It is not often that clowns, with their wide painted smiles and diamond eyes, are associated with anything other than fun and gaiety¹; however, there is a tragic medical condition whose manifestation mocks this very image. Its name is ichthyosis foetalis, but thanks to people who insensitively take it for its entertainment value, you probably have seen photos of afflicted babies in shocker sites under the heading 'harlequin babies'².

A word of warning - this article is for the purpose of serious information and not for entertainment or shock. Therefore, it is not recommended to do a web search for images of these foetuses, unless you are emotionally prepared for it.

Note that Ichthyosis Foetalis should not be confused with 'Harlequin colour change', an unrelated condition where a baby appears strikingly flushed on one side of their body and pale on the other after having laid on their side. 'Harlequin colour change' is harmless and resolves with time.

What is ichthyosis foetalis?

The term ichthyosis³ refers to the spectrum of congenital, hereditary skin diseases manifested as roughening and thickening of the horny layer of the skin (known as hyperkeratosis), producing dryness and scaling. Of these, ichthyosis foetalis (also known as harlequin ichthyosis, ichthyosis congenital and keratosis diffusa foetalis) is the most severe. The term by which most laypeople know it, harlequin foetus, is coined from the skin deformation which causes the foetus's mouth to be pulled open in grotesque mimicry of a clown's smile, and by the triangular and diamond-shaped pattern of the hyperkeratosis reminiscent of the costumes and make-up of 17th Century harlequins.

History

The first mention of this disease is in the diary of one Reverend Oliver Hart of Charleston, South Carolina who, in 1750 wrote:

On Thursday, April ye 5, 1750, I went to see a most deplorable object of a child, born the night before of one Mary Evans in 'Chas'town. It was surprising to all who beheld it, and I scarcely know how to describe it. The skin was dry and hard and seemed to be cracked in many places, somewhat resembling the scales of a fish. The mouth was large and round and open. It had no external nose, but two holes where the nose should have been. The eyes appeared to be lumps of coagulated blood, turned out, about the bigness of a plum, ghastly to behold. It had no external ears, but holes where the ears should be. The hands and feet appeared to be swollen, were cramped up and felt quite hard. The back part of the head was much open. It made a strange kind of noise, very low, which I cannot describe. It lived about forty-eight hours and was alive when I saw it.

Manifestation

Ichthyosis foetalis is primarily an affliction of the skin, although other systems are affected as a result of the skin disorder and deformities.

Harlequin babies are often born prematurely, and have lower than normal birth weights. They are born with dense plate-like scales forming a massive horny shell around their body. These scales or plaques measure up to 4-5 cm on a side and are usually diamond- or triangular-shaped. 'Splits' between these scales reveal erhythematous moist fissures, whose bright red colour is in stark contrast to the lighter-coloured scales. This shell impedes movement, and the fissures cause the protective skin barrier to be compromised, thus leaving the foetus susceptible to infection.

The facial features of the afflicted are very severely deformed as a result of the skin disorder. The eyes, which are most prominent, are red and bulbous, the eyelids turned inside out. Because the foetus's eyes are highly susceptible to trauma, they often bleed upon birth, thus giving them the bulbous red-eye appearance. The lips, like the eyelids, are turned inside out and pulled by the dry skin into the visage of a clown's smile. The ears are often very poorly developed with rudimentary auricles (the outer projecting portion of the ear), or they may be absent alltogether. Nasal hypoplasia⁴ is also apparent.

Because of the scaling of the skin, the limbs are often deformed to the extent that movement is restricted, and may be undersized and incompletely formed. Polydactyly (the condition where one has more than the usual number of digits) has also been observed. The scales may sometimes also constrict blood-flow to the limbs, which results in swelling or in severe cases, gangrene.

What causes it

The genetic and biochemical basis of ichthyosis foetalis is poorly understood. The inheritance of this trait is thought to be autosomal recessive; ie, the defect is on a non-sex chromosome, and the condition will only manifest if both parents contribute this defective gene. The recessive inheritance theory has been supported by evidence from several family reports by Bustamente and Tejeda (1950), Lattuada and Parker (1951) and Thomson and Wakeley (1921); however, consanguinity is rare in the reported cases, thus making this condition hard to explain and suggesting that there may be a new dominant mutation (where only one copy of the defective gene is needed for the condition to manifest). It was further reported in 2001 that a male baby with this affliction suffered a deletion of the long arm of chromosome 18, thus suggesting that the gene for harlequin ichthyosis may lie within this region. A case study of a harlequin foetus whose father had psoriasis also suggested the possibility of a relationship between harlequin ichthyosis and psoriasis.

Abnormalities of the afflicted foetus's skins are linked to the abnormal structure and function of lamellar granules originating from the Golgi apparatus⁵ of keratin-producing cells in the horny outer layer of the epidermis, whose function is to secrete lipids that maintain the skin barrier at the interface between the grainy cell layer and the layer where the skin becomes the horny layer. Harlequin foetuses either do not have these granules, or have defective ones, which results in massive loss of water between the layers of skin. The lack of a class of enzymes known as hydrolases further prevents shedding of skin cells, thus causing overgrowth of the horny layer of skin. Defects involving a protein called phosphatase (which converts the protein profilaggrin in the keratin-making cells into filaggrin, which allows dense packing of keratin filaments in these cells), has further been implicated in the manifestation of this condition because the filaggrin needs to break down before the shedding of skin occurs. Furthermore, it is known that four genetic disorders of keratin production (one of which is harlequin ichthyosis) are linked to structural defects in the fibrillar proteins in keratin-producing cells, known as tonofibrils.

It was recently on the news that a research team led by the Queen Mary's School of Medicine and Dentistry in London has identified the mutated form of a gene called ABCA 12 in 11 of 12 patients involved in their ichthyosis foetalis studies which may be responsible for this condition. It is believed that ABCA 12 plays a critical role in the proper formation of the lamellar granules mentioned earlier.

Frequency

Ichthyosis foetalis is very rare, with an incidence of one in 300,000 births. There is no racial or sex predilection.

Morbidity and mortality

In general, harlequin foetuses do not survive for very long. In the past, the life expectancy for a harlequin foetus was about two weeks; however, intensive supportive care and the use of drugs has prolonged the lifespan of these babies and some have made it into adulthood. However, the average lifespan is much lower, and the babies usually suffer from physical developmental delay, although intellectual development has been reported to be normal.

Because of the skin disorder, harlequin babies are prone to temperature disregulation because their thickened skin prevents normal sweat gland function and heat loss, which can lead to extremely high body temperatures. Due to restrictions of chest-wall expansion (owing to the rigid shell), conditions such as respiratory distress, hypoventilation and respiratory failure may occur. Furthermore, excessive water-loss from the skin layers may also lead to electrolyte imbalances, causing rapid heart-rates (tachycardia) and poor urine output. The central nervous system may also become affected - abnormalities in metabolism may cause seizures, and restriction of spontaneous movements makes it difficult for physicians to assess the foetus's neurological condition. Furthermore, fissures in the skin cause compromise in the foetus's first line of defence, very often leading to severe infections.

Death is often due to dehydration, systemic infection or impaired respiration.

Diagnosis

Diagnosis of ichthyosis foetalis may be performed as early as 17 weeks into the pregnancy, from amniotic fluid samples which will reveal overproduction of keratin and abnormal lipid droplets; foetal skin biopsy performed 20 weeks into the gestation will confirm the diagnosis, thus giving the parents the option of aborting the pregnancy. If there is doubt regarding either, late-term pregnancy ultrasonographs will pick up the characteristic physical features of the condition.

Treatment and care

Harlequin babies require intensive and extensive care for the duration of their lives. Other than requiring constant and careful monitoring of vitals, their eyes need to be continually protected using ophthalmic lubricants, and intubations or IV drips are often required because they feed poorly. Sterile environments have to be maintained to hinder infection, and frequent administration of salt solutions followed by lubricants is required to soften the skin and facilitate the shedding of skin cells.

Treatment of harlequin babies with a battery of medication ranging from oral retinoids (drugs used in the treatment of psoriasis) to antiseptics and topical paraffin ointments to soften the skin have been reported as successful in improving the condition of harlequin babies.

Other than treatment of the babies, the parents themselves will need support. Like many other congenital disorders, parents with harlequin babies will need to learn to care for the babies, and most will need extensive counselling to deal with reality of bringing up a child who will never grow up. It is fortunate that, in addition to the development of medical science and therapy regimes, there is also a small but growing circle of ichthyosis foetalis support groups to help both parent and child cope with the disorder.

References

Akiyama, M, 1999: 'The pathogenesis of severe congenital ichthyosis of the neonate,' Journal of Dermatological Science Vol 21(2): 96-104.

Bustamente, W and M Tejeda, 1950: 'Ichthyosis foetalis gravis in two successive pregnancies,' Journal of Pediatrics Vol 36, 501-504.

Chittick, EJ et al, 2002: 'Harlequin ichthyosis in two greater kudu (Tragelaphus strepsiceros).' Veterinary Pathology Vol 39, 751-756.

Dale, BA and E Kam, 1993: 'Harlequin ichthyosis. Variability in expression and hypothesis for disease mechanism,' Archive of Dermatology, Vol 129(11): 1471-1477.

Fleck, RM et al, 1989: 'Harlequin ichthyosis: an ultrastructural study,' Journal of the American Academy of Dermatology, Vol 21(5 Pt 1), 999-1006.

Kouskoukis, C, A Minas and D Tousimis, 1982: 'Ichthyosis congenital fetalis (harlequin foetus),' International Journal of Dermatology, Vol. 21:347-348.

Lattuada, HP and MS Parker, 1951: 'Congenital ichthyosis,' American Journal of Surgery Vol. 82, 236-239.

Internet Medical Resources

• A case of harlequin foetus with psoriasis in his family
• Foundation for ichthyosis and related skin types
• Harlequin-type ichthyosis
• Ichthyosis congenital, harlequin foetus type
• Ichthyosis foetalis
• Ichthyosis Support Group (ISG)
• Key to severe skin disease found