INTRODUCTION:

The ichthyoses, also called disorders of keratinization or disorders of cornification, are a heterogeneous group of disorders characterized by a generalized scaling of the skin of varying severity. The great majority of ichthyoses are inherited, but acquired forms can develop in the setting of malignancy, autoimmune or infectious disease, and nutritional deficiency.

Received on 31.03.2015 Modified on 15.04.2015

Research J. Pharm. and Tech. 8(5): May, 2015; Page 587-596

DOI: 10.5958/0974-360X.2015.00098.0

The molecular basis and pathophysiology of most inherited ichthyoses has been clarified by the identification of causative mutations in over 50 genes encoding structural proteins or enzymes involved in a broad variety of cellular functions, from DNA repair to skin barrier homeostasis ^[1]. Abnormalities in any of these components result in a rather stereotypic epidermal response with epidermal hyperplasia and the formation of excess stratum corneum accompanied by abnormal desquamation and visible accumulation of scales on the skin’s surface ^[2].

What is harlequin ichthyosis?

Harlequin ichthyosis is a severe genetic disorder that mainly affects the skin. Infants with this condition are born with very hard, thick skin covering most of their bodies. The skin forms large, diamond-shaped plates that are separated by deep cracks (fissures). These skin abnormalities affect the shape of the eyelids, nose, mouth, and ears, and limit movement of the arms and legs. Restricted movement of the chest can lead to breathing difficulties and respiratory failure.^[3]

Irish Toddler Battles Harlequin Ichthyosis(Figure 1)^[3]

The skin normally forms a protective barrier between the body and its surrounding environment. The skin abnormalities associated with harlequin ichthyosis disrupt this barrier, making it more difficult for affected infants to control water loss, regulate their body temperature, and fight infections. Infants with harlequin ichthyosis often experience an excessive loss of fluids (dehydration) and develop life-threatening infections in the first few weeks of life.^[4] It used to be very rare for affected infants to survive the newborn period. However, with intensive medical support and improved treatment, people with this disorder now have a better chance of living into childhood and adolescence.

How common is harlequin ichthyosis?

Harlequin ichthyosis is very rare; its exact incidence is unknown.^[5]

What genes are related to harlequin ichthyosis?

Mutations in the ABCA12 gene cause harlequin ichthyosis. The ABCA12 gene provides instructions for making a protein that is essential for the normal development of skin cells. This protein plays a major role in the transport of fats (lipids) in the outermost layer of skin (the epidermis). Some mutations in the ABCA12 gene prevent the cell from making any ABCA12 protein. Other mutations lead to the production of an abnormally small version of the protein that cannot transport lipids properly.^[6] A loss of functional ABCA12 protein disrupts the normal development of the epidermis, resulting in the hard, thick scales characteristic of harlequin ichthyosis.^[7]

How do people inherit harlequin ichthyosis?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.^[8]

Background:

Harlequin ichthyosis is the most severe form of autosomal recessive congenital ichthyosis.^[9] Harlequin ichthyosis is characterized by a profound thickening of the keratin layer in fetal skin. The affected neonate is born with a massive, horny shell of dense, platelike scale and contraction abnormalities of the eyes, ears, mouth, and appendages.

This armor limits movement and compromises the protective skin barrier, leaving the newborn susceptible to metabolic abnormalities and infection.

The term harlequin derives from the newborn's facial expression and the triangular and diamond-shaped pattern of hyperkeratosis. The newborn's mouth is pulled wide open, mimicking a clown's smile.

The underlying genetic abnormality in harlequin ichthyosis is a mutation in the lipid-transporter gene ABCA12 on chromosome 2.^[10]

Immunohistocytochemical examination of the skin reveals characteristic abnormalities in the structure of lamellar granules and in the expression of epidermal keratin.

In the past, harlequin ichthyosis was uniformly fatal. Improved survival has been achieved with intense supportive care and systemic retinoid therapy in the neonatal period. Patients who survive manifest a debilitating, persistent ichthyosis similar to severe congenital ichthyosiform erythroderma.^[11,12]

Pathophysiology:

This disease primarily affects the skin. Other systems may be significantly compromised by the hyperkeratosis and concomitant deformities. Neonates are often born prematurely.

Marked eclabium and ectropion are present secondary to the taut, unyielding skin. The ears may be absent or poorly developed. The arms, feet, and digits have flexion contractures and may be hypoplastic. The skin barrier is severely compromised, leading to excessive water loss, electrolyte abnormalities, temperature dysregulation, and an increased risk of life-threatening infection. ^[13] The tight, armorlike scale can restrict respiration. Poor feeding and impaired intestinal absorption are common.

Epidemiology:

Frequency- International- More than 100 cases of harlequin ichthyosis have been reported.

Mortality/Morbidity- The mortality for harlequin ichthyosis rate is high, with worldwide figures approaching 50%. With neonatal intensive care and oral retinoid therapy, more babies survive the newborn period than in the past. A review of 45 cases was found 25 survivors (56%), ranging in age from 10 months to 25 years. Twenty deaths (44%) occurred from day 1 to day 52 and were as likely to be caused by respiratory failure as fulminant sepsis.^[14]

Race- No racial predilection is known for harlequin ichthyosis. A higher incidence may be encountered in cultures where parental consanguinity is common.^[15]

Sex- Sex distribution appears to be equal.

History:

Harlequin ichthyosis manifests at birth. Harlequin ichthyosis may or may not have been diagnosed prenatally in a high-risk family. The history should explore the following questions:

· Is the couple consanguineous?

· Does the couple have another child with ichthyosis?

· Does the family have a history of severe skin disorders?^[16]

· Do the parents or family members have a history of intrauterine or neonatal death?

· What was the expected date of delivery?

· Were decreased fetal movements or intrauterine growth retardation noted during the pregnancy?

· Did the mother undergo prenatal ultrasonography?^[17]

· Were prenatal procedures (eg, amniocentesis, chorionic villus sampling) performed?

Physical:

The following findings may be noted on physical examination:

· Skin: Severely thickened skin with large, shiny plates of hyperkeratotic scale is present at birth. Deep, erythematous fissures separate the scales.

· Eyes: Severe ectropion is present. The free edges of the upper and lower eyelids are everted, leaving the conjunctivae and cornea at risk for desiccation and trauma.

· Ears: The ears are flattened with absent retroauricular folds. The pinnae may be small and rudimentary or absent.^[18]

· Lips: Severe traction on the lips causes eclabium and a fixed, open mouth. This may result in feeding difficulties.

· Nose: Nasal hypoplasia and eroded nasal alae may occur. The nares can be obstructed.

· Extremities: The limbs are encased in the thick, hyperkeratotic skin, resulting in flexion contractures of the arms, the legs, and the digits. Limb motility is poor to absent. ^[19]Circumferential constriction of a limb or digit can occur, leading to distal swelling, ischemic necrosis and autoamputation. Hypoplasia of the fingers, toes, and fingernails is reported. Polydactyly is described.

· Temperature dysregulation: Thickened skin prevents normal sweat gland function and heat loss. The infants are heat intolerant and can become hyperthermic.

· Respiratory status: Restriction of chest-wall expansion can result in respiratory distress, hypoventilation, and respiratory failure.^[20]

· Hydration status: Dehydration from excess water loss can cause tachycardia and poor urine output.

· Central nervous system: Metabolic abnormalities can cause seizures. CNS depression can be a sign of sepsis or hypoxia. Hyperkeratosis may restrict spontaneous movements, making neurologic assessment difficult.

Causes:

Genetic Factors- Mutations in ABCA12, a gene that encodes adenosine triphosphate (ATP)-binding cassette transporter (ABC), subfamily A, member 12, in chromosome region 2q35, underlie this disorder.^[21,22]Patients with harlequin ichthyosis usually have functional null mutations in the ABCA12 gene. Missense mutations in ABCA12 may result in milder autosomal recessive congenital ichthyosis phenotypes such as lamellar ichthyosis and congenital ichthyosiform erythroderma.^[23,24]

Mutations in lipid transporter ABCA12 cause HI. (A) In the granular layer(Figure 2)^[23]

The ABC superfamily of genes encodes proteins that transport a number of substrates across cell membranes.^[25] ABCA12 encodes a transmembrane protein that mediates lipid transport.

This ABCA12 -mediated lipid-transfer system is essential to the transfer of lipids from the cytosol of the corneocyte into lamellar granules. Lamellar granules are intracellular granules that originate from the Golgi apparatus of keratinocytes in the stratum corneum. These granules are responsible for secreting lipids that maintain the skin barrier at the interface between the granular cell layer and the cornified layer in the upper epidermis.^[26] The extruded lipids are arranged into lamellae in the intercellular space with the help of concomitantly released hydrolytic enzymes. The lamellae form the skin's hydrophobic sphingolipid seal.

In harlequin ichthyosis, the ABCA12 -mediated transfer of lipid to lamellar granules is defective. The lamellar granules themselves are morphologically abnormal or absent. Normal extrusion of lipid from these granules into the extracellular space cannot occur, and lipid lamellae are not formed. This defective lipid "mortar" between corneocyte "bricks" results in aberrant skin permeability and lack of normal corneocyte desquamation.^[27,28,29]

In vitro studies have demonstrated normalization of lipid transport when the wild-type ABCA12 gene is transferred to keratinocytes of patients with harlequin ichthyosis.^[30]

The exact mechanism whereby the ABCA12 mutation results in severe hyperkeratosis at birth remains to be elucidated. In vitro studies suggest that dysregulation of keratinocyte differentiation during fetal development plays an important role.^[31]

One patient with a de novo deletion of chromosome arm 18q has been reported.^[31]

Histopathologic, Ultrastructural and Biochemical Factors- Histopathologic, ultrastructural, and biochemical studies have identified several characteristic abnormalities in the skin of patients with harlequin ichthyosis.

The 2 main abnormalities involve lamellar granules and the structural proteins of the cell cytoskeleton. The relationship between mutations in the gene ABCA12 and abnormal lamellar granules is well documented.^[32] The pathophysiology of the other abnormalities documented below has yet to be elucidated.

Abnormal Lamellar Granule Structure and Function- All patients with harlequin ichthyosis have absent or defective lamellar granules and no extracellular lipid lamellae. Cultured epidermal keratinocytes from patients that carry ABCA12 mutations have demonstrated disturbed intracytoplasmic glucosylceramide transport.^[33,34] The lipid abnormality is believed to allow excessive transepidermal water loss. Lack of released lamellar granule enzymes prevents desquamation, resulting in a severe retention hyperkeratosis.

Harlequin ichthyosis, the most severe form of autosomal recessive congenital ichthyosis (ARCI), is a recessive form of ichthyosis(Figure 3)^[34]

Abnormal Conversion Of Profilaggrin to Filaggrin- Profilaggrin is a phosphorylated polyprotein residing in keratohyalin granules in keratinocytes in the granular cell layer. During the evolution to the corneal layer, profilaggrin converts to filaggrin by means of dephosphorylation. Filaggrin allows dense packing of keratin filaments. Its subsequent breakdown into amino acids occurs prior to desquamation of the stratum corneum.

Some patients have a persistence of profilaggrin and an absence of filaggrin in the stratum corneum. A defect in protein phosphatase activity and subsequent lack of conversion of profilaggrin to filaggrin is hypothesized.^[35]

Abnormal Expression of Keratin- Disturbed keratinocyte differentiation during fetal development is believed to play an important role in the pathogenesis of the harlequin ichthyosis phenotype at birth.^[36] In utero studies have shown that expressions of markers of late keratinocyte differentiation are highly dysregulated, suggesting a role for ABCA12 in keratinocyte differentiation.^[37] Expression of the proteases kallikrein 5 and cathepsin D, which are required for normal desquamation, was found to be dramatically reduced.^[38]

Keratin filament density is low in most patients. Expression of certain keratins is abnormal in some patients and normal in others. How this altered expression of structural proteins influences desquamation is uncertain.

Abnormal Keratohyalin Granules- Keratohyalin granules are identified by antifilaggrin antibodies and can be abnormal in some patients with harlequin ichthyosis. They can be large and stellate, small and rounded, or absent.

Symptoms of harlequin ichthyosis:

Signs of harlequin ichthyosis in newborns include:

· Thick skin plates that crack and split

· Distorted facial features

Tight skin around eyes and mouth (may force eyelids and lips to turn inside out and affect ability to feed)^[39]

Restricted breathing (when chest or abdomen is affected)

Hands and feet that are small, swollen and partially flexed

· Deformed ears or ears fused to the head (may appear to be missing)

High blood sodium levels^[39]

Harlequin Ichthyosis(Figure 4)^[39]

Diagnostic Considerations:

· Collodion baby: A parchment like membrane at birth is associated with other forms of ichthyosis, most commonly lamellar ichthyosis or congenital ichthyosiform erythroderma.

· Restrictive dermopathy

· Lamellar ichthyosis^[40]

· Self-healing lamellar ichthyosis of the newborn

· Conradi disease

· Trichothiodystrophy

· Gaucher syndrome

· Neu–Laxova syndrome^[41]

Laboratory Studies:

Genetic testing for mutations in the ABCA12 gene is available. Complete sequence analysis of the coding region of this gene is performed to identify specific mutations. Peripheral blood cells or cells from a buccal smear from affected individuals are required. Prenatal diagnosis is available for fetuses with suspected harlequin ichthyosis who may or may not have a family history of the disorder.^[42]

The following laboratory investigations may be helpful in the newborn period to identify complications of harlequin ichthyosis:

· Check the WBC count and blood cultures for signs of infection.

· Closely monitor serum electrolyte levels, which may be abnormal secondary to dehydration.

· Check BUN and creatinine levels for signs of renal failure.

· Monitor hemoglobin levels because anemia is reported.

Imaging Studies:

Prenatal ultrasonography, particularly 3-dimensional (3D) ultrasonography, may show features suggestive of harlequin ichthyosis. These include rudimentary ears, flexion contractures, and floating particles in the amniotic fluid.^[43,44,45]

Toes hyperflexed and fixed(Figure 5)^[44]

Prenatal 3D ultrasonography has also been successful in identifying the typical morphology of a harlequin fetus. This has been particularly helpful in antenatal diagnosis of infants with no family history of harlequin ichthyosis. Characteristic features include a large and gaping mouth, aplasia of the nose, abnormal limbs, and bulging eyes. Growth restriction and polyhydramnios are also described.

Two-dimensional ultrasonography can also demonstrate features of harlequin ichthyosis but not until late in the second trimester, when enough keratin buildup is present to be sonographically detectable. Short feet may be an early marker for harlequin ichthyosis. This may be detectable in the early second trimester before other signs of harlequin ichthyosis are noticeable.^[46]

Our diagnosis based on the ultrasound findings was ichthyosis. The pregnancy was terminated at 30 weeks of gestations.(Figure 6)^[46]

Chest radiography may be indicated if respiratory distress is present postnatally.

Renal ultrasonography may be indicated if renal failure or poor urine output is evident or if findings from the physical examination are abnormal. Renal dysplasia has been described in harlequin ichthyosis.

Procedures:

Before genetic testing was available for harlequin ichthyosis, fetal skin biopsy was sometimes used to detect ultrastructural changes consistent with harlequin ichthyosis.^[47] Fetal skin biopsy can help in detecting harlequin ichthyosis as early as 19 weeks' gestation. Biopsy samples from a number of sites in the fetus reveal characteristic changes on all skin surfaces except the mucous membranes. Amniotic fluid samples obtained as early as 17 weeks' gestation have also demonstrated hyperkeratosis and abnormal lipid droplets in the cornified cells.

Histopathologic Findings:

The stratum corneum is thick and compact. Hyperkeratosis may be more marked around hair follicles compared with the interfollicular epidermis. The histopathologic hallmark is an extraordinary thickened and compact orthokeratotic stratum corneum, although in some cases parakeratosis has been observed. Cells within the stratum corneum are abnormally keratinized. Granular, spinous, and basal cell layers appear unremarkable.^[48]Inflammatory cells may infiltrate the papillary dermis. Hair follicles show marked, concentric accumulation of keratotic material around hair shafts, which is considered a diagnostic feature of harlequin ichthyosis and has been used to establish the diagnosis prenatally.

Electron microscopy reveals absent or abnormal lamellar granules within the granular layer keratinocytes. Lamellae are absent in the intercellular spaces between the granular cell layer and the cornified cell layer. Densely packed lipid droplets and vacuoles are seen within the cytoplasm of the aberrantly cornified cells of the stratum corneum. These lipid inclusions involve the entire skin surface but are more evident on the palms and the soles.^[49] Keratohyalin granules may be absent, normal, or abnormally small and globular. Keratin intermediate filaments within granular cells may have reduced density.

Medical Care:

Ensure that the patient's airway, breathing, and circulation are stable after delivery. Early intubation may be required.Babies require intravenous access. Peripheral access may be difficult and umbilical cannulation may be necessary. Place infants in a humidified incubator. Monitor temperature, respiratory rate, heart rate, and oxygen saturation. Once stabilized, transfer newborn with harlequin ichthyosis to a NICU.

Baby Brenna - Harlequin ichthyosis(Figure 7)^[50]

Exposure keratitis results from ectropion of the eyelids. Apply ophthalmic lubricants frequently to protect the conjunctivae.^[50] Bathe infants twice daily and use frequent wet sodium chloride compresses followed by application of bland lubricants to soften hard skin. Dilute bleach baths may reduce the risk of skin infection.^[51]

Topical keratolytics (eg, salicylic acid) are not recommended in newborns because of potential systemic toxicity.

According to Rajpopat et al, early retinoid treatment (by day 7) may require prompt consideration, as these medications can take some days to obtain.^[52].

Tazarotene, a topical retinoid, has been reported to be beneficial.^[53,54]

Intravenous fluids are almost always required. Neonates with harlequin ichthyosis initially do not feed well and may require tube feeding.^[55]Consider excess cutaneous water losses in daily fluid requirement calculations. Monitor serum electrolyte levels. A risk of hypernatremic dehydration exists.

Maintain a sterile environment to avoid infection. Take frequent cultures of the skin. Growth of pathogenic organisms (eg, Staphylococcus aureus, Pseudomonas aeruginosa) indicates risk of sepsis. Draw blood cultures because sepsis can occur quickly in affected infants.

Hyperkeratosis causing constriction of limbs, digits, or nasal obstruction may need to be surgically removed.^[56]

Consultations:

Early formation of a multidisciplinary team is recommended and may include the following:

· Neonatologist

· Dermatologist

· Medical geneticist

· Ophthalmologist

· Ear-nose-throat specialist

· Plastic surgeon

· Dietician

· Social worker

· Occupational therapist

Medication Summary:

Enhanced survival and decreased morbidity is reported with the use of systemic retinoids; however, numerous infants have survived without systemic retinoid therapy.^[57] Retinoids bind to specific retinoic acid receptors and regulate gene transcription. They influence keratinocyte differentiation, normalize abnormal keratinocyte proliferation, and mediate desquamation of hyperkeratotic scale. Rajpopat et al recommend frequent application of emollients to ease this shedding of thick plates when retinoids are given.^[58]

Etretinate was first used for the treatment of this disorder in 1985. An effective dose of 1 mg/kg/d was established. Etretinate is no longer available, but it has been replaced by other retinoids with improved safety profiles.^[59]

Acitretin, a carboxylic acid derivative of etretinate, is the retinoid most commonly prescribed in neonates with harlequin ichthyosis.^[60]Initial doses of 0.5 mg/kg/d are recommended. Improvement in hyperkeratosis, ectropion, and eclabium is reported. The duration of therapy is variable, and continuous, long-term, daily therapy may be required. The daily dose can be titrated to the degree of ichthyosis.

Rajpopat et al reported that of 24 babies given oral retinoids, 20 received acitretin, 2 received etretinate, and 2 received isotretinoin. Twenty of the 24 treated patients survived (83%).^[61]

A topical retinoid (tazarotene) has been used to treat local and mechanical circulatory problems caused by hyperkeratosis.^[62,63]

Isotretinoin has also been used in harlequin ichthyosis. The reported dose is 0.5 mg/kg/d. Treatment is usually initiated within the first few days of life and given orally. Case reports have documented improvement in pliability of the skin, limb movements, sucking, and eyelid closing within a week of starting therapy. Treatment has been continued for several years in some patients, and it may be required indefinitely to prevent relapse.

Liver function and serum lipid levels should be monitored during retinoid therapy. Clinical monitoring for skeletal adverse effects should be done periodically. Before retinoid therapy is considered, discuss the expected outcome and the potential adverse effects with the parents.

Retinoid-like Agents:

These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes. They modulate keratinocyte differentiation.

Isotretinoin (Amnesteem, Claravis, Sotret)-

Synthetic 13-cis isomer of naturally occurring tretinoin (trans -retinoic acid). Both agents structurally related to vitamin A.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.^[64]

Acitretin (Soriatane)-

Metabolite of etretinate and related to retinoic acid and retinol (vitamin A). Mechanism of action unknown but thought to exert therapeutic effect by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells.^[64]

Further Inpatient Care:

Continue careful attention to skin care and use of emollients during retinoid therapy.

Infants with harlequin ichthyosis can be successfully breastfed or bottle-fed as the eclabium improves.^[65] Involving occupational therapy to aid in feeding strategies is advised. Carefully monitor weight gain and intake. Affected infants are at risk of failure to thrive.

Physical bonding between the parents and the baby should be encouraged.

Further Outpatient Care:

Infants are discharged from the hospital when their cutaneous symptoms are improving, feeding and weight gain are established, and they are free of infection.

Social and psychological support should be provided for the parents/caregivers.^[66]

The primary care physician should closely monitor the infants for growth, development, social issues, and skin surveillance. A dermatologist should monitor affected infants for ongoing assessment and for monitoring of retinoid therapy.

Adverse effects of retinoid therapy (eg, mucocutaneous dryness, aberrant liver function tests, hyper triglyceridemia, benign intracranial hypertension) should be noted. Serum AST, ALT, total cholesterol, and triglyceride levels should initially be obtained on a monthly basis. The clinician should be cognizant of the musculoskeletal abnormalities that can occur with long-term retinoid therapy.

Follow-up with an ophthalmologist is required. Recurrent exposure keratitis can be a problem as a result of persistent ectropion.

Complications:

Infants who survive the newborn period have a lifelong, severe ichthyosiform erythroderma.

Recurrent skin infections may continue after the newborn period.

Contractures and painful fissuring of the hands and the feet may occur. Rajpopat et al reported palmoplantar keratoderma in 52% of survivors, causing pain and delay in walking.^[67]

Pruritus was reported in 44% of patients, heat and cold intolerance was found in 36%, reduced sweating was found in 28%, and photosensitivity and pigmented macules was found in 1 patient each.Poor hair growth and nail deformities were common. Hearing impairment may result from obstruction of the ear canals by skin debris.

Developmental delay and normal intellectual development are described. Rajpopat et al reported that most school-aged survivors were attending mainstream schools, although many needed additional help.^[68]

Growth must be closely monitored. Short stature is common and weight below average. Nutritional rickets due to vitamin D deficiency is reported.^[68] This is likely due to defective vitamin D synthesis in the abnormal skin, calcium loss, and reduced exposure to sunlight.

Inflammatory arthritis and permanent contractures may occur.Hypothyroidism and juvenile idiopathic arthritis have been reported in a patient with harlequin ichthyosis.^[69]

Prognosis:

An overall survival rate of 56% (25 of 45 patients) was found in a multicenter retrospective study reported by Rajpopat et al.A Japanese survey of 16 patients reported survival of 81.3% (13 of 16 patients).^[68]

Respiratory failure, fulminant sepsis, or a combination of both are the most common causes of death in affected newborns.^[70]

Although increased survival has been associated with administration of systemic retinoids, improved outcomes may be a result of advances in neonatal intensive care.

Patient Education:

Advise parents and caregivers that the baby’s appearance will improve after the neonatal period. Emphasize the need for attention to skin lubrication and for compliance with systemic therapy. Teach them to recognize signs of infection.

Congenital ichthyoses can have devastating medical and social consequences. Parents should communicate with other families who have been similarly affected. Patient organizations (eg, The Foundation for Ichthyosis and Related Skin Types [FIRST]) are available in several countries to provide support to families.^[71]

Notable Cases:

· Nusrit "Nelly" Shaheen (born 1984) is the oldest known survivor with the condition; she lives in the UK, and was one of nine children. Four of her eight siblings also suffered from the condition but died as young children. Shaheen lives an active lifestyle and in 2008 was studying sports coaching and leadership at Hereward College.^[72]

Hunter Steinitz (born 1994) is one of only twelve Americans suffering from the disease and is profiled on the National Geographic "Extraordinary Humans: Skin" special.^[73]

· 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)^[74] is the second oldest person in the United States living with the disease, and the first ever to give birth. Turner's son does 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. ^[75] Doctors told his mother Lisa van Dyk that he was the first case of Harlequin Ichthyosis in Africa, and that she has a one-in-four chance to have another child with the disease.

CONCLUSION:

Management of HI requires a multidisciplinary approach from the outset. The disease is not always fatal and is associated with extracutaneous manifestations. Although there is some delay in achieving developmental milestones, many children are able to attend a mainstream school with appropriate support and adults can enter higher education and live independently. Awareness of this information will provide greater understanding of the disease for those who care for patients with HI.

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