Case Report

Obstet Gynecol Sci 2020;63(1):94-97

https://doi.org/10.5468/ogs.2020.63.1.94
pISSN 2287-8572 · eISSN 2287-8580

Prenatal diagnosis of harlequin ichthyosis: a case report

Mudunuri Vijayakumari, MD1, Desai. Kamalakar Reddy, MD2, Madhavilatha Routhu, DMRD3,
Manasvi Vuchuru, MD4, Nallamilli Sunitha Reddy, DNB2
1
Department of Radiology, Osmania Medical College, Hyderabad; 2Sravya Diagnostics, Hyderabad; 3Department of Radiology, MGM Hospital,
Warangal; 4Department of Radiology Niloufer Hospital, Hyderabad, Telangana, India

Harlequin ichthyosis (HI) is a rare and severe form of ichthyosis and is characterized by thickened, hard, armor-like
plates of skin that cover the entire body. This disease is caused by mutations in the adenosine triphosphate-binding
cassette transporter protein A12 gene, and the pattern of inheritance is autosomal recessive. Prenatal sonographic
diagnosis of HI has not been frequently reported. Here, we report a case of HI detected at 28 weeks of gestation
and discuss with the sonographic findings and a brief review of literature. The diagnosis was reached mainly based
on 2-dimensional and 3-dimensional ultrasound findings. Three-dimensional ultrasound applications help recognize
facial morphology, and thus, greatly contributes to prenatal diagnoses.
Keywords: Harlequin ichthyosis; Neonates; Keratinizing disorder; Prenatal diagnosis

Introduction been used for the diagnosis of this rare disorder [4].

The most severe form of autosomal recessive congenital ich-

thyosis is harlequin ichthyosis (HI) [1]. HI is a rare congenital Case report
disorder that carries a very high perinatal mortality. Neonates
with HI usually do not survive beyond the first few days of A 30-year-old woman (gravida 3, para 2, D1, L1) presented in
life. Ichthyoses are a group of disorders characterized by the second trimester at 24 weeks gestation for a routine an-
whitish or dark brown scales on the skin of almost the en- tenatal checkup. The patient had one infant previously that
tire body [2]. The tightness of the skin pulls the area around was affected by HI. In the present pregnancy, a fetal anomaly
the eyes and the mouth, forcing the eyelids and lips to turn scan was performed using a 3.5 MHz linear transducer on an
inside out, and exposing the red inner linings. Moreover, the Esaote machine. Two-dimensional (2D) and 3D sonographic
chest and abdomen of the infant may be severely restricted, examinations were performed. The examinations revealed a
making breathing and eating difficult. Globally, the newborn single live intrauterine gestation in breech presentation, and
appears to be encased in a tight, parchment-like membrane. no significant abnormalities were detected at this time. In
The clinical features at birth include eclabium, ectropion,
dense plate-like scales covering the entire body, an absent/
flat nose, and flattened ears. Flexion contractures of the Received: 2018.12.05. Revised: 2019.07.04. Accepted: 2019.07.15.
limbs are also frequently observed [3]. The hands and feet Corresponding author: Madhavilatha Routhu, DMRD
may be hypoplastic and partially flexed. The disease primarily Department of Radiology, MGM Hospital, MG Rd, Mattewada,
affects the skin; however, other systems can be compromised Sherpura, Warangal, Telangana 506007, India
E-mail: [email protected]
significantly due to hyperkeratosis and tight armor-like scales https://orcid.org/0000-0003-1044-0467
which may restrict respiration. Neonates are typically born
prematurely, and males and females are affected equally. In Articles published in Obstet Gynecol Sci are open-access, distributed under the terms of
the Creative Commons Attribution Non-Commercial License (http://creativecommons.
patients with a family history, HI is diagnosed by fetal skin org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution,
biopsy. In addition to ultrasonography, DNA analyses from and reproduction in any medium, provided the original work is properly cited.

amniocentesis and chorionic villus sampling (CVS) have also Copyright © 2020 Korean Society of Obstetrics and Gynecology

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 Mudunuri Vijayakumari, et al. Harlequin ichthyosis

view of the patient’s prior history, an ultrasound with 3D and mity of all joints of the limbs was noted (Fig. 2C). As this is
4D real-time sonography was performed at 28 weeks. At an autosomal recessive condition, the parents were advised
this examination, the fetus was still in breech presentation, to participate in fetal blood sampling for DNA banking and
and there was polyhydramnios with internal echoes in the mutation analysis of the adenosine triphosphate-binding
amniotic fluid (Fig. 1A). Intrauterine growth restriction was cassette transporter protein A12 (ABCA12) gene, and to
evident. The fetal face showed hypoechoic masses located consent to having a skin biopsy for histopathological ex-
anterior to each orbit (Fig. 1B). The fetus showed a flat facial amination. However, the parents declined to participate
profile with an absent nose (Fig. 1C), a large, gaping, wide due to financial constraints. A family and medical history
open mouth (Fig. 1D), and a dysplastic ear (Fig. 2A). The fetal revealed consanguinity, but there was no history of HI
limbs showed mild flexion deformities with restricted move- cases in previous generations.
ments. The toes appeared to be short, and the fingers were
held in fixed flexion (Fig. 2B). Physicians counseled the par-
ents about the fetus’s poor prognosis and complications. A Discussion
spontaneous vaginal delivery occurred at 32 weeks, and the
baby died after 12 hours. At birth, the infant showed char- Congenital ichthyoses can be divided into 3 subtypes: lamel-
acteristics typical of HI. These included ectropion (complete lar ichthyosis, nonbullous congenital ichthyosiform erythro-
eversion of eyelids with occlusion of eyes), eclabium (eversion derma, and HI [5]. HI is the most severe form of congenital
of the lips), and thickened and fissured skin. Flexion defor- ichthyosis. The first description of HI was made in 1750 by

A B C D

Fig. 1. (A) Polyhydramnios with echogenic internal echoes. (B) Edematous eyelids. (C) Three-dimensional image showing ectropion and
eclabium and fixed and hyperflexed fingers which are typical features of HI. (D) Fetal face showing characteristic features of ichthyosis.
Left: protruding eyes; right: showing open mouth with thick lips.

A B C

Fig. 2. (A) Showing dysplastic ears. (B) Fixed and hyperflexed fingers. (C) After birth showing typical features of thick scaly skin, ecclabi-
um, absent nose ectropion and fixed flexion deformity of toes and fingers.

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Reverend Oliver Hart, and the first case of antenatal diagno- in the ABCA12 gene. However, ultrasonography can also
sis was reported in 1983 [6]. The overall incidence of HI is 1 diagnose HI, and this is particularly important as it allows
in 300,000 births [7,8]. HI is a congenital epidermal disorder antenatal diagnosis even in cases with no family history of
that shows abnormal and diffuse hyperkeratosis and loss of the disease. Early sonographic diagnosis is difficult, and most
the protective skin barrier. In humans, normal cornification of of cases are diagnosed in the third trimester. Hence, prenatal
the skin begins between 14 and 16 weeks of gestation. The ultrasonography can establish the diagnosis of HI in the early
ABCA12 gene is essential for providing instructions on how third trimester.
to make a protein that is required for normal skin cell devel- HI is a rare autosomal recessive disorder with high sub-
opment. This protein plays an important role in the trans- sequent recurrence. DNA analysis for ABCA12 mutations
port of lipids in the epidermis. Mutations in ABCA12 gene can be offered to suspected cases and to families who have
prevent the cell from making the ABCA12 protein. A loss of previously been affected. The prenatal ultrasonography
function in the ABCA12 protein disrupts the normal develop- findings suggestive of a harlequin fetus are atypical facial
ment of the epidermis. This subsequently results in extreme dysmorphism, a large open mouth, the absence of typical
thickening of the keratin layer of the skin and the forma- nasal morphology, partitioned cystic formations in front of
tion of hard scales [9]. Most of affected neonates die within the eyes, the absence of typical ear morphology, thick skin,
hours or days after birth due to sepsis, electrolyte imbalance, minimal fetal movement with stiff limbs in a semi-flexed
or mechanical restriction of breathing [10] secondary to re- position, limb anomalies with hypoplastic fingers, toes, and
stricted chest expansion and prematurity. Thickened, cracked short phalanges, clubfoot, shriveled hands that do not open,
skin leads to impaired temperature regulation and increased hyperechogenic amniotic fluid, and an absence of associated
risk of infection. The most common sonographic features ob- visceral anomalies. 3D imaging is essential for understanding
served in HI are a large open mouth, a flat nose, ectropion, the 2D images and enabling diagnosis of HI. The characteris-
short feet, and abnormal limb position. Intrauterine growth tic features in prenatal ultrasonography tend to appear late,
restriction, polyhydramnios/oligohydramnios, increased so scans should be repeated even when the second trimester
echogenicity of amniotic fluid, and floating membranes may anatomy scan is normal. In addition, these scans can help in
also be associated with HI. Because eclabium and ectropion situations when a DNA diagnosis is unavailable.
manifest in the third trimester, a diagnosis of HI based solely
on these findings occurs too late. However, achieving an
early sonographic diagnosis of HI is difficult. Short feet may Conflict of interest
be an early marker for HI, especially in families with a history
of siblings affected by HI [11,12]. The other early feature is No potential conflict of interest relevant to this article was
fixed, extremely hyperflexed toes, as described in a study by reported.
Vijayaraghavan et al. [13]. A literature review found that the
earliest diagnosis by 3D occurred at 22 weeks in cases with
a previous history, whereas in unsuspected cases the earliest Ethical approval
diagnosis was made at 30 weeks [14]. Differential diagnoses
include arthrogryposis, aplasia cutis, Gaucher disease (collo- The study was approved by the Institutional Review Board of
dion baby), Sjogren-Larsson syndrome, Conradi-Hunermann- Kakatiya Medical Colleges SVP Road Rangampet Street, Wa-
Happle syndrome, Neu Laxova syndrome, and trichothio- rangal, Telangana (ECR/840/Inst/TG/2016) and performed in
dystrophy [15]. HI is an autosomal recessive condition, and accordance with the principles of the Declaration of Helsinki.
parents who have already had an affected child have a 25% Written informed consents were obtained.
risk of recurrence in each pregnancy [16]. Consequently, the
high recurrence rate allows a prenatal diagnosis to be per-
formed for families at risk. HI can be diagnosed using either Patient consent
amniocentesis or CVS. Both of these procedures are used to
obtain a DNA sample from the fetus to look for mutations The patients provided written informed consent for the pub-

96 www.ogscience.org
 Mudunuri Vijayakumari, et al. Harlequin ichthyosis

lication and the use of their images. and management of harlequin ichthyosis. Pediatr Der-
matol 2014;31:539-46.
9. U.S. National Library of Medicine. Genetics Home Ref-
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