Periodontal disease in patients with WHIM syndrome.

AIM: WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome is a rare combined primary immunodeficiency disease caused by gain-of-function (GOF) mutations in the chemokine receptor CXCR4 and includes severe neutropenia as a common feature. Neutropenia is a known risk factor for periodontitis; however, a detailed periodontal evaluation of a WHIM syndrome cohort is lacking. This study aimed to establish the evidence base for the periodontal status of patients with WHIM syndrome. MATERIALS AND METHODS: Twenty-two adult WHIM syndrome patients and 22 age- and gender-matched healthy volunteers (HVs) were evaluated through a comprehensive medical and periodontal examination. A mouse model of WHIM syndrome was assessed for susceptibility to naturally progressing or inducible periodontitis. RESULTS: Fourteen patients with WHIM syndrome (63.6%) and one HV (4.5%) were diagnosed with Stage III/IV periodontitis. No WHIM patient presented with the early onset, dramatic clinical phenotypes typically associated with genetic forms of neutropenia. Age, but not the specific CXCR4 mutation or absolute neutrophil count, was associated with periodontitis severity in the WHIM cohort. Mice with a Cxcr4 GOF mutation did not exhibit increased alveolar bone loss in spontaneous or ligature-induced periodontitis. CONCLUSIONS: Overall, WHIM syndrome patients presented with an increased severity of periodontitis despite past and ongoing neutrophil mobilization treatments. GOF mutations in CXCR4 may be a risk factor for periodontitis in humans.

Unraveling the impact of primary immunodeficiency disorders on the microbiota of dental caries in children through 16S rRNA gene-based metagenomic analysis.

Background/aim: Dental caries is a frequently occurring and multifactorial chronic disease in children resulting from the interaction of cariogenic bacteria and host susceptibility. The aim of this study was to elucidate the impacts of primary immunodeficiency disorders (PIDs) on microbiota of dental caries in children by 16S rRNA gene-based metagenomic analysis. Materials and methods: Enrolled in this study were 15 children with primary PID with caries (PID group) and 15 healthy children with caries as a control (CG). The DMFT index, saliva flow rate, and buffering capacity of each participant were assessed before the metagenomic analyses were conducted. For taxonomic profiling, the reads were obtained by high-throughput sequencing of the V3-V4 hypervariable region of 16S rRNA. Results: The DMFT score, saliva flow rate, and buffering capacity of the groups were similar. The flow rate and buffering capacity had no correlation with the number of species with 95% confidence. The metagenomic analysis resulted in the identification of 2440 bacterial species in all of the samples. Among the 50 most prevalent species present at ≥1% relative abundance, Prevotella melaninogenica and Prevotella salivae were differentially more abundant in the PID group. The PID group and CG showed similar species richness and evenness, but 4 of the 5 samples with the highest Shannon-Weiner and Inverse Simpson indices belonged to the PID group. The Spearman test results for correlation of the species in the PID subgroups showed that Prevotella oris had a positively correlated relationship with both Scardovia wiggsiae and Saccharibacteria genera incertae sedis. Conclusion: This study provided insight into the caries microbiota of children with immunodeficiency diseases. Differentially abundant species, novel bacterial associations, and unique bacterial species were disclosed in the PID samples, indicating the role of the immune system in altering the caries microbiota. The prominent bacterial species and associations in the PID group should be suspected in regard to their link with present or future diseases.

Clinical and immunological assessment of APDS2 with features of the SHORT syndrome related to a novel mutation in PIK3R1 with reduced penetrance.

Monoallelic loss-of-function (LOF) mutations in the phosphatidylinositol 3-kinase (PIK3R1) gene affecting the inter-Src homology 2 domain of the p85α regulatory subunit of phosphoinositide--3-kinase δ (PI3Kδ) cause the activated PI3K δ syndrome (APDS2). APDS2 is defined as a primary antibody deficiency, developmental abnormalities within the B and T lymph cell compartments, and immune dysregulation. The genetic defect of APDS2 is shared with that of the SHORT syndrome, characterized by short stature, joint hyperextensibility, ocular depression, Rieger anomaly, and delayed tooth eruption. LOF variants in an intronic splice site (c.1425+1G.C/A/T) in the PI3KR1 gene have been identified in patients affected with both APDS2 and SHORT syndrome. Herein, we report a novel c.1644-1648del (p.Asp548Glufs*6) variant in a pediatric patient with the APDS2-related immunodeficiency, who presents with mild phenotypic features of the SHORT syndrome, congenital chest wall deformity, and IgE-mediated food allergy. The same variant was also identified in the patient's hitherto asymptomatic mother, implicating an incomplete penetrance. Regular monitoring by a multidisciplinary team under the pediatric clinical immunologist's supervision to implement appropriate diagnostic procedures and treatment modalities is of paramount importance. Further studies are required to better define the genotype-phenotype correlation in patients with the PIK3R1 gene mutations and to better delineate the mutual relationship between APDS2 and the SHORT syndrome.

"Oral Manifestations of Patients with Inherited Defect in Phagocyte Number or Function" a systematic review.

INTRODUCTION: Inherited phagocyte defects are one of the subgroups of primary immunodeficiency diseases (PIDs) with various clinical manifestations. As oral manifestations are common at the early ages, oral practitioners can have a special role in the early diagnosis. MATERIALS AND METHODS: A comprehensive search was conducted in this systematic review study and data of included studies were categorized into four subgroups of phagocyte defects, including congenital neutropenia, defects of motility, defects of respiratory burst, and other non-lymphoid defects. RESULTS: Among all phagocyte defects, 12 disorders had reported data for oral manifestations in published articles. A total of 987 cases were included in this study. Periodontitis is one of the most common oral manifestations. CONCLUSION: There is a need to organize better collaboration between medical doctors and dentists to diagnose and treat patients with phagocyte defects. Regular dental visits and professional oral health care are recommended from the time of the first primary teeth eruption in newborns.

APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant.

Activated PI3K δ syndrome (APDS) is a primary immunodeficiency caused by heterogeneous germline gain-of-function mutations which ultimately lead to the hyperactivation of the phosphoinositide-3-kinase δ (PI3K δ). PI3K δ exists as a heterodimer composed of a catalytic and a regulatory subunit. APDS type 2 is caused by mutations in the PIK3R1 gene affecting the p85α regulatory subunit. SHORT syndrome is a rare multisystem disorder characterized by short stature, hyperextensible joints, ocular depression, Rieger anomaly, and tooth eruption delay. The primary causes of SHORT syndrome are heterozygous loss-of-function mutations in the PIK3R1 gene. The combination of APDS2 and SHORT syndrome is rare, with few cases reported to date. Here we describe a 17-year-old female with phenotypic features consistent with SHORT syndrome and history of sinopulmonary infections and hypogammaglobulinemia. Invitae immunodeficiency panel genetic testing revealed a pathogenic loss-of-function variant in an intronic splice site in the gene PIK3R1 (c.1425 + 1G > C). This pathogenic variant had been previously associated with APDS2; however, it had not been associated with SHORT syndrome. The exact mechanisms linking both conditions are yet to be identified. This case report emphasizes the importance of screening for comorbidities associated with SHORT syndrome in APDS2 patients and vice versa.

Schimke XLID syndrome results from a deletion in BCAP31.

A family with three affected males and a second family with a single affected male with intellectual disability, microcephaly, ophthalmoplegia, deafness, and Involuntary limb movements were reported by Schimke and Associates in 1984. The affected males with Schimke X-linked intellectual disability (XLID) syndrome (OMIM# 312840) had a similar facial appearance with deep-set eyes, downslanting palpebral fissures, hypotelorism, narrow nose and alae nasi, cupped ears and spacing of the teeth. Two mothers had mild hearing loss but no other manifestations of the disorder. The authors considered the disorder to be distinctive and likely X-linked. Whole genome sequencing in the single affected male available and the three carrier females from one of the families with Schimke XLID syndrome identified a 2 bp deletion in the BCAP31 gene. During the past decade, pathogenic alterations of the BCAP31 gene have been associated with deafness, dystonia, and central hypomyelination, an XLID condition given the eponym DDCH syndrome. A comparison of clinical findings in Schimke XLID syndrome and DDCH syndrome shows them to be the same clinical entity. The BCAP31 protein functions in endoplasmic reticulum-associated degradation to promote ubiquitination and destruction of misfolded proteins.

Recurrent necrotizing cellulitis, multi-organ autoimmune disease and humoral immunodeficiency due to a novel NFKB1 frameshift mutation.

BACKGROUND: Mutations in NFKB1(nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) are associated with a variety of clinical symptoms, including lymphadenopathy, splenomegaly, hepatomegaly, autoimmune haemolytic anaemia, arthralgia, recurrent respiratory tract infections and post-operative necrotizing cellulitis. CASE PRESENTATION: We describe a case of a 47-year-old man, who presented with deep necrotizing cellulitis after incision of a submucous abscess by a dentist. Surgical intervention led to a massive progress. Pyoderma gangraenosum (PG) was diagnosed clinically and confirmed histopathologically. High dose corticosteroids and intravenous immunoglobulins (IVIG) improved wound healing dramatically. Until now, immune mediated inflammation events not only affected the skin, but also multiple inner organs, i.e. the heart, lungs and gut. Sequencing of all coding exons of NFKB1 revealed a heterozygous 1bp deletion in exon 23 predicting a frameshift starting at codon Ala891 and resulting in a subsequent stop codon at position 6 in the new reading frame: NM_003998.4: c.2671del; p.(Ala891Glnfs*6) Acute episodes were always successfully treated with corticosteroids, IVIG and concomitant antibiotics. To prevent further exacerbations, the patient receives IVIG once a month, low-dose corticosteroids and methotrexate. CONCLUSION: This is the first case of a patient with recurrent necrotizing cellulitis and immune mediated multi-organ involvement (heart, lungs, intestine) carrying the novel frameshift mutation c.2671del (p.Ala891Glnfs*6) in NFKB1 effectively treated with IVIG, low-dose corticosteroids and methotrexate.

Craniofacial and Craniocervical Features in Cartilage-Hair Hypoplasia: A Radiological Study of 17 Patients and 34 Controls.

Background: Biallelic mutations in the non-coding RNA gene RMRP cause Cartilage-hair hypoplasia (CHH), a rare skeletal dysplasia in which the main phenotypic characteristic is severe progressive growth retardation. Objective: This study compared the cranial dimensions of individuals with CHH to healthy subjects. Methods: Lateral skull radiographs of 17 patients with CHH (age range 10 to 59 years) and 34 healthy individuals (age range 10 to 54 years) were analyzed for relative position of the jaws to skull base, craniofacial height and depth, as well as vertical growth pattern of the lower jaw, anterior cranial base angle, and the relationship between the cervical spine and skull base. Results: We found that the length of the upper and lower jaws, and clivus were significantly decreased in patients with CHH as compared to the controls. Anterior cranial base angle was large in patients with CHH. Basilar invagination was not found. Conclusion: This study found no severe craniofacial involvement of patients with CHH, except for the short jaws. Unexpectedly, mandibular deficiency did not lead to skeletal class II malocclusion. Clinical Impact: Although the jaws were shorter in patients with CHH, they were proportional to each other. A short posterior cranial base was not associated with craniocervical junction pathology.

Primary Immunodeficiencies With Defects in Innate Immunity: Focus on Orofacial Manifestations.

The field of primary immunodeficiencies (PIDs) is rapidly evolving. Indeed, the number of described diseases is constantly increasing thanks to the rapid identification of novel genetic defects by next-generation sequencing. PIDs are now rather referred to as "inborn errors of immunity" due to the association between a wide range of immune dysregulation-related clinical features and the "prototypic" increased infection susceptibility. The phenotypic spectrum of PIDs is therefore very large and includes several orofacial features. However, the latter are often overshadowed by severe systemic manifestations and remain underdiagnosed. Patients with impaired innate immunity are predisposed to a variety of oral manifestations including oral infections (e.g., candidiasis, herpes gingivostomatitis), aphthous ulcers, and severe periodontal diseases. Although less frequently, they can also show orofacial developmental abnormalities. Oral lesions can even represent the main clinical manifestation of some PIDs or be inaugural, being therefore one of the first features indicating the existence of an underlying immune defect. The aim of this review is to describe the orofacial features associated with the different PIDs of innate immunity based on the new 2019 classification from the International Union of Immunological Societies (IUIS) expert committee. This review highlights the important role played by the dentist, in close collaboration with the multidisciplinary medical team, in the management and the diagnostic of these conditions.