Journal of Perinatology (2010) 30,66–72 r 2010 Nature Publishing Group All rights reserved. 0743-8346/10 $32 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Perinatal management of harlequin : a case report and literature review

HB Harvey, MG Shaw and DS Morrell Department of , University of North Carolina, Chapel Hill, NC, USA

congenital icthyosiform erythroderma. This latter presentation Harlequin ichthyosis (HI) is a rare and severe form of congenital ichthyosis. dominates for the remainder of the patient’s life. Linked to deletion and truncation mutations of a keratinocyte lipid Infants with HI have historically succumbed in the perinatal transporter, HI is characterized by diffuse epidermal hyperkeratinization and period to sepsis, respiratory failure and infections, poor nutrition defective desquamation. At birth, the HI phenotype is striking with thick and electrolyte imbalances. In the past 20 years, however, the hyperkeratotic plate-like scales with deep dermal fissures, severe ectropion prognosis of HI infants has improved due to advances in neonatal and , among other findings. Over the first months of life, the intensive care and targeted oral therapy. Despite this, little hyperkeratotic covering is shed, revealing a diffusely erythematous, scaly has been reported about the daily management of HI infants , which persists for the remainder of the patient’s life. Although HI during the early inpatient stage. We report a case of HI treated with infants have historically succumbed in the perinatal period related to their acitretin focusing on the multi-faceted management of the disease profound epidermal compromise, the prognosis of HI infants has vastly in the inpatient setting. Given the rareness of the disease and the improved over the past 20 years. Here, we report a case of HI treated with lack of treatment guidelines, we hope that our experience may be acitretin, focusing on the multi-faceted management of the disease in the of use to assist future teams taking care of these special patients. inpatient setting. A review of the literature of the management of HI during the perinatal period is also presented. Journal of Perinatology (2010) 30, 66–72; doi:10.1038/jp.2009.100 Case Keywords: harlequin ichthyosis; neonatal; management; retinoid 6 The 347-week Hispanic male infant was delivered at an outside hospital by cesarean section (due to repeat) after premature rupture of membranes. He was born to a nonconsanguinous Introduction couple with no family history of skin disorders or previous children Harlequin ichthyosis (HI) is the rarest and the most severe form of with skin disorders. He had an uncomplicated prenatal course congenital ichthyosis. Inherited in an autosomal recessive manner, except the fetal ultrasound was interpreted as showing facial and HI is primarily associated with mutations causing functional extremity abnormalities. His APGAR scores were 5 and 9 at 1 and defects in the keratinocyte lipid transporter adenosine triphosphate- 5 min, respectively. He weighed 2.58 kg at birth. binding cassette A12.1,2 Dysfunctional or absent adenosine At delivery, he was noted to have generalized edema with thick triphosphate-binding cassette A12 protein causes a disturbance in hyperkeratotic plates over his entire body and scalp and associated lamellar granule lipid and protease transport in granular layer deep erythematous fissures (Figure 1). His face was distorted as a keratinocytes, resulting in epidermal hyperkeratinization and result of taut scales and his ears were bound to the scalp by tight defective desquamation.3,4 At birth, neonates with HI are covered by keratinous skin obscuring the pinnae (Figure 2). He also had a thick hyperkeratotic plate-like covering of stratum corneum with severe ectropion, eclabium and diffuse alopecia. His hands and feet deep dermal fissures. Other findings common with this disorder were tight and edematous with contracted digits showing dusky include severe ectropion and eclabium, alopecia, digital tapering at distal ends and decreased capillary refill. He had diffuse contractures and growth delays. Over the first months of life, the decreased range of motion, especially in the digits, wrists, elbows, hyperkeratotic covering is shed, leaving the skin diffusely knees and ankles secondary to skin tautness. As it was unnecessary erythematous and scalyFphenotypically suggestive of nonbullous for diagnosis, histopathology was not performed. The infant was transferred to our neonatal intensive care unit Correspondence: Dr MG Shaw, Department of Dermatology, University of North Carolina, within hours of delivery. The patient was followed by a medical 3100 Thurston-Bowles Bldg., UNC CB# 7287, Chapel Hill, NC 27599, USA. E-mail: [email protected] team consisting of neonatologists, dermatologists (consulted day of Received 9 February 2009; revised 9 June 2009; accepted 14 June 2009 life (DOL) 1), infectious disease specialist (consulted DOL 11), Perinatal management of harlequin ichthyosis HB Harvey et al 67

nutritionists and nurses. Key elements of the treatment plan during the neonatal period included skin care, sepsis monitoring and treatment, pain control, and management of ectropion and digital contractures. The patient was stable from birth on room air, but was maintained in a mist tent for several weeks. He was quickly transitioned from nothing by mouth and total parenteral nutrition to his goal enteral feeds by DOL 8. Owing to his increased metabolic demands, he initially was fed a 26 kcal formula, but he was transitioned to a standard premature infant (22 kcal) formula before discharge. On DOL 1, the patient was started on acitretin (1 mg kgÀ1 per day) with regular monitoring of liver function tests, lipids, triglycerides and complete blood count. In addition to pharmacotherapy, white petrolatum was applied over the entire body surface every 6 h. Other topical medications or preparations were avoided because of the likelihood of systemic absorption and concerns about their ophthalmic safety in light of the bilateral ectropion. Bathing of the patient was limited to once daily with normal saline. After several weeks, the patient started shedding the thick hyperkeratotic plates revealing skin consistent with generalized erythematous ichthyosis. Plates of scale on the trunk and appendages were essentially resolved by DOL 30, whereas moist scale remained longer on the face and scalp. On DOL 13, he was noted to have a murmur and tachycardia. He received his first blood transfusion on that day and a second on DOL 25 due to a hematocrit of 29.4 (normal range 31 to 55). He was started on a multivitamin with iron for anemia of premature, Figure 1 Patient at birth: generalized edema with thick hyperkeratotic plates which was discontinued due to stable hematocrits before discharge. over his entire body and scalp and associated deep erythematous fissures. An echocardiogram on DOL 13 showed a mild pulmonary artery stenosis and a left-to-right shunt through the atria consistent with either a patent foramen ovale or an atrial septal defect. A repeat echocardiogram on DOL 27 showed a patent foramen ovale, which was monitored clinically without further intervention. Given the patient’s increased susceptibility to sepsis and a persistent mild tachycardia, the patient was immediately started on ampicillin and gentamicin after delivery until initial blood cultures were confirmed negative at 48 h. The patient was closely monitored for sepsis with a low threshold for sepsis work-up for the duration of his inpatient stay. Strict protective precautions were observed by the treatment team and visitors at all times to reduce iatrogenic infections. Despite these efforts, the patient had positive blood cultures multiple times during the hospitalization including Candida albicans, coagulase-negative Staphylococcus sensitive only to vancomycin and Klebsiella oxygtoca. The patient was started on prophylactic fluconazole and penicillin VK on DOL 27. Figure 2 Patient at birth: facial distortion secondary to taut scales with severe ectropion, eclabium and diffuse alopecia. After a 6-week course, the fluconazole was discontinued and he remains on penicillin VK indefinitely. In addition to systemic plastic surgeons (consulted DOL 7) and ophthalmologists infections, he was treated for three episodes of conjunctivitis. (consulted DOL 2). He was also cared for by ancillary staff Gram-positive and -negative rods (not further identified) grew on including physical and occupational therapist, social workers, culture of purulent eye discharge on DOL 27. He was treated with

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5 days of tobramycin at that time and with 5-day courses of improvement. He continues to have a conductive hearing loss and erythromycin for clinical conjunctivitis on DOL 39 and 52. Around be followed by otolaryngology. At 1 year of life he was in the 15th 1 month of life, he was noted to have low g immunoglobulin levels percentile for height, less than 5th percentile for weight and 10th and received two courses of intravenous immunoglobulin. No percentile for head circumference. According to his physical further immunology work-up was done. therapist, the patient is physically able (not limited by his skin) to As pain secondary to truncal fissures discourages deep breathing achieve developmental milestones but these are greatly delayed by and increases the risk of pulmonary complications, pain his apprehensions about independent or assisted movement. At age management was achieved on transfer to our institution at DOL 1 of 18 months, the patient was unable to sit, crawl or walk. The with fentanyl at 2 mgkgÀ1 intravenously every 2 h and adjunctive importance of daily physical and occupational exercises done with sucrose sips as needed. After several weeks, his pain medications family members was stressed to the parents. The patient is now 2 changed to acetaminophen every 6 h for the remainder of the years old and able to run, jump and talk. He continues to be hospitalization. Ophthalmology recommended Lacri-lube every followed by physical and occupational therapy, dermatology, hour to both eyes to manage the ectropion and prevent secondary ophthalmology and otolaryngology along with his primary care . Plastic surgery recommended conservative management physician. of digital contractures with thin sterile gauze rolls be placed in the palms and soles to prevent contracture progression and daily physical therapy to promote digital and joint movement. In Discussion addition, soft splinting of the hands/feet encouraged gradual digital Harlequin ichthyosis is a rare characterized by extension between physical therapy sessions. No specific treatment defective keratinization and desquamation of the epidermis. The was required for eclabium. On DOL 33, he failed his bilateral genetic mutations underlying HI result in dysfunction of adenosine newborn hearing test. More detailed testing on DOL 83 revealed a triphosphate-binding cassette A12, a protein involved in conductive hearing loss. After saline drops were applied to both intracellular lipid transport, and cause abnormal lamellar granule external auditory canals for several days, improvement in the secretion in the epidermis.2,3,5 Consequently, important lipids and deficit was noted on DOL 96, but he did not achieve normal proteases are not secreted into the interstitial space between hearing while he was an inpatient. Genetics was consulted on granular layer keratinocytes. The absence of interstitial lipid DOL 6 and discussed the inherited nature of HI with the parents. delivery results in a profoundly abnormal epidermal permeability The parents declined genetic testing, as they did not plan to have barrier and increased transcutaneous water losses.6 The body additional children. responds by stimulating cytokine cascades and epidermal The patient was transferred to a community hospital closer to hyperplasia, which, in turn, results in the epidermal the family’s home on DOL 39 where he was stable and similar and inflammation characteristic of HI.7 Likewise, it has been intensive medical care continued. He received his routine theorized that a concomitant absence of interstitial proteases premature vaccinations roughly on schedule including Hepatitis B, prevents corneodesmosomes that link superficial keratinocytes to Respiratory Syncytial Virus, Diphtheria Tetanus Pertussis, underlying keratinocytes from being digested.4,7 As a result, these Inactivated Polio, Haemophilus influenza and Pneumococcal superficial keratinocytes are unable to undergo normal (conjugate). On DOL 72, he was changed from Lacri-lube to desquamation, which results in the accumulation of stratum carboxymethocel. corneum. On DOL 105, the patient was discharged home. The patient Abnormal desquamation dominates the early neonatal received hourly home sessions of physical therapy twice weekly and phenotype of HI, which is manifested by a thick, plate-like occupational therapy once weekly. During these sessions they encasement of accumulated stratum corneum. The rigid covering worked on range of motion exercises, movement initiation and fine contains numerous erythematous fissures that reach deep into the motor skills. The parents continued to apply white petrolatum to , which dramatically increases susceptibility to infection. the patient’s entire skin surface four times a day for the first year of Other early findings associated with HI, including ectropion and life. In addition, they placed carboxymethocel in his eyes every 3 h eclabium, are attributable to the restrictions in mobility and while awake. The patient was bathed daily with phisoderm. Over development caused by the rigid epidermal encasement. As the HI the year, acitretin was tapered from 0.5 to 0.2 mg kgÀ1 per day newborn experiences terrestrial life, the body senses the profound dosed on every third day. At 6 months of life, tazoratene 0.1% epidermal barrier defect caused by the paucity of lipids in the cream was added for application to the scalp, elbows, knees, palms epidermal interstitial space and responds by attempting to repair and soles. The patient remained on antimicrobial prophylaxis with the defect through massive epidermal hyperplasia. A dramatic penicillin VK twice daily. By 6 months of age, the ectropion phenotypic shift ensues, characterized by shedding of the improved enough to permit closure of his eyes when sleeping; plans rigid stratum corneum encasing the body. An underlying for surgical correction of the ectropion were delayed given this epidermal surface of diffuse with fine scaling is revealed.

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loss. However, given the compromised epidermal barrier and the likelihood of systemic absorption, other topical treatments should be chosen wisely. Topical keratinolytics frequently used in adulthood (, alpha hydroxyl acids and ) are not appropriate in the neonatal period due to potential systemic toxicity from increased cutaneous absorption. Moreover, as systemic retinoid therapy achieves adequate keratinolysis, these potentially toxic topical agents are largely unnecessary. Lastly, bathing and soaking can reduce the risks of , replenish moisture in the skin and promote the softening and shedding of the thick stratum corneum. The deep cutaneous fissures of HI are very painful, making pain management an important issue in the care of these patients. Acutely, pain associated with truncal fissures discourages deep breathing and increases the risk of pulmonary complications. In the long term, inadequate neonatal pain control has been associated with developmental delay and abnormal stressor responses.10–12 However, it is important to balance pain and over-sedation as an over-medicated neonate can have feeding issues and suffer respiratory depression. Some of the other co-morbidities associated with HI may require consultation with other medical specialists. Ectropion is a common feature associated with HI and is present in all of the cases described in the literature. Although management of ectropion is best handled by ophthalmologists, perinatal care teams can initiate Figure 3 Patient at 4 months: after shedding the plates of scale, the underlying treatment with artificial tears (Lacri-lube) applied to the eye and epidermal surface of diffuse erythema with fine scaling is revealed. exposed conjunctiva every 2 h and antibiotic ointment until ophthalmologist can be consulted. Hand contractures, another This differing cutaneous phenotype, which most resembles complication associated with HI, may require a surgical consult, as nonbullous congenital icthyosiform erythroderma, dominates the gangrene of the distal digits can occur if contractures go untreated. remainder of the patient’s life.8 The nonbullous congenital In addition, physiotherapy is an important aspect of early and icthyosiform erythroderma-like phenotype offers moreFbut by no long-term care, as it decreases contractures and promotes increased means normalFepidermal protection (Figure 3). In fact, the range of motion of joints. importance of systemic , a key therapy for HI, is largely As true in our patient, sepsis remains a constant threat in the due to their ability to accelerate the shedding of the hyperkeratotic first month before the deep fissures have healed and continues to encasement, promoting the phenotypic shift. be a leading cause of death in these patients throughout infancy. Early management of HI generally includes a humidified For this reason, close monitoring for signs of sepsis and aggressive incubator, temperature regulation, nutrition replacement, skin and treatment of bacterial or fungal infections are essential. In light of eye care, pain control, physiotherapy, and infection control. this risk, some treatment teams have gone beyond heightened A humidified incubator with strict temperature regulation is surveillance, favoring prophylactic treatment. Although antibiotic essential for mitigating the large transcutaneous losses of water and/or antifungal prophylaxis may seem intuitive in patients with and heat caused by the dysfunctional epidermal permeability severely compromised skin barriers like those of HI, there exists barrier. Even in the incubator setting, these losses, compounded by little clinical evidence for such prophylaxis. Although no studies chronic inflammation, constitute a significant caloric drain for HI deal with HI directly, the appropriateness of antibiotic prophylaxis infants and can lead to growth retardation if calories are not has been studied in burn patients with similar barrier compromise. replaced. Consequently, nutritional supplementation is essential in These studies indicate that antibiotic prophylaxis in childhood HI neonates, who can require as much as 25% more calories per burns does not reduce the rate of wound infection or subsequent day than comparable neonates.6,9 Skin care is also a constant focus sepsis.13–15 In fact, antibiotic prophylaxis may even be detrimental in these patients. Emollients should be generously applied to the by favoring the growth of P. aeruginosa in burn wounds and skin multiple times per day to provide the infant with protection enhancing the risk of candidemia.15 Of interest, in one of the HI against foreign pathogens and help prevent transcutaneous water cases reported in which antibiotic prophylaxis was administered,

Journal of Perinatology Perinatal management of harlequin ichthyosis HB Harvey et al 70 the HI infant died on day 21 from a systemic infection with Candida wound infection.18,19 Thus, longer courses of antifungal P. aeruginosa.16 treatment or even systemic prophylaxis may benefit HI infants with Antifungal prophylaxis has also been debated in neonatal burn confirmed Candida wound infection. Nevertheless, the impaired populations. Compelling evidence suggests that topical prophylaxis barrier of burn patients is distinct from that of HI patients and a with nystatin significantly reduces the incidence of Candida direct correlation cannot be implied. wound infection and systemic in burn patients.17 In Systemic retinoids have become a mainstay of therapy in contrast, the value of systemic antifungal prophylaxis has not been disorders of keratinization, and HI is no exception.20 In neonates shown in burn patients.18 There is, however, compelling data with HI, early use of systemic retinoids promotes accelerated showing the incidence of re-infection, and subsequent death, is shedding of the hyperkeratotic plates, whereas continued much higher for patients who have had a confirmed episode of use reduces scale and improves ectropion and eclabium.

Table 1 Previous cases of harlequin ichthyosis treated with systemic retinoids

Citation no. Year Retinoid:dosage Result Discharge date Case specifics

This study 2008 ACI:1 mg kgÀ1 Plates of scale on the trunk and appendages 15 weeks Prophylaxis with fluconazole and penicillin VK. Petrolum per day were essentially resolved by DOL 30 jelly applied to fissures. Hearing loss and developmental delays Rajpar et al.27 2006 ACI:0.5 mg kgÀ1 per day Singh et al.28 2001 ACI:1 mg kgÀ1 Skin showed clinical improvement after 6 weeks per day 1 month of treatment Chan et al.23 2003 ACI:1 mg kgÀ1 Persistent erythroderma, fine scaling 4 weeks Prophylaxis against skin and systemic infections with IV per day ampicillin and gentamicin, and topical mupirocin applied to fissures Mukhopadhyay 2006 ET:1 mg kgÀ1 and Agarwal29 per day Ward and 1989 ET:1.3 mg kgÀ1 Skin greatly improved at 2 weeks of age Jones30 per day Lawlor and 1985 ET:1 mg BID Improvement of ectropion correlated with Peiris31 skin improvement Prasad et al.9 1994 ET:1 mg TID Skin gradually softened and the hard yellow Died at 22 months from cardiorespiratory arrest after plaques separated revealing erythematous, admission with 37.2 1C temperature and dry, neglected scaly surface beneath skin. Blood cultures grew Staphylococcus aureus Prasad et al.9 1994 ET:1 mg TID MRSA from skin at 2 weeks, not isolated from blood, no parenteral ABX; At 5 weeks, Pseudomonas (P.) aeruginosa isolated from skin swabs of areas of ischemia and gangrene on bony prominences and tips of fingers and toes, child subsequently died of DIC Chan et al.23 2003 ET:1 mg kgÀ1 Within 2 weeks of starting Etretinate, there was 8 weeks Ectropion was complicated by Acinetobacter infection per day remarkable improvement with generalized thinning of scales and decreased ectropion Haftek et al.32 1996 ET:1 mg kgÀ1 Thick scales detached from the underlying per day skin and were removed on DOL 16. Clinical picture evolved towards a severe ichthyotic erythroderma of the NBCIE type Gunes16 2003 ET:unspecified Prophylaxis against skin and systemic infections with cefazolin and gentamicin; P. aeruginosa isolated in blood and skin cultures DOL 15, tx with Imipenem and amikacin, died on DOL 21 due to sepsis from ecthyma gangrenosum caused by P. aeruginosa Roberts33 1989 ISO:0.5 mg kgÀ1 Shedding of thick plates after 1 week 8 weeks per day

Abbreviations: ABX, antibiotics; ACI, acitretin; DOL, day of life; ET, etretinate; ISO, ; MRSA, methicillin-resistant Staphylococcus aureus.

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Retinoids should be started as soon after delivery as possible. The feeding early on, HI infants treated with systemic retinoids have particular retinoid therapy and doses chosen by previous teams are been reported to effectively suckle after 2 weeks of treatment.9 By shown in Table 1. Acitretin has become the preferred retinoid fostering parental bonding and addressing issues of acceptance because its shorter half-life provides a better safety profile.20 while the newborn is still an inpatient, the medical team can help Moreover, acitretin when compared with etretinate has been ensure that parents are psychologically prepared to take over care associated with reduced severity of side effects, including less severe when the infant is discharged. Lastly, as the day-to-day headaches, mucocutaneous dryness and skin irritation.20,21 management of HI remains complex even after discharge, it is Furthermore, etretinate has been off the market in the United States important that a social worker be involved early to help structure a since 2001. As alterations of lipids and liver function tests can be comprehensive discharge plan that will provide the caretakers with seen with the use of retinoids including acitretin, pre-therapeutic support during the transition from hospital to home.26 assessment and occasional monitoring of a complete blood count, In summary, HI is a severe disorder of the skin that presents a urea, liver function tests, creatinine, cholesterol, triglyceride levels formidable challenge for even the most skilled perinatal teams. and urinalysis is necessary. Toxic, irreversible musculoskeletal side Nevertheless, we believe that the complex management of these effects (including osteoporosis, periosteal plucking, slender long patients can be best achieved by using a multidisciplinary approach bones and premature epiphyseal closure) have been associated with characterized by strong communication, both among the medical chronic use of high-dose systemic retinoids. However, these adverse team and with the family. Although HI is very rare, with the musculoskeletal side effects have not been associated with lower exception of oral retinoids, the general treatment approach doses typically used to treat HI and other forms of ichthyosis, even reviewed above could be implemented in the management of other when used for periods greater than 10 years.21 Despite the low risk disorders of keratinization affecting neonates. of complications, it is important to titrate the patient to the lowest effective dose of acitretin over the first year of life to minimize Conflict of interest musculoskeletal side effects. In addition to blood work mentioned The authors declare no conflict of interst. above, periodic monitoring of vitamin D levels in HI infants may be warranted, as a recent report suggests an increased incidence of References vitamin D deficiencies in patients with congenital ichthyosis.22 The role of the medical team must go beyond optimizing the 1 Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arital K et al. Mutations in ABCA12 in harlequin ichthyosis and functional rescue by corrective gene physical health of the patient to include issues affecting the transfer. J Clin Invest 2005; 115: 1777–1784. parental bonding and home life. The appearance of the HI neonate 2 Kelsell DP, Norgett EE, Unsworth H, Teh MT, Cullup T, Mein CA et al. Mutations in is striking and intimidating for seasoned medical practitioners, ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum much less expectant parents. Thus, it is important to assemble the Genet 2005; 76(5): 794–803. appropriate medical team early including a dermatologist, 3 Sakai K, Akiyama M, Sugiyama-Nakagiri Y, McMillan JR, Sawamura D, Shimizu H. geneticist and pediatric intensivist who can meet with parents to Localization of ABCA12 from Golgi apparatus to lamellar granules in human upper epidermal keratinocytes. Exp Dermatol 2007; 16(11): 920–926. discuss their concerns and provide them with a sense of life after 4 Elias PM, Williams ML, Holleran WM, Jiang YJ, Schmuth M. Pathogenesis of discharge. Given the appearance of the neonate, it is not permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid uncommon for parents to harbor profound feelings of guilt, shame metabolism. J Lipid Res 2008; 49(4): 697–714. or grief. One mother even considered suicide because she was 5 Milner ME, O’Guin WM, Holbrook KA, Dale BA. Abnormal lamellar granules in unable to face the prospect of raising a child with HI.23 In other harlequin’s ichthyosis. J Invest Dermatol 1992; 99: 824–829. 6 Moskowitz DG, Fowler AJ, Heyman MB, Cohen SP, Crumrine D, Elias PM et al. cases, this has manifested as neglect of the child by the parents Pathophysiologic basis for growth failure in children with ichthyosis: an evaluation after discharge, that is, refusing to take the child out of the of cutaneous ultrastructure, epidermal permeability barrier function, and energy 23 house. With this in mind, parents might benefit from speaking expenditure. J Pediatr 2004; 145: 82–92. with a mental health specialist or counselor about their feelings 7 Williams ML. Neonatal phenotypes in the ichthyoses. Ped Derm 2004; 21(3): 308–309. and fears during the newborn’s inpatient stay. Also, parent–child 8 Akiyama M. Pathomechanisms of harlequin ichthyosis and ABCA transporters in interaction in the early neonatal period, particularly skin-to-skin human diseases. Arch Dermatol 2006; 142: 914–918. 9 Prasad RS, Pejaver RK, Hassan A, al Dusari S, Wooldridge MA. Management and contact, has been repeatedly shown to be essential for building the follow-up of harlequin siblings. Br J Dermatol 1994; 130(5): 650–653. foundation of the parent–child relationship. To foster this bonding 10 Grunau RE, Holsti L, Haley DW, Oberlander T, Weinberg J, Solimano A et al. Neonatal and reduce parental fears of harming their infants through casual procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm contact, parents should be encouraged to participate in their infants in the NICU. Pain 2005; 113: 293–300. newborn’s care.24,25 Parents can be readily trained to apply 11 Grunau RE, Whitfield MF, Fay T, Holsti L, Oberlander T, Rogers ML. Biobehavioural reactivity to pain in preterm infants: a marker of neuromotor development. Dev Med emollients to their infant’s skin and to aid with baths. Child Neuro 2006; 48: 471–476. Breastfeeding should also be encouraged. Though restrictions 12 Anand KJ, Hall RW. Controversies in neonatal pain: an introduction. Semin Perinatol associated with the rigid epidermal covering may preclude breast 2007; 31: 273–274.

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