Harlequin Ichthyosis Disorder

 

Mr. Bibin Kurian

Lecturer, Dept of Child Health Nursing,

Smt. Radhikabai Meghe Memorial College of Nursing, Sawangi (M), Wardha, Maharashtra.

 

ABSTRACT:

Background: The Harlequin Ichthyosis disorder is a rare genetic condition, due to which infants are born with a thick, yellow and very hard skin. The skin has large, diamond-shaped plates separated by deep fissures, much like a fish's. Therefore, taking from the Greek word ikthys and the Latin word ichthyos, both, meaning fish. The disease has been known since 1750, and was first described in the diary of a cleric from Charleston, South Carolina.

 

 

INTRODUCTION:

The other names of this condition are Harlequin baby syndrome, HI, Ichthyosis Congenita and Harlequin Fetus Type. This is an extremely rare and severe inherited (genetic) ichthyosis.  There are approximately five such children born in the UK each year and some may be stillborn.  The name comes from the appearance of the skin at birth.¹ In an extremely rare case, a baby girl with a severe congenital disorder and near-total missing external body skin was born at Lata Mangeshkar Medical College and Hospital on Saturday, Jun 11. The case was diagnosed as Harlequin Ichthyosis disorder. A 23-year-old woman from Amravati gave birth to the girl. But the child died after struggling for her life for two days.²

 

 

DEFINITION

It is a very rare but severe autosomal recessive congenital genetic skin disease, which causes thickening of the stratum corneum of the epidermis. It is a heterogeneous group of nonsyndromic disorders of keratinization.³

Harlequin ichthyosis is characterized by a profound thickening of the keratin layer in fetal skin. At birth, the child’s whole body is encased in’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 moisturize and protect the skin.⁴

 

INCIDENCE

Approximately 200 cases of harlequin ichthyosis have been reported. The incidence is calculated to be around 1 case in 300,000 births.⁵ No racial predilection is known for harlequin ichthyosis. A higher incidence may be encountered in cultures where parental consanguinity is common. Sex distribution appears to be equal. The father as well as the mother can be carriers of the mutated ABCA12 gene for the disorder to be transferred to the infant.¹³

 

CAUSES

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.⁶

 

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.⁷

 

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.⁷

 

DIAGNOSIS

The diagnosis of Harlequin-type Ichthyosis relies on history collection, physical examination and certain laboratory tests. Prenatal diagnosis of harlequin ichthyosis is made by analysis of fetal DNA obtained by chorionic villus sampling or amniocentesis. In the absence of a family history, a prenatal diagnosis of harlequin ichthyosis can be suspected or identified by ultrasonography.⁸

 

Investigations in the newborn with harlequin ichthyosis are performed to identify the gene mutation, to monitor supportive care, and to identify complications.

History collection:

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

·      Are the parents consanguineous?

·      Have they had a previous child with ichthyosis?

·      Does the family have a history of severe skin disorders?

·      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?

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

 

Physical Examination:

The following findings may be noted on physical examination in the newborn period:

·      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. The external auditory canal may be obstructed by scale.

·      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 mobility is poor to absent. 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 infant is heat intolerant and can become hyperthermic.

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

·      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.⁸

 

Laboratory Studies:

Genetic testing for mutations in the ABCA12 gene is available. Carrier testing is available for relatives after the proband’s mutation are identified. Prenatal diagnosis is available for fetuses with suspected harlequin ichthyosis that may or may not have a family history of the disorder.

 

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

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

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

·      Monitor serum calcium and glucose, as hypocalcemia and hypoglycemia may occur.

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

·      Monitor hemoglobin levels because severe anemia is reported.⁹

 

Imaging Studies:

Prenatal ultrasonography, particularly 3-dimensional ultrasonography, may show features suggestive of harlequin ichthyosis. 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, bulging eyes, rudimentary ears, flexion contractures, and floating particles in the amniotic fluid. Growth restriction and polyhydramnios are also described.¹⁴

 

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. Renal dysplasia has been described in harlequin ichthyosis.¹⁰

 

Procedures:

Before genetic testing was available, fetal skin biopsy was sometimes used to detect ultrastructural changes consistent with harlequin ichthyosis. Fetal skin biopsy could help in detecting harlequin ichthyosis as early as 19 weeks' gestation. Biopsy samples from a number of sites in the fetus revealed 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.

 

Fetal skin biopsy is no longer performed for diagnosis of harlequin ichthyosis.¹⁰

 

Histopathologic Findings: Cells within the stratum corneum are abnormally keratinized. 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.⁹

 

Other Tests: 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.

 

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

·      Physical therapist.

 

MANAGEMENT

There is no cure for this disorder. All the medical science can do is try to keep the baby alive. Newborns with harlequin ichthyosis require management in a neonatal intensive care unit.

 

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.

 

Exposure keratitis results from ectropion of the eyelids. Apply ophthalmic lubricants frequently to protect the conjunctivae

 

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.

 

Topical keratolytics (eg, salicylic acid) are not recommended in newborns because of potential systemic toxicity. Early retinoid treatment (by day 7) may require prompt consideration, as these medications can take some days to obtain.

 

Tazarotene, a topical retinoid, has been reported to be beneficial.

 

Intravenous fluids are almost always required. Consider excess cutaneous water losses in daily fluid requirement calculations. Monitor serum electrolyte levels. A risk of hypernatremic dehydration exists.

 

Neonates with harlequin ichthyosis initially do not feed well and may require tube feeding.

 

Maintain a sterile environment to avoid infection. Take frequent cultures of the skin. Growth of pathogenic organisms (eg, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella) indicates risk of sepsis. Draw blood cultures because sepsis can occur quickly in affected infants.¹¹

 

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. 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.¹²

 

Surgical treatment

Hyperkeratosis causing constriction of limbs, digits, or nasal obstruction may need to be treated surgically.¹⁵

 

PROGNOSIS

The mortality for harlequin ichthyosis rate is high, with worldwide figures approaching 50%. Respiratory failure, fulminant sepsis, or a combination of both is the most common causes of death in affected newborns.⁹

 

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 may wish to 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.

 

LONG-TERM MONITORING

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.

 

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, hypertriglyceridemia, and benign intracranial hypertension) should be noted. Serum AST, ALT, total cholesterol, and triglyceride levels should initially be obtained on a monthly basis initially. The clinician should be cognizant of the musculoskeletal abnormalities that can occur with long-term retinoid therapy, if treatment is continued.

 

Follow-up with an ophthalmologist is required. Recurrent exposure keratitis can be a problem as a result of persistent ectropion.¹⁰

 

COMPLICATIONS

Complications in the neonatal period include the following:

·      Sepsis

·      Respiratory compromise

·      Dehydration, hypernatremia, hypocalcemia, hypoglycemia

·      Hyperthermia

·      Feeding difficulty

·      Nasal obstruction

·      Conjunctivitis, keratitis

·      Limb or digital constriction, ischemia

 

Severe ichthyosiform erythroderma, recurrent skin infections, contractures and painful fissuring of the hands and the feet, pruritus, heat and cold intolerance, reduced sweating, photosensitivity and pigmented macules, poor hair growth, nail deformities, hearing, developmental delay, short stature, weight below average, nutritional rickets due to vitamin D deficiency, inflammatory arthritis, permanent contractures, hypothyroidism and juvenile idiopathic arthritis are some of the other complications found.¹³

 

CONCLUSION :

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.

 

REFERENCE: 

1.     "Harlequin Ichthyosis". Archived from the original on October 14, 2008. Retrieved 2008-11-10.

2.     "India's first ‘Harlequin Baby’ born without any external skin dies two days after birth". India TV. 2016-06-14. Retrieved 2016-06-14.

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.     "Harlequin Ichthyosis". http://www.shhirt.org.uk. Retrieved 18 February 2015. External link in |website=(help)

5.     Ahmed, H; O'Toole, E (2014). "Recent advances in the genetics and management of Harlequin Ichthyosis". Pediatric Dermatology 31 (5): 539-46.

6.     Julie Prendiville, MBBCh Clinical Professor in Pediatrics, University of British Columbia Faculty of Medicine; Head, Division of Pediatric Dermatology, British Columbia's Children's Hospital, Canada

7.     Julie Prendiville, MBBCh is a member of the following medical societies: American Academy of Dermatology, Royal College of Physicians and Surgeons of Canada, Society for Pediatric Dermatology.

8.     Akiyama, M (2010). "ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts". Hum Mutat (31): 1090. PMID 20672373.

9.     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. PMID 26473995.

10.   Akiyama M. The pathogenesis of severe congenital ichthyosis of the neonate. J Dermatol Sci. 1999 Sep; 21(2):96-104.

11.   Thomas, C. Harlequin Ichthyosis, Treating a Rare Hereditary Disorder. Advance for Physician Assistants. December 2000: 32 – 48.

12.   Koochek A, Choate KA, Milstone LM. Harlequin Ichthyosis: Neonatal Management and Identification of a New ABCA12 Mutation. Pediatr Dermatol. 2014 Mar. 31(2):e63-4. 

13.   Rajpopat S, Moss C, Mellerio J, et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol. 2011 Jun. 147(6):681-6.

14.   Bongain A, Benoit B, Ejnes L, Lambert JC, Gillet JY. Harlequin fetus: three-dimensional sonographic findings and new diagnostic approach. Ultrasound Obstet Gynecol. 2002 Jul. 20(1):82-5.

15.   Koochek A, Choate KA, Milstone LM. Harlequin Ichthyosis: Neonatal Management and Identification of a New ABCA12 Mutation. Pediatr Dermatol. 2014 Mar. 31(2):e63-4. 

 

 

 

 

 

 

 

 

Received on 30.08.2016           Modified on 11.09.2016

Accepted on 26.09.2016           © A&V Publication all right reserved