Harlequin-type ichthyosis is agenetic disorder that results in thickened skin over nearly the entire body at birth.[4] The skin forms large, diamond/trapezoid/rectangle-shaped plates that are separated by deep cracks.[4] These affect the shape of the eyelids, nose, mouth, and ears and limit movement of the arms and legs.[4] Restricted chest movement can lead to breathing difficulties.[4] These plates fall off over several weeks.[3] Other complications can includepremature birth, infection, problems with body temperature, anddehydration.[4][5] The condition is the most severe form ofichthyosis (except for syndromes that include ichthyosis, for example,Neu–Laxova syndrome), a group of genetic disorders characterised by scaly skin.[8]
There is no cure for the condition.[8] Early in life, constantsupportive care is typically required.[3] Treatments may include moisturizing cream,antibiotics,etretinate orretinoids.[3][5] Around half of those affected die within the first few months;[7] however, retinoid treatment can increase chances of survival.[9][8] Children who survive the first year of life often have long-term problems such asred skin, jointcontractures and delayed growth.[5] The condition affects around 1 in 300,000 births.[7] It was first documented in a diary entry by Reverend Oliver Hart in America in 1750.[6]
A child with Harlequin-type ichthyosis. Visible plates on the skin and changes in the appearance of the ears and fingers, are symptoms of Harlequin-type ichthyosis.[10]
Newborns with harlequin-type ichthyosis present with thick, fissured armor-platehyperkeratosis.[11] Sufferers feature severe cranial and facial deformities. The ears may be very poorly developed or absent, as may the nose. Theeyelids may be everted (ectropion), which leaves the eyes and the area around them very susceptible to infection.[12] Babies with this condition often bleed during birth. Thelips are pulled back by the dry skin (eclabium).[13]
Joints sometimes lack movement and may be below the normal size.Hypoplasia is sometimes found in the fingers.Polydactyly has been found on occasion. The fish mouth appearance, mouth breathing, andxerostomia place affected individuals at extremely high risk for developing rampant dental decay.[14]
People with this condition are extremely sensitive to changes in temperature due to their hard,cracked skin, which prevents normal heat loss. The skin also restrictsrespiration, which impedes thechest wall from expanding and drawing in enough air. This can lead tohypoventilation andrespiratory failure. Patients are oftendehydrated, as their plated skin is not well suited to retaining water.[13]
Two genetic mechanisms that can result in harlequin-type ichthyosis
Harlequin-type ichthyosis is caused by a loss-of-function mutation in theABCA12 gene. This gene is important in regulatingprotein synthesis for the development of the skin layer. Mutations in the gene cause impairedtransport oflipids 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 andcongenital ichthyosiform erythroderma-like presentation.[15][16]
ABCA12 is anATP-binding cassette transporter (ABC transporter), which is a member of a large family of proteins thathydrolyze ATP to transport cargo across cell membranes. ABCA12 is thought to be a lipid transporter inkeratinocytes necessary for lipid transport intolamellar granules during the formation of the lipid barrier in the skin.[17]
The diagnosis of harlequin-type ichthyosis relies on both physical examination and 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 theABCA12 gene.[18] A skin biopsy 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.
Constant care is required to moisturize and protect the skin. The hard outer layer eventually peels off, exposing the vulnerable inner layers of thedermis. Early complications result from infection due to fissuring of thehyperkeratotic plates andrespiratory distress due to physical restriction of chest wall expansion.[19]
Management includes supportive care and treatment of hyperkeratosis and skin barrier dysfunction. A humidified incubator is generally used.Intubation is often required untilnares are present. Nutritional support with tube feeding is essential untileclabium resolves and infants can begin nursing.Ophthalmologic consultation is useful for the early management ofectropion, which is initially pronounced and resolves as scales are shed. Liberal application ofpetroleum jelly is needed multiple times daily.
In addition, carefuldebridement of constrictive bands of hyperkeratosis should be performed to avoiddigital ischemia.[19] Cases of digitalautoamputation ornecrosis have been reported due to cutaneous constriction bands. Relaxation incisions have been used to prevent this complication.[19]
In the past, the disorder was nearly always fatal, whether due todehydration, infection (sepsis), restrictedbreathing 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. Improvedneonatal intensive care and early treatment withoral retinoids, such as the drugisotretinoin, may improve survival.[13][9] Early oral retinoid therapy has been shown to soften scales and encouragedesquamation.[20] 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 weeks.
Most infants do not live past a week. Those who survive can live from around 10 months to 25 years thanks to advanced medicine.[22]
A study published in 2011 in theArchives of Dermatology concluded: "Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. Survival has increased with improved neonatal care and the early introduction of oral retinoids.[23]
The disease has been known since 1750 and was first described in the diary of Rev. Oliver Hart fromCharleston, South Carolina:
"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."[24]
Theharlequin-type designation comes from the diamond shape of the scales at birth (resembling the costume ofArlecchino).
Devan Mahadeo (June 11, 1985 – January 23, 2023) was born inTrinidad and Tobago and lived to be 37 years old. He was involved in theSpecial Olympics for over 17 years and participated in both theWinter and Summer Games. He earned silver medals in football at Dublin, Ireland, in 2003 and Shanghai, China, in 2007, bronze infloor hockey at the 2013 Winter Games in Pyeongchang,South Korea, and gold at the 2015Special Olympics World Games in Los Angeles, California.[25][26]
Andrea Aberle (1969 – 2021) died at 51 years old, making her one of the longest-surviving individuals with harlequin ichthyosis, both in the US and globally. She lived in California with her husband before she died from skin-related complications.[27]
Nusrit "Nelly" Shaheen (born in 1984) ofCoventry, England, was one of nine children. Four of her eight siblings also had the condition but died as young children. As of March 2017, Shaheen was among the oldest individuals with harlequin-type ichthyosis, at 33 years old).[28][29][30]
Ryan Gonzalez (born in 1986)[31] was 18 as of 2004, and was featured in an episode ofMedical Incredible.
Stephanie Turner (1993[32] – 2017[33]) third oldest in the US with the same condition, and the first ever to give birth. Turner's two children do not have the disease. She died on March 3, 2017, at age 23.[34]
Mason van Dyk (born 2013), despite being given a life expectancy of one to five days, was 5 years old as of July 2018.[35] Doctors told his mother, Lisa van Dyk, that he was the first case of harlequin ichthyosis in South Africa, and that she has aone-in-four chance of having another child with the disease.[36]
Hunter Steinitz (born October 17, 1994) as of June 2010 was 16 and one of only twelve Americans living with the disease, and was profiled onNational Geographic's "Extraordinary Humans: Skin" special.[37]
Mui Thomas (born in 1992 in Hong Kong) was 24 as of 2016 and qualified as the first rugby referee with harlequin ichthyosis.[38]
A female baby born inNagpur,India in June 2016 died after two days. She was the first case of harlequin ichthyosis reported in India.[39][40][41]
Hannah Betts was born with the condition in 1989 inGreat Britain, and died in 2022 at 32 years old.[42]
Ng Poh Peng was born in 1991 inSingapore. Doctors had not expected her to live past her teenage years. As of 2017, she was 26 years old.[43]
Evan Fasciano, born in 2011 inConnecticut, United States, was 13 as of April 2024.[44]
^Mitsutake, S; Suzuki, C; Akiyama, M; et al. (2010). "ABCA12 dysfunction causes a disorder in glucosylceramide accumulation during keratinocyte differentiation".J Dermatol Sci.60 (2):128–9.doi:10.1016/j.jdermsci.2010.08.012.PMID20869849.
^abcTanahashi, K; Sugiura, K; Sato, T; Akiyama, M (2016). "Noteworthy clinical findings of harlequin ichthyosis: digital autoamputation caused by cutaneous constriction bands in a case with novel ABCA12 mutations".Br J Dermatol.174 (3):689–91.doi:10.1111/bjd.14228.PMID26473995.S2CID34511814.
^Waring, J. I. (1932). "Early mention of a harlequin fetus in America".Archives of Pediatrics & Adolescent Medicine.43 (2): 442.doi:10.1001/archpedi.1932.01950020174019.
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