Harlequin Ichthyosis: Report of 2 Cases Seen At The National Skin Centre

BULLETIN FOR MEDICAL PRACTITIONERS

Dr Chan Yuin Chew*, Dr Tay Yong Kwang**, Clinical A/Prof Giam Yoke Chin***

* Associate Consultant Dermatologist, National Skin Centre

** Senior Consultant Dermatologist, Changi General Hospital

*** Senior Consultant Dermatologist, National Skin Centre

Abstract

Harlequin ichthyosis is a rare and severe congenital erythrodermic ichthyosis characterised at birth by hyperkeratotic plates covering the entire body, ectropion, eclabium, poorly developed ears, as well as contractures of hands and feet. Two Chinese children, a 2-year-old boy and an 11-year-old girl, presented with these classical features as well as alopecia and loss of eyebrows and lashes. The boy was small for his age and was discovered to have hypothyroidism at the age of 18 months. At 6 years of age, the girl developed symmetrical polyarthritis associated with positive rheumatoid factor and radiological evidence of erosive arthritis, suggestive of juvenile rheumatoid arthritis. Early therapy with oral retinoids in both children accelerated shedding of the hyperkeratotic plates as well as improved ectropion and eclabium. A multidisciplinary approach is vital in the management of this severe lifelong disease.

Introduction

Harlequin ichthyosis is a rare and severe, erythrodermic, likely autosomal recessive, ichthyosis that causes a distinctive appearance at birth. In the past, it was invariably associated with stillbirth or early neonatal death due to causes such as prematurity, respiratory compromise, infection, hypothermia and dehydration. Since 19851, several survivors of this disease have been reported. The outcome has been variable, with most eventuating in a morphology resembling severe nonbullous ichthyosiform erythroderma. These survivors have a severe lifelong disease, and management of both the medical as well as the psychosocial aspects of the disease is vital.

Patient 1

A 2-year-old Chinese boy was born prematurely at 34 weeks to non-consanguineous parents. He was delivered via Caesarean section for maternal premature labour and foetal breech presentation. The child had small malformed ears, ectropion and eclabium. The entire body was covered with tight and thick plate-like scales with subsequent fissuring. His mother was well antenatally. No foetal abnormalities were detected during abdominal ultrasound scans performed at 20 and 30 weeks of gestation.

The neonate was placed in intensive care nursery for the initial 4 weeks and tube-fed in the first week. Prophylaxis against skin and systemic infection was carried out with intravenous ampicillin and gentamicin, and topical mupirocin to fissures. Emollients, aqueous cream, emulsifying ointment and olive oil were applied to the skin and tetracycline ointment and artificial tears to his eyes.

He developed anaemia, which responded to oral haematinics. Physiotherapy was initiated to prevent hand contractures. From the first day of life, the neonate was treated with oral acitretin 2.5 mg/day (1mg/kg/day). Baseline screening tests performed included liver function test, skeletal X-ray, cranial ultrasound and echocardiography, which were normal. He was discharged from hospital after a month (Fig 1, 2).

The child continued to have erythroderma, fine scaling and bilateral ectropion. Oral acitretin was maintained at 0.5 mg/kg/day till the age of 9 months. He is currently receiving emollients only. There was no deterioration in his skin condition after cessation of acitretin. He had normal developmental milestones but was small for his age. Due to his poor growth, he was investigated and, at the age of 18 months, was discovered to have hypothyroidism. He is currently on thyroxine replacement therapy.

Patient 2

This 11-year-old Chinese girl was delivered via Caesarean section for breech presentation at 37 weeks of gestation. Birth weight was 2250g. At birth, she had tight and thick plate-like scales with fissures (Fig 3). She had small malformed ears, ectropion, eclabium and her fingers were fixed in flexion by tight skin. An ultrasound scan done at 36 weeks of gestation did not detect any foetal abnormalities. She is the first child of non-consanguineous parents. Her two younger siblings were unaffected.

During the neonatal period she was nursed in the intensive care nursery in a high humidity incubator and tube-fed in the first week. The skin was infected and treated with intravenous ampicillin and sulbactam, topical mupirocin and tulle gras dressing. Despite these measures, her severe ectropion was complicated by Acinetobacter infection. Neosporin® (neomycin sulphate, polymyxin B sulphate, zinc bacitracin) ophthalmic ointment, artificial tears and moist eye-pads were applied to the eyes. Emulsifying ointment was applied as an emollient. Hand physiotherapy was carried out early to prevent contractures. She was discharged from hospital after 2 months. Oral etretinate at a dose of 1mg/kg/day was initiated at the age of 36 days when her condition had stabilised. Within 2 weeks, there was remarkable improvement with generalised thinning of scales and decreased ectropion.

She was maintained on oral etretinate therapy at a dose of 0.8 to 1 mg/kg/day over the next 2 years and subsequently 0.2 to 0.3 mg/kg/day from age 2 to 6 years (Fig 4). At 7 years of age, etretinate was replaced by acitretin, which was maintained at a dose of 0.2 mg/kg/ day. She remained erythrodermic, was intolerant to heat and had several episodes of pneumonia and skin infections. At 6 years of age, she developed symmetrical swelling of wrists, ankles as well as some proximal interphalangeal joints and metacarpophalangeal joints of the hands. There was radiological evidence of erosive arthritis involving these joints. The erythrocyte sedimentation rate was 35 mm/hr and rheumatoid factor 47 u/ml (normal<20). Anti-nuclear antibody and antiextractable nuclear antigen screen were negative. She was diagnosed to have juvenile rheumatoid arthritis by the paediatric rheumatologist and was treated with prednisolone, NSAIDs and methotrexate with clinical and radiological improvement.

She remained short, her present height being 118 cm and weight, 23 kg (both 3rd percentile). Oral acitretin was stopped 2 months prior to her 11th birthday. Her skin condition remains stable 6 months after stopping acitretin.

Discussion

Both our patients show the classical features of harlequin ichthyosis. They have large, thick, yellow-brown, adherent plaques covering the entire body. Soon after birth, the cast splits, producing deep red fissures extending into the dermis. There is severe ectropion and eclabium. The nose and ears appear rudimentary. The oedematous hands and feet are either encased in hard casts or covered with a mucoid membrane. The digits are well formed underneath. Movement is restricted, and respiratory insufficiency may result from limited chest expansion. This restriction to movement may be a factor for breech presentation in these 2 children. Ineffective sucking causes feeding difficulties, leading to hypoglycaemia, dehydration and acute renal failure. Temperature instability and infection commonly supervene.

Harlequin ichthyosis is a disorder of keratinisation related to abnormal epidermal differentiation and metabolism. Defects in keratin expression and epidermal lipid deposition have been reported in harlequin ichthyosis2,3. Cultured keratinocytes of harlequin ichthyosis show excessive cornification and failure of desquamation. A study of 10 clinically similar cases (from 8 separate families) showed defective lamellar bodies and intercellular lipid lamellae. There is abnormal, but variable, keratin and filaggrin expression, suggesting genetic heterogeneity 4,5. The association with hypothyroidism has been reported previously.6-8 However, the association with juvenile rheumatoid arthritis has not been previously described. This association with autoimmune disease is probably coincidental.

Detailed genetic counselling is required for affected families. Prenatal diagnostic testing, including foetal skin biopsy, amniocentesis and ultrasound, is available in specialised centres. With foetal skin biopsy, diagnosis is possible in the late second trimester.

Intensive neonatal supportive care is responsible for improved early survival. This involves placement in a humidified incubator, temperature regulation, nutrition & fluid replacement, infection control, skin and eye care as well as physiotherapy. Most of the long-term survivors of harlequin ichthyosis in the literature had been given oral retinoids early in life.9-12 However, the apparent benefit of early retinoid therapy in harlequin ichthyosis is difficult to assess and not all survivors have received it.4 Early acitretin therapy accelerates shedding of hyperkeratotic plates as well as improve ectropion and eclabium. However, these children have severe lifelong ichthyosis. Short stature and failure to thrive are observations well recognised by parents and physicians who care for the children. However, before attributing growth retardation to harlequin ichthyosis, hypothyroidism should be excluded.

Management of patients with harlequin ichthyosis requires a multi-disciplinary approach. Neonatal care provided by an experienced neonatologist and a competent nursing team is important for the early survival of the neonate. A paediatric dermatologist is required to advise on the optimal management of the skin as well as the initiation of early retinoid therapy. The expertise of a medical counsellor is necessary in the counselling of the affected family and their relatives. After the neonatal period, management of the patient and his family by a team comprising of a paediatric dermatologist, a paediatrician, a child psychologist and a medical counsellor is important. Psychosocial support of the affected families is vital in the management of this lifelong disease.

References

1. Lawlor F, Peiris S. Harlequin foetus successfully treated with etretinate. Br J Dermatol 1985; 112:585.
2. Craig JM, Goldsmith LA, Baden HP. An abnormality of keratin in the harlequin foetus. Pediatrics 1970; 46:437-40.
3. Buxman MM, Goodkin PE, Fahrenback WH, Dimond RL. Harlequin ichthyosis with an epidermal lipid abnormality. Arch Dermatol 1979; 115:189-93.
4. Dale BA, Holbrook KA, Fleckman P, Kimball JR, Brumbaugh S, Sybert VP. Heterogenenity in harlequin ichthyosis, an inborn error of epidermal keratinisation. J Invest Dermatol 1990; 94:6-18.
5. Dale BA, Kam E. Harlequin ichthyosis: variability in expression and hypothesis for disease mechanism. Arch Dermatol 1993; 129:1471-7.
6. Thompson MS, Walkeley CPG. The harlequin fetus. Obstet J Gynaec Brit Comm 1921; 28:198-203.
7. Hess JH, Shultz OT. Keratosis diffusa fetalis (Ichthyosis congenital). Am J Dis Child 1921; 21:357-88.
8. Kingley LB. Ichthyosis congenital with unusual complications. Arch Dermatol Syphil 1926; 13:90-105.
9. Roberts LJ. Long term survival of a harlequin fetus. J Am Acad Dermatol 1989; 212:335-9.
10. Ward PS, Jones RD. Successful treatment of a harlequin fetus. Arch Dis Child 1989; 64:1309-11.
11. Lawlor F. Progress of a harlequin fetus to non-bullous ichthyosiform erythroderma. Paediatrics 1988; 82:870-3.
12. Rogers M, Scraf C. Harlequin baby treated with etretinate. Pediatr Dermatol 1989; 6:216-21.

DEDICATED TO EXCELLENCE IN DERMATOLOGY
By National Skin Centre (Singapore)
Copyright (C) 1995 - National Skin Centre (Singapore 

 

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