NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder.

NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare, and only 1 patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report 3 additional patients with a de novo deletion encompassing NR4A2: 2 patients have deletions encompassing only NR4A2 gene and 1 patient has a deletion including NR4A2 and the first exon of GPD2. Our patients presented a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder. We suggest that NR4A2 haploinsufficiency is implicated in neurodevelopmental disorder with high penetrance.

EFNB2 haploinsufficiency causes a syndromic neurodevelopmental disorder.

Ephrin B2, one of the ligand of the EphB receptors, is involved in a complex signaling pathway regulating the development of the nervous system, neuronal migration, erythropoiesis and vasculogenesis. We report a patient with a de novo variant in EFNB2 and a family in which segregates a 610-kb deletion at chromosome 13q33 encompassing only ARGLU1 and EFNB2 genes. The de novo variant was observed in a patient with anal stenosis, hypoplastic left ventricle and mild developmental delay. The deletion was identified in 2 sibs with congenital heart defect and mild developmental delay. One of the affected sibs further had myoclonic epilepsy and bilateral sensorineural hearing loss. The carrier mother was apparently asymptomatic. Because EFNB2 is located in the subtelomeric region of 13q chromosome, we reviewed the previous reports of terminal 13q deletion. We suggest that haploinsufficiency of the EFNB2 could be at the origin of several clinical features reported in 13qter deletions, including intellectual disability, seizures, congenital heart defects, anorectal malformation and hearing loss.

INTU-related oral-facial-digital syndrome type VI: A confirmatory report.

Oral-facial-digital (OFD) syndromes are a subgroup of ciliopathies distinguished by the co-occurrence of hamartomas and/or multiple frenula of the oral region and digital anomalies. Several clinical forms of OFD syndromes are distinguished by their associated anomalies and/or inheritance patterns, and at least 20 genetic types of OFD syndromes have been delineated. We describe here a child with preaxial and postaxial polydactyly, lingual hamartoma, a congenital heart defect, delayed development and cerebellar peduncles displaying the molar tooth sign. Whole-exome sequencing and SNP array identified compound heterozygous variants in the INTU gene, which encodes a protein involved in the positioning of the ciliary basal body. INTU is a subunit of the CPLANE multiprotein complex essential for the assembly of IFT-A particles and intraflagellar transport. This report of a second patient with INTU-related OFD syndrome and the further delineation of its neuroimaging and skeletal phenotype now allow INTU-related OFD syndromes to be classified within the OFD syndrome type VI group. Patients display a phenotype similar to that of mice with a hypomorphic mutation of Intu, but with the addition of a heart defect.

Remission of acromegaly after treatment withdrawal in patients controlled by cabergoline alone or in combination with octreotide: results from a multicenter study.

PURPOSE: Remission of acromegaly has been reported after somatostatin analogs withdrawal, but not after withdrawal of combination therapy with cabergoline, and only in case reports of patients controlled by cabergoline alone. METHODS: To establish the remission rates (normal IGF-1 for age/sex: IGF-1 ≤ 1.00 xULN) after withdrawal of combined treatment with octreotide LAR and cabergoline and of cabergoline alone, we prospectively studied 16 patients with acromegaly controlled by those treatments in the preceding 2 years as part of a larger study on remission of acromegaly after withdrawal of different medical treatments. RESULTS: Among 97 patients with controlled acromegaly included in the entire study, only 16 patients had been on combination therapy (n = 12) or cabergoline alone (n = 4). At 8 weeks after treatment withdrawal, three patients (19%) were in remission (short-term remission). At 60 weeks (long-term remission), IGF-1 levels were still in the normal range in two patients (12.5%) and remained normal up to 108 weeks after treatment withdrawal (last visit). One patient had been treated with cabergoline alone and another one with combination of octreotide and cabergoline before treatment withdrawal. CONCLUSION: Remission of acromegaly after treatment withdrawal seems to be uncommon in patients controlled by cabergoline, either as monotherapy or in combination with octreotide. In the future, larger studies and/or meta-analysis will be necessary to accurately establish the remission rates of acromegaly after withdrawal of cabergoline with or without somatostatin analogs.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Midshaft Clavicular Fractures - Osteosynthesis with Minimally Invasive Technique.

BACKGROUND: Fractures of the clavicle are one of the most common fractures in modern orthopaedics and traumatology practice. Knowing the mechanism of trauma, and it's pathophysiological elements, it's clear distinction and it's individual features are essential to the development of more new and effective methods for their treatment, and the minimising of postoperative complications. AIM: The aim of this paper was to present the results of our patients treated with minimally invasive plate osteosynthesis (MIPO). MATERIAL AND METHODS: Between January 2011 and March 2013, 12 patients were treated with MIPO technique. The mean age was 47.5 years (range, 16-79 years). Outcomes and complications of clinical treatment were reviewed. RESULTS: All fractures healed within a mean period of 4.9 months (range, 2-10 months). Regarding complications, there was no occurrence of implant failure or deep infection. There were no nonunions, but one 79-year-old man had a delayed union. Almost of all the cases didn't need bending of the plate. Seven plates were removed by their hopes. And there weren't any cases that required new incisions. CONCLUSIONS: A pre-contoured plate anatomically configured to fit the clavicle was easier to apply. MIPO technique for midshaft clavicle fractures may be a good option.

Diaphyseal Fractures of the Forearm in Adults, Plating Or Intramedullary Nailing Is a Better Option for the Treatment?

BACKGROUND: Fractures of the radius and ulna occupy a large field of the modern traumatology. Therefore, these fractures are a major subject in modern orthopaedics and traumatology. The study of the mechanisms of the trauma, and the pathophysiological changes that occur are of great importance for the development of ever more efficient and varied ways of the treatment and prophylactics of this type of fracture. AIM: The aim of this paper was to study the pattern of the diaphyseal fractures of the forearm in adults, to decide the modalities of surgical management, to observe the period of fracture healing clinically and radiologically, as well to study the rehabilitation of the patients. MATERIAL AND METHODS: The present study included 45 cases of diaphyseal fractures of both bones forearm in adults presenting to the orthopaedic outpatient department. For all the patients a detailed history was taken. A thorough clinical examination was carried out, required X-rays were taken, and initial treatment was given and admitted as in all patients. After careful pre-operative planning and evaluation for anaesthetic fitness, patients were operated for the fractures of both bone forearms. Twenty-three cases with 46 fractures were treated by open reduction and rigid fixation with DCP & Semi-tubular plates and 22 cases with 44 fractures were treated by closed reduction and fixation with "Talwarkar" intramedullary square nails. RESULTS: United results were found in 100% of plating group vs. 86% in the nailing group. Delayed and non-union results were found in 9% of the nailing group only. Average time to union in weeks was 9.4 weeks in the plating group vs. 10.2 weeks in the nailing group. CONCLUSION: Open reduction and internal fixation with compression plates with strict adherence to surgical technique is the gold standard method of treatment in both bones forearm fractures with excellent results than closed reduction, internal fixation with "Talwarkar" square nails which is also again a simple method with better results than conservative methods.

Treatment of Pediatric Open Supracondylar Humerus Fractures: Case Report.

BACKGROUND: Open supracondylar fractures of the humerus are rare in children, and the treatment strategy for these fractures is yet to be standardised. AIM: We present the case of a 7-year-old boy with open supracondylar humerus fracture that was managed with an external wrist fixator. CASE PRESENTATION: A 7-year-boy was brought to our department with pain in the right arm after a fall from a height about 3 hours before admission. On examination, the elbow was found to be markedly swollen with restriction of movement of the right arm. A 4-cm-wide wound was also observed on the flexural aspect of the elbow, indicating severe contamination of the fractured site. Neurological examination revealed restriction of hand movement and decreased sensations, which suggested the possibility of nerve injuries. CONCLUSION: A good clinical outcome was achieved in this case, without the development of any complications over a 6-month follow-up period.

Scapular Fractures in Blunt Chest Trauma - Self-Experience Study.

AIM: The aim of this retrospective study was to report the scapular fractures in patients with blunt chest trauma and to present the type and the frequency of associated thoracic injuries. MATERIAL AND METHODS: Nine patients with fractures of the scapula were included in the study. The mechanisms of the injury, the type of scapular fractures and associated thoracic injuries were analysed. RESULTS: Scapular fractures were caused by high-energy blunt chest trauma. The body of the scapula was fractured in all scapular fractures. In all cases, scapular fractures were associated with other thoracic injuries (average 3.25/per case). Rib fractures were present in eight patients, fractured clavicula - in four cases, the affection of pleural cavity - in eight of the patients and pulmonary contusion in all nine cases. Eight patients were discharged from the hospital up to the 15th day. One patient had died on the 3rd day because of postconcussional lung oedema. CONCLUSIONS: The study confirms the role of scapular fractures as a marker for the severity of the chest trauma (based on the number of associated thoracic injuries), but doesn't present scapular fractures as an indicator for high mortality in blunt chest trauma patients.

Molecular characterization of 39 de novo sSMC: contribution to prognosis and genetic counselling, a prospective study.

Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.

3D position of pericentromeric heterochromatin within the nucleus of a patient with ICF syndrome.

ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome is a rare autosomal recessive disorder characterised by severe immunodeficiency, craniofacial anomalies and chromosome instability. Chromosome analyses from blood samples show a high frequency of decondensation of pericentromeric heterochromatin (PH) and rearrangements involving chromosomes 1 and 16. It is the first and, as far as we know, the only disease associated with a mutation in a DNA methyltransferase gene, DNMT3B, with significant hypomethylation of the classical satellite DNA, the major component of the juxtacentromeric heterochromatin. To better understand the complex links between the hypomethylation of the satellite DNA, the cytogenetic anomalies and the clinical features of ICF syndrome, we performed three-dimensional (3D) FISH on preserved cells from a patient with a suspected ICF phenotype. Analysis of DNMT3B did not reveal any mutation in our patient, making this case an ICF type 2. The results of 3D-FISH showed a statistically significant change in the intranuclear position of PH of chromosome 1 in cells of the patient as compared to normal cells. It is difficult to understand how a defect in the methylation pathway can be responsible for the various symptoms of this condition. From our observations we suggest a mechanistic link between the reorganisation of the nuclear architecture and the altered gene expression.

Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.

BACKGROUND: The 22q13.3 deletion syndrome (or Phelan-McDermid syndrome, MIM 606232) is characterized by developmental delay, absent or severely delayed speech, neonatal hypotonia, autistic behavior, normal to accelerated growth, and minor dysmorphic facial features. Among the three genes in the minimal critical region (from the centromere to the telomere: SHANK3, ACR and RABL2B), the defect in the SHANK3 gene is considered to be the cause of the neurobehavioral symptoms. OBJECTIVE: We describe the molecular characterization of a de novo interstitial del(22)(q13.3q13.3) disrupting the SHANK3 gene in a child with a phenotype compatible with the 22q13.3 deletion syndrome. METHODS: Clinical work-up included clinical histories, physical, neurological, and ophthalmological examinations, and imaging of the brain. Commercially available MLPA for subtelomeric analysis, FISH specific probes and quantitative real-time PCR were used to characterize the rearrangement. RESULTS: Subtelomere analysis by MLPA showed a discrepancy between P036B and P070 kits (MCR Holland): the P070 MLPA 22q probe (targeting the ARSA gene) showed a deletion but the P036B one (targeting the RABL2B gene) showed a normal result. FISH analysis using LSI TUPLE1/LSI ARSA (Vysis) probes confirmed deletion of ARSA, whereas FISH with N25/N85A3 (Cytocell) probes, targeting the SHANK3 locus was normal. Supplemented FISH analysis using BAC clones allowed us to specify the centromeric breakpoint region of the interstitial deletion between clones RP11-354I12 and RP11-232E17, at less than 2 Mb from the telomere. Quantitative real-time PCR of exon 5, 22 and 24 and intron 9 of SHANK3 showed that the telomeric breakpoint occurred between intron 9 and exon 22. CONCLUSIONS: These data highlight the difficulty of performing an appropriate test aimed at looking for cryptic 22q13.3 deletion. Furthermore, the molecular characterization of this interstitial 22q13.3 deletion contributes to the clinical and genetic delineation of the 22q13.3 deletion syndrome.

2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features?

BACKGROUND: Genome-wide screening of patients with mental retardation using array comparative genomic hybridisation (CGH) has identified several novel imbalances. With this genotype-first approach, the 2q22.3q23.3 deletion was recently described as a novel microdeletion syndrome. The authors report two unrelated patients with a de novo interstitial deletion mapping in this genomic region and presenting similar "pseudo-Angelman" phenotypes, including severe psychomotor retardation, speech impairment, epilepsy, microcephaly, ataxia, and behavioural disabilities. METHODS: The microdeletions were identified by array CGH using oligonucleotide and bacterial artificial chromosome (BAC) arrays, and further confirmed by fluorescence in situ hybridisation (FISH) and semi-quantitative polymerase chain reaction (PCR). RESULTS: The boundaries and sizes of the deletions in the two patients were different but an overlapping region of about 250 kb was defined, which mapped to 2q23.1 and included two genes: MBD5 and EPC2. The SIP1 gene associated with the Mowat-Wilson syndrome was not included in the deleted genomic region. DISCUSSION: Haploinsufficiency of one of the deleted genes (MBD5 or EPC2) could be responsible for the common clinical features observed in the 2q23.1 microdeletion syndrome, and this hypothesis needs further investigation.

Effects of an awareness symposium on perception of Libyan physicians regarding telemedicine.

The awareness of health care providers, particularly physicians, towards telemedicine is pivotal to its development. In this study we distributed questionnaires among Libyan physicians attending a medical symposium on telemedicine, held in the period 28 February-1 March, 2005. The sample comprised 28 males and 13 females from different specialties and from different parts of the country. Most reported being confused (53.7%) or unaware (14.6%) regarding telemedicine before the symposium. Afterwards, 12.2% were confused, 39.0% showed excellent understanding and 48.8% reported fair understanding; 97.6% supported the implementation of telemedicine in the country and appreciated the importance of establishing remote health services.

Effects of an awareness symposium on perception of Libyan physicians regarding telemedicine

The awareness of health care providers, particularly physicians, towards telemedicine is pivotal to its development. In this study we distributed questionnaires among Libyan physicians attending a medical symposium on telemedicine, held in the period 28 February-1 March, 2005. The sample comprised 28 males and 13 females from different specialties and from different parts of the country. Most reported being confused [53.7%] or unaware [14.6%] regarding telemedicine before the symposium. Afterwards, 12.2% were confused, 39.0% showed excellent understanding and 48.8% reported fair understanding; 97.6% supported the implementation of telemedicine in the country and appreciated the importance of establishing remote health services

Semilobar holoprosencephaly prenatal diagnosis: an unexpected complex rearrangement in a de novo apparently balanced reciprocal translocation on karyotype.

We report a semilobar holoprosencephaly (HPE) in a post-intracytoplasmic-sperm-injection pregnancy. It was suggested by ultrasonography (US), documented on karyotype, identified with magnetic resonance imaging (MRI), established after birth and confirmed on post-mortem autopsy. An amniocentesis revealed a de novo apparently balanced reciprocal translocation 46,XY, t(7;8) (q31.3;q12). Fluorescence in situ hybridization (FISH) identified a deletion in the region of the Sonic Hedgehog gene (SHH) on der(8); nevertheless, the subtelomeric regions for chromosomes 7 and 8 were present. The parents decided to continue the pregnancy; a boy was born and survived for 3 days. The brain autopsy confirmed the semilobar HPE previously noted on US and MRI. Further, band-specific FISH revealed, in addition to SHH deletion, the presence of an inversion in the 7q translocated material on der(8). The parents' karyotypes were normal. An unexpected complex rearrangement was present in a de novo apparently balanced reciprocal translocation in a semilobar HPE.

Prenatal diagnosis and characterization of an analphoid marker chromosome 16.

We report on a fetus with intrauterine growth retardation and multiple malformations diagnosed on ultrasound at 32 weeks. Examination of amniotic fluid cells in culture showed a 47,XY, i(16)(q10), +mar karyotype. Chromosome analysis of both parents was normal. Using spectral karyotyping, we identified the marker chromosome as a mitotically stable acentric marker chromosome derived from chromosome 16. Further studies using subtelomeric fluorescent probes confirmed the presence of an isochromosome for the long arm of chromosome 16 and showed that the acentric marker chromosome derived from the short arm of chromosome 16 leading to a trisomy for the long arm of chromosome 16. After genetic counseling, the parents decided to terminate the pregnancy. Fetal autopsy showed a male fetus with ambiguous external genitalia, cardiac malformation, megacystis and limbs anomalies as observed in other cases of trisomy for the long arm of chromosome 16. In addition, fetal brain examination showed vermian and olfactory bulb hypoplasia.

Alterações do líquido peritoneal decorrentes de biópsia hepática e renal guiadas por laparoscopia em equinos

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Heteromorphism 18ph+ : with or without reproductive consequences?

Heteromorphism or chromosomal variants are usually attributed to structural variations in constitutive heterochromatin. In the case of chromosome 18, 25 cases of 18ph+ have been reported to date. Using the Primed In Situ Labelling technique (PRINS) to study 2 new cases of 18ph+, we have been able to confirm their molecular nature and assuming a mechanism of formation. Although such chromosomal variants are usually thought to have no adverse clinical consequence, a review of the literature shows that many cases were diagnosed because of recurrent abortion, malformed or mentally retarded children suggesting the possible relationship between 18ph+ and such clinical outcomes.