Harlequin ichthyosis

Author: Dr Anthony Honigman, Monash University, Victoria, Australia. DermNet NZ Editor-in-Chief: A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. February 2018. 


What is harlequin ichthyosis?

Harlequin ichthyosis is a rare and severe form of ichythyosis that results in hard, thickened armour-like plates of skin covering the entire body from birth.  

Harlequin ichthyosis is also called harlequin-type ichythosis, and harlequin fetus. Note that harlequin syndrome refers to a different condition characterised by asymmetrical, progressive and segmental sweat loss (also known as progressive isolated segmental anhidrosis), and to unilateral sweating and flushing on the chest, neck and face. Harlequin change describes rapidly fluctuating unilateral erythema in neonates.

Harlequin fetus

Who gets harlequin ichthyosis?

Harlequin ichthyosis is rare and males and females are affected in equal numbers.   It affects approximately one in 300,000 births [2]

No racial predilection is known for harlequin ichthyosis.  A higher incidence may be encountered in cultures where parental consanguinity is common [3].

What causes harlequin ichthyosis?

The inheritance of harlequin ichthyosis is autosomal recessive. It is due to mutations in the ABCA 12 (ATP-binding cassette sub-family A member 12) gene.  The ABCA 12 gene is believed to encode a transporter protein involved in the transport of epidermal lipids across cell membranes and is essential for normal skin development.

Some mutations in the ABCA12 gene prevent the cell from making any ABCA12 protein. Other mutations lead to the production of an abnormally small version of the protein that cannot transport lipids properly. A loss of functional ABCA12 protein disrupts the normal development of the epidermis, resulting in the hard, thick scales characteristic of harlequin ichthyosis [4].

What are the clinical features of harlequin ichthyosis

Cutaneous features

  • Skin changes are present at birth. 
  • The skin is severely thickened with large, shiny plates of hyperkeratotic scale.
  • Deep erythematous fissures separate the scales.

Face

  • Severe ectropion affecting the eyelids leaves the conjunctivae and cornea at risk of desiccation, infection and trauma. 
  • The nose may be poorly developed with the patient exhibiting nasal hypoplasia, eroded nasal alae and obstructed nares
  • The ears may be poorly developed, flattened or absent. 
  • Retroauricular folds and the pinnae may be small or absent, and the external auditory canal may be obstructed by scale
  • Traction of the lips causes eclabium.

Extremities

  • The limbs are encased in thick, hyperkeratotic skin.
  • Hypoplasia and polydactyly of the fingers and toes may occur.

Thermal dysregulation

  • Thickened skin prevents normal sweat gland function and heat loss.
  • Excessive fluid loss leads to dehydration.
  • Rise in body temperature can cause heat stroke.

What are the complications of harlequin ichthyosis?

  • The cutaneous abnormalities associated with harlequin ichthyosis disrupt the normal skin barrier. 
  • Poor immunity to infections may be life-threatening. 
  • Thick, hyperkeratotic skin may cause contractures and constriction of the limbs (including digits) leading to swelling, necrosis and autoamputation.
  • Respiration is also restricted.  The rigid skin impedes chest wall expansion, leading to hypoventilation and respiratory failure.

How is harlequin ichthyosis diagnosed?

The diagnosis of harlequin ichthyosis relies on physical examination and genetic laboratory investigations.

Genetic testing for a loss of function mutation on the ABCA12 gene is the most specific diagnostic test for harlequin ichthyosis.

  • Mutations in the gene may cause impaired transport of lipids in the skin and shrunken versions of proteins responsible for skin development.
  • Less severe mutations result in a collodion membrane and congenital ichthyosiform erythroderma-like presentation [4,5].

Biopsy of skin may reveal hyperkeratotic skin cells on histology.

What is the differential diagnosis for harlequin ichthyosis?

The differential diagnosis includes the other forms of inherited ichthyosis:

Sjögren-Larsson syndrome

  • Sjögren-Larsson syndrome is caused by an inborn error of metabolism resulting in the deficiency of an enzyme, fatty aldehyde dehydrogenase (FALDH), which is needed to produce normal oils and fats in the body.
  • Clinical features include ichthyosis, cerebral palsy and intellectual impairment.

Gaucher disease

  • Gaucher disease is an autosomal recessive inborn error in glucosylceramidase, which may present as collodion baby with developmental and neurological problems.

Trichothiodystrophy

X-linked chondrodysplasia punctata (Conradi-Hünermann-Happle syndrome)

  • X-linked chondrodysplasia punctata is caused by a defect in cholesterol biosynthesis due to mutation in the gene coding for emopamil binding protein (EBP).
  • Leads to early gestational lethality in males.
  • Leads to cicatricial scarring, alopecia, patchy/diffuse ichthyosis that may resolve into atrophoderma and hyperpigmentation, punctuate calcification in epiphyseal cartilage, asymmetrical rhizomelic (proximal) limb shortening, cataracts, and deafness in females.

What is the treatment for harlequin ichthyosis?

There is no cure for harlequin ichthyosis and treatment is centred around protecting the skin and preventing infection.

After birth, the thick plate-like outer layer of skin eventually splits and peels, leaving vulnerable inner layers of the dermis exposed.  Most harlequin infants will need one-on-one nursing care for the first several weeks of life.  Antibiotic treatment may also be necessary to prevent or treat infection during this time.

Softening emollients, especially those containing urea, salicylic acid or alpha hydroxyl acids, are particularly effective after bathing while the skin is still moist.  These products work to keep the skin moisturised and pliable, while preventing cracking and fissuring that can lead to secondary bacterial infection.

Early systemic treatment with oral retinoids (such as acitretin or isotretinoin) has also been shown to heal skin fissures, soften or resolve plate-like scales, and improve overall survival [6].

What is the outcome for harlequin ichthyosis?

In the past, harlequin ichthyosis infants rarely survived the first few days of life.  With advancements in neonatal care, the survival rate has improved, with worldwide figures approaching 50% [3]. 

Children who survive the neonatal period usually evolve to a less severe phenotype but continue to develop fish-like scales, retention of waxy, yellowing material in seborrhoeic areas, generalised poor hair growth and scarring alopecia.  Harlequin ichthyosis survivors may continue to suffer from temperature dysregulation, have contractures of digits, arthralgias, failure to thrive, hypothyroidism, and short stature.            

 

Related Information

References

  1. A Case of General Seborrhœa or “Harlequin” Fetus J. Bland Sutton Med Chir Trans. 1886; 69: 291–296.1. PMCID: 2121560
  2. Ahmed H, O'Toole EA. Recent advances in the genetics and management of harlequin ichthyosis. Pediatr Dermatol. 2014 Sep-Oct. 31 (5):539-46. PubMed.
  3. Rajpopat S, Moss C, Mellerio J, et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases.Arch Dermatol. 2011 Jun. 147(6):681-6. PubMed.
  4. Kelsell DP, Norgett EE, Unsworth H et al. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet. 2005 May;76(5):794-803. Epub 2005 Mar 8. PubMed Central.
  5. Akiyama, M (2010). ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts. Hum Mutat. 31 (10): 1090–6. PubMed.
  6. Chang, LM; Reyes, M (2014). A case of harlequin ichthyosis treated with isotretinoin. Dermatol Online J. 20 (2): 2. Journal.

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