Harlequin ichthyosis is the most severe form of autosomal recessive congenital ichthyosis.[1] Harlequin ichthyosis is characterized by a profound thickening of the keratin layer in fetal skin. The affected neonate is born with a massive, horny shell of dense, platelike scale and contraction abnormalities of the eyes, ears, mouth, and appendages, as is shown in the images below.
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Harlequin ichthyosis. Courtesy of Dr Bernice Krafchik.
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Harlequin ichthyosis. Courtesy of Jason K Rivers, MD, FRCPC, and Dr Lawler.
The term harlequin derives from the facial appearance and the triangular and diamond-shaped pattern of hyperkeratosis. The newborn's mouth is pulled wide open, mimicking a clown's smile.
Marked eclabium and ectropion are present secondary to the taut, unyielding skin. The ears may be absent or poorly developed. The arms, feet, and digits have flexion contractures and may be hypoplastic. The skin barrier is severely compromised, leading to excessive water loss, electrolyte abnormalities, temperature dysregulation, and an increased risk of life-threatening infection. The tight, armorlike scale can restrict respiration. Poor feeding and impaired intestinal absorption are common.
This disease primarily affects the skin. Other systems may be significantly compromised by the hyperkeratosis and concomitant deformities. Neonates are often born prematurely.
The underlying genetic abnormality in harlequin ichthyosis is a mutation in the lipid-transporter gene ABCA12 on chromosome 2.
Immunohistocytochemical examination of the skin reveals characteristic abnormalities in the structure of lamellar granules and in the expression of epidermal keratin.
In the past, harlequin ichthyosis was uniformly fatal. Improved survival has been achieved with intense supportive care and systemic retinoid therapy in the neonatal period. Patients who survive manifest a debilitating, persistent ichthyosis similar to severe congenital ichthyosiform erythroderma.[1, 2]
Other Medscape articles on ichthyosis include Hereditary and Acquired Ichthyosis Vulgaris, Lamellar Ichthyosis, X-Linked Ichthyosis, and Ichthyosis (ophthalmology focus).
Mutations in ABCA12, a gene that encodes adenosine triphosphate (ATP)-binding cassette transporter (ABC), subfamily A, member 12, in chromosome region 2q35, underlie this disorder.[3, 4] Patients with harlequin ichthyosis usually have functional null mutations in the ABCA12 gene. The mutations may be homozygous or compound heterozygous.[5] Missense mutations in ABCA12 result in milder autosomal recessive congenital ichthyosis phenotypes such as lamellar ichthyosis and congenital ichthyosiform erythroderma.[1, 4, 6]
The ABC superfamily of genes encodes proteins that transport a number of substrates across cell membranes.[6] ABCA12 encodes a transmembrane protein that mediates lipid transport.
This ABCA12 -mediated lipid-transfer system is essential to the transfer of lipids from the cytosol of the corneocyte into lamellar granules. Lamellar granules are intracellular granules that originate from the Golgi apparatus of keratinocytes in the stratum corneum. These granules are responsible for secreting lipids that maintain the skin barrier at the interface between the granular cell layer and the cornified layer in the upper epidermis. The extruded lipids are arranged into lamellae in the intercellular space with the help of concomitantly released hydrolytic enzymes. The lamellae form the skin's hydrophobic sphingolipid seal.
In harlequin ichthyosis, the ABCA12 -mediated transfer of lipid to lamellar granules is defective. The lamellar granules themselves are morphologically abnormal or absent. Normal extrusion of lipid from these granules into the extracellular space cannot occur, and lipid lamellae are not formed. This defective lipid "mortar" between corneocyte "bricks" results in aberrant skin permeability and lack of normal corneocyte desquamation.[7, 8, 9]
In vitro studies have demonstrated normalization of lipid transport when the wild-type ABCA12 gene is transferred to keratinocytes of patients with harlequin ichthyosis.[10]
One patient with a de novo deletion of chromosome arm 18q has been reported.[11]
Histopathologic, ultrastructural, and biochemical factors
Histopathologic, ultrastructural, and biochemical studies have identified several characteristic abnormalities in the skin of patients with harlequin ichthyosis.
The two main abnormalities involve lamellar granules and the structural proteins of the cell cytoskeleton. The relationship between mutations in the gene ABCA12 and abnormal lamellar granules is well documented. The pathophysiology of the other abnormalities documented below has yet to be elucidated.
Abnormal lamellar granule structure and function
The pivotal role of lamellar granules in maintaining a normal skin barrier is described in the Genetic factors bullet points at the beginning of this section.
All patients with harlequin ichthyosis have absent or defective lamellar granules and no extracellular lipid lamellae. Cultured epidermal keratinocytes from patients that carry ABCA12 mutations have demonstrated disturbed intracytoplasmic glucosylceramide transport.[6, 10] The lipid abnormality is believed to allow excessive transepidermal water loss. Lack of released lamellar granule enzymes prevents desquamation, resulting in a severe retention hyperkeratosis.
Abnormal conversion of profilaggrin to filaggrin
Profilaggrin is a phosphorylated polyprotein residing in keratohyalin granules in keratinocytes in the granular cell layer. During the evolution to the corneal layer, profilaggrin converts to filaggrin by means of dephosphorylation. Filaggrin allows dense packing of keratin filaments. Its subsequent breakdown into amino acids occurs prior to desquamation of the stratum corneum.
Some patients have a persistence of profilaggrin and an absence of filaggrin in the stratum corneum. A defect in protein phosphatase activity and subsequent lack of conversion of profilaggrin to filaggrin is hypothesized.[6]
Abnormal expression of keratin
Disturbed keratinocyte differentiation during fetal development is believed to play an important role in the pathogenesis of the harlequin ichthyosis phenotype at birth.[6] In utero studies have shown that expression of markers of late keratinocyte differentiation is highly dysregulated, suggesting a role for ABCA12 in keratinocyte differentiation.[12] Expression of the proteases kallikrein 5 and cathepsin D, which are required for normal desquamation, was found to be dramatically reduced.[12]
Keratin filament density is low in most patients. Expression of certain keratins is abnormal in some patients and normal in others. How this altered expression of structural proteins influences desquamation is uncertain.
Abnormal keratohyalin granules
Keratohyalin granules are identified by antifilaggrin antibodies and can be abnormal in some patients with harlequin ichthyosis. They can be large and stellate, small and rounded, or absent.
Approximately 200 cases of harlequin ichthyosis have been reported.[5] The incidence is calculated to be around 1 case in 300,000 births.[5]
Race
No racial predilection is known for harlequin ichthyosis. A higher incidence may be encountered in cultures where parental consanguinity is common.[13]
The mortality for harlequin ichthyosis rate is high, with worldwide figures approaching 50%. A review of 45 cases by Rajpopat et al found 25 survivors (56%), ranging in age from 10 months to 25 years. Twenty deaths (44%) occurred from day 1 to day 52 and were as likely to be caused by respiratory failure as fulminant sepsis.[13] A Japanese survey of 16 patients reported survival of 81.3% (13 of 16 patients).[14] Respiratory failure, fulminant sepsis, or a combination of both are the most common causes of death in affected newborns.[13]
Advise parents and caregivers that the baby’s appearance will improve after the neonatal period. Emphasize the need for attention to skin lubrication and for compliance with systemic therapy. Teach them to recognize signs of infection.
Congenital ichthyoses can have devastating medical and social consequences. Parents may wish to communicate with other families who have been similarly affected. Patient organizations (eg, The Foundation for Ichthyosis and Related Skin Types [FIRST]) are available in several countries to provide support to families.
Harlequin ichthyosis manifests at birth. Harlequin ichthyosis may or may not have been diagnosed prenatally in a high-risk family. The history should explore the following questions:
Are the parents consanguineous?
Have they had a previous child with ichthyosis?
Does the family have a history of severe skin disorders?
Do the parents or family members have a history of intrauterine or neonatal death?
What was the expected date of delivery?
Were decreased fetal movements or intrauterine growth retardation noted during the pregnancy?
Did the mother undergo prenatal ultrasonography?
Were prenatal procedures (eg, amniocentesis, chorionic villus sampling) performed?
The following findings may be noted on physical examination in the newborn period:
Skin: Severely thickened skin with large, shiny plates of hyperkeratotic scale is present at birth. Deep, erythematous fissures separate the scales.
Eyes: Severe ectropion is present. The free edges of the upper and lower eyelids are everted, leaving the conjunctivae and cornea at risk for desiccation and trauma.
Ears: The ears are flattened with absent retroauricular folds. The pinnae may be small and rudimentary or absent. The external auditory canal may be obstructed by scale.
Lips: Severe traction on the lips causes eclabium and a fixed, open mouth. This may result in feeding difficulties.
Nose: Nasal hypoplasia and eroded nasal alae may occur. The nares can be obstructed.
Extremities: The limbs are encased in the thick, hyperkeratotic skin, resulting in flexion contractures of the arms, the legs, and the digits. Limb mobility is poor to absent. Circumferential constriction of a limb or digit can occur, leading to distal swelling, ischemic necrosis and autoamputation. Hypoplasia of the fingers, toes, and fingernails is reported. Polydactyly is described.
Temperature dysregulation: Thickened skin prevents normal sweat gland function and heat loss. The infant is heat intolerant and can become hyperthermic.
Respiratory status: Restriction of chest-wall expansion can result in respiratory distress, hypoventilation, and respiratory failure.
Hydration status: Dehydration from excess water loss can cause tachycardia and poor urine output.
Central nervous system: Metabolic abnormalities can cause seizures. CNS depression can be a sign of sepsis or hypoxia. Hyperkeratosis may restrict spontaneous movements, making neurologic assessment difficult.
Infants who survive the newborn period have a lifelong, severe ichthyosiform erythroderma.
Recurrent skin infections may continue after the newborn period.
Contractures and painful fissuring of the hands and the feet may occur. Rajpopat et al reported palmoplantar keratoderma in 52% of survivors, causing pain and delay in walking.[13]
Pruritus was reported in 44% of patients, heat and cold intolerance was found in 36%, reduced sweating was found in 28%, and photosensitivity and pigmented macules were found in one patient each.[13] Poor hair growth and nail deformities were common. Hearing impairment may result from obstruction of the ear canals by skin debris.
Developmental delay and normal intellectual development are described. Rajpopat et al reported that most school-aged survivors were attending mainstream schools, although many needed additional help.[13]
Growth must be closely monitored. Short stature is common and weight below average. Nutritional rickets due to vitamin D deficiency is reported.[13] This is likely due to defective vitamin D synthesis in the abnormal skin, calcium loss, and reduced exposure to sunlight.
Inflammatory arthritis and permanent contractures may occur.[13] Hypothyroidism and juvenile idiopathic arthritis have been reported in a patient with harlequin ichthyosis.[15]
Harlequin ichthyosis can be associated with ostium secundum atrial septal defect. A 2019 case series reported that echocardiography revealed this cardiac abnormality in harlequin ichthyosis patients.[16] However, the ostium secundum atrial septal defect was noted to close spontaneously. These need to be monitored over time.
A diagnosis of harlequin ichthyosis is usually made by clinical examination in the newborn.
Prenatal diagnosis of harlequin ichthyosis is made by analysis of fetal DNA obtained by chorionic villus sampling or amniocentesis.
In the absence of a family history, a prenatal diagnosis of harlequin ichthyosis can be suspected or identified by ultrasonography.
Investigations in the newborn with harlequin ichthyosis are performed to identify the gene mutation, to monitor supportive care, and to identify complications.
Genetic testing for mutations in the ABCA12 gene is available. Complete sequence analysis of the coding region of this gene is performed to identify specific mutations. Peripheral blood cells or cells from a buccal smear from affected individuals are required. Extensive information regarding genetic testing for harlequin ichthyosis is available from GeneDx. Carrier testing is available for relatives after the proband's mutation is identified. Prenatal diagnosis is available for fetuses with suspected harlequin ichthyosis who may or may not have a family history of the disorder.[6] For genetic diagnosis, obtaining mRNA from hair follicle epithelial cells, which are analogous to keratinocytes in the interfollicular epidermis, is convenient and minimally invasive. This is an extremely promising next-generation sequencing that is available.[17]
Certain laboratory investigations may be helpful in the newborn period to identify complications of harlequin ichthyosis.
A WBC count and skin and blood cultures can be performed to investigate for signs of infection.
Serum electrolyte levels may be abnormal secondary to dehydration.
Monitor serum calcium and glucose, as hypocalcemia and hypoglycemia may occur.
Check BUN and creatinine levels for signs of renal failure.
Monitor hemoglobin levels because severe anemia is reported.
Chest radiography may be indicated if respiratory distress is present postnatally.
Renal ultrasonography may be indicated if renal failure or poor urine output is evident. Renal dysplasia has been described in harlequin ichthyosis.
Further investigations should be based on the history and findings from physical examination.
Prenatal diagnosis
Prenatal ultrasonography, particularly 3-dimensional ultrasonography, may show features suggestive of harlequin ichthyosis. This has been particularly helpful in antenatal diagnosis of infants with no family history of harlequin ichthyosis. Characteristic features include a large and gaping mouth, aplasia of the nose, abnormal limbs, bulging eyes, rudimentary ears, flexion contractures, and floating particles in the amniotic fluid.[13, 18, 19, 20] Growth restriction and polyhydramnios are also described.
Two-dimensional ultrasonography can also demonstrate features of harlequin ichthyosis but not until late in the second trimester, when enough keratin buildup is present to be sonographically detectable. The snow flake sign is also demonstrable in some cases. Short feet may be an early marker for harlequin ichthyosis. This may be detectable in the early second trimester before other signs of harlequin ichthyosis are noticeable.[15]
Before genetic testing was available, fetal skin biopsy was sometimes used to detect ultrastructural changes consistent with harlequin ichthyosis.[5] Fetal skin biopsy could help in detecting harlequin ichthyosis as early as 19 weeks' gestation. Biopsy samples from a number of sites in the fetus revealed characteristic changes on all skin surfaces except the mucous membranes. Amniotic fluid samples obtained as early as 17 weeks' gestation have also demonstrated hyperkeratosis and abnormal lipid droplets in the cornified cells.
Fetal skin biopsy is no longer performed for diagnosis of harlequin ichthyosis.
The stratum corneum is thick and compact. Hyperkeratosis may be more marked around hair follicles compared with the interfollicular epidermis. The histopathologic hallmark is an extraordinarily thickened and compact orthokeratotic stratum corneum, although in some cases parakeratosis has been observed. Cells within the stratum corneum are abnormally keratinized. Granular, spinous, and basal cell layers appear unremarkable. Inflammatory cells may infiltrate the papillary dermis. Hair follicles show marked, concentric accumulation of keratotic material around hair shafts, which is considered a diagnostic feature of harlequin ichthyosis and has been used to establish the diagnosis prenatally.
Electron microscopy reveals absent or abnormal lamellar granules within the granular layer keratinocytes. Lamellae are absent in the intercellular spaces between the granular cell layer and the cornified cell layer. Densely packed lipid droplets and vacuoles are seen within the cytoplasm of the aberrantly cornified cells of the stratum corneum. These lipid inclusions involve the entire skin surface but are more evident on the palms and the soles. Keratohyalin granules may be absent, normal, or abnormally small and globular. Keratin intermediate filaments within granular cells may have reduced density.
Patient's airway, breathing, and circulation stability to be accessed after delivery. Early intubation may be required.[21] Babies require intravenous access. Peripheral access may be difficult and umbilical cannulation may be necessary. Premature infants may need a humidified incubator. Monitor temperature, respiratory rate, heart rate, and oxygen saturation. Discussion about the aggressiveness of the intensive care is made on a patient-by-patient basis, and palliative support must be offered when appropriate to the parents. Pain control is important owing to deep fissuring, and opioids may be necessary in some neonates.[22]
Exposure keratitis results from ectropion of the eyelids. Apply ophthalmic lubricants frequently to protect the conjunctivae.[23]
Bathe infants twice daily and use frequent wet sodium chloride compresses followed by application of bland lubricants to soften hard skin. Dilute bleach baths may reduce the risk of skin infection.[24]
Topical keratolytics (eg, salicylic acid) are not recommended in newborns because of potential systemic toxicity.
According to Rajpopat et al, early retinoid treatment (by day 7) may require prompt consideration, as these medications can take some days to obtain.[13] See Medication.
Tazarotene, a topical retinoid, has been reported to be beneficial.[24, 25]
Intravenous fluids are almost always required.[24] Consider excess cutaneous water losses in daily fluid requirement calculations. Monitor serum electrolyte levels. A risk of hypernatremic dehydration exists.
Neonates with harlequin ichthyosis initially do not feed well and may require tube feeding.[13]
Maintain a sterile environment to avoid infection. Take frequent cultures of the skin. Growth of pathogenic organisms (eg, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella) indicates risk of sepsis. Draw blood cultures because sepsis can occur quickly in affected infants.
Further inpatient care
Continue careful attention to skin care and use of emollients during retinoid therapy.
Infants with harlequin ichthyosis can be successfully breastfed or bottle-fed as the eclabium improves.[26] Involving occupational therapy to aid in feeding strategies is advised. Carefully monitor weight gain and intake. Affected infants are at risk of failure to thrive.
Physical bonding between the parents and the baby should be encouraged.
Hyperkeratosis causing constriction of limbs, digits, or nasal obstruction may need to be treated surgically. Neonates can have compartmental syndrome due to the dense scales and need superficial and sometimes dermal release for preventing ischemia and possible limb loss.[21, 24, 27]
Infants are discharged from the hospital when their cutaneous symptoms are improving, feeding and weight gain are established, and they are free of infection.
Social and psychological support should be provided for the parents/caregivers.[5]
The primary care physician should closely monitor the infants for growth, development, social issues, and skin surveillance. A dermatologist should monitor affected infants for ongoing assessment and for monitoring of retinoid therapy.
Adverse effects of retinoid therapy (eg, mucocutaneous dryness, aberrant liver function tests, hypertriglyceridemia, benign intracranial hypertension) should be noted. Serum AST, ALT, total cholesterol, and triglyceride levels should initially be obtained on a monthly basis initially. The clinician should be cognizant of the musculoskeletal abnormalities that can occur with long-term retinoid therapy, if treatment is continued.
Follow-up with an ophthalmologist is required. Recurrent exposure keratitis can be a problem as a result of persistent ectropion.
Enhanced survival and decreased morbidity is reported with the use of systemic retinoids; however, infants have survived without systemic retinoid therapy.[21] Retinoids bind to specific retinoic acid receptors and regulate gene transcription. They influence keratinocyte differentiation, normalize abnormal keratinocyte proliferation, and mediate desquamation of hyperkeratotic scale. Rajpopat et al recommend frequent application of emollients to ease this shedding of thick plates when retinoids are given.[13]
Etretinate was first used for the treatment of this disorder in 1985. An effective dose of 1 mg/kg/d was established. Etretinate is no longer available and has been replaced by other retinoids with improved safety profiles.
Acitretin, a carboxylic acid derivative of etretinate, is the retinoid most commonly prescribed in neonates with harlequin ichthyosis.[7, 28] Initial doses of 0.5 mg/kg/d are recommended.[13] Improvement in hyperkeratosis, ectropion, and eclabium is reported. The duration of therapy is variable, and continuous, long-term, daily therapy may be required. The daily dose can be titrated to the degree of ichthyosis. In infants, the oral acitretin can be dissolved (10-mg capsules) in Ora-Plus solution for precise weight-based dosing.[29]
Rajpopat et al reported that of 24 babies given oral retinoids, 20 received acitretin, 2 received etretinate, and 2 received isotretinoin. Twenty of the 24 treated patients survived (83%).[13]
A topical retinoid (tazarotene) has been used to treat local and mechanical circulatory problems caused by hyperkeratosis.[24, 25]
Isotretinoin has also been used in harlequin ichthyosis. The reported dose is 0.5 mg/kg/d. Treatment is usually initiated within the first few days of life and given orally. Case reports have documented improvement in pliability of the skin, limb movements, sucking, and eyelid closing within a week of starting therapy. Treatment has been continued for several years in some patients.
Liver function and serum lipid levels should be monitored during retinoid therapy. Clinical monitoring for skeletal adverse effects should be done periodically. Before retinoid therapy is considered, discuss the expected outcome and the potential adverse effects with the parents.
Clinical Context:
Synthetic 13-cis isomer of naturally occurring tretinoin (trans -retinoic acid). Both agents structurally related to vitamin A.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.
Clinical Context:
Metabolite of etretinate and related to retinoic acid and retinol (vitamin A). Mechanism of action unknown but thought to exert therapeutic effect by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells.
Fnu Nutan, MD, FACP, Assistant Professor, Department of Dermatology, Virginia Commonwealth University School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine
Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine
Disclosure: Nothing to disclose.
Julie Prendiville, MBBCh, Clinical Professor in Pediatrics, University of British Columbia Faculty of Medicine; Head, Division of Pediatric Dermatology, British Columbia's Children's Hospital, Canada
Disclosure: Nothing to disclose.
Wen Lyn Ho, MBBCh, BAO(HON), MRCPI, Clinical Fellow in Pediatric Dermatology, British Columbia Children’s Hospital, Canada
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Sheila Au, MD, to the development and writing of this article.
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