Harlequin-type ichthyosis

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Harlequin-type ichthyosis
Other namesHarlequin ichthyosis, [1] ichthyosis fetalis, keratosis diffusa fetalis, harlequin fetus, [2] : 562  ichthyosis congenita gravior [1]
Harlequin fetus.JPG
Harlequin-type ichthyosis, 1886
Specialty Dermatology
Symptoms Very thick skin which cracks, abnormal facial features [3] [4]
Complications Breathing problems, infection, problems with body temperature, dehydration [4]
Usual onsetPresent from birth [3]
Causes Genetic (autosomal recessive) [3]
Diagnostic method Based on appearance and genetic testing [5]
Differential diagnosis Ichthyosis congenita, Lamellar ichthyosis [3]
Treatment Supportive care, moisturizing cream [3]
Medication Antibiotics, etretinate, retinoids [3]
Prognosis Death in the first month is relatively common [6]
Frequency1 in 300,000 [7]

Harlequin-type ichthyosis is a genetic 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 movement of the chest can lead to breathing difficulties. [4] These plates fall off over several weeks. [3] Other complications can include premature birth, infection, problems with body temperature, and dehydration. [4] [5] The condition is the most severe form of ichthyosis (except for syndromes that include ichthyosis, for example, Neu–Laxova syndrome), a group of genetic disorders characterised by scaly skin. [8]

Contents

Harlequin-type ichthyosis is caused by mutations in the ABCA12 gene. [4] This gene codes for a protein necessary for transporting lipids out of cells in the outermost layer of skin. [4] The disorder is autosomal recessive and inherited from parents who are carriers. [4] Diagnosis is often based on appearance at birth and confirmed by genetic testing. [5] Before birth, amniocentesis or ultrasound may support the diagnosis. [5]

There is no cure for the condition. [8] Early in life, constant supportive care is typically required. [3] Treatments may include moisturizing cream, antibiotics, etretinate or retinoids. [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 as red skin, joint contractures 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]

History

The disease has been known since 1750, and was first described in the diary of Rev. Oliver Hart from Charleston, 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." [10]

The harlequin-type designation comes from the diamond shape of the scales at birth (resembling the costume of Arlecchino).

Signs and symptoms

A child with Harlequin-type ichthyosis.Visible plates on the skin, as well as a change in the appearance of the ears and fingers,which are symptoms of Harlequin-type ichthyosis. TJOD-14-138-g4.jpg
A child with Harlequin-type ichthyosis.Visible plates on the skin, as well as a change in the appearance of the ears and fingers,which are symptoms of Harlequin-type ichthyosis.

Newborns with harlequin-type ichthyosis present with thick, fissured armor-plate hyperkeratosis. [12] 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. [13] Babies with this condition often bleed during birth. The lips are pulled back by the dry skin (eclabium). [14]

Joints are sometimes lacking in 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, and xerostomia place affected individuals at extremely high risk for developing rampant dental decay. [15]

Patients with this condition are extremely sensitive to changes in temperature due to their hard, cracked skin, which prevents normal heat loss. The skin also restricts respiration, 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. [14]

Cause

Two genetic mechanisms that can result in harlequin-type ichthyosis True homozygous versus compound heterozygous.png
Two genetic mechanisms that can result in harlequin-type ichthyosis

Harlequin-type ichthyosis is caused by a loss-of-function mutation in the ABCA12 gene. This gene is important in the regulation of protein synthesis for the development of the skin layer. Mutations in the gene 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. [16] [17]

ABCA12 is an ATP-binding cassette transporter (ABC transporter), which are members of a large family of proteins that hydrolyze ATP to transport cargo across cell 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 in the skin. [18]

Diagnosis

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 the ABCA12 gene. 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

Constant care is required to moisturize 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. [19]

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 present. 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 scales are shed. Liberal application of petroleum jelly is needed multiple times a day. In addition, careful debridement of constrictive bands of hyperkeratosis should be performed to avoid digital ischemia. [19]

Cases of digital autoamputation or necrosis have been reported due to cutaneous constriction bands. Relaxation incisions have been used to prevent this morbid complication. [19]

Prognosis

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. Improved neonatal intensive care and early treatment with oral retinoids, such as the drug isotretinoin, may improve survival. [14] [9] Early oral retinoid therapy has been shown to soften scales and encourage desquamation. [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 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 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. [21] Survivors can also develop fish-like scales and retention of a waxy, yellowish material in seborrheic areas, with ear adhered to the scalp.[ citation needed ]

The oldest known survivor is Nusrit "Nelly" Shaheen, who was born in 1984 and is in relatively good health as of June 2021. [22] [23] Most infants do not live past a week. Those who do survive can live from anywhere around 10 months to 25 years thanks to advanced medicine. [24]

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." [25]

Epidemiology

The condition occurs in roughly 1 in 300,000 people. As an autosomal recessive condition, there is a higher likelihood of consanguinity. [7]

Notable cases

Related Research Articles

<span class="mw-page-title-main">Ichthyosis</span> Family of genetic skin disorders

Ichthyosis is a family of genetic skin disorders characterized by dry, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cause and mode of inheritance. Ichthyosis comes from the Greek ἰχθύςichthys, literally 'fish', since dry, scaly skin is the defining feature of all forms of ichthyosis.

<span class="mw-page-title-main">Ichthyosis vulgaris</span> Skin disorder

Ichthyosis vulgaris is a skin disorder causing dry, scaly skin. It is the most common form, and one of the mildest forms, of ichthyosis, affecting around 1 in 250 people. For this reason it is known as common ichthyosis. It is usually an autosomal dominant inherited disease, although a rare non-heritable version called acquired ichthyosis exists.

<span class="mw-page-title-main">Lamellar ichthyosis</span> Medical condition

Lamellar ichthyosis, also known as ichthyosis lamellaris and nonbullous congenital ichthyosis, is a rare inherited skin disorder, affecting around 1 in 600,000 people.

<span class="mw-page-title-main">Epidermolytic hyperkeratosis</span> Medical condition

Epidermolytic ichthyosis (EI), is a rare and severe form of ichthyosis that affects around 1 in 300,000 people. It is caused by a genetic mutation, and thus cannot be completely cured without some form of gene therapy.

<span class="mw-page-title-main">Darier's disease</span> Medical condition

Darier's disease (DAR) is a rare, inherited skin disorder that presents with multiple greasy, crusting, thick brown bumps that merge into patches. It is an autosomal dominant disorder discovered by French dermatologist Ferdinand-Jean Darier.

<span class="mw-page-title-main">Keratosis pilaris</span> Skin condition characterized by small bumps caused by overproduction of keratin

Keratosis pilaris is a common, autosomal-dominant, genetic condition of the skin's hair follicles characterized by the appearance of possibly itchy, small, gooseflesh-like bumps, with varying degrees of reddening or inflammation. It most often appears on the outer sides of the upper arms, thighs, face, back, and buttocks; KP can also occur on the hands, and tops of legs, sides, or any body part except glabrous (hairless) skin. Often the lesions can appear on the face, which may be mistaken for acne or folliculitis.

<span class="mw-page-title-main">X-linked ichthyosis</span> Medical condition

X-linked ichthyosis is a skin condition caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males. XLI manifests with dry, scaly skin and is due to deletions or mutations in the STS gene. XLI can also occur in the context of larger deletions causing contiguous gene syndromes. Treatment is largely aimed at alleviating the skin symptoms. The term is from the Ancient Greek 'ichthys' meaning 'fish'.

<span class="mw-page-title-main">Meleda disease</span> Medical condition

Meleda disease (MDM) or "mal de Meleda", also called Mljet disease, keratosis palmoplantaris and transgradiens of Siemens, is an extremely rare autosomal recessive congenital skin disorder in which dry, thick patches of skin develop on the soles of the hands and feet, a condition known as palmoplantar hyperkeratosis. Meleda Disease is a skin condition which usually can be identified not long after birth. This is a genetic condition but it is very rare. The hands and feet usually are the first to show signs of the disease but the disease can advance to other parts of the body. Signs of the disease include thickening of the skin, on hands and soles of feet, which can turn red in color. There currently is no cure and treatment is limited, but Acitretin can be used in severe cases.

<span class="mw-page-title-main">ABCA12</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family A member 12 also known as ATP-binding cassette transporter 12 is a protein that in humans is encoded by the ABCA12 gene.

Conradi–Hünermann syndrome is a rare type of chondrodysplasia punctata. It is associated with the EBP gene and affects between one in 100,000 and one in 200,000 babies.

<span class="mw-page-title-main">Genodermatosis</span> Medical condition

Genodermatosis is a hereditary skin disease with three inherited modes including single gene inheritance, multiple gene inheritance and chromosome inheritance. There are many different types of genodermatosis, the prevalence of genodermatosis ranges from 1 per 6000 people to 1 per 500,000 people. Genodermatosis has influence on the texture, color and structure of skin cuticle and connective tissue, specific lesion site and clinical manifestations on the body vary depending on the type. In the spite of the variety and complexity of genodermatosis, there are still some common methods that can help people diagnose. After diagnosis, different types of genodermatosis require different levels of therapy including interventions, nursing interventions and treatments. Among that, research of therapy for some new, complex and rare types are still in the developing stage. The impact of genodermatosis not only can be seen in body but also can be seen in all aspects of patients' life, including but not limited to psychological, family life, economic conditions and social activities. Accordingly, the patients need treatment, support and help in these areas.

<span class="mw-page-title-main">Ichthyosis bullosa of Siemens</span> Medical condition

Ichthyosis bullosa of Siemens is a type of familial, autosomal dominant ichthyosis, a rare skin disorder. It is also known as bullous congenital ichthyosiform erythroderma of Siemens or ichthyosis exfoliativa. It is a genetic disorder with no known cure which is estimated to affect about 1 in 500,000 people.

Eclabium means the turning outwards of the lip. Eclabium comes from the Greek word "ek" meaning "out," and the Latin word "labium" meaning "lip." This deformation occurs in most babies born with harlequin type ichthyosis, caused by genetic defects. Eclabium can severely impact the quality of life. There are ways to predict if a child will have this condition before they are born through genetic testing. For patients who suffer from eclabium due to improper wound healing, there are different treatment options available to restore the lips back to normal or at least to the point where they are not a hazard to the patients quality of life. Periodontitis can also cause eclabium. As eclabium is a symptom, it is treated by addressing its cause. When the underlying disease is treated, the eclabium tends to go away as well.

Congenital ichthyosiform erythroderma, also known as nonbullous congenital ichthyosiform erythroderma, is a rare type of the ichthyosis family of skin diseases which occurs in 1 in 200,000 to 300,000 births. The disease comes under the umbrella term autosomal recessive congenital ichthyosis, which include non-syndromic congenital ichthyoses such as harlequin ichthyosis and lamellar ichthyosis.

<span class="mw-page-title-main">Neonatal acne</span> Medical condition

Neonatal acne, also known as acne neonatorum, is a type of acne that develops in newborns, typically before 6 weeks of life. It presents with open and closed comedones on the cheeks, chin and forehead.

<span class="mw-page-title-main">Neutral lipid storage disease</span> Congenital autosomal recessive disorder

Neutral lipid storage disease is a congenital autosomal recessive disorder characterized by accumulation of triglycerides in the cytoplasm of leukocytes, muscle, liver, fibroblasts, and other tissues. It commonly occurs as one of two subtypes, cardiomyopathic neutral lipid storage disease (NLSD-M), or ichthyotic neutral lipid storage disease (NLSD-I) which is also known as Chanarin–Dorfman syndrome), which are characterized primarily by myopathy and ichthyosis, respectively. Normally, the ichthyosis that is present is typically non-bullous congenital ichthyosiform erythroderma which appears as white scaling.

Ichthyosis hystrix is a group of rare skin disorders in the ichthyosis family of skin disorders characterized by massive hyperkeratosis with an appearance like spiny scales. This term is also used to refer to a type of epidermal nevi with extensive bilateral distribution.

Trichorrhexis invaginata is a distinctive hair shaft abnormality that may occur sporadically, either in normal hair or with other hair shaft abnormalities, or regularly as a marker for Netherton syndrome. The primary defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone, allowing for intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft.

Ichthyosis prematurity syndrome (IPS) is a dermatological disease with known genetic causes. This syndrome is a rare subcategory of autosomal recessive congenital ichthyosis (ARCI). It is associated with complications in the mid-trimester of a pregnancy leading to premature births. Although most prevalent in individuals of Scandinavian origin, there have also been scattered cases in people of Japanese, Italian and Indian ethnicity. This disorder is also referred to as ichthyosis congenital type IV.

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome is a rare cutaneous condition characterized by ichthyosis and keratoderma.

References

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  17. ↑ 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   1199369 . PMID   15756637.
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  20. ↑ Chang, LM; Reyes, M (2014). "A case of harlequin ichthyosis treated with isotretinoin". Dermatol Online J. 20 (2): 2. doi: 10.5070/D3202021540 . PMID   24612573.
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