Harlequin-type ichthyosis

Not to be confused with Harlequin syndrome.
Harlequin-type ichthyosis
Synonyms harlequin ichthyosis,[1] hyosis fetalis, keratosis diffusa fetalis, harlequin fetus,[2]:562 ichthyosis congenita gravior[1]
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
MeSH D017490
Orphanet 457

Harlequin-type ichthyosis is a very rare severe genetic disease, which causes thickening of the skin.[3] At birth, the child’s whole body is encased in an 'armor' of thick white plates of skin, separated with deep cracks. In addition, the eyes, ears, penis, and limbs 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.

It is an autosomal recessive congenital ichthyosis, which is a group of nonsyndromic disorders of keratinization. It is associated with a mutation in the gene for the protein ABCA12.[4] The disease can be diagnosed in the uterus by way of fetal skin biopsy or by analysis of amniotic fluid cells obtained by amniocentesis. Common features of the disease can be recognized 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.[5]

Constant care is required to moisturise and protect the skin.[6] The overall rate of Harlequin ichthyosis is 1 in 300,000 births.[7] The harlequin-type designation comes from the diamond shape of the scales at birth (resembling the costume of Arlecchino).

Signs and symptoms

Newborns with Harlequin-type ichthyosis present with thick, fissured armor-plate hyperkeratosis.[8] 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.[9] 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.[10]

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. Patients 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.[11][12] 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.[13] 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.[14]

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.[15] Early oral retinoid therapy has been shown to soften scales and encourage desquamation.[16] 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.[17] 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.[18] 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."[19]

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."[20]

Notable cases

References

  1. 1 2 Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
  2. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
  3. ↑ Shibata, Akitaka; Akiyama, Masashi (2015). "Epidemiology, medical genetics, diagnosis and treatment of harlequin ichthyosis in Japan". Pediatrics International. 57 (4): 516–22. doi:10.1111/ped.12638. PMID 25857373.
  4. ↑ David Kelsell, P.; Elizabeth Norgett, E.; Unsworth, Harriet; Teh, Muy-Teck; Cullup, Thomas; Mein, Charles A.; Patricia Dopping-Hepenstal, J.; Beverly Dale, A.; Tadini, Gianluca; Fleckman, Philip; Karen Stephens, G.; Virginia Sybert, P.; Susan Mallory, B.; Bernard North, V.; David Witt, R.; Sprecher, Eli; E. M. Taylor, Aileen; Ilchyshyn, Andrew; Cameron Kennedy, T.; Goodyear, Helen; Moss, Celia; Paige, David; John Harper, I.; Bryan Young, D.; Irene Leigh, M.; Robin Eady, A.J.; Edel O'Toole, A. (2005). "Mutations in ABCA12 Underlie the Severe Congenital Skin Disease Harlequin Ichthyosis". The American Journal of Human Genetics. 76 (5): 794–803. doi:10.1086/429844. PMC 1199369Freely accessible. PMID 15756637.
  5. ↑ Rathore, S; David, LS; Beck, MM; Bindra, MS; Arunachal, G (2015). "Harlequin Ichthyosis: Prenatal Diagnosis of a Rare Yet Severe Genetic Dermatosis". J Clin Diagn Res. 9 (11): QD04-6. doi:10.7860/JCDR/2015/15250.6705. PMC 4668483Freely accessible. PMID 26675324.
  6. ↑ "Harlequin Ichthyosis". http://www.shhirt.org.uk. Retrieved 18 February 2015. External link in |website= (help)
  7. ↑ Ahmed, H; O'Toole, E (2014). "Recent advances in the genetics and management of Harlequin Ichthyosis". Pediatric Dermatology. 31 (5): 539–46. doi:10.1111/pde.12383.
  8. ↑ Harris, AG; Choy, C; Pigors, M; Kelsell, DP; Murrell, DF (2016). "Cover image: Unpeeling the layers of harlequin ichthyosis". Br J Dermatol. 174 (5): 1160–1. doi:10.1111/bjd.14469. PMID 27206363.
  9. ↑ Kun-darbois, JD; Molin, A; Jeanne-pasquier, C; Pare, A; Benateau, H; Veyssiere, A (2016). "Facial features in Harlequin ichthyosis: Clinical finding about 4 cases.". Rev Stomatol Chir Macillofac Chir Orale. 117 (1): 51–3. doi:10.1016/j.revsto.2015.11.007. PMID 26740202.
  10. ↑ Vergotine, RJ; De lobos, MR; Montero-fayad, M (2013). "Harlequin ichthyosis: a case report". Pediatr Dent. 35 (7): 497–9. PMID 24553270.
  11. ↑ 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. doi:10.1002/humu.21326. PMID 20672373.
  12. ↑ Kelsell, DP; Norgett, EE; Unsworth, H; et al. (2005). "Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis". Am J Hum Genet. 76 (5): 794–803. doi:10.1086/429844. PMC 1199369Freely accessible. PMID 15756637.
  13. ↑ 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. PMID 20869849.
  14. ↑ Tanahashi, 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. PMID 26473995.
  15. ↑ Rajpopat, S; Moss, C; Mellerio, J; et al. (2011). "Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases". Arch Dermatol. 147 (6): 681–6. doi:10.1001/archdermatol.2011.9. PMID 21339420.
  16. ↑ Chang, LM; Reyes, M (2014). "A case of harlequin ichthyosis treated with isotretinoin". Dermatol Online J. 20 (2): 2. PMID 24612573.
  17. ↑ Chan, YC; Tay, YK; Tan, LK; Happle, R; Giam, YC (2003). "Harlequin ichthyosis in association with hypothyroidism and rheumatoid arthritis". Pediatr Dermatol. 20 (5): 421–6. doi:10.1046/j.1525-1470.2003.20511.x. PMID 14521561.
  18. 1 2 Alison Jones (May 9, 2008). "Nelly is a real diamond girl". Birmingham Post. Retrieved 2008-11-10.
  19. ↑ Rajpopat, Shefali; Moss, Celia; Mellerio, Jemima; Vahlquist, Anders; Gånemo, Agneta; Hellstrom-Pigg, Maritta; Ilchyshyn, Andrew; Burrows, Nigel; Lestringant, Giles; Taylor, Aileen; Kennedy, Cameron; Paige, David; Harper, John; Glover, Mary; Fleckman, Philip; Everman, David; Fouani, Mohamad; Kayserili, Hulya; Purvis, Diana; Hobson, Emma; Chu, Carol; Mein, Charles; Kelsell, David; O'Toole, Edel (2011). "Harlequin Ichthyosis". Archives of Dermatology. 147 (6): 681–6. doi:10.1001/archdermatol.2011.9. PMID 21339420.
  20. ↑ 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.
  21. ↑ "Harlequin Ichthyosis". Archived from the original on October 14, 2008. Retrieved 2008-11-10.
  22. ↑ Sean D. Hamill (June 27, 2010). "City girl aims to educate about her skin disease". Pittsburgh Post-Gazette. Retrieved 2010-06-27.
  23. ↑ Man Survives Rare Skin-Shedding Disease: Harlequin Ichthyosis Usually Fatal At Birth, 10News.com San Diego; posted November 16, 2004; backup at WayBack Machine
  24. ↑ Mid-South woman with rare genetic condition defies odds, deliverers healthy baby, by Ursula Madden; at Fox19 Cincinnati; posted Aug 26, 2013; retrieved Aug 27, 2013
  25. ↑ 'People ask me if I've been in a fire', says mother, 23, with rare condition which causes her skin to grow seven times faster than normal, Daily Mail, 2 December 2015
  26. ↑ News24 (Dec 31, 2014). "21-month-old boy defies the odds, thrives living with Harlequin Ichthyosis". News24. Retrieved 2015-01-01.
  27. ↑ "'Girl behind the face' tackles cyber bullies". scmp.com.
  28. ↑ "Nagpur: Harlequin baby dies two days after birth". hindustantimes.com/. 2016-06-13. Retrieved 2016-06-14.
  29. ↑ "India's first 'Harlequin Baby' born without any external skin dies two days after birth". India TV. 2016-06-14. Retrieved 2016-06-14.

Further reading

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