Poikiloderma with neutropenia: Genotype‐ethnic origin correlation, expanding phenotype and literature review

Abstract

Poikiloderma with neutropenia (PN), is a rare genodermatosis associated with patognomic features of poikiloderma and permanent neutropenia. Three common recurrent mutations of related gene, USB1, were considered to be associated with three different ethnic origins. The most common recurrent mutation, c.531delA, has been detected in seven Caucasian patients in the literature. In this paper, we present review of all patients from the literature and report two additional patients of Turkish ancestry with the diagnosis of PN. The diagnosis of these two PN patients were made clinically and confirmed by molecular analysis which detected the most common recurrent mutation, c.531delA. Genotype-ethnic origin correlation hypothesis, therefore, has been strengthened with this result. Short stature in PN, is a common finding, which until now has never been treated with growth hormone (GH). One of our patients is the first patient with attempted treatment of short stature via GH administration. Finally, both of our patients had high-pitched voice and vocal cord nodules which might be considered as additional clinical findings not associated with PN before.

Poikiloderma with neutropenia in a Tunisian patient with a novel C16orf57 gene mutation

“…A moderate normocytic normochromic anemia persisted in our patient since the age of 4 months and it was likely due to the inflammatory process and the recurrent infections. The skin biopsy showed previously reported histologic features of a late‐stage evolution of PN skin lesions, with a moderate inflammation infiltrate and rare melanophages suggesting the diagnosis of minor forms of congenital ichthyosis characterized by hyperkeratosis with sparse upper dermis infiltrate . Primary hypothyroidism is a new finding, not previously reported in patients with PN.…”

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

“…This is the first report of a homozygous missense being associated with disease in USB1, as to date all 19 disease-causing variants reported in USB1 are predicted to be loss of function (splicing, nonsense or frame shift). 13 Segregation analysis confirmed an autosomal recessive mode of inheritance, and homozygous variants were confirmed in an additional 4 affected siblings within these families (Figure 2A). In silico analysis of mutations on USB1 crystal structure (PDB id: 4W7H, Figure 2D) revealed that both p.His179MetfsTer86 and p.Gln225Ter truncates several α-helices and β-sheets in USB1 ( Figure 2E,F).…”

“…13,14,20,23,24 In the remaining families we have provided strong genetic and in silico evidence that the identified mutations are pathogenic. This study has demonstrated that the pleotropic clinical phenotype of DC markedly overlaps with the recognized disease entities LIG4 syndrome, Dubowitz syndrome and PN as well as the recently recognized ECTDS.…”

“…The key presenting features of PN are poikiloderma with noncycling neutropenia, recurrent infections, short stature and nail abnormalities. 13 The typical clinical features associated with ECTDS are short stature, nail dystrophy, abnormal oral pigmentation, and keratoderma and hyperkeratosis of the hands and feet.…”

Incomplete splicing of neutrophil-specific genes affects neutrophil development in a zebrafish model of poikiloderma with neutropenia

“…3 The actual number of reported patients is quite limited, mostly because several PN patients have many similar clinical manifestations with dyskeratosis congenita and Rothmund-Thomson syndrome. 4,5 To date, 40 patients with PN have been reported, [6][7][8][9][10][11][12][13][14][15][16] containing 19 different mutations in the C16orf57 gene that encodes a 265-amino-acid protein, referred to as USB1 (U Six Biogenesis 1). 17,18 In some studies, this protein has also been referred to as MPN1 (Mutated in Poikiloderma with Neutropenia).…”