Harlequin Ichthyosis Workup
- Author: Julie Prendiville, MBBCh; Chief Editor: Dirk M Elston, MD more...
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.
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.
The following laboratory investigations may be helpful in the newborn period to identify complications of harlequin ichthyosis:
- Check the WBC count and skin and blood cultures for signs of infection.
- Closely monitor serum electrolyte levels, which 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.
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.[4, 15, 16, 17] 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. 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.
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.
Before genetic testing was available, fetal skin biopsy was sometimes used to detect ultrastructural changes consistent with harlequin ichthyosis. 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.
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 extraordinary 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.
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.
Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010 Oct. 63(4):607-41. [Medline].
Lawlor F. Progress of a harlequin fetus to nonbullous ichthyosiform erythroderma. Pediatrics. 1988 Dec. 82(6):870-3. [Medline].
Ahmed H, O'Toole EA. Recent advances in the genetics and management of harlequin ichthyosis. Pediatr Dermatol. 2014 Sep-Oct. 31 (5):539-46. [Medline].
Rajpopat S, Moss C, Mellerio J, et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol. 2011 Jun. 147(6):681-6. [Medline].
Shibata A, Akiyama M. Epidemiology, medical genetics, diagnosis and treatment of harlequin ichthyosis in Japan. Pediatr Int. 2015 Aug. 57 (4):516-22. [Medline].
Lefevre C, Audebert S, Jobard F, et al. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet. 2003 Sep 15. 12(18):2369-78. [Medline].
Akiyama M. ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts. Hum Mutat. 2010 Oct. 31(10):1090-6. [Medline].
Akiyama M. The roles of ABCA12 in epidermal lipid barrier formation and keratinocyte differentiation. Biochim Biophys Acta. 2014 Mar. 1841(3):435-440. [Medline].
Elias PM, Williams ML, Holleran WM, Jiang YJ, Schmuth M. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res. 2008 Apr. 49(4):697-714. [Medline]. [Full Text].
Scott CA, Rajpopat S, Di WL. Harlequin ichthyosis: ABCA12 mutations underlie defective lipid transport, reduced protease regulation and skin-barrier dysfunction. Cell Tissue Res. 2013 Feb. 351(2):281-8. [Medline].
Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arita K, et al. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. J Clin Invest. 2005 Jul. 115(7):1777-84. [Medline]. [Full Text].
Stewart H, Smith PT, Gaunt L, Moore L, Tarpey P, Andrew S, et al. De novo deletion of chromosome 18q in a baby with harlequin ichthyosis. Am J Med Genet. 2001 Sep 1. 102(4):342-5. [Medline].
Thomas AC, Tattersall D, Norgett EE, O'Toole EA, Kelsell DP. Premature terminal differentiation and a reduction in specific proteases associated with loss of ABCA12 in Harlequin ichthyosis. Am J Pathol. 2009 Mar. 174(3):970-8. [Medline].
Berg C, Geipel A, Kohl M, Krokowski M, Baschat AA, Germer U, et al. Prenatal sonographic features of Harlequin ichthyosis. Arch Gynecol Obstet. 2003 Apr. 268(1):48-51. [Medline].
Bongain A, Benoit B, Ejnes L, Lambert JC, Gillet JY. Harlequin fetus: three-dimensional sonographic findings and new diagnostic approach. Ultrasound Obstet Gynecol. 2002 Jul. 20(1):82-5. [Medline].
Watson WJ, Mabee LM Jr. Prenatal diagnosis of severe congenital ichthyosis (harlequin fetus) by ultrasonography. J Ultrasound Med. 1995 Mar. 14(3):241-3. [Medline].
Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis. Pediatr Dermatol. 2003 Sep-Oct. 20(5):421-6. [Medline].
Milstone LM, Choate KA. Improving outcomes for harlequin ichthyosis. J Am Acad Dermatol. 2013 Nov. 69(5):808-9. [Medline].
Chua CN, Ainsworth J. Ocular management of harlequin syndrome. Arch Ophthalmol. 2001 Mar. 119(3):454-5. [Medline].
Koochek A, Choate KA, Milstone LM. Harlequin Ichthyosis: Neonatal Management and Identification of a New ABCA12 Mutation. Pediatr Dermatol. 2014 Mar. 31(2):e63-4. [Medline].
Liu RH, Becker B, Gunkel J, Teng J. Rapid improvement in digital ischemia and acral contracture in a collodion baby treated with topical tazarotene. J Drugs Dermatol. 2010 Jun. 9(6):713-6. [Medline].
Ripmeester P, Dunn S. Against all odds: breastfeeding a baby with harlequin ichthyosis. J Obstet Gynecol Neonatal Nurs. 2002 Sep-Oct. 31(5):521-5. [Medline].
Tontchev G, Silverberg NB, Shlasko E, Henry C, Roberts JL, Roth MZ. Techniques for toddlers: linear band incision for harlequin ichthyosis with associated compartment syndrome. Pediatr Dermatol. 2014 Sep-Oct. 31 (5):625-9. [Medline].
Harvey HB, Shaw MG, Morrell DS. Perinatal management of harlequin ichthyosis: a case report and literature review. J Perinatol. 2010 Jan. 30(1):66-72. [Medline].