X-Linked Ichthyosis Workup

Updated: Jun 09, 2022
  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
  • Print

Laboratory Studies

Diagnosis of patients with X-linked ichthyosis and female carriers is based on biochemical and genetic analysis. Genetic analysis currently is the most accurate diagnostic method in most patients. X-linked ichthyosis can be diagnosed by assaying STS activity in the placenta or in the skin fibroblasts, keratinocytes, or lymphocytes of patients after birth. Patients show a deficiency of arylsulfatase C, which can be demonstrated by biochemical testing.

Polymerase chain reaction (PCR) and Southern blot testing are useful for the genetic diagnosis of X-linked ichthyosis, although a few patients with X-linked ichthyosis carrying point mutations rather than deletions may be missed. PCR is not applicable for carrier detection. Both multiplex quantitative fluorescent PCR (QF-PCR) and fluorescence in situ hybridization (FISH) are effective to detect the complete deletion mutation of the STS gene and identify the female carrier. [35] Multiplex QF-PCR appears to be more convenient and automatic compared with FISH. [36]

X-linked ichthyosis can be diagnosed prenatally using fluorescence in situ hybridization. [37] Maternal peripheral blood metaphase spreads may display 2 hybridization signals on one of the X chromosomes (1 in the STS region [band Xp22.3] and 1 in the centromeric region), but only 1 hybridization signal (in the X centromeric region) on the other X chromosome; therefore, one of the X chromosomes has a deletion in the band Xp22.3 region, a result consistent with the carrier status for STS deficiency and X-linked ichthyosis. In metaphase spreads from amniotic fluid samples, the X chromosome shows 1 hybridization signal in the control region, but no hybridization signal in the STS region. Therefore, the X chromosome of this male fetus has a deletion in the STS region, a result consistent with X-linked ichthyosis.

The deficit in placental STS blocks placental steroid synthesis, resulting in excretion of maternal urinary steroids in much lower amounts than normal. Incorporating unconjugated estriol in maternal serum into the calculation of risk increases the yield of screenings performed during pregnancy for detection of fetal chromosomal and structural anomalies. The differential diagnosis of low and undetectable levels of unconjugated estriol in maternal serum includes X-linked ichthyosis and serious fetal pathologies (eg, adrenal insufficiency, anencephaly, Down syndrome). To diagnose X-linked ichthyosis, examine the urine of these pregnant women for low levels of nonhydrolyzed sulfated steroids.


Other Tests

A patient with X-linked ichthyosis and pre-Descemet corneal dystrophy had a microdeletion within Xp22.3 containing the steroid sulfatase gene, which was detected using microarray-based comparative genomic hybridization, confirming this clinical diagnosis. [38]


Histologic Findings

Histologic changes of X-linked ichthyosis often are subtle. Biopsy specimens from ichthyotic skin with mild scaling may appear normal. Specimens obtained from regions of thick scaling (eg, anterior aspect of legs, extensor aspect of arms) show mild-to-moderate compact laminated eosinophilic orthokeratotic hyperkeratosis, with a normal or slightly thickened granular layer 3-4 cells thick, mild acanthosis, well-preserved rete ridges, and a sparse perivascular and periappendageal lymphohistiocytic infiltrate.

Ultrastructurally, keratohyaline granules are increased in size and number. Normal-appearing keratinocytes appear linked by desmosomal disks all the way up into the stratum corneum, where the anucleated cells have increased numbers of melanosomes, which may account for the dark coloration of scaling in X-linked ichthyosis.