A PARTICULAR CASE OF AUTOSOMAL RECESSIVE PROGRESSIVE SYMMETRICAL ERYTHROKERATODERMA (PSEK) AND A REVIEW OF THE LITERATURE

: Case report A A 10-year-old female patient born from non-consanguineous healthy parents after a regular pregnancy developed, at the age of 3 months, diffuse hyperkeratotic, pruritic plaques on her face, forearms, wrists, perineal and sacral regions in a mosaic pattern distribution, growing progressively. Laboratory and instrumental investigations, and a skin biopsy were performed

Once the parents' informed consent was obtained, several diagnostic investigations were performed, including genetic testing of the patient and both her parents, a skin  biopsy of one of the lesions, blood tests, and instrumental examinations.
In the suspicion of Chanarin Dorfman Syndrome and keratinopathic ichthyoses, a gene panel was performed, including ABHD5, KRT1, KRT2, KRT9, and KRT10 genes. Only the maternal variant p.Ala517Gly of uncertain significance in KRT2gene was found but not considered causative of the lesions. Molecular analysis of GJB2 and GJB4 genes did not show any alteration. Genetic  investigation revealed the pathogenic hemizygous variant c.879G>A in the paternal allele (heterozygous father), known to be associated with the autosomal recessive form of progressive symmetrical erythrokeratodermia [1].
A deletion on the corresponding maternal allele was also demonstrated. Furthermore, in our patient, molecular analysis of the KRT2 gene detected a genetic variant that causes the replacement of an alanine residue with a glycine residue at the 517 positions of the encoded protein chain, which has been classified as an uncertain significance variant. The latter represents a genetic variant classified by specific informatic predictive tools as benign or uncertain, with a 3/1000 allele frequency in the general population.
Histology of the lesions showed acanthosis and orthokeratotyc hyperkeratosis in a basket-weave pattern.
While laboratory exams were within normal ranges, the peripheral blood smear showed an infiltrate of neutrophils and monocytes presenting intracytoplasmic vacuoles, a "Jordans' anomaly" finding. Abdomen ultrasound and otoacoustic emissions showed no alteration as long as the child's neuropsychiatric and eye examination. The clinical picture, supported by histology and laboratory examinations, led to the clinical diagnosis of autosomal recessive PSEK and was confirmed by genetic analysis of the KDSR gene.
Treatment with oral acitretin at the initial dose of 5 mg daily was then started, associated with topical emollients, which led to a reduction of hyperkeratosis and a progressive resolution of the lesions on the face and scalp (Figures 1b, c; 2b-f; 3b-d; 4c; 5b,c).
The most interesting feature was the further evolution, with the onset of sparing areas within the lesions clinically suggestive of revertant mosaicism (Figures 2d-f; 3d). The patient is currently followed by our Rare Disease Inpatient, still on oral retinoid treatment with isotretinoin 10mg daily.

DISCUSSION
Progressive Symmetrical Erythrokeratodermia (PSEK), also known as Gottron syndrome, is a rare genetic skin disorder representing one of the Mendelian forms of erythrokeratoderma, together with erythrokeratoderma variabilis (EKV), Vohwinkel syndrome and a syndrome of erythrokeratoderma, ichthyosis, and cardiomyopathy (EKC syndrome) [1].
PSEK inheritance is usually autosomal dominant and often results from heterozygosity for a de novo mutation [2]. Genetic penetrance can be incomplete, and the clinical expressivity is variable [2]. In 2017, Boyden et al. [1] described four patients with biallelic variations in the KDSR gene (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, which caused a new phenotype included in the progressive symmetric erythrokeratoderma spectrum with autosomal recessive inheritance. The latter mutation corresponds to the one found in our patient who, in addition to that, presented the p.Ala517Gly genetic variant of the KRT2 gene of benign or uncertain significance.
Clinically, PSEK is characterized by fixed hyperkeratotic plaques on an erythematous base, with a symmetric distribution on extremities, buttocks, and occasionally face and torso. The lesions slowly become progressive in number and size, usually stabilizing after puberty, but without spontaneous remission [2].
Thrombocytopenia is another distinctive feature of the disease. It could be explained by the defective enzyme activity in KDSR, resulting in an impaired biosynthesis of acylceramide and sphingolipids, which represent key cofactors in developing cytoskeleton in keratinocytes and platelets. In literature, four affected patients are described with piastrinopenia [18,19] due to the same share affected pathway in skin and platelets.
Diagnosis of PSEK is based on clinical examination, typical histologic findings, and genetic testing.
Treatment options include topical keratolytics and retinoids in milder cases, while systemic therapy with retinoids is the first-line choice for moderate to severe manifestations [2].
Retinoids have proven to increase sphingosine acylation and upregulate sphingomyelinase, thus stimulating the ceramide salvage pathway and sphingomyelinase pathway, which produce ceramides independent of KDSR. Thus, the effectiveness of the therapy may be due, at least in part, to the compensation for a genetic defect in the ceramide de novo synthesis pathway, via pharmacologic induction of alternative pathways for ceramide generation [1].
When reported, outcomes show a good response to therapy in six patients [2,[9][10][11][12]16], but with a relapse of the lesions after discontinuation of the treatments in 2 of them [9,16], in one patient on acitretin and topical keratolytics no improvement was observed [8], and 3 patients were treated with acitretin without any benefit. None of the cases reported a revertant behavior of the lesions, as in our patient.
CONCLUSION This is the first case of Progressive Symmetrical Erythrokeratodermia associated with both the c.879G>A genomic variant in the KDSR gene and the p.Ala517Gly genetic variant of the KRT2 gene. It has to be proven whether this genetic association is coincidental or a phenotype-determining factor.Furthermore, a clinical picture suggestive of revertant mosaicism was observed in our patient, which, to date, has never been described in the literature. Based on reported cases, systemic therapy with oral retinoids in association with topical keratolytics was started and is still ongoing, with a progressive improvement of the lesions maintained over time.