Harlequin-type ichthyosis

Not to be confused with Harlequin syndrome.

Harlequin-type ichthyosis
File:Harlequin fetus.JPG Harlequin fetus (1886)
Classification and external resources
Specialty	Dermatology
ICD-10	Q80.4
ICD-9-CM	757.1
OMIM	242500
DiseasesDB	30052
eMedicine	derm/192
Patient UK	Harlequin-type ichthyosis
MeSH	D017490
Orphanet	457

Harlequin-type ichthyosis (also known as harlequin baby, harlequin ichthyosis, hyosis fetalis, keratosis diffusa fetalis, harlequin fetus, and ichthyosis congenita gravior), is a severe genetic skin disease, which causes thickening of the stratum corneum of the epidermis. It is a type of autosomal recessive congenital ichthyosis, which is a heterogeneous group of nonsyndromic disorders of keratinization. The overall incidence of Harlequin ichthyosis is 1 in 300,000 births. At birth, the child’s whole body is encased in an 'armour' of thick white plates of skin, separated with deep cracks. In addition, the eyes, ears, penis, and the appendages may be abnormally contracted. Because of resultant cracked skin in locations where normal skin would fold, it is easily pregnable by bacteria and other contaminants, which can result in serious risk of fatal infection. Constant care is required to moisturise and protect the skin.

The harlequin-type designation comes from the diamond shape of the scales at birth (resembling the costume of Arlecchino), caused by severe hyperkeratosis. The disease can be diagnosed in the uterus by way of fetal skin biopsy or by morphologic analysis of amniotic fluid cells obtained by amniocentesis. Doctors can now usually recognize common features of the disease through ultrasound, and follow up with 3D ultrasound to diagnose the condition. Ultrasound can reveal abnormal facial features with ectropion, eclabium, short foot length, incurved toes, clenched fists, poor delineation of nostrils, and polyhydramnios.

It is associated with a mutation in the gene for the protein ABCA12.

Signs and symptoms

Newborns with Harlequin-type ichthyosis present with thick, fissured armor-plate hyperkeratosis. Sufferers feature severe cranial and facial deformities. The ears may be very poorly developed or absent entirely, as may the nose. The eyelids may be everted (ectropion), which leaves the eyes and the area around them very susceptible to infection. Babies with this condition often bleed during birth. The lips are pulled back by the dry skin (eclabium). Joints are sometimes lacking in movement, and may be below the normal size. Hypoplasia is sometimes found in the fingers. Polydactyly has also been found on occasion. In addition, the fish mouth appearance, mouth breathing, and xerostomia place affected individuals at extremely high risk for developing rampant dental decay.

Patients with this condition are extremely sensitive to changes in temperature due to their hard cracked skin, which prevents normal heat loss. Respiration is also restricted by the skin, which impedes the chest wall from expanding and drawing in enough air. This can lead to hypoventilation and respiratory failure. Harlequins are often dehydrated, as their plated skin is not well suited to retaining water.

Diagnosis

The diagnosis of Harlequin-type Ichthyosis relies on both physical examination and certain laboratory tests. Physical assessment at birth is vital for the initial diagnosis of Harlequin ichthyosis. Physical examination reveals characteristic symptoms of the condition especially the abnormalities in the skin surface of newborns. Abnormal findings in physical assessments usually result in employing other diagnostic tests to ascertain the diagnosis. Genetic testing is the most specific diagnostic test for harlequin ichthyosis. This test reveals a loss of function mutation on the ABCA12 gene. This gene is important in the regulation of protein synthesis for the development of the skin layer. Mutations in the gene may cause impaired transport of lipids in the skin layer and may also lead to shrunken versions of the proteins responsible for skin development. Less severe mutations result in a collodion membrane and congenital ichthyosiform erythroderma-like presentation. ABCA12 is an ATP binding cassette (ABC) transporter, and is a member of a large family of proteins that hydrolyze ATP to transport cargo across membranes. ABCA12 is thought to be a lipid transporter in keratinocytes necessary for lipid transport into lamellar granules during the formation of the lipid barrier. Biopsy of skin may be done to assess the histologic characteristics of the cells. Histological findings usually reveal hyperkeratotic skin cells, which leads to a thick, white and hard skin layer.

Treatment and prognosis

Constant care is required to moisturise and protect the skin. The hard outer layer eventually peels off, leaving the vulnerable inner layers of the dermis exposed. Early complications result from infection due to fissuring of the hyperkeratotic plates and respiratory distress due to physical restriction of chest wall expansion. Management includes supportive care and treatment of hyperkeratosis and skin barrier dysfunction. A humidified incubator is generally used. Intubation is often required until nares are patent. Nutritional support with tube feeds is essential until eclabium resolves and infants can begin nursing. Ophthalmology consultation is useful for the early management of ectropion, which is initially pronounced and resolves as scale is shed. Liberal application of petrolatum is needed multiple times a day. In addition, careful debridement of constrictive bands of hyperkeratosis should be performed to avoid digital ischemia. Cases of digital autoamputation or necrosis have been reported due to cutaneous constriction bands. Relaxation incisions have been used to prevent this morbid complication.

In the past, the disorder was nearly always fatal, whether due to dehydration, infection (sepsis), restricted breathing due to the plating, or other related causes. The most common cause of death was systemic infection and sufferers rarely survived for more than a few days. However, improved neonatal intensive care and early treatment with oral retinoids, such as the drug Isotretinoin (Isotrex), may improve survival. Early oral retinoid therapy has been shown to soften scales and encourage desquamation. After as little as two weeks of daily oral isotretinoin, fissures in the skin can heal, and plate-like scales can nearly resolve. Improvement in the eclabium and ectropion can also be seen in a matter of weeks. Children who survive the neonatal period usually evolve to a less severe phenotype, resembling a severe congenital ichthyosiform erythroderma. Patients continue to suffer from temperature dysregulation and may have heat and cold intolerance. Patients can also have generalized poor hair growth, scarring alopecia, contractures of digits, arthralgias, failure to thrive, hypothyroidism, and short stature. Some patients develop a rheumatoid factor-positive polyarthritis. Survivors can also develop fish-like scales and retention of a waxy, yellowish material in seborrheic areas, with ear adhered to the scalp.

The oldest known survivor is Nusrit "Nelly" Shaheen, who was born in 1984 and is in relatively good health as of May 9, 2008. Lifespan limitations have not yet been determined with the new treatments.

A study published in 2011 in the Archives of Dermatology concluded, "Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. With improved neonatal care and probably the early introduction of oral retinoids, the number of survivors is increasing."

History

The disease has been known since 1750, and was first described in the diary of a cleric from Charleston, South Carolina, the Rev. Oliver Hart:

"On Thursday, April the 5th, 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."

Notable cases

• Nusrit "Nelly" Shaheen (born 1984) is the oldest known survivor with the condition; she resides in Coventry, and was one of nine children in a Pakistani Muslim household. Four of her eight siblings also had the condition but died as young children. Shaheen lives an active lifestyle and in 2008 was studying sports coaching and leadership at Hereward College.
• Hunter Steinitz (born 1994) is one of only twelve Americans living with the disease and is profiled on the National Geographic "Extraordinary Humans: Skin" special.
• Ryan Gonzalez (born 1986) is the oldest person in the United States living with the disease. He was featured in an episode of Medical Incredible.
• Stephanie Turner (born 1992) is the second oldest person in the United States living with the disease, and the first ever to give birth. Turner's two children do not have the disease.
• Mason van Dyke, despite being given a life expectancy of one to five days, was 21 months old and active, as of December 31, 2014. Doctors told his mother Lisa van Dyke that he was the first case of Harlequin Ichthyosis in South Africa, and that she has a one-in-four chance to have another child with the disease.

External links

• A Case Of Harlequin Fetus With Psoriasis In His Family. Article from the Internet Journal of Pediatrics and Neonatology.
• Medical Article Harlequin Ichthyosis article from Foundation for Ichthyosis and Related Skin Types
• Profile of 15-year-old surviving Harlequin
• Hospital photos and diagrams
• Information from the U.S. National Institutes of Health
• Genetic information
• Foundation for Ichthyosis Research in MONACO