Primary Failure of Dental Eruption Due to Variants Parathyroid Hormone Receptor 1: Retrospective Study and Proposal of Guidelines Treatment.

OBJECTIVE: Primary failure of eruption is characterized by a nonsyndromic defect in tooth eruption in the absence of mechanical obstruction. It is correlated to rare heterozygous variants in the parathyroid hormone receptor 1 gene. The management of primary failure of eruption is complex because many therapies are ineffective. The present study aimed to compare the clinical outcomes of our patients with the findings reported in the literature, and to propose a treatment guideline based on the literature and our experience. METHODS: Retrospective study of patients affected by primary dental eruption failure in the department and analyse of the results and compare with those of the litterature. RESULTS: Twelve patients belonging to 5 families (9 males, 3 females; 13-52 y old) diagnosed and treated in the maxillofacial surgery and stomatology department of the Lille University Hospital were included. All patients showed posterior tooth involvement, and most patients showed bilateral defects. None of the affected teeth had coronal alveolar bone, whereas 6 patients showed root resorption in the affected teeth. Genetic analyses, performed on 11 patients, identified a parathyroid hormone receptor 1 disease-causing variant in 7 of them (63%). Multidisciplinary treatment was required to rehabilitate these patients. Orthodontic interventions, even at an early age, are difficult in affected teeth, which are often blocked or have internal resorption. Moreover, retention of these affected teeth during growth leads to dentoskeletal malocclusions, requiring difficult surgical management in the long term. Therefore, early extraction of these teeth is frequently recommended once the diagnosis has been confirmed. An implant-borne prosthetic rehabilitation can then be achieved at the end of growth after correction of the jaw discrepancy. In case of a late diagnosis, other surgical or noninvasive techniques may be used depending on the clinical situation. Distraction osteogenesis or segmental osteotomy could be discussed for patients with mild phenotypes. CONCLUSIONS: Early diagnosis of primary eruption defects is crucial to offer appropriate management as early as possible, and so to avoid late complicated treatments.

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset.

INTRODUCTION: The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect. METHODS: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort. RESULTS: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8-74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients. CONCLUSION: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

The natural history of a family with aortic dissection associated with a novel ACTA2 variant.

Disease-causing heterozygous variants in the ACTA2 gene cause an autosomal dominant heritable thoracic aortic disease (HTAD) with thoracic aortic aneurysm and dissection as main phenotype, and occasional extravascular abnormalities such as livedo reticularis. ACTA2-HTAD accounts for an important part of non-syndromic HTAD, with detection rates varying between 1.5-21% according to different studies. A consensus statement for the screening and management of patients with pathogenic ACTA2 variants has been recently published by the European reference network for rare vascular diseases (VASCERN). However, management of ACTA2 patients is often challenged by extremely variable inter- and intra-familial clinical courses of the disease. Here we report a family harboring a disease-causing ACTA2 variant. The proband and two siblings presented with acute type A aortic dissection and rupture involving nondilated aortic segments before the age of 30. Their mother died at 49 years-old from type B aortic dissection and rupture. Genetic testing revealed the heterozygous novel p.(Pro335Arg) variant in the ACTA2 gene in the proband and in the affected siblings. The clinical history of this family highlights the difficulty of adopting effective prevention strategies in ACTA2 patients.

Cerebral cavernous malformations associated to meningioma: High penetrance in a novel family mutated in the PDCD10 gene.

Multiple familial meningiomas occur in rare genetic syndromes, particularly neurofibromatosis type 2. The association of meningiomas and cerebral cavernous malformations (CCMs) has been reported in few patients in the medical literature. The purpose of our study is to corroborate a preferential association of CCMs and multiple meningiomas in subjects harbouring mutations in the PDCD10 gene (also known as CCM3). Three members of an Italian family affected by seizures underwent conventional brain Magnetic Resonance Imaging (MRI) with gadolinium contrast agent including gradient echo (GRE) imaging. The three CCM-causative genes were sequenced by Sanger method. Literature data reporting patients with coexistence of CCMs and meningiomas were reviewed. MRI demonstrated dural-based meningioma-like lesions associated to multiple parenchymal CCMs in all affected individuals. A disease-causative mutation in the PDCD10 gene (p.Gln112PhefsX13) was identified. Based on neuroradiological and molecular data as well as on literature review, we outline a consistent association between PDCD10 mutations and a syndrome of CCMs with multiple meningiomas. This condition should be considered in the differential diagnosis of multiple/familial meningioma syndromes. In case of multiple/familial meningioma the use of appropriate MRI technique may include GRE and/or susceptibility-weighted imaging (SWI) to rule out CCM. By contrast, proper post-gadolinium scans may aid defining dural lesions in CCM patients and are indicated in PDCD10-mutated individuals.

Transumbilical single-access laparoscopic perforated gastric ulcer repair.

INTRODUCTION: In patients presenting with peritonitis, laparoscopy offers the possibility of diagnosis as well as treatment, with less abdominal trauma, reduced postoperative pain, and shorter hospital stay. CASE REPORT: A 30-year-old woman, presenting with diffuse abdominal pain and free pneumoperitoneum, was submitted to transumbilical single-access laparoscopy. The procedure was performed using a standard 11-mm reusable trocar in the umbilicus and curved reusable instruments inserted transumbilically without trocars. The cavity exploration showed a perforated gastric ulcer at the anterior surface of the prepyloric area. A gastric suture repair, omentoplasty, and lavage of the cavity were performed. RESULTS: The umbilical incision was 15 mm and laparoscopy lasted 86 minutes. Use of painkillers was minimal, and the patient was discharged on the fifth postoperative day. After 6 months, the umbilical scar was no visible. CONCLUSIONS: Transumbilical single-access laparoscopy can be proposed in selected patients presenting perforated gastric ulcer, with the main advantage of improved cosmetic results.