Keywords
Adenosine triphosphate binding cassette A12 - fetal - gene - harlequin - magnetic
resonance imaging
Introduction
Harlequin ichthyosis (HI) or Ichthyosis fetalis (IF) is a rare and severe hereditary
skin disorder with autosomal recessive inheritance.[[1],[2]] It is a unique condition because of its peculiar clinical appearance and very high
perinatal mortality.
The syndrome occurs in about 1 in 300,000 births.[[3]] Till 2003 (most recent data), 138 cases of HI have been reported. Since 1989, nearly
12 cases of HI have been diagnosed by ultrasound. The first description of congenital
ichthyosis was given in 1750 by Hart.[[4]] The first case of prenatal diagnosis of HI was reported in 1983, which was based
on skin biopsy under fetoscopy in a patient who had two infants previously affected
by the syndrome.[[5]] The first case of prenatal sonographic diagnosis of HI was reported by Mihalko
et al. in 1989.[[6]] Finally, the causative gene ABCA12 (Adenosine triphosphate binding cassette A12) was discovered in 2005. Most of the
neonates are born prematurely with low Apgar scores.[[7]] Most of the neonates succumb within days of birth due to mechanical restriction
of breathing due to reduced chest movements, pneumonia, sepsis, and electrolyte imbalance.[[8]]
The aim of the present study is to provide emphasis on MRI combined with genetic analysis
which is a more effective diagnostic method as stated by Wang et al.[[9]]
With the advancement in ultrasound resolution and knowledge of the condition, prenatal
diagnosis can be made. However, final diagnosis is done only after prenatal invasive
tests are performed or after birth of the fetus.
Case History
A 28-year-old primigravida with 31 weeks of gestation assigned by last menstrual period
(LMP) with consanguineous marriage and with no significant medical history was referred
for fetal MRI.
There was a suspicion of anterior encephalocele on an ultrasound done at the same
gestation age. With ultrasound the diagnosis did not provide any abnormality at 20
weeks. Fetal MRI was performed on Philips-Ingenia 3.0T MR system after taking informed
written consent.
T2-weighted fast (turbo) spin-echo (SE) was done in axial, coronal, and sagittal planes
with TE of 80 ms and TR of 1500 ms. T1-weighted two-dimensional gradient echo (GRE)
was done in axial plane with TE of 1.81 ms and TR of 4.23 ms. An additional diffusion-weighted
sequence was done.
There was polyhydramnios assessed subjectively. There was no evidence of any calvarial
defect or encephalocele. Eversion of bilateral eyelids (ectropion) was seen [[Figure 1]]. There were T2 hyperintense and T1 hypointense (not shown) lesions over both orbits
in the region of eyelids [[Figure 2]]. The mouth was wide-open like a fish with slightly protruded tongue [[Figure 3]] which was persistent on all sequences. These findings lead us to search for other
associated features. There was flat nose [[Figure 3]]. Clinical picture of the neonate few hours after delivery showed ectropion, bilateral
supraorbital swellings and wide open mouth [[Figure 4]]. Limbs were persistently seen in semiflexed position [[Figure 5A] and [B]]. Toes were constantly in the plantarflexed (incurved) position [[Figure 5C]] and fingers were clenched [[Figure 5D]] in every sequence. Upon very close observation, there were focal discontinuities
along the skin surface over the anterior chest wall with a skin flap [[Figure 6]]. Immediate postpartum clinical picture of the neonate showed semi flexed limbs,
incurved toes clenched fingers and skin fissuring [[Figure 7]].
Figure 1: Sagittal T2-weighted image of the fetus showing eversion of the eyelid (arrow)
Figure 2 (A and B): Sagittal T2-weighted image (A) of the fetus showing hyperintense cystic swelling
in supraorbital location (arrow). Axial image (B) showing the cystic swelling on both
sides (arrows)
Figure 3: Sagittal T2-weighted image of the fetus showing wide-open mouth (thick arrow) and
flat nose (arrow)
Figure 4: Clinical picture of the neonate few hours after delivery showing ectropion (thin
arrow), bilateral supraorbital swellings (chevron), and wide-open mouth (also seen
in Figure 7)
Figure 5 (A-D): Sagittal T2-weighted image (A) of the fetus showing semiflexed lower limb (arrow),
(B) semiflexed upper limb (arrow), (C) showing incurved toes (arrow), and (D) showing
clenched fingers (arrow)
Figure 6 (A-C): Axial (A) and sagittal (B) T2-weighted images of the fetus showing irregular skin
surface with focal areas of discontinuities (arrow) along the anterior chest wall
(C) and small focal skin flap, possibly due to exfoliation (arrow)
Figure 7: Immediate postpartum clinical picture of the neonate showing semiflexed limbs (thin
arrow), incurved toes (arrowhead), clenched fingers (chevron), and skin fissuring
which corresponds to the imaging findings
The constellation of findings raised the possibility of HI. The retrospective ultrasound
examination showed similar findings. The possible diagnosis of HI was given on MRI.
The couple was offered prenatal invasive testing to diagnose the said condition but
they refused. The female infant was born prematurely at 35 weeks. All the clinical
features of HI were present. The infant died on day 3 of life. Clinical exome sequencing
of neonate revealed a homozygous variant in ABCA12 gene with possibility of autosomal recessive congenital ichthyosis type 4B (harlequin).
Discussion
Ichthyoses belong to the group of genodermatoses, characterized by hyperkeratosis
and desquamation of the epidermis. Harlequin fetus (OMIM#242500) is the most severe
form of congenital ichthyosis.[[10]] Clinical features of a new born with HI reveals thickened, whitish to yellowish
colored, armor-like skin with fissures that divide the skin into polygonal or diamond-shaped
sections with reddish oozing cracks all over the body, ectropion, eclabium, and a
round, persistently open mouth. The nose is flat with deformed ears. The limbs are
usually in semiflexed position. Other features include the absence of scalp hair,
eyebrows, and eyelashes.[[1],[11]] Toes are persistently in the plantarflexed (incurved) position and there are persistent
clenched fingers.[[12]]
Abnormal keratinocyte lamellar granules are a typical hallmark of HI skin.[[13]] In the human fetus, cornification of the skin begins between 14 and 16 weeks of
gestation. Under light microscopy, skin from harlequin fetuses shows hyperkeratosis
with hypertrophy of the horny layers.[[4]]
Causative gene ABCA12 (Adenosine triphosphate binding cassette A12) was discovered in 2005. Severe ABCA12 deficiency causes defective lipid transport via lamellar granules (LG) in keratinizing
epidermal cells, resulting in the HI phenotype.[[13],[14],[15]]ABCA12 is a keratinocyte lipid transporter associated with LG formation and lipid transport
via LG on the surface of keratinocytes.[[14],[15]] Previously, the prenatal diagnosis had been established with fetal skin biopsy
with fetoscopy using an electron microscope.[[14],[15]] The discovery of this gene enabled prenatal diagnosis of HI by chorionic villus
or amniotic fluid sampling in the earlier stages of pregnancy, particularly in cases
of previously affected pregnancies.
Diagnostic imaging features include those described above. There may be polyhydramnios
debris in amniotic fluid. The characteristic features which lead to suspicion of HI
and which are constantly present are, bilateral ectropion with cystic swellings in
front of the eyes, persistently wide-open mouth, eclabium, persistently semiflexed
limbs, and constantly plantarflexed (incurved) toes.[[12],[16]] The features of HI are typically seen in late gestation so the second-trimester
scan can be normal in most of the cases.[[12]] With the above features diagnosis of HI can be achieved with fair confidence particularly
in patients with no previous infant diagnosed with HI. With the history of HI in previous
pregnancy, early diagnosis of HI can be achieved with prenatal invasive tests as there
is 25% recurrence risk in each pregnancy.
Conclusion
HI is a rare autosomal recessive genetic disorder presenting in utero which is extremely
difficult to diagnose with imaging. It is important for the radiologist to be aware
of this disease entity and should specifically look for the characteristic imaging
findings of HI. These findings may appear during the late second or early third trimester
and may be suspected on ultrasound and confirmed on MRI. Prenatal genetic diagnosis
should be advice to couples with previously affected infants.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
