Harlequin Ichtyosis is an autosomal recessive genetic disorder due to the mutation of the
ABCA12 gene in the chromosomal region 2q35. This gene belongs to a superfamily of ATP-binding cassettes, involved in the transport of biomolecules across the cell membrane, in the differentiation of keratinocytes and in the formation of the epidermal lipid barrier [
4‐
8]. Mutations are classified as homozygous (same mutation in both alleles) or compound heterozygous (different mutations on each allele) [
9]. Ominous outcome is usually associated with homozygous mutations. Our patients were carriers of a compound heterozygosity. Parents transmit the pathology to 25% of their children: they transmit the mutation of the ABCA12 gene in duplicate, at each conception, regardless of the sex of the unborn child; half of the children can be healthy carriers (heterozygous for the mutation of the ABCA12 gene, meaning having a single mutation of the disease gene), 25% healthy. However, some children with HI show no mutations of the ABCA12 gene, suggesting that the genetic basis underlying HI is still far from to be clear [
9]. In HI babies, skin is markedly thickened, the hard stratum corneum cracks soon after birth and leads to deep erythematous fissures delimiting geometric skin plates, with alopecia, ectropion, eclabium, and flattened ears. Dehydration, hindered thermoregulation, increased metabolic demands, feeding disorders, respiratory distress, fingers fixed in flexion by tight skin and increased risk of infection may occur [
1,
10]. Skin of survivors evolves to generalized erythema and scaling, often with associated palmoplantar keratoderma. Developmental delay is frequently described as well [
9]. The first line therapy of HI is oral retinoids and should be started early as much as possible [
11,
12]. The use of incubators with 50–85% humidification, the skin care with emollients and advanced dressing for fissures, eyes care with artificial tears and the close monitoring of possible extracutaneous complications are strongly recommended [
1,
9,
11,
12]. In some patients the surgical debridement of the joints of the hands and feet is inevitable, to allow movement and to avoid finger/toe’s necrosis. Concerning the drug therapy, acitretin at the dose of 0.5–1 mg/kg/day is the most used among different retinoids in neonates, thanks to less severe side effects compared to other compounds [
13,
14]. Retinoid administration may be discontinued by 6 months of age [
11,
12]. It is still unclear whether the use of oral synthetic derivatives of vitamin A in neonates is associated with bones demineralization and/or fractures, as suggested by some authors. Only few case reports exist [
1,
15]. Sitek et al. reported the case of an infant affected by HI treated with oral acitretin who developed osteopenia and multiple diaphyseal fractures of the four limbs [
16]. In both our patients acitretin was successful and interrupted after few months, because the improvement of facial deformities and the skin thickening, without bone demineralization and/ or fractures. However, our infants developed a precocious JIA, a pediatric chronic inflammatory disease, rarely reported in HI patients so early in the life. Chan et al. reported the case of a 11-year-old Chinese girl affected by erosive arthritis with rheumatoid factor-positive, diagnosed as polyarticular JIA at 6 years. The child was successfully treated with prednisolone and NSAIDs up to the age of 9 and then with methotrexate at the dose of 0,5 mg/Kg/week also, because the poor control of symptoms with prednisolone alone [
17]. The clinical improvement of erythema and arthritis was not associated with the parallel improvement of the hyperkeratosis and scaling. The child underwent etretinate therapy from 36 days to 6 years, when the drug was replaced by acitretin. Authors conclude the report warned about erosive arthritis, as an adverse event associated with etretinate therapy. To date this side effect of etretinate administration is not reported in the literature. Our patients were treated for a short time (10 months and 1 month for patients 1 and 2 respectively) and we think that acitretin may not have been the cause of JIA in them. The first line therapy for JIA was started with ibuprofen. Both patients underwent intra-articular long-acting glucocorticoid injections, with additional weekly oral methotrexate administered to the patient 2, as in the 6 years old patient reported by Carbogno et. Al [
18]. Clement et al. reported a 14-year-old boy, who suffered from both HI and JIA, managed with traditional NSAIDs and methylsulphone COX-2 inhibitors [
19]. Authors recommended to adequately treat JIA, because the because the reduction of mobility worsens contracture and joint swelling, accentuates skin lesions and increases the risk of infection. Another 17-years-old case, who developed JIA at the age of 10, underwent bilateral total hip replacement, after initial treatment with etoricoxib and etanercept [
20].
The relationship between JIA, HI and oral retinoid therapy has not been yet elucidated. Although
ARBCA12 gene is not associated with known immunologic cells defects, it has been proved that its mutations lead to an impairment of the outermost layer of the skin, which is the first mechanism of defence against microbes (especially Gram-positive bacteria) capable of causing disseminated infections. JIA related risk has been associated both to infections during the first year of life [
21] and to the extensive use of antibiotics early in the life [
22]. With regards to this hypothesis, it has been supposed that the antibiotic treatment could cause JIA though changes in microbiome [
23]. Of note, disbyosis in children with JIA has been documented [
24] and it is not of univocal interpretation, as it also could be the expression of the inflammation derangement status, linked to the chronicity of the disease. Our patients may support this hypothesis, because they both presented recurrent infections treated with antibiotics. It may be of interest testing HI patients with arthritis for described JIA genetic association (i.e. HLA polymorphism). To date our patient 1 has gone to complete and persistent remission of his monoarticular involvement at one-year evaluation. The patient 2, despite the start of methotrexate therapy, presents persistent tenosynovitis of both ankles at 2 months evaluation, while joints and tendons of the hands, treated with glucocorticoids injections, have undergone clinical and ultrasound remission. Periodic follow-up and treatment adjustments have been planned in both children.