DOI: 10.1111/pde.

13770

Pediatric
CASE REPORT Dermatology

ABCA12 homozygous mutation in harlequin ichthyosis: Survival

without systemic retinoids

Amit Sharma MD1  | Arlene Rozzelle MD2 | Jagdish Desai MD3 | 

Tor A. Shwayder MD, LRAM4  | Esther Kisseih MD1 | Justin R. Bryant DO, MBA5 | 
Prashant Agarwal MD1

1
Department of Neonatal-Perinatal, 
Children's Hospital of Michigan, Abstract
 Neonatal-Perinatal Medicine, Harlequin ichthyosis (HI) is associated with high mortality. Early systemic retinoids
Detroit, Michigan
2
are widely used, although their use remains debatable. We reported two neonates
Department of Plastic Surgery, Children's
Hospital of Michigan, Detroit, Michigan with homozygous mutations in ABCA12 consistent with harlequin ichthyosis who
3
Department of Neonatal-Perinatal,  survived to discharge home with intensive care and without use of systemic
University of Mississippi Medical Center,
retinoids.
Jackson, Mississippi
4
Department of Pediatric Dermatology, 
KEYWORDS
Henry Ford Hospital, Detroit, Michigan
5 ichthyosis, neonatal, retinoids
Department of Plastic Surgery, Beaumont
Hospital—Farmington Hills, Farmington Hills,
Michigan

Correspondence
Amit Sharma, MD, Department of Neonatal-
Perinatal, Children's Hospital of Michigan,
Neonatal-Perinatal Medicine, Detroit, MI.
Email: dramit55555@gmail.com

1 |  I NTRO D U C TI O N
Harlequin ichthyosis (HI) is the most severe and rare form of congen-
ital ichthyosis. It is an autosomal recessive disorder caused by patho-
genic variants in ABCA12.1 Patients are at high risk for mortality from
septicemia, respiratory compromise, hypothermia, and dehydration.
Use of early systemic retinoids in management of infants with HI has
been successful in some. We report two infants with HI and homo-
zygous mutations in ABCA12 who survived to discharge home with
intensive care without use of systemic retinoids.
2 |  R E P O RT O F C A S E S
2.1 | Case 1
A 28-­
year-­
old Yemeni woman with limited prenatal care pre-
sented with premature rupture of membranes at 36 2/7 weeks
with breech fetal presentation. A vigorous 2710-­g birthweight
male infant was delivered by cesarean section and did not require
any respiratory support. At birth, he was noticed to have general-
ized diffuse thick plaquelike scaly plates separated by deep fis-
sures; ectropion; eclabium; flexion contractures at bilateral knees;
and tapered, small, contracted fingers and toes, consistent with
diagnosis of HI (Figure 1). A previous infant with similar appear-
ance expired at 6 days of life. Mother denied consanguinity. He
was placed in a heated humidified incubator, total parenteral nu-
trition was administered, and enteral feeding was introduced via
oro-­g astric tube and gradually advanced. He received daily bleach
baths and liberal application of petrolatum ointment to skin and
lubricant eye ointment to eyes. Decision was made not to start
retinoids after discussion between dermatology and family. Serial
skin debridement and plaque removal with atraumatic, blunt re-
lease of contracture was done for chest, eyelids, mouth, and digits,
followed by the rest of the body.
Genetic testing revealed homozygous mutations in exon 23 of
ABCA12 (c.3256A>T; p.lys1086term), consistent with HI.

Pediatric Dermatology. 2019;1–3. © 2019 Wiley Periodicals, Inc. |  1

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2       Pediatric
Dermatology
F I G U R E   1   Patient at birth: generalized edema with thick
hyperkeratotic plates over his entire body and scalp
By week 3, he was able to open and close both eyelids. On day
29, he had a fever and was started on broad-­spectrum antibiot-
ics. The blood culture grew Candida albicans, and a 3-­week course
of amphotericin B was given. Eclabium improved gradually, and
he was nippling all feeds by week 7. Humidity in incubator was
slowly decreased, and the infant was successfully transferred to a
crib around 10 weeks of age. At 11 weeks, he had increased work
of breathing and required intubation and mechanical ventilation.
Sepsis evaluation revealed Pseudomonas aeruginosa bloodstream
infection, and 2 weeks of antibiotics were administered. With
serial debridement, range of motion improved gradually over the
next few weeks. He was discharged home on week 15 with appear-
ance of congenital ichthyosiform erythroderma (Figure 2).
2.2 | Case 2
A 26-­year-­old Lebanese woman was referred for fetal ultrasonographic
evaluation at 30 weeks gestation, which showed bilateral cystic struc-
tures at the position of the orbits; suspected thick and everted eyelids
with protruding appearance (ectropion); and fixed, widely open mouth,
associated with constantly protruding tongue with outward turned
lips (eclabium) with hands appearing clenched. Flexion contractures
were noted at wrists and elbows. A diagnosis of HI was suspected. She
subsequently presented with premature rupture of membranes at 35
4/7 weeks, and a 2215-­g birthweight girl was delivered by vaginal de-
livery with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively.
She was able to maintain oxygenation without any respiratory support.
The infant had eclabium, ectropion, and severe contractures at
bilateral wrists and ankles; and tapered, small, contracted fingers
and toes. The skin showed extensive hyperkeratosis, diffuse yellow
thick plaques, separated by deep fissures with erythematous skin
overlying the entire body surface area. She was placed in a humid-
ified, heated incubator with contact isolation precautions. Serum
electrolytes were monitored closely and intravenous fluid adminis-
tration was adjusted accordingly. Nutrition was provided via an oro-­
gastric tube and total parental nutrition. She received daily (0.01%
SHARMA et al.
F I G U R E   2   Patient at 4 mos: after shedding the plates of scale
hypochlorite) bleach baths, and liberal amounts of petrolatum oint-
ment were applied to skin and lubricant eye ointment to eyes. Based
on the discussion with the dermatologist and family, decision was
made not to start systemic retinoids. Genetic testing revealed ho-
mozygous mutations in ABCA12, c.3882G>A; p.Trp1294Term, con-
sistent with harlequin ichthyosis. The parents denied consanguinity.
Around 2 weeks of life, edema of fingers due to constriction from
tight, thick hyperkeratotic circular bands with threatened autoampu-
tation was relieved by a bedside linear band atraumatic release pro-
cedure. By week 3, most of the thick plaques on trunk, arms, and legs
had shed, although thick plaques remained on scalp, eyelids, face, and
ear pinnae. Humidity in the incubator was slowly decreased, and the
infant was transferred to a crib around 5 weeks. She developed a scalp
abscess around 7 weeks of age, which required incision and drainage
and oral antibiotics. Over the next few weeks, the pseudocontractures
of the extremities, fingers, and toes and bilateral ectropion gradually
improved, with dramatic improvement in the range of motion of all ex-
tremities and complete closure of the eyes. She was discharged home
on day 72 with appearance of congenital ichthyosiform erythroderma.
3 | D I S CU S S I O N
Harlequin ichthyosis is a severe, frequently lethal autosomal reces-
sive genetic disorder due to mutations in the gene ABCA 12 encod-
ing the adenosine triphosphate-­binding cassette (ABC) transporter
protein.1,2 Genotype-­
phenotype correlations are uncertain. In a
review of 38 cases of HI by Rajpopat et al, 11 of 21 survivors had
compound heterozygous mutations. All deaths (n = 17) occurred in
infants with homozygous mutations.3
Treatment of HI needs to be aggressive in regard to environment
(Neonatal Intensive Care Unit setting, humidity, temperature), electro-
lyte monitoring, infection prevention and monitoring, topical skin treat-
ments, and surgical approaches. Early systemic retinoid may improve
survival and is increasingly used for management of HI.4-6 A retrospec-
tive study assessing the clinical outcome of HI revealed that 83% of
SHARMA et al.
infants treated with retinoid survived compared to 24% survival among
3
infants who did not receive systemic retinoid. However, a majority of
deaths occurred in this study in the first 3 days of life, whereas only
45% of treated survivors received oral retinoid within this time frame,
suggesting that this cohort may have contained infants more likely to
survive irrespective of treatment. Systemic retinoid treatment can have
both acute and chronic toxicity, and aggressive nonmedical manage-
ment can be successful, as it was in our patients, and so it may be a
reasonable approach.
ORCID
Amit Sharma  https://orcid.org/0000-0002-2033-5313
Tor A. Shwayder  https://orcid.org/0000-0001-9531-0164
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How to cite this article: Sharma A, Rozzelle A, Desai J, et al.
ABCA12 homozygous mutation in harlequin ichthyosis:
Survival without systemic retinoids. Pediatr Dermatol.
2019;00:1–3. https://doi.org/10.1111/pde.13770