The pathological condition known as Harlequin ichthyosis (HI) is a severe but extremely rare form of congenital ichthyosis. This disorder affects significantly the process of keratinization. During the keratinization procedure, the epidermal skin layer differentiates to form the stratum corneum ^[1][2][3][4][1,2,3,4]. Epidermal keratinization begins approximately between the 20th and 24th week of the gestational period [5]. Thus far, it is known that HI is caused mostly by the truncation of ABCA12 gene mutations [6]. This specific gene is responsible for the regulation of lipid-transporting proteins in the epidermis. Mutations cause severe imbalances to the homeostasis of the stratum corneum [7]. Scientists are making efforts to identify all the possible mutations that are responsible for the clinical manifestation of HI. A recent case study suggested that the phenotype of HI is specifically determined by the novel ABCA12 mutation, p.Gly-1508Val [8]. Another recent case study found novel deleterious intronic variants that could lead to the most severe manifestations of the disease [9].

The prevalence of the disorder is approximately 1 out of 300,000 infants [4]. There is no significant association between sex and race with the incidence of HI [4]. Until recently, fetuses affected by HI were either stillborn or died as newborns a few days after birth. Thankfully, in the last two decades, the use of advanced therapy protocols, such as retinoids and novel procedures, has allowed several infants to exceed this narrowed period of time and survive longer ^[1][2][3][4][1,2,3,4].

There are three distinct subtypes of HI (Table 1). The differentiation among these subtypes is based mostly on the reported skin abnormalities. The abnormalities on the lamellar structure of the epidermis are caused not only by the dysregulation of the lipid transportation but also by the severe desquamation due to the hydrophobic nature of the lipids. These anomalies are caused by the loss of the normal function of the ABCA12 gene ^[10][11][10,11]. The skin is sensitive to epidermal “fractures” and to excessive fissures’ formation due to the significant lack of connective substance ^[10][11][10,11].

The first common abnormality is the irregular formation of the lamellar granule structure, which appears as a shortness of aberrant granules. Additionally, lipid droplets are detected in the vacuoles and the stratum corneum. The abnormal lamellar form can lead to extreme water reduction due to the hydrophobic properties of lipids. Another common irregularity is the abnormal conversion of profilaggrin to filaggrin. This atypical conversion leads to the excessive production of filaggrin and the inability to form a strong keratin complex. Other severe irregularities entail the expression of keratin and the detection of keratohyalin granules, either regular or irregular ^{[11][12][13][14]}[11,12,13,14].

The abovementioned abnormalities can negatively affect the desquamation process and lead to the distinguish characteristics of the disease; an armor-like thick and fissured stratum corneum [14]. Further evidence suggests that calcium may be related to the development of HI because of its significant role in the differentiation of the epidermis ^[14][15][14,15]. Calpains are a distinctive form of proteolytic enzymes, activated by calcium. There is indication that these enzymes are essential for the signal transduction processes during differentiation ^[14][15][14,15].

The literature reports a variety of symptoms that are related to HΙ. The most prominent and conspicuous ones are responsible for the name of the disease: brown or white skin, grooved or cracked, eclabium, ectropion, nasal hypoplasia, lack of external ears, sparse scalp hair, short limbs, hypoplastic digits, and complete absence of eyebrows and eyelashes ^[13][14][13,14]. Hypoventilation, respiratory failure, and respiratory depression are also reported among the symptoms, attributed to the confinement of the pectoral wall by the armor-like skin. In addition, there are central nervous system traits of the disease, such as seizures, that raise concerns [16]. Due to the cracked skin, infants also suffer excessive dehydration which can lead to severe metabolic dysregulation. Finally, infants face significant feeding problems and gastrointestinal disorders, leading to malnutrition [16].

A detailed family history record is quite valuable, as it could lead to the identification of a variety of possible risk factors such as genetic reports, siblings affected by the disease, consanguinity, and history of other abnormalities that affect keratotic skin [17]. The genetic pathology of Harlequin ichthyosis has been well known in the literature for several years and has also been shown in the official classification of inherited ichthyoses [17]. A common clinical method used for the diagnosis of HI is ultrasonography [18]. Diagnosis can also be made by either 2D or 3D ultrasonography according to the manifestation of specific symptoms (i.e., cystic formation in front of the eyes, limb anomalies, and hypoechogenic amniotic fluid). Until the identification of the ABCA12 gene, a fetal skin biopsy was the preferred method of prenatal diagnosis, performed at the 20–24th week of gestation. It should be noted that light microscopy may also give a falsely negative outcome during the interpretation of the biopsy samples, based on the sites of the tissue collection ^[19][20][19,20]. Nowadays, the standard technique for the detection of HI is next-generation sequencing (NGS). Nevertheless, clinical investigation and ultrasonography are, in most cases, adequate and, therefore, necessary for a safe diagnosis [21].

Regarding the surgical management of HI, the case studies presented in the literature are limited. Surgical cases offer valuable knowledge, focusing on digital ichthyosis, a common manifestation among HI patients, which threatens the neurovascular integrity of the upper limbs ^[6][22][6,22]. Circumferential release and subsequent Z-plasty reconstruction result in beneficial outcomes in cases of congenital constriction bands ^[6][22][6,22]. It is essential to assess the surgical management of HI and, therefore, emphasis was given to surgical reports.

Apart from the management of the disease, parents should be given appropriate support by social workers and psychologists. As most infants do not survive the neonatal period, it is crucial for the family to cope with the possibility of their probable loss [23]. In addition to the NICU (Neonatal Intensive Care Unit), the infant has to face a number of surgical procedures, such as reconstructive surgery and skin grafts, in order to manage the skin injuries and to treat the extremities and the eyelids ^[2][24][2,24]. Inevitably, the infant’s quality of life will be seriously affected due to the constant medical follow ups and medication intake ^[25][26][25,26]. There is also high probability for these children to develop psychological disorders, mainly due to the fact of their appearance ^[25][26][25,26].

2. Management of Harlequin Ichthyosis

HI is a severe but rare disorder that is fatal for newborn infants. In order to deal with this unique medical challenge and increase the survival rates, a multidisciplinary team of physicians, among other experts, is essential. Researchers have already focused on the genetical aspect of the disease. Despite knowledge of the responsible gene, the mutations present several disparities among each case, leading to a variety of symptoms and affecting the survival rates. Utter comprehension of ABCA12 gene mutations is vital for managing the disorder. The pathophysiological mechanisms responsible for the disease’s manifestation are associated with the mutations created in the genome and, therefore, researchers suggest that this knowledge will increase the survival rates after birth ^[6][7][8][9][6,7,8,9]. The affected patients will face several challenges, especially during the neonatal period. In order to deal with this dire situation, genetic investigation is not enough. It is essential for physicians to have at hand effective guidelines, confirmed by the international literature. As time is of the essence, proper instructions could make the difference. The limited literature resources for HI led physicians to the implementation of managing methodologies and treatments from other ichthyosis cases or even similar dermatological disorders. In regard to surgical preparation and management, there have already been many approaches. Admission to an NICU should not be avoided and increased humidity is essential. Applying topical retinoids has been suggested as alternative to surgery but with no satisfactory results in most cases. Moreover, their combination with surgery did not manage to control the relapse of the disease. Alternatives, such as vitamin D intake, should be considered in order to avoid the retinoids’ side effects and investigate further the possibility of better outcomes. Limb encasement and constriction may also lead to autoamputation due to the presence of tissue necrosis. Therefore, confirmation of any possible limb confinement should be a reminder for surgical assessment. Operation using local anesthesia mitigates risk related to airway obstruction; however, parental counseling before the surgical procedure should include information regarding possible complications, due to the possibility of infections, and other recovery plans. Nowadays, novel research focuses on the immune system and the full characterization of the immunological profiling of these patients, as it may lead to therapeutic approaches that have not yet been implemented ^[27][61]. Other skin disorders, such as psoriasis and atopic dermatitis, share the same immune characteristics as HI. For instance, the immunoactivity is similar to the allergic reactions including IL-17 signaling. The scientific community should investigate further the possibility of immunotherapy, such as monoclonal antibodies. Another novel perspective is the topical application of enzymes that are involved in desquamation [11]. Kallikrein proteases were found on experiments with mice to mitigate the hyperkeratosis when topically applied. This evidence suggests that the lack of proteolytic enzymes due to presence of ABCA12 gene mutations could be the main culprits in the pathophysiology of HI. Cooperation with parents is also essential in order to avoid serious predicaments ^[28][62]. It is vital for the survival of the infant that parents understand the situation and the possible options (both pharmaceutical and surgical) in order to avoid behaviors that may endanger the child further. At the moment, the most common surgical interventions are autologous skin grafts. However, because of the high possibility of sepsis and bacterial infections in the epidermis and the skin layer, invasive procedures should be treated with extreme caution. On the other hand, for some cases, such as nasal occlusion, endotracheal intubation is unavoidable ^[22][29][22,58]. Therefore, it is an undeniable fact that HI surgical and general management can be quite challenging and specific guidelines will make the difference.