INTRODUCTION

Autosomal recessive congenital ichthyoses are a group of skin disorders of genetic origin and heterogeneous phenotypes. They include harlequin ichthyosis, lamellar ichthyosis and bullous congenital ichthyosiform erythroderma^1). Harlequin ichthyosis, also known as diffuse fetal keratosis, is a severe, very rare and usually fatal disorder^2). Its incidence is 1 per 300,000 live births. Its inheritance pattern is autosomal recessive due to mutation of the adenosine triphosphate-binding protein A12 (ABCA12) gene, which causes alterations in lipid transport in the epidermis(^3,4).

Harlequin ichthyosis is a condition with a peculiar clinical appearance, as the cutaneous alteration and accumulation of scales produce widespread hyperkeratotic plaques, whitish or dark brown in color, with deep fissures almost all over the body. Other features include ectropion, fish mouth and limb contractures(^1). Ultrasonography and genetic analysis are useful tools for prenatal diagnosis(^3). A case of prenatal diagnosis of harlequin ichthyosis is presented.

CASE REPORT

An 18-year-old, primigravid female patient was referred for prenatal high-risk consultation for abnormal fetal facial findings on routine fetal ultrasound at 28 weeks. The patient regularly attended prenatal consultation at her center and the pregnancy had been uncomplicated. Routine ultrasound at 12 and 20 weeks showed no fetal abnormalities. The results of noninvasive prenatal tests for Down syndrome, neural tube defects and trisomy 18 were negative. The parents were distantly related and denied a history of family genetic disorders, hereditary skin disorders or contact with pesticides and radioactive substances.

Standard ultrasound showed intrauterine pregnancy with male fetus in breech presentation and biometry corresponding to 24 weeks. Amniotic fluid volume was decreased for gestational age (below the 10th percentile) with echogenic and cloudy appearance and dense floating particles. Fetal facial features included markedly thickened upper and lower lip and fish mouthlike shape, bilateral eyelid eversion (ectropion), short nasal bone with flat nose, deformed ears, and congenital cataract. In addition, deformed spine, limb anomalies with hypoplastic and flexed fingers and toes were also observed (Figure 1). Fetal movements were scarce. Three-dimensional ultrasound imaging confirmed the abnormal findings (Figure 2). Prenatal diagnosis suggested the possibility of harlequin ichthyosis. The parents gave permission to perform amniocentesis to evaluate the fetal karyotype, which showed no chromosomal abnormalities.

Figure 1 Ultrasound image of harlequin ichthyosis. The arrow points to A) Ectropion, B) O-shaped mouth, C) thickened skin and D) spinal deformity 

Figure 2 Three-dimensional ultrasound image of harlequin ichthyosis. 

At 30 weeks, the patient attended the obstetric emergency room due to uterine contractions, vaginal bleeding and decreased fetal movements. Ultrasound evaluation showed absence of fetal heart rate, for which reason uterine evacuation was decided. Stillbirth of 1,300 grams and 25 centimeters in length was obtained. On physical examination the skin was dry and thickened (consistent with hyperkeratosis), irregularly divided by deep erythematous fissures between thick, yellowish plaques, resembling thick scales that affected the entire body surface. There was also eversion of upper and lower eyelids, fish mouth, flat flared nose and abnormally flattened ears with fused lobes. The extremities were in a persistent semi-flexed position, with contractures in the fingers and incurved toes (Figure 3).

Figure 3 Stillbirth with harlequin ichthyosis 

A skin sample was taken from the thorax and sent to anatomic pathology. Microscopic evaluation showed extremely thick stratum corneum, indicative of hyperkeratosis, with sparse skeletal muscle cells in dermis and subcutaneous cellular tissue (Figure 4). DNA sequencing revealed the homozygous ABCA12 variant indicative of autosomal recessive congenital ichthyosis. All findings were compatible with a diagnosis of harlequin ichthyosis.

Figure 4 Image of skin biopsy histology of harlequin ichthyosis showing hyperkeratosis of the stratum corneum of the epidermis. 

DISCUSSION

Harlequin ichthyosis is a form of severe genodermatosis characterized by hyperkeratosis and desquamation of the epidermis(5). Its estimated incidence is 1 case per 300,000 births, without sexual predisposition, with autosomal recessive floating in the amniotic fluid (snowflake sign^)(6). Ultrasound diagnosis can usually be made with certainty in the third trimester, because skin keratinization begins at 22-24 weeks of gestation. Three-dimensional ultrasonography contributes to the evaluation of facial morphology. However, it does not replace two-dimensional ultrasonography^3).

DNA sequencing analysis in cases of harlequin ichthyosis is reliable and conclusive^4). Diagnosis is based on identifying ABCA12 mutations(^1). The protein is a member of the superfamily of ATP-dependent transporters, which bind and hydrolyze various molecules across membranes or vesicles^8). This protein is present in lamellar granules of keratinocytes that regulate lipid trafficking^9). The diagnosis can be confirmed by chorionic villus sampling or amniotic fluid sampling^10). In patients with a family history, fetoscopy with skin biopsy and ultrastructural examination of amniotic fluid cells may be useful, although it is not currently recommended due to advances in non-invasive tests such as ultrasound(^11).

The main differential diagnosis of harlequin ichthyosis in the prenatal period is Neu-Laxova syndrome. Fish mouth, absence of microcephaly and lack of edema are typical of harlequin ichthyosis, while cataracts and short umbilical cord are characteristic of Neu-Laxova syndrome^11). On the other hand, fetal harlequin ichthyosis can be confused with fetal macroglossia and fetal congenital tumor-like fetal angioma^12). However, macroglossia is always associated with genetic disorders such as Down syndrome and Beckwith-Wiedemann syndrome^13). The thickened tongue in fetal congenital hemangioma usually shows increased blood flow on color Doppler(^14).

Differential diagnoses in neonates include arthrogryposis, aplasia cutis, Gaucher disease, Sjogren-Larsson syndrome, Conradi-Hunermann-Happle syndrome and trichothiodystrophy(^15). Severe cases can easily be misdiagnosed as epidermolysis bullosa or syndromic ichthyosis(^9).

Those neonates with harlequin ichthyosis have a distinctive clinical appearance, with thickened, whitish to yellowish, armor-like skin, with fissures dividing the skin into polygonal or diamond-shaped sections and reddish cracks all over the body(^7). This is accompanied by ectropion and a persistently open, round mouth. There is no definitive treatment for this condition. The prognosis is poor and the likelihood of neonatal death is high, despite supportive medical treatment. Most deaths occur shortly after delivery due to infections, heat loss, dehydration, electrolyte disturbances or respiratory distress^3).

In conclusion, harlequin ichthyosis is an autosomal recessive genetic disorder, rare and usually fatal in the first days of life. Prenatal genetic diagnosis should be advised for couples with previously affected children. Characteristic features on prenatal ultrasound tend to appear late, so evaluations should be repeated in the third trimester, even when the second trimester anatomic examination is normal.