The term harlequin fetus is used to describe an extremely severe form of skin disease in which affected infants have thick, plate-like scales all over their bodies. This abnormality is present from birth. It leads to disfiguration of the facial features and limited movement of the arms, legs, fingers, and toes. Most affected infants die during the first several weeks of life, although longer-term survivors have been reported.
Description
Harlequin fetus represents the most severe presentation of inherited ichthyosis. The word ichthyosis, which is derived from the Greek word for fish, is a descriptive term used for a group of inherited disorders in which the skin is markedly thickened, ridged, and cracked. The term "harlequin ichthyosis" is therefore used interchangeably with "harlequin fetus." Other synonyms over time have included fetal ichthyosis, ichthyosis intrauterina, keratosis diffusa fetalis, congenital diffuse maligna keratoma, and malignant keratosis.
The ichthyoses as a group are due to a variety of underlying metabolic abnormalities. However, the net effect of each abnormality is the same: keratinization, or differentiation of the cells which make up the skin, does not occur normally. The ichthyoses are separated based on their clinical features and the age at which symptoms appear.
Ichthyosis of the newborn refers to those disorders that present either at birth or shortly thereafter. Each newborn ichthyosis may be due to a different genetic abnormality, even when there is some similarity between clinical features. The harlequin fetus, however, is such a distinct and striking disorder that it is rarely confused with other types of ichthyosis. Affected infants have thick, armor-like skin with deep cracks running in different directions all over their bodies. This gives the appearance of diamond-shaped plaques. The word "harlequin" is often used to describe a variegated pattern, or a combination of patches on a solid background of a contrasting color. The severe skin abnormality leads to an open, fish-mouth appearance as well as a turning outward of the eyelids. Abnormalities of the internal organs are uncommon but have been reported in some individuals. Death often occurs early due to severe skin infection.
Genetic profile
Harlequin fetus (HF) is inherited as an autosomal recessive condition. As such, a child must inherit two copies of the HF gene in order to be affected. The presence of one HF gene and one normal gene is consistent with being a gene carrier. Carriers are normal but face a risk of having an affected child with another HF carrier. This risk is 25%, or a one in four chance, that two carriers will each pass on an HF gene to his or her offspring. This risk applies to each pregnancy two carriers have together. Conversely, there is also a 75% chance that two carriers would have an unaffected child.
A gene for harlequin fetus has not yet been identified. It has been speculated that this condition actually represents a varied group of genetic abnormalities, all of which cause a similar clinical picture. This is possible given the number of steps involved in keratinization. If so, it is likely that a different abnormal gene is present in different families.
Demographics
According to the Foundation for Ichthyosis and Related Skin Types (F.I.R.S.T.), harlequin fetus is a very rare form of congenital ichthyosis. There is limited data available to provide a specific incidence figure. However, F.I.R.S.T. provides one estimate as approximately one in every 200,000 individuals. Like other autosomal recessive conditions, HF has been observed more often among the children of consanguineous, or related, couples, such as first cousins, etc. Biologically related individuals are much more likely to carry the same recessive gene and, hence, have offspring with autosomal recessive disorders. Children with HF have, however, also been born to unrelated parents.
Signs and symptoms
Infants affected with harlequin ichthyosis have a striking and unique appearance at birth. Their skin is unusually thick, off-white in color, with deep, moist cracks running in different directions. The facial appearance is distorted with marked ectropion, or turning outward (eversion) of the eyelids. The lips also appear to be turned outward. This is referred to as eclabium. The external ears are absent or flattened against the side of the head. The hands and feet are also grayish-white in color. The fingers and toes appear malformed, in part due to the thick scale that surrounds them but probably also due to interference with blood flow to the digits from the constrictions. Nails and body hair may be missing. There is limited mobility of arms and legs.
A consistent pattern of associated internal abnormalities has not been identified in infants with HF. However, abnormalities of the central nervous system, kidneys, and lungs have been described in some affected individuals. Short stature has been observed in those infants who have survived the newborn period.
Diagnosis
A diagnosis of HF is possible based on clinical examination after birth. However, in order to confirm a diagnosis of this particular type of ichthyosis, a skin biopsy is strongly recommended. A sample of skin is submitted for electron microscopy. This specific type of technical examination can identify the characteristic changes within the epidermal cells associated with hyperkeratosis, or overgrowth of the stratum corneum. The cells of the stratum corneum contain protein, keratin, and act as a protective barrier along the surface of the body. The process by which new epidermal cells are formed and gradually changed into the cells of the stratum corneum is referred to as keratinization. It is controlled by a number of different metabolic pathways, and an abnormality at any point can theoretically lead to conditions such as ichthyosis or other serious skin abnormalities.
Prenatal diagnosis of harlequin ichthyosis has been accomplished by biopsy of the fetal skin and microscopic analysis of cells from a sample of amniotic fluid. This is usually accomplished by a combination of fetoscopy and amniocentesis. The cellular changes associated with hyperkeratosis begin during the latter part of the second trimester of pregnancy. Prenatal diagnosis of HF has been achieved usually around 21-23 weeks gestation. In 1999, a Japanese group was able to successfully diagnosis HF at the earlier gestational age of 19 weeks in an at-risk family.
Realistically, prenatal diagnosis for HF is available only to those couples that have already had at least one affected child. Based on that family history, the parents will be carriers of a gene for HF and thus at 25% risk of having another affected child. Since a gene for HF has not been identified, carrier testing in the general population is not possible. Also, prenatal ultrasound alone will not detect many of the features associated with HF, particularly in a low-risk patient population.
Treatment and management
Infants with HF have a tendency to be born prematurely. Thus, if a prenatal diagnosis of HF has been made, and the family wishes to continue the pregnancy, the woman and her doctor can devise a plan for more intensive monitoring of the remainder of her pregnancy.
Immediate care of a newborn with HF must focus on the following: temperature control, as well as prevention of dehydration, malnutrition, and infection. Infants who are born prematurely may also have breathing problems requiring placement of a breathing tube.
In 1998, guidelines were published for the care of any newborn with a severe form of congenital ichthyosis, including HF:
The infant should be placed in a humidified incubator immediately after delivery. Antibiotics should be administered via an intravenous (IV) line as a safeguard against infection. An IV should also be used to provide water and nutrients until the infant can suck sufficiently.
Medication for pain management should be provided, as needed.
Sponge baths or tub soaking and the application of skin moisturizers with antibiotics should be performed twice a day to soften the skin and reduce scaliness.
Creams or ointments containing the drug etretinate should be used to decrease the amount of scale. Etretinate has been a successful mode of treatment for some infants with HF, although treated infants still died at relatively young ages due to complications from their disorder. Careful monitoring for etretinate-related side effects in children, such as bone toxicity, is recommended.
Artifical tear treatments for infants with severe ectropion.
Prognosis
Most infants with harlequin fetus ichthyosis die within the first few days to weeks of life. Common causes of death include respiratory complications because of prematurity or constriction by the thick scale, dehydration, malnutrition, or severe skin infection. Longer-term survivors have been reported but these children have required intensive, on-going medical care. Etretinate has been an effective form of treatment for some infants but its use has only been for short periods of time since the affected infants have still died. Even with treatment, the ichthyosis does not completely go away. However, over time, the eversion of eyelids and lips gradually resolves. Large, thin scales with reddish edges gradually replace the cracked, thick skin. Variable neurological impairment has been reported among survivors, and, even with attentive medical care, sudden death may still occur.
BOOKS
Baden, Howard P. "Ichthyosiform Dermatoses." In Emery and Rimoin's Principles and Practice of Medical Genetics. Edited by David L. Rimoin, J. Micheal Connor, and Reed E. Pyeritz. 3rd ed. St. Louis, MO: Churchill Livingstone, 1997, pp. 1205-1214.
"Disorders of Keratinization." In Nelson's Textbook of Pediatrics. Edited by Richard E. Behrman, Robert M. Kliegman, and Hal B. Jenson. 16th ed. Philadelphia: W.B. Saunders, 2000, p. 2007.
PERIODICALS
Akiyama, Masashi. "Severe Congenital Ichthyosis of the Neonate." International Journal of Dermatology 37 (1998): 722-728.
Akiyama, Masashi, Kaoru Suzumori, and Hiroshi Shimizu. "Prenatal Diagnosis of Harlequin Ichthyosis by the Examination of Keratinized Hair Canals and Amniotic Fluid Cells at 19 Weeks Estimated Gestational Age." Prenatal Diagnosis 19 (February 1999): 167-171.
Pejaver, Ranjan K., et al. "Etretinate in the Management of Harlequin Siblings." Indian Journal of Pediatrics 65 (March-April 1998): 320-323.
ORGANIZATIONS
Foundation for Ichthyosis and Related Skin Types. 650 N. Cannon Ave., Suite 17, Landsdale, PA 19446. (215) 631-1411 or (800) 545-3286. Fax: (215) 631-1413. <http://www.scalyskin.org>.
National Registry for Ichthyosis and Related Disorders. University of Washington Dermatology Department, Box 356524, 1959 N.E. Pacific, Rm. BB1353, Seattle, WA 98195-6524. (800) 595-1265 or (206) 616-3179. <http://www.skinregistry.org>.
