Harlequin Ichthyosis Workup

Updated: May 07, 2019
  • Author: Fnu Nutan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
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Approach Considerations

A diagnosis of harlequin ichthyosis is usually made by clinical examination in the newborn. 

Prenatal diagnosis of harlequin ichthyosis is made by analysis of fetal DNA obtained by chorionic villus sampling or amniocentesis.

In the absence of a family history, a prenatal diagnosis of harlequin ichthyosis can be suspected or identified by ultrasonography. 

Investigations in the newborn with harlequin ichthyosis are performed to identify the gene mutation, to monitor supportive care, and to identify complications.


Laboratory Studies

Genetic testing for mutations in the ABCA12 gene is available. Complete sequence analysis of the coding region of this gene is performed to identify specific mutations. Peripheral blood cells or cells from a buccal smear from affected individuals are required. Extensive information regarding genetic testing for harlequin ichthyosis is available from GeneDx. Carrier testing is available for relatives after the proband's mutation is identified. Prenatal diagnosis is available for fetuses with suspected harlequin ichthyosis who may or may not have a family history of the disorder. [6] For genetic diagnosis, obtaining mRNA from hair follicle epithelial cells, which are analogous to keratinocytes in the interfollicular epidermis, is convenient and minimally invasive. This is an extremely promising next-generation sequencing that is available. [17]

Certain laboratory investigations may be helpful in the newborn period to identify complications of harlequin ichthyosis.

A WBC count and skin and blood cultures can be performed to investigate for signs of infection.

Serum electrolyte levels may be abnormal secondary to dehydration.

Monitor serum calcium and glucose, as hypocalcemia and hypoglycemia may occur.

Check BUN and creatinine levels for signs of renal failure.

Monitor hemoglobin levels because severe anemia is reported.


Imaging Studies

Chest radiography may be indicated if respiratory distress is present postnatally.

Renal ultrasonography may be indicated if renal failure or poor urine output is evident. Renal dysplasia has been described in harlequin ichthyosis.

Further investigations should be based on the history and findings from physical examination.

Prenatal diagnosis

Prenatal ultrasonography, particularly 3-dimensional ultrasonography, may show features suggestive of harlequin ichthyosis. This has been particularly helpful in antenatal diagnosis of infants with no family history of harlequin ichthyosis. Characteristic features include a large and gaping mouth, aplasia of the nose, abnormal limbs, bulging eyes, rudimentary ears, flexion contractures, and floating particles in the amniotic fluid. [13, 18, 19, 20] Growth restriction and polyhydramnios are also described.

Two-dimensional ultrasonography can also demonstrate features of harlequin ichthyosis but not until late in the second trimester, when enough keratin buildup is present to be sonographically detectable. The snow flake sign is also demonstrable in some cases. Short feet may be an early marker for harlequin ichthyosis. This may be detectable in the early second trimester before other signs of harlequin ichthyosis are noticeable. [15]



Before genetic testing was available, fetal skin biopsy was sometimes used to detect ultrastructural changes consistent with harlequin ichthyosis. [5] Fetal skin biopsy could help in detecting harlequin ichthyosis as early as 19 weeks' gestation. Biopsy samples from a number of sites in the fetus revealed characteristic changes on all skin surfaces except the mucous membranes. Amniotic fluid samples obtained as early as 17 weeks' gestation have also demonstrated hyperkeratosis and abnormal lipid droplets in the cornified cells.

Fetal skin biopsy is no longer performed for diagnosis of harlequin ichthyosis.


Histopathologic Findings

The stratum corneum is thick and compact. Hyperkeratosis may be more marked around hair follicles compared with the interfollicular epidermis. The histopathologic hallmark is an extraordinarily thickened and compact orthokeratotic stratum corneum, although in some cases parakeratosis has been observed. Cells within the stratum corneum are abnormally keratinized. Granular, spinous, and basal cell layers appear unremarkable. Inflammatory cells may infiltrate the papillary dermis. Hair follicles show marked, concentric accumulation of keratotic material around hair shafts, which is considered a diagnostic feature of harlequin ichthyosis and has been used to establish the diagnosis prenatally.


Other Tests

Electron microscopy reveals absent or abnormal lamellar granules within the granular layer keratinocytes. Lamellae are absent in the intercellular spaces between the granular cell layer and the cornified cell layer. Densely packed lipid droplets and vacuoles are seen within the cytoplasm of the aberrantly cornified cells of the stratum corneum. These lipid inclusions involve the entire skin surface but are more evident on the palms and the soles. Keratohyalin granules may be absent, normal, or abnormally small and globular. Keratin intermediate filaments within granular cells may have reduced density.