AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Ichthyosis fetalis, also known as harlequin ichthyosis (HI), is the most severe form of congenital ichthyosis and 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. This armor limits movement and compromises the protective skin barrier, leaving the newborn susceptible to metabolic abnormalities and infection.

The term harlequin derives from the newborn's facial expression and the triangular and diamond-shaped pattern of hyperkeratosis. The newborn's mouth is pulled wide open, mimicking a clown's smile.

The underlying genetic abnormality in HI has been identified as a mutation in the lipid-transporter gene ABCA12 on chromosome 2. The presence of homozygous mutations in affected individuals supports an autosomal recessive pattern of inheritance.

Immunohistocytochemical examination of the skin reveals characteristic abnormalities in the structure of lamellar granules and in the expression of epidermal keratin.

In the past, HI 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 other autosomal recessive ichthyoses, such as lamellar ichthyosis (LI) or nonbullous congenital ichthyosiform erythroderma.

Pathophysiology

This disease primarily affects the skin. Other systems are significantly compromised by the hyperkeratosis and concomitant deformities. Neonates are often born prematurely.

Marked eclabium and ectropion is 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.

Frequency

International

More than 100 cases have been reported.

Mortality/Morbidity

The mortality rate is high. With neonatal intensive care and the advent of retinoid therapy, some babies have survived the newborn period. They are still at risk of dying from systemic infection, which is the most common cause of death.

Race

No racial predilection is known.

Sex

No increased risk based on sex is known.

CLINICAL

Section 3 of 11  

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History

This condition manifests at birth. It may or may not have been diagnosed prenatally in a high-risk family. The history should carefully explore the following questions:

• Is the couple consanguineous?
• Does the couple have another 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, fetal skin biopsy) performed?

Physical

• 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 at risk for desiccation and trauma.
• Ears: The pinnae may be small and rudimentary or absent.
• Lips: Severe traction on the lips causes eclabium and a fixed, open mouth.
• Nose: Nasal hypoplasia and eroded nasal alae may occur.
• Extremities
• • The limbs are encased in the thick, hyperkeratotic skin, resulting in flexion contractures of the arms, the legs, and the digits. Limb motility is poor to absent. Circumferential constriction of a limb can occur, leading to distal swelling or even gangrene.
  • 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 infants are 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.

Causes

• Genetic factors
• • The genetic basis of HI has recently been identified. Mutations in a gene known as ABCA12 (adenosine triphosphate [ATP]-binding cassette transporter, subfamily A, member 12), in chromosome region 2q35, underlie this disorder. Patients with HI are usually homozygous for this mutation; this finding suggests an autosomal recessive inheritance.
  • The ABC superfamily of genes encodes proteins that transport a number of substrates across cell membranes. ABCA12 is thought to encode a transmembrane protein that mediates lipid transport.
  • This ABCA12-mediated lipid-transfer system is thought to be 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. 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 HI, the ABCA12-mediated transfer of lipid to lamellar granules is absent. The lamellar granules themselves are morphologically abnormal or absent. Normal extrusion of lipid from these granules into the intercellular 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.
  • The exact mechanism of this transport abnormality has yet to be elucidated. One hypothesis involves abnormal calcium-mediated signaling by means of calpains. Calpains are calcium-activated neutral proteases that are essential to normal epidermal differentiation. Calpains are consistently underexpressed in patients with HI compared with the general population.
  • The pivotal role of ABCA12 in HI is supported by in vitro data. Studies have demonstrated normalization of lipid transport when the wild-type ABCA12 gene is transferred to keratinocytes of patients with HI.
  • A mild disorder, LI type 2 (LI-2) also involves mutations in the ABCA12 gene. The phenotypic difference between the 2 disorders has been explained on the basis of differing genotypic variants. Nonsense mutations in ABCA12 are seen in HI, whereas missense mutations underlie LI-2.
  • Other chromosomal abnormalities are described in association with HI. One patient with a de novo deletion of chromosome arm 18q has been reported.
• Histologic, ultrastructural, and biochemical factors
• • Histologic, ultrastructural, and biochemical studies have identified several characteristic abnormalities in the skin of patients with HI.
  • The 2 main abnormalities involve lamellar granules and the structural proteins of the cell cytoskeleton. The relationship between the HI 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 HI have absent or defective lamellar granules and no intercellular lipid lamellae. The lipid abnormality is believed to allow excessive transepidermal water loss. Lack of released hydrolases 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 with HI 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.
• Abnormal expression of keratin
• • Keratinocyte cell cultures have yielded interesting and heterogeneous findings among patients with HI.
  • 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 HI.
  • They can be large and stellate, small and rounded, or absent.

DIFFERENTIALS

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Other Problems to be Considered

Collodion baby (a newborn with LI)
Self-healing LI of the newborn
Conradi disease
Trichothiodystrophy
Recessive X-linked ichthyosis
Restrictive dermopathy

WORKUP

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Lab Studies

• Genetic testing for mutations in the ABCA12 gene is available. Complete sequence analysis of the coding region of this gene is done to identify specific mutations. Peripheral blood cells or cells from a buccal smear from affected individuals are required. Extensive information regarding genetic testing for HI 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 HI who may or may not have a family history of the disorder.
• The following laboratory investigations may be helpful in the newborn period to identify complications of HI:
• • Check the WBC count and blood cultures for signs of infection.
  • Closely monitor serum electrolyte levels, which may be abnormal secondary to dehydration.
  • Check BUN and creatinine levels for signs of renal failure.
  • Monitor hemoglobin levels because anemia is reported.

Imaging Studies

• Prenatal ultrasonography, particularly 3-dimensional (3D) ultrasonography, may show features suggestive of HI. See Special Concerns.
• 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 or if findings from the physical examination are abnormal. Renal dysplasia has been described in HI.
• No other specific imaging studies are indicated. Further investigations should be based on the history and findings from physical examination.

Procedures

• Skin biopsy at any cutaneous site (including the palms and the soles, excluding mucous membranes) shows characteristic histologic and ultrastructural features.

Histologic Findings

The stratum corneum is thick and compact. Hyperkeratosis may be more marked around hair follicles compared with the interfollicular epidermis. Parakeratosis and orthokeratosis may be present, particularly on the fingers and the toes. Cells within the stratum corneum are abnormally keratinized. Granular, spinous, and basal cell layers appear unremarkable. Inflammatory cells may infiltrate the papillary dermis.

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.

TREATMENT

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Medical Care

• Ensure that the patient's airway, breathing, and circulation are stable after delivery. Babies require intravenous access. Peripheral access may be difficult. Umbilical cannulation may be necessary.
• Place infants in a humidified incubator. Monitor temperature, respiratory rate, heart rate, and oxygen saturation. Prevent hyperthermia.
• Once stabilized, transfer newborns with HI to a level 3 neonatal nursery.
• Exposure keratitis results from ectropion of the eyelids. Apply ophthalmic lubricants frequently to protect the conjunctivae. Bathe infants twice daily. Use frequent applications of wet sodium chloride compresses followed by bland lubricants to soften hard skin and to facilitate desquamation. Topical keratolytics (eg, salicylic acid) are not recommended in newborns because of potential systemic toxicity.
• Intravenous fluids are almost always required; neonates initially do not feed well. Consider excess cutaneous water losses in daily fluid requirement calculations. Monitor serum electrolyte levels. A risk of hypernatremic dehydration exists.
• Maintain a sterile environment to avoid infection. Take frequent cultures of the skin. Growth of pathogenic organisms (eg, Staphylococcus aureus, Pseudomonas aeruginosa) indicates risk of sepsis. Draw blood cultures because sepsis can occur quickly in affected infants. A consensus does not exist regarding the use of prophylactic antibiotics.

Consultations

• Neonatologist
• Dermatologist
• Medical geneticist
• Social worker

MEDICATION

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Enhanced survival and decreased morbidity is reported with the use of systemic retinoids for HI. 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.

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, but it has been replaced by other retinoids with improved safety profiles.

Isotretinoin is a retinoid that has been used in HI. 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, and it may be required indefinitely to prevent relapse.

Acitretin, a carboxylic acid derivative of etretinate, has also been used in neonates with HI. Initial doses of 1 mg/kg/d have been used with success. 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.

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.

Topical tazarotene 0.05% gel has been used successfully in patients with other congenital ichthyoses, with good clinical response and minimal adverse effects. However, no specific reports of its use and efficacy in patients with HI are available.

Topical tacrolimus has been used in LI with good results, but systemic levels were reported. Again, its use in HI has not been reported.

Drug Category: Retinoids

These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes. They modulate keratinocyte differentiation.

Drug Name	Acitretin (Soriatane)
Description	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.
Adult Dose	None; HI is a pediatric condition
Pediatric Dose	1 mg/kg/d initially; duration of therapy variable and continuous; long-term daily therapy may be required; titrate daily dose to degree of ichthyosis
Contraindications	Absolute: Pregnancy or woman likely to become pregnant or intends to become pregnant within 3 y of treatment or who cannot use reliable contraception during treatment and for at least 3 y afterward; noncompliance with contraception; nursing mothers; concurrent use of methotrexate (increased liver toxicity) or tetracyclines (pseudotumor cerebri); hypersensitivity Relative: obesity, leukopenia; moderate-to-severe cholesterol or triglyceride elevation; clinically hepatic or renal dysfunction
Interactions	Increases toxicity of methotrexate (avoid concomitant use); coadministration with alcohol may result in formation of etretinate, which has long half-life (>120 d)
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Women of childbearing age must be able to comply with effective contraception; contraception should be continued for at least 3 y after treatment; etretinate may form and takes about 2-3 y to clear from body; caution in impaired renal or liver function; test aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) before therapy, q1-2wk until stable, and then at intervals as clinically indicated

FOLLOW-UP

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Further Inpatient Care

• Continue careful attention to skin care and use of emollients during retinoid therapy.
• Infants with HI can be successfully breastfed or bottle-fed as the eclabium improves. Involving occupational therapy to aid in feeding strategies is advised.
• Carefully monitor weight gain and intake. Affected infants are at risk of failing to thrive.
• Nutritional rickets is described in patients with LI and X-linked ichthyosis. It is likely secondary to defective vitamin D synthesis in the abnormal epidermis, increased calcium loss through the skin, and poor exposure to sunlight. Although not specifically described in HI, all patients with disorders of keratinization might be at risk.

Further Outpatient Care

• Infants are discharged from the hospital when their cutaneous symptoms are improving, feeding and weight gain are established, and they are free of infection.
• 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 of the underlying disorder and for monitoring of retinoid therapy.
• Adverse effects of retinoid therapy (eg, mucocutaneous dryness, aberrant liver function tests, hypertriglyceridemia) should be noted. Serum AST, ALT, total cholesterol, and triglyceride levels should initially be obtained on a monthly basis.

  The clinician should be cognizant of the musculoskeletal abnormalities that can occur with long-term retinoid therapy.

• Ophthalmology follow-up may be required. Recurrent exposure keratitis can be a problem.

Transfer

• Once stabilized, newborns with HI should be transferred to a level 3 neonatal nursery.

Complications

• Gram-positive and gram-negative sepsis has been reported after the newborn period.
• Children who survive have skin changes that resemble nonbullous congenital ichthyosiform erythroderma, with chronic erythroderma and a fine scale over the whole body.
• Severe ichthyosis with eclabium and ectropion can relapse. Contractures and painful fissuring of the hands and the feet may occur without adequate topical or systemic therapy.

Prognosis

• Fulminant sepsis remains the most common cause of death in affected infants.
• Life expectancy is unknown. Survival to age 14 years is reported.
• Both normal intellect and developmental delay are described. In general, intellectual development is thought to be normal.
• In patients who survive, growth and development must be closely monitored. Severe failure to thrive from excessive cutaneous protein loss is reported.
• Short stature is common. Thyroid function must be checked in all patients with HI who have failure to thrive and short stature. Hypothyroidism is reported in HI.
• Rheumatoid arthritis has been reported in a patient with HI.

Patient Education

• Emphasize the need for attention to skin lubrication and for compliance with systemic therapy.
• Teach parents and caregivers to recognize signs of infection.
• It may be helpful for parents to communicate with other families who have been similarly affected. The congenital ichthyoses can have devastating medical and social consequences.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The physician must take time to discuss systemic retinoid therapy with the parents, including long- and short-term risks and limitations of the treatment.
• The family must be aware that, despite clinical improvement with systemic retinoid therapy, the prognosis of this disorder is guarded.

Special Concerns

• DNA-based prenatal testing is now available for HI, and it is the investigation of choice for prenatal diagnosis of this condition. Current information regarding the timing and logistics of prenatal diagnosis of HI is available from GeneDx.
• Before genetic testing was available for HI, fetal skin biopsy was sometimes used to detect ultrastructural changes consistent with HI. Fetal skin biopsy can help in detecting HI as early as 19 weeks' gestation. Biopsy samples from a number of sites in the fetus reveal 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.
• Prenatal 3D ultrasonography has also been successful in identifying the typical morphology of a harlequin fetus. This has been particularly helpful in antenatal diagnosis of infants with no family history of HI. Characteristic features include a large and gaping mouth, aplasia of the nose, abnormal limbs, and bulging eyes. Growth restriction and polyhydramnios are also described.
• Two-dimensional ultrasonography can also demonstrate features of HI but not until late in the second trimester, when enough keratin buildup is present to be sonographically detectable. Short feet may be an early marker for HI. This may be detectable in the early second trimester before other signs of HI are noticeable.
• Termination is contraindicated late in gestation; however, prenatal identification of an affected neonate may allow parents and physicians to best prepare for the baby's delivery.

MULTIMEDIA

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Media file 1:  Ichthyosis fetalis. Courtesy of Dr Bernice Krafchik.
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Media file 2:  Ichthyosis fetalis. Courtesy of Jason K Rivers, MD, FRCPC, and Dr Lawler.
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REFERENCES

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• Differentials
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• Suzumori K, Kanzaki T. Prenatal diagnosis of harlequin ichthyosis by fetal skin biopsy; report of two cases. Prenat Diagn. Jul 1991;11(7):451-7. [Medline].
• Thacher TD, Fischer PR, Pettifor JM, et al. Nutritional rickets in ichthyosis and response to calcipotriene. Pediatrics. Jul 2004;114(1):e119-23. [Medline].
• Uitto J. The gene family of ABC transporters - novel mutations, new phenotypes. Trends Mol Med. Jun 28 2005;epub ahead of print:[Medline].
• Unamuno P, Pierola JM, Fernandez E, et al. Harlequin foetus in four siblings. Br J Dermatol. Apr 1987;116(4):569-72. [Medline].
• Watson WJ, Mabee LM Jr. Prenatal diagnosis of severe congenital ichthyosis (harlequin fetus) byultrasonography. J Ultrasound Med. Mar 1995;14(3):241-3. [Medline].

Article Last Updated: Sep 8, 2006