Harlequin Ichthyosis (Harlequin Fetus, Harlequin baby, Ichthyosis congenita gravior)

Are You Confident of the Diagnosis?

What you should be alert for in the history

The clinical diagnosis of harlequin ichthyosis is supported by a history of premature birth, encasement of the neonate in a hard, armor-like shell of thickened stratum corneum, ectropion and eclabium in all affected infants.

Characteristic findings on physical examination

Characteristic findings include a severely hyperkeratotic stratum corneum that immobilizes the baby and cracks shortly after birth to form firm, polygonal, yellow-brown adherent plates separated by wide, deep, erythematous fissures (resembling a harlequin clown, hence the name) (Figure 1). The rigidity of the skin causes severe ectropion with conjunctival edema and eclabium. The ears and nasal cartilage are rudimentary and microcephaly can occur. The digits are well formed, but their encasement causes flexion contractures and mitten deformity. There may be digital as well as auricular synechiae, which can lead to conductive hearing loss.

Circulation is impaired, sometimes resulting in loss of digits. Scalp hair may or may not be present, but eyelashes and eyebrows are usually absent. Movement restriction causes respiratory insufficiency and impaired suckling. Other rare reported organ abnormalities include renal tubular defects, lung hypoplasia, cervical hemivertebrae, micromelia, polydactyly, enlarged or absent thymus, thyroid aplasia, and patent ductus arteriosus.

Prior to the past 20 years, most patients died in the first few days or weeks of life from sepsis, pneumonia, hypoventilation, and temperature instability; however, improvements in intensive neonatal care and systemic retinoid therapy have improved outcomes. In the largest review to date, 25 of 65 (56%) of patients survived the neonatal period. All were started on systemic retinoids. Survivors develop severe, exfoliative ichthyosiform erythroderma. These children often experience delayed growth and development, but most have normal intelligence.

Expected results of diagnostic studies

Histopathology shows massive orthokeratotic hyperkeratosis and hyperkeratotic plugging of the hair follicles and eccrine ducts. Electron microscopic examination shows absent or malformed lamellar bodies with vacuolar change in the granular layer, missing extracellular lipids, and lipid inclusions or remnant organelles in the stratum corneum. Similar findings, however, can be seen in transglutaminase positive nonbullous congenital ichthyosiform erythroderma and are therefore not specific. A diagnostic feature of harlequin ichthyosis sometimes used in prenatal diagnosis is marked concentric accumulation of keratotic material around hair shafts.

Diagnosis confirmation

The differential diagnosis of harlequin ichthyosis includes collodion baby (lamellar ichthyosis, nonlbullous congenital ichthyosiform erythroderma), lethal restrictive dermopathy, and Neu-Laxova syndrome. Harlequin ichthyosis is distinguished by a greater severity of hyperkeratosis, eclabium, and ectropium at birth. Missense mutations in ABCA12 cause lamellar ichthyosis type 2, whereas truncations or deletions cause harlequin ichthyosis.

Lethal restrictive dermopathy presents with intrauterine growth retardation, congenital contractures, tight skin, and ectropion; however, neonates do not develop hyperkeratosis and scaling. Tight, hyperkeratotic skin and rudimenatry facial features are also present in Neu-Laxova syndrome; however this disorder is also assoicated with transulcent skin, exopthalmos, lissencephaly, limb deformities, syndactyly, and many other congenital malformations.

Who is at Risk for Developing this Disease?

Harlequin ichthyosis appears to have autosomal recessive inheritance. Affected neonates have been born to both cosanguineous and non-cosanguineous parents. There is no racial predilection and it occurs equally in males and females. The condition is extremely rare. The incidence is unknown.

What is the Cause of the Disease?

Etiology

Harlequin ichthyosis is caused by a loss of function mutation (either truncation or deletion) in the ATP Binding Casette gene ABCA12 on chromosome 2q25. The gene encodes a lamellar body membrane protein involved in lipid transport, including glucosylceramide. Lamellar bodies are incorrectly formed and lipids are not properly secreted into the intercellular spaces. The lipid layer in the epidermis does not form, resulting in abnormal barrier function. The hyperkeratosis is most likely caused by a lack of desquamation.

Pathophysiology

A recent study demonstrated that the abnormal lamellar body system prevents the proteases necessary for corneodesmosome dissolution from being transported to the stratum corneum. Abnormalities in keratin, involucrin and fillagrin have also been variably reported, suggesting that the function of ABCA12 may not be limited to lipid loading.

Systemic Implications and Complications

Resticted ventilation dramatically reduces postnatal survival. The abnormal epidermal barrier leads to increased susceptibility to infection and increased transepidermal water loss, resulting in dehydation, temperature instability, and electrolyte imbalances. Decreased suckling can lead to hypoglycemia and dehydration which can cause seizures and renal insufficiency respectively. There has been one report of hypothyroidism and one report of juvenile rheumatoid arthritis associated with harlequin ichthyosis. Fifty percent of deaths in the neonatal period are due to sepsis.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Medical Treatment	Surgical Procedures	Physical Modalities
Admission to NICU	Ophthalmology consult	Humidified Incubator
Nutrition supplementation	Release of digital contractures if circulation is impaired	Physical therapy
Emollients and bathing	Compartment syndrome- General Surgery consult for liberal fasciotomies to help with ventilation may be required until retinoids take effect.
Pain control	Contact F.I.R.S.T. medical advisory board
Systemic Retinoids

Optimal Therapeutic Approach for this Disease

One of the most important components of treatment is early intensive nursing care. Meticulous skin care, sepsis monitoring and treatment, temperature regulation, nutrition replacement, pain control and management of ectropion and digital contractures are all essential. A humidified incubator with temperature regulation mitigates transepidermal loss of water and heat. Because cutaneous losses and chronic inflammation can increase caloric requirements to as much as 25% more than healthy neonates, infants require aggressive nutritional supplementation.

Skin care with application of emollients multiple times daily protects the skin against microbes and decreases transcutaneous water loss. Caution with other topicals must be exercised given the increased risk of systemic absorption with a defective epidermal barrier. Frequent bathing and soaking can replace mositure, reduce skin infections, and promote shedding of thick scale. Pain control encourages adequate respirations and decreases the risk of pulmonary complications.

Ectropion should be managed by ophthalmologists, however, artificial tears and antibiotic ointment may be initiated in the interim. Hand contractures may require surgical therapy, as gangrene of the distal digits can occur if left untreated. Early and continued physical therapy is important for promoting range of motion of the joints.

In addition to vigilant surveillance for signs of sepsis, some advocate prophylactic antibiotics; however this topic is highly controversial. Mental health specialists and social workers should be involved early to provide psychological support and help families transition from the hospital to home.

Systemic retinoids cause shedding of thick plates of skin and improvement in ectropion and eclabium within 2-3 weeks and should be initiated immediately after birth. Patients can then be tapered to the lowest effective dose, with many patients maintaining a good response after discontinuation. Even without early systemic retinoids, some neonates have shown spontaneous improvement.

Corrective gene transfer has been demonstrated in cultured keratinocytes, thus suggesting gene therapy as a viable future treatment.

Patient Management

Because dyslipidemia and transaminitis can occur with systemic retinoids, the following blood tests should be checked prior to initiation of therapy and regularly thereafter: complete blood count, creatinine and blood urea nitrogen, liver function tests, cholesterol and triglyceride levels, and urinalysis.

Toxic musculoskeletal side effects such as osteoporosis and premature epiphyseal closure can also occur with chronic high-dose systemic retinoids. Though these adverse effects have not been seen with the lower doses of retinoids used to treat harlequin ichthyosis (Acitretin, Etretinate, or Isotretinoin 0.5 to 1mg/kg per day), it is still important to titrate the medication to the lowest effective dose.

Monitoring vitamin D levels has also been suggested, as low vitamin D has been reported in patients with congenital ichthyoses. If the levels are low, vitamin D supplemention should be recommended.

Unusual Clinical Scenarios to Consider in Patient Management

The psychological impact this condition has on the parents, caregivers and the patients should not be overlooked. The appearance of the neonate can ignite feelings of profound guilt, shame, fear and grief in the parents. A multidisciplinary team including a dermatologist, pediatric intensivist, geneticist, mental health specialist, and social worker should be assembled to discuss the parents’ concerns and help them envision life after discharge.

Skin-to-skin contact and breastfeeding should be encouraged to foster parent-child bonding. Parents should be trained and encouraged to participate in the newborn’s care.

What is the Evidence?

Richard, G, Schachner, LA, Hansen, RC. “Harlequin Ichthyosis”. Pediatric dermatology. 2011. pp. 597-9. (This is a concise review of the condition.)

Oji, V, Tadini, G, Akiyama, M, Bardon, CB. “Revised Nomenclature and Classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Soreze 2009”. J Am Acad Dermatol. vol. 63. 2010. pp. 607-41. (This is a new classification of disorders of cornification.)

Harvery, HB, Shaw, MG, Morrell, DS. “Perinatal management of harlequin ichthyosis: a case report and literature review”. J Perinatal. vol. 30. 2010. pp. 66-72. (Review and classification system of the icthyoses.)

Thomas, AC, Tattersall, D, Norgett, EE, O’Toole, EA, Kelsell, DP. “Premature terminal differentiation and a reduction in specific proteases associated with loss of ABCA12 in harlequin ichthyosis”. Am J Pathol. vol. 174. 2009. pp. 970-8. (Discusses the genetic basis of harlequin icthyosis.)

Akiyama, M, Sugiyama-Nakagiri, Y, Sakai, K, McMillan, JR, Goto, M, Arita, K. “Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer”. J Clin Invest. vol. 115. 2005. pp. 1777-84. (Discusses gene defects and potential therapeutic interventions.)

Yanagi, T, Akiyama, M, Sakai, K, Nagasaki, A. “DNA-based prenatal exclusion of harlequin ichthyosis”. J Am Acad Dermatol. vol. 58. 2008. pp. 653-6. (Discusses the prenatal diagnosis.)

Chan, YC, Tay, YK, Tan, LK, Happle, R, Giam, YC. “Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis”. Pediatr Dermatol. vol. 20. 2003. pp. 421-6. (Report of rare associated case of hypothyroidism and juvenile rheumatoid arthritis with harlequin icthyosis.)

Rogers, M, Scarf, C. “Harlequin baby treated with etretinate”. Pediatr Dermatol. vol. 6. 1989. pp. 216-21. (Report of an infant treated with etretinate.)

Akiyama, M. “Pathomechanisms of harlequin ichthyosis and ABCA transporters in human diseases”. Arch Dermatol. vol. 142. 2006. pp. 914-8. (Nice reveiw of the genetic defect seen in harlequin icthyosis.)

Thomas, AC, Sinclair, C, Mahmud, N. “Novel and recurring ABCA12 mutations associated with harlequin ichthyosis”. Br J Dermatol. vol. 158. 2008. pp. 611-3. (More information on the genetic basis of disease.)

Choate, KA, Williams, ML, Elias, PM, Khavari, PA. “Transglutaminase 1 expression in a patient with features of harlequin ichthyosis: Case report”. J Am Acad Dermatol. vol. 38. 1998. pp. 325-9. (Case report looking at the expression of the transglutaminase 1 protein.)

Rajpopat, S, Moss, C, Melerio, J. “Harlequin icthyosis, A review of clinical and molecular findings in 45 cases”. Arch Dermatol. vol. 147. 2011. pp. 681-6. (Multicenter review of 45 cases of harlequin icthyosis. Overall survival rate found to be 56%. Most cases of death in the first 3 months due to sepsis or repiratory failure. Eighty-three percent of harlequin icthyosis patients treated with oral retinoids survived.)

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