What XLPDR is? Information about diagnosis and therapies, updated to 2019

What we know about the disease:

X-linked reticulate pigmentary disorder (XLPDR; OMIM accession code 301220) is a rare entity characterized by both recurrent infections and sterile inflammation developing in the first years of life (Anderson et al., 2005; Starokadomskyy et al., 2016). XLPDR was first recognized by Partington in a large family in Ontario, Canada (Partington et al., 1989). Since the original report, a total of 16 families have been reported worldwide (Anderson et al., 2005; Nilay et al., 2015; Partington et al., 1989; Pezzani et al., 2013; Soo et al., 2010; Starokadomskyy et al., 2016, 2017).

The cardinal feature of the disorder is diffuse reticulate hyperpigmentation, along with a series of systemic manifestations: hypohidrosis, reccurent infections, and immune deficiency (Starokadomskyy et al., 2016). Diffuse skin hyperpigmentation with a distinctive reticulate pattern is universally evident by early childhood (Starokadomskyy et al., 2017), and this is later followed in many patients by hypohidrosis (which can be severe enough to place patients at risk for hyperthermia). In addition to the dermatologic manifestations, most patients also have characteristic facial features including upswept coarse hair and flared eyebrows. Males with XLPDR often display susceptibility to recurrent bacterial and fungal lung infections, particularly pneumonia, leading to bronchiectasis, which is often misdiagnosed as cystic fibrosis. More than half of the patients also display intestinal inflammations leading to enterocolitis, sterile cornea inflammation resulting in impaired vision, and urinary tract infections and inflammations leading to urethral strictures. Female carriers are known to have only restricted pigmentary changes along Blaschko’s lines with incomplete penetrance (Soo et al., 2010; Starokadomskyy et al., 2016).

Previously, we reported that XLPDR is caused by a recurrent intronic mutation in the POLA1 gene, resulting in missplicing and partial POLA1 protein deficiency (Starokadomskyy et al., 2016). POLA1 encodes the catalytic subunit of DNA polymerase-α (Pol-α), which in vertebrates exists in a stable complex with Primase. Together with a DNA helicase that unwinds chromosomal DNA, known as the minichromosome maintenance (MCM) complex, Pol-α/Primase is responsible for initiating DNA replication. Our prior studies identified that POLA1 deficiency in XLPDR is not profound enough to impair DNA replication and cellular proliferation, but unexpectedly activates the type I interferon response, which is the likely explanation for the autoinflammatory manifestations of the disease (Starokadomskyy et al., 2016). However, the mechanism behind the immunodeficiency observed in these patients has remained elusive.

What else we can be done:

1) Creation of clinical XLPDR PCR diagnostics (required approx. 2-3 clinicists, ~ $ 10.000 budget to develop a clinical genetic test for XLPDR intronic mutation). Till today there is no clinical genetic diagnostics kit for XLPDR. We have all material to help someone to build up this diagnostics (we cannot do paperwork, which is the most tedious part of the new medical diagnostics kit). The major problem of this project is lack of patients, that makes big hospitals reluctant to invest in new diagnostics. We have PCR primers validated for research purposes. This may serve as a basis for the diagnosis of new patients.

2) JAK/STAT inhibitors. There is one clinical trial on similar syndrome proving its efficacy. Doctors can refer to this paper. Expected non-target effect is temporary immunodeficiency. The major problem of this direction is lack of patients, that makes big hospitals reluctant to invest in new therapeutic schemes.

3) Genetic editing: we are thinking of gene therapy aiming to fix the POLA1 mutation in immune progenitors in the bone marrow. Some data suggests that specific deficiency of POLA1 in immune cells may be responsive for the most of inflammatory phenotype. However, the budget of the study is around $ 5.000.000 – 10.000.000, which includes creation of mouse model to test the therapy on mice, and after multiple preclinical trials a therapy on human should be tested in clinical trials at designated NIH facility. The major problem of this direction is that there is a danger of non-target effects (e.g. tumor grow, or excessive immune reaction).

Please be advised that all doctors are welcome to contact me directly with new cases or questions.

Peter Starokadomskyy, PhD
Research Scientist
UT Southwestern Medical Center
Department of Internal Medicine
5323 Harry Hines Blvd.
Room J5.126
Dallas, TX 75390 – U.S.A.
Tel: 214-648-8005
Fax: 214-648-2022
Email: Questo indirizzo email è protetto dagli spambots. È necessario abilitare JavaScript per vederlo.
Web-site: http://www.utsouthwestern.edu/labs/burstein