a false negative
FISH result
c. A very small number of cases carrying point muta- tions instead of deletions at the STS gene: unde- tectable by Southern blot or PCR
d. Carrier detection i. STS enzyme assay
ii. FISH technique especially useful in carrier detection since the enzymatic assay often pro- vides inconclusive results
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib (given that the mother is a carrier) i. 50% of male sibs affected
ii. 50% of female sibs carriers b. Patient’s offspring
i. Affected male patients a) Male offspring normal b) All female offspring carriers ii. Affected female patients (heterozygous)
a) 50% of male offspring affected b) 50% of female offspring carriers iii. Affected female patients (homozygous)
a) All male offspring affected b) All female offspring carriers 2. Prenatal diagnosis
a. Maternal plasma demonstrating low or undetectable estriol levels in routine maternal serum screening, which is associated with the following conditions:
i. Placental steroid sulfatase deficiency ii. Fetal death
iii. Miscarriages iv. Anencephaly
v. Fetal adrenal hypoplasia
vi. High-dose corticosteroid therapy
vii. Aneuploidies a) Down syndrome b) Triploidy
viii. Smith-Lemli-Opitz syndrome in rare cases b. Maternal urine and plasma profiles of affected fetuses
indicating a primary placental sulfatase deficiency (low estriol levels)
c. Amniocentesis
i. Elevated sulfated steroids in the amniotic fluid ii. FISH to detect deletion in one copy of X chro-
mosome at region Xp22.3 using steroid sulfatase probe
d. Skin biopsy through fetoscopy to measure sulfated steroid
3. Management
a. Spontaneous improvement in most cases with age and during summer months and hardly require any treatment b. Attempt to diminish the abnormal cohesion of corneocytes by facilitating their separation in the milder forms
i. Topical keratolytics ii. Emollients
iii. Hydrating agents
c. Retinoids for potential treatment in severely affected patients
d. Liarozole, a imidazole derivative which inhibit cytochrome P450 to increase the level of endoge- nous retinoid acid by blocking its P450-dependent catabolism
e. Examination of male patients to detect cryptorchidism which has an increased risk of testicular cancer
REFERENCES
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Fig. 3. Abnormal FISH analysis showed a deletion in the steroid sul- fatase critical region on the X chromosome [del(X)(p22.3p22.3)(STS-)]
in a male fetus (upper photo). The case was ascertained because of undetectable UE3 from maternal serum screen. The lower photo (FISH) showed a normal XX control.
1060 X-LINKED ICHTHYOSIS
Fig. 1. A sporadic case of X-linked ichthyosis showing thick, large, polygonal, dark-brown scales involving the extensor.
Fig. 2. X-linked ichthyosis affecting 3 boys in a family.
