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\begin{document}

\title{Harlequin Ichthyosis: a case report and literature review.}



\author[1]{Abhigan  Shrestha}%
\author[2]{prince biswas}%
\author[3]{sajina shrestha}%
\author[4]{shumneva shrestha}%
\author[5]{romana riyaz}%
\author[6]{Muhammad Hassnain Nawaz}%
\author[7]{Labiba hossainy}%
\affil[1]{M Abdur Rahim Medical Medical College Hospital}%
\affil[2]{Rajshahi University}%
\affil[3]{KIST Medical College}%
\affil[4]{Tribhuvan University Institute of Medicine}%
\affil[5]{Shadan Institute of Medical Sciences}%
\affil[6]{Dinajpur Medical College}%
\affil[7]{Shaheed Ziaur Rahman Medical College}%


\vspace{-1em}



  
  \date{March 13, 2025}


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\selectlanguage{english}
\begin{abstract}
Harlequin Ichthyosis is a rare autosomal recessive disorder occurring in
1: 3,000,000 birth characterized by thick keratin skin with scaly
appearance. Preterm deliveries, early marriage and consanguinity of
marriage are some risk factors. Antenatal checkup of DNA for ABCA12
mutation helps in diagnosis but USG in places where not available.%
\end{abstract}%



\sloppy


\textbf{Harlequin Ichthyosis: a case report and literature review.}

Abhigan Babu Shrestha\textsuperscript{1}, Prince
Biswas\textsuperscript{2}, Sajina Shrestha\textsuperscript{3}, Romana
Riyaz\textsuperscript{4}, Muhammad Hassnain Nawaz\textsuperscript{1},
Shumneva Shrestha\textsuperscript{5}, Labiba Hossainy\textsuperscript{6}

\textsuperscript{1} M Abdur Rahim Medical College, Dinajpur, Bangladesh.

\textsuperscript{2} Rajshahi Medical College, Rajshahi, Bangladesh.

\textsuperscript{3} KIST Medical College, Imadol, Patan, Nepal.

\textsuperscript{4} Shadan Institute of Medical Sciences and Research,
Hyderabad, Telangana, India.

\textsuperscript{5}MaharajgunjMedical Campus, Institute of Medicine,
Tribhuvan University, Kathmandu, Nepal.

\textsuperscript{6} Department of Pediatrics, Shaheed Ziaur Rahman
Medical College Hospital, Bogra, Bangladesh.

Corresponding author: ABS

Email: abigan17@gmail.com

Author contribution: ABS: conceptualization; RR, MHN, SS: writing
manuscript; ABS and SS: manuscript editing and writing; PB: patient
information collection; LH: supervisor. All authors reviewed the article
and agreed on submission.

Consent statement: Informed written consent has been taken from the
patient and will be provided on request.

Acknowledgement: No authors has been funded for this manuscript.

Abstract:

Harlequin Ichthyosis is a rare autosomal recessive disorder occurring in
1: 3,000,000 birth characterized by thick keratin skin with scaly
appearance. Preterm deliveries, early marriage and consanguinity of
marriage are some risk factors. Antenatal checkup of DNA for ABCA12
mutation helps in diagnosis but USG in places where not available.

Keywords: harlequin ichthyosis, ichthyosis congenital, genetic disorder,
ABCA12 mutation.

\textbf{Introduction:}

Harlequin ichthyosis (HI) is the most dangerous form of the autosomal
recessive congenital~ichthyosis characterized with thickening of keratin
part of the baby's~skin and~a gross thick scaly appearance, which is
triangular or diamond pattern.\textsuperscript{1} The name takes origin
from its characteristic facial appearance as the face is pulled wide
open in manner of a clowns smile. Marked ectropion and eclabium with
absent or poorly developed ears and nose, mobility limitation of joints
are some of the clinical features of HI.\textsuperscript{1} As the skin
barrier is severally compromised there is excessive water loss and
electrolyte abnormalities followed by temperature dysregulation and
increase risk of infections. Because of these reason HI is usually fatal
albeit aggressive management.

\textbf{Case presentation:}

A 20 years old pregnant woman was admitted to our Pediatrics department
for her second pregnancy due to preterm, premature rupture of membrane
and obstetric pain. Her gestational age of pregnancy was approximately
36 weeks based on the first day of the last menstrual period. No
remarkable complication were seen in the last ultrasound examination
(USG) at 28\textsuperscript{th} weeks of pregnancy. She had negative
history of consanguinity of marriage, any relevant past medical history
and her family members reporting such condition. She denied of having
any allergy history and was immunized against Tetanus Toxoid and
Covid-19 vaccine. Her first child died due to neonatal jaundice after 5
days of birth via caesarean section few years ago.

Her physical examinations were all normal and initial conservative
treatment was given along with Inj. Dexamethasone 5mg, 2.5 ampoule IM
stat. Then, the patient was counselled for caesarean section mode of
delivery.

A female, 2.5 kg baby with Harlequin Ichthyosis was born. Figure 1. HI
features were noted by the presence of thick skin with deep fissures,
general hyperkeratinization, cyanosis, flat fontanels, ectropion,
immature eyes and auricles, bradycardia, bradypnea, and moaning in the
physical examination. Her APGAR score was 3 in the
1\textsuperscript{st}minute and the 5\textsuperscript{th} minute.
Immediately, she was referred to neonatal intensive care unit. However,
the father of the child was unwilling for the treatment despite several
attempts of counseling and had to be discharged with a risk bond.

Patient's parents perspective:

The patient's parents belonged from a lower-middle-income family and
didn't had enough money for the management. In addition, they mentioned
about the social stigmata being a important role to not to treat the
baby. According to their statement, they weren't informed about such
condition on their previous USG reports nor performed any anomaly scan
of the fetus. However, we counselled them about the genetic condition
and need for caution in the future pregnancies with proper test to
detect HI.

\textbf{Discussion:}

Harlequin ichthyosis, also called as keratosis diffusa foetalis or
ichthyosis congenital, is a rare disorder found equally in both
sexes\textsuperscript{1} with an overall incidence of 1:300,000 births.
Currently, more than 100 cases have been described in the
literature.\textsuperscript{2} The first case was reported by Oliver
Hart in 1750.\textsuperscript{3} This condition is usually seen in
premature babies, early pregnancies, preterm delivery, and more often in
consanguineous marriages.\textsuperscript{4,5} In such cases, vaginal
delivery is generally the norm while in high-risk pregnancies, caesarean
delivery is performed. In our case, the young mother presented with
obstetric pain and preterm premature rupture of membrane as an obstetric
emergency and caesarean delivery was performed. The recurrence of this
condition in the subsequent pregnancy is estimated to be
25\%.\textsuperscript{6} Hence, it is crucially important to counsel the
parents regarding the genetic disorder and its probability in their next
conception.

HI is clinically diagnosed at birth with the typical presentation of
large, coarse, shiny, yellowish brown, generalized hyper-keratinized
sticky plates resulting in constricted mobility in upper and lower limbs
with clasped fists and incurved toes. Later, deep fissures or cracks
occur on these hard plates that spread to the dermis. Neonates with HI
have growth retardation, eclabium, edema, microcephaly, and
ectropion.\textsuperscript{7} Ear appendages, nostrils look undeveloped
and immature.\textsuperscript{8} Additionally, neonates have
hypothermia, hypoglycemia, water and electrolytes imbalance,
dehydration, infections, sepsis, inadequate feeding habits, renal
failure, and more often respiratory complications as a result of limited
chest expansion and skeletal abnormalities, eventually leading to death
in the early days of life.\textsuperscript{9,10}

Later in surviving patients, the hyperkeratotic scales fall off in the
first few months, leaving an overlying persistent erythematous skin. In
our patient, all these features were present suggestive of HI. Several
studies have reported the presence of mutations in the ABCA12
(Adenosine-triphosphate-Binding Cassette A12) gene encoding a protein
for lipid transport in the skin are involved in the pathophysiology of
the disease. The ABCA12 gene on chromosome 2 translates a protein
involved in keratinocyte lipid transport across the epidermis of the
skin which helps in the physiological development of skin and controls
the progression of desquamation. The lack of normal ABCA12 function of
transportation of lipids from the cytosol to the lamellar granules
results in defective skin permeability and accumulation of
scales.\textsuperscript{11,12}

Prenatal diagnosis is important and helps in early detection of the
disease. Chorionic villous sampling and microscopic analysis of the
amniotic fluid cells and USG especially 3D USG for assessment of the
shape of the fetal mouth particularly during the early third trimester
of pregnancy have been useful for early
detection.\textsuperscript{13}Akiyama et al. specified the first
DNA-based prenatal diagnosis of HI by direct sequential analysis of
ABCA12 gene mutation from amniotic fluid cells and established the
efficiency of early DNA-based prenatal diagnosis.\textsuperscript{14}

In addition to this, obtaining a detailed account of family history,
previous obstetric history, consanguinity between the parents, and the
presence of other dermatological disorders in other offspring is equally
important.\textsuperscript{15} Postnatal diagnosis includes a skin
biopsy that probably shows structural abnormalities of lamellar granules
and epidermal keratin expression and is confirmed by testing for ABCA12
gene mutation. Generally, the late phenotypic expression of this
condition possesses a challenge and leads to missed or delayed diagnosis
on prenatal scans.\textsuperscript{12} Similarly in our case, there was
no remarkable complication noted in the last ultrasound examination at
28 weeks of pregnancy. Hence, the gross appearance of the fetus is
usually insufficient for diagnosis. To prevent complications and tackle
its associated comorbidities multi-disciplinary team management is
required.

Initial management necessitates monitoring in Neonatal intensive care
unit settings (NICU) including supportive therapy to maintain quality of
life by use of humidified incubator for monitoring temperature
regulation. Intubation helps with the airway and breathing. Maintenance
of fluids, electrolytes, and nutritional support through umbilical
cannulation as access to peripheral veins becomes difficult. Limb
contracture leads to amputation due to the presence of tissue necrosis
and gangrene. Hence, it should be a reminder for surgical intervention
using autologous skin grafts with the utmost care, physiotherapy,
analgesia for painful deep fissures and proper infection
control.\textsuperscript{16} Eye care by artificial tears lubrication
and frequent evaluation by ophthalmologists is recommended. Repeated
blockage of the ear canal may occur and debridement is often required.
Mild ointments should be applied to make skin soft and soaking with
saline compressions helps in desquamation. Further repeated skin culture
would be crucial to detect harmful microorganisms.\textsuperscript{8}

A comprehensive case series comprising 45 patients assessed by Rajpot et
al. suggested early oral retinoids, aid in the shedding of
hyperkeratotic scales, with an overall survival rate of more than
50\%.\textsuperscript{17} Some studies have shown systemic retinoids can
improve survival rates but have both acute and chronic
toxicity.\textsuperscript{18} In addition, genetic counselling and
molecular investigation of the ABCA12 gene should be considered in
subsequent pregnancies as an autosomal recessive disease has been
recognized. Studies should further investigate the possible use of
immunotherapy.

Critical factors in this patient's management include cooperation and
educating the family about the outcomes and options because HI has a
social disgrace in our country linked with lack of Knowledge and
awareness of the disease and to avoid further endangering the child. Our
patient was discharged on request after birth due to non-compliance by
her father.

\textbf{Conclusion:}

HI is a severe lethal disorder yet preventable with proper antenatal
checkup. In low-middle income countries like Bangladesh, it is highly
important to focus on routine Antenatal follow-up for at least four
times. Although DNA analysis for ABC12 mutation will help to diagnose
the case in prenatal period, this might be tough in developing nations.
Alternative approach is via USG during second trimester, but in our case
a single USG couldn't catch the anomaly hence, repeated USG is highly
advisable.

Data availability statement: Not applicable.

Funding statement: No funding was received for this study.

Conflict of interest disclosure: None declared.

Ethics approval statement: Not applicable.

Patient consent statement: A formal written consent was obtained from
the patients parents for drafting this manuscript.

Permission to reproduce material from other sources: Not applicable.

Clinical trial registration: Not applicable.

\textbf{References:-}

1. Thomas AC, Cullup T, Norgett EE, et al. ABCA12 is the major harlequin
ichthyosis gene.\emph{J Invest Dermatol}. 2006;126(11):2408-2413.
doi:10.1038/sj.jid.5700455

2. Ramteke S, Agrawal A, Shrivastava J. Harlequin Icthyosis: A Rare
Disorder. \emph{Indian J Case Reports}. Published online September 27,
2016:69-71. doi:10.32677/IJCR.2016.v02.i03.007

3. Javed T, Afzal MF, Khan HI. Harlequin fetus: a case report. \emph{J
Pak Assoc Dermatol}. 2005;15(4):348-350. Accessed September 18, 2022.
http://www.jpad.com.pk/index.php/jpad/article/view/670

4. Tayebi N, Yazdani K, Naghshin N. The prevalence of congenital
malformations and its correlation with consanguineous marriages.
\emph{Oman Med J}. 2010;25(1):37-40. doi:10.5001/omj.2010.9

5. Holden S, Ahuja S, Ogilvy-Stuart A, Firth HV, Lees C. Prenatal
diagnosis of Harlequin ichthyosis presenting as distal arthrogryposis
using three-dimensional ultrasound. \emph{Prenat Diagn}.
2007;27(6):566-567. doi:10.1002/pd.1727

6. Couto PA, Pastore MC, Ara\selectlanguage{ngerman}újo JCN, et al. Harlequin Ichthyosis: Case
Report. \emph{Journal of the Portuguese Society of Dermatology and
Venereology}. 2019;77(1):55-58.
https://revista.spdv.com.pt/index.php/spdv/article/download/984/619/

7. Dyer JA, Spraker M, Williams M. Care of the newborn with ichthyosis.
\emph{Dermatol Ther}. 2013;26(1):1-15.
doi:10.1111/j.1529-8019.2012.01555.x

8. Salehin S, Azizimoghadam A, Abdollahimohammad A, Babaeipour-Divshali
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2013;18(11):1004-1005. https://www.ncbi.nlm.nih.gov/pubmed/24520234

9. Tahir A, Tariq SM, Haider SA, Hasan M. Ichthyosis Congenita,
Harlequin Type: A Fatal Case Report.\emph{Cureus}. 2018;10(10):e3524.
doi:10.7759/cureus.3524

10. Kelsell DP, Norgett EE, Unsworth H, et al. Mutations in ABCA12
underlie the severe congenital skin disease harlequin ichthyosis.
\emph{Am J Hum Genet}. 2005;76(5):794-803. doi:10.1086/429844

11. Fatima S, Rafiq A, Majid Z. Harlequin ichthyosis in an infant born
to a father with eczema.\emph{J Trop Pediatr}. 2015;61(2):143-145.
doi:10.1093/tropej/fmu072

12. Rathore S, David LS, Beck MM, Bindra MS, Arunachal G. Harlequin
Ichthyosis: Prenatal Diagnosis of a Rare Yet Severe Genetic Dermatosis.
\emph{J Clin Diagn Res}. 2015;9(11):QD04-QD06.
doi:10.7860/JCDR/2015/15250.6705

13. Shimizu A, Akiyama M, Ishiko A, Yoshiike T, Suzumori K, Shimizu H.
Prenatal exclusion of harlequin ichthyosis; potential pitfalls in the
timing of the fetal skin biopsy. \emph{Br J Dermatol}.
2005;153(4):811-814. doi:10.1111/j.1365-2133.2005.06778.x

14. Akiyama M, Titeux M, Sakai K, et al. DNA-based prenatal diagnosis of
harlequin ichthyosis and characterization of ABCA12 mutation
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doi:10.1038/sj.jid.5700617

15. Ogbe W Z, Alarabi TGM. Harlequin ichthyosis: A case report of severe
presentation in Eritrea.\emph{Clin Case Rep}. 2020;8(11):2152-2154.
doi:10.1002/ccr3.3076

16. Tsivilika M, Kavvadas D, Karachrysafi S, Sioga A, Papamitsou T.
Management of Harlequin Ichthyosis: A Brief Review of the Recent
Literature. \emph{Children}. 2022;9(6). doi:10.3390/children9060893

17. Rajpopat S, Moss C, Mellerio J, et al. Harlequin ichthyosis: a
review of clinical and molecular findings in 45 cases. \emph{Arch
Dermatol}. 2011;147(6):681-686. doi:10.1001/archdermatol.2011.9

18. Sharma A, Rozzelle A, Jahnke MN, et al. ABCA12 homozygous mutation
in harlequin ichthyosis: Survival without systemic retinoids.
\emph{Pediatr Dermatol}. 2019;36(3):339-341. doi:10.1111/pde.13770

Figure legends:

Figure 1. Extensive areas of diamond-like skin and fissuring
characteristic of harlequin ichthyosis.\selectlanguage{english}
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