Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity

Variations of the small heterodimer partner (SHP, NR0B2) gene, an atypical nuclear receptor that inhibits transactivation by hepatocyte nuclear factor (HNF)-4alpha, are associated with obesity among Japanese. The purpose of the study was to evaluate the prevalence of SHP variants among obese Danish men. Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early-onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR-RFLP. Functional analyses of the identified coding region variants were performed in both MIN6-m9 and HepG2 cell lines. A total of five novel variants, including three missense variants (c.100C>G [p.R34G], c.278G>A [p.G93D], and c.415C>A [p.P139H]) and two silent variants (c.65C>T [p.Y22Y] and c.339G>A [p.P113P]) were identified. Moreover, the previously reported c.512G>C [p.G171A] polymorphism was identified. The 171A allele was not associated with obesity (p = 0.07). The 34G, 93D, and 139H-alleles were rare variants, which were found only among obese subjects. Among the four coding region variants, the 93D-allele showed a reduced in vitro inhibition of the HNF-4alpha transactivation of the HNF-1alpha promoter expression when expressed in MIN6-m9 and HepG2 cell lines (p<0.01). In contrast to reported findings among obese Japanese, functional variants are rare among Danish men. A functional 93D variant of SHP was identified in 1 out of 750 obese and in none of 795 nonobese control subjects. Further large-scale population studies are necessary to assess the clinical impact of this rare variant on obesity risk among European subjects.     

Phenotype delineation of ZNF462 related syndrome

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.     

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype,a new cohort of 86 patients

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.     

Short implants (≤8 mm) compared to standard length implants (>8 mm) in conjunction with maxillary sinus floor augmentation: a systematic review and meta-analysis

The objective was to test the hypothesis of no difference in the treatment outcome after the installation of short implants (≤8 mm) in the posterior part of the maxilla compared to standard length implants (>8 mm) in conjunction with maxillary sinus floor augmentation (MSFA) using the lateral window technique, after an observation period of ≥3 years. A search of the MEDLINE, Embase, and Cochrane Library databases, in combination with a hand-search of relevant journals, was conducted. The search yielded 1102 titles. Finally, three studies that fulfilled the inclusion criteria were included. All were considered to have a low risk of bias. Meta-analyses revealed no significant differences in implant survival or peri-implant marginal bone loss between the two treatment modalities. However, the use of standard length implants in conjunction with MSFA was characterized by a tendency towards more peri-implant marginal bone loss. There was no statistically significant difference between the two treatment modalities with regard to overall patient satisfaction. Short implants seem to be a suitable alternative to standard length implants in conjunction with MSFA. However, further randomized controlled trials with larger patient samples and an observation period of more than 3 years are needed before one treatment modality might be considered superior to the other.     

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α₂δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.     

Chronic Pancreatitis and the Hepatobiliary System

Alcohol-induced chronic pancreatitis involving the head of pancreas may have profound effects on the hepatobiliary system. The natural history, complications, and management of the syndrome are presented, using selected cases to emphasize important features. Chronic pancreatitis can cause mechanical obstruction to both the distal common bile duct and the proximal pancreatic duct. In the common bile duct this will result in proximal dilatation above the stenosis with bile stasis. Possible sequelae are ascending cholangitis, cholecystitis, biliary calculi formation, and secondary biliary cirrhosis. The mechanical effects of stricture of the proximal pancreatic duct may exacerbate pancreatic dysfunction. The clinicopathological spectrum of chronic pancreatitis with biliary obstruction encompasses three clinical types–"transient,""recurrent." and "persistent." The widespread effects of the syndrome are evident from the involvement of pancreas, proximal pancreatic duct, papilla of Vater, liver, peripheral biliary tree, common bile duct, gallbladder, and reticuloendothelial system. Essential to management is surgery which should be considered when there is objective evidence of obstruction to the common bile duct. Choledochoduodenostomy is the preferred type of operation. If dilatation is mild and jaundice transient, conservative therapy with careful observation is advocated.     

Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.     

Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non‐syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y‐box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi‐quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.     

Histological evaluation of healing after transalveolar maxillary sinus augmentation with bioglass and autogenous bone

Objectives: The aim was to evaluate histologically the outcome of a bioglass and autogenous bone (at 1 : 1 ratio) composite implantation for transalveolar sinus augmentation. Methods: In 31 patients, during implant installation ca. 4 months after sinus augmentation, biopsies were harvested through the transalveolar osteotomy by means of a trephine bur and non‐decalcified sections through the long axis of the cylinder were produced. After a strict selection process, taking into account the presurgical residual bone height and biopsy length, 8 and 15 biopsies representing the new tissues formed inside the sinus and the transalveolar osteotomy, respectively, qualified for analysis. The tissue fractions occupied by newly formed bone (mineralized tissue+bone marrow), soft connective tissue, residual biomaterial+empty spaces, and debris inside the sinus cavity or the transalveolar osteotomy were estimated. Results: Bone and connective tissue fraction in the newly formed tissues inside the sinus cavity averaged 23.4 ± 13.2% and 54.1 ± 23.5%, respectively. Residual biomaterial, empty spaces, and debris averaged 1.9 ± 3.5%, 10.5 ± 6.3%, and 8.4 ± 14.5%, respectively. In the transalveolar osteotomy, bone and connective tissue fraction averaged 41.6 ± 14.3% and 46.1 ± 13%, respectively, while the amount of residual biomaterial, empty spaces, and debris was 2.8 ± 5%, 4.7 ± 1.9%, and 3.2 ± 2.6%, respectively. Statistically significant differences between the sinus cavity and the transalveolar osteotomy were found only for bone and empty spaces' values (P=0.02 and 0.04, respectively). Conclusion: Sinus augmentation with a bioglass and autogenous bone composite is compatible with bone formation that, in a short distance from the floor of the sinus, shows similar density as that reported previously for other commonly used bone substitutes. New bone fraction inside the transalveolar osteotomy was almost twice as much as in the sinus cavity, while the amount of residual biomaterial was much less than that inside the sinus. To cite this article :
Stavropoulos A, Sima C, Sima A, Nyengaard J, Karring T, Sculean A. Histological evaluation of healing after transalveolar maxillary sinus augmentation with bioglass and autogenous bone.
Clin. Oral Impl. Res. 23 , 2012; 125–131.
doi: 10.1111/j.1600‐0501.2011.02161.x