Publications by authors named "Ivan Ivanovski"

37 Publications

The fate of orally administered sialic acid: First insights from patients with -acetylneuraminic acid synthase deficiency and control subjects.

Mol Genet Metab Rep 2021 Sep 26;28:100777. Epub 2021 Jun 26.

Center for Molecular Diseases, Division of Genetic Medicine, University of Lausanne and University Hospital of Lausanne, Switzerland.

Background: In NANS deficiency, biallelic mutations in the -acetylneuraminic acid synthase () gene impair the endogenous synthesis of sialic acid (-acetylneuraminic acid) leading to accumulation of the precursor, -acetyl mannosamine (ManNAc), and to a multisystemic disorder with intellectual disability. The aim of this study was to determine whether sialic acid supplementation might be a therapeutic avenue for NANS-deficient patients.

Methods: Four adults and two children with NANS deficiency and four adult controls received oral NeuNAc acid (150 mg/kg/d) over three days. Total NeuNAc, free NeuNAc and ManNAc were analyzed in plasma and urine at different time points.

Results: Upon NeuNAc administration, plasma free NeuNAc increased within hours ( < 0.001) in control and in NANS-deficient individuals. Total and free NeuNAc concentrations also increased in the urine as soon as 6 h after beginning of oral administration in both groups. NeuNAc did not affect plasma and urinary ManNAc, that remained higher in NANS deficient subjects than in controls (day 1-3; all  < 0.01). Oral NeuNAc was well tolerated with no significant side effects.

Discussion: Orally administered free NeuNAc was rapidly absorbed but also rapidly excreted in the urine. It did not change ManNAc levels in either patients or controls, indicating that it may not achieve enough feedback inhibition to reduce ManNAc accumulation in NANS-deficient subjects. Within the limitations of this study these results do not support a potential for oral free NeuNAc in the treatment of NANS deficiency but they provide a basis for further therapeutic approaches in this condition.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251509PMC
September 2021

De Garengeot hernia masquerading as a painless groin lump: a case report.

J Surg Case Rep 2021 Jul 9;2021(7):rjab291. Epub 2021 Jul 9.

Department of Surgery, Wexford General Hospital, Wexford, Ireland.

De Garengeot's hernia is a rare subtype of femoral hernia in which the appendix is located within the herniated sac. These cases are important to report as both the diagnosis and treatment are quite challenging. We present a case of a 68-year-old gentleman with few months history of a lump in the right groin that gave him mild discomfort but no other symptoms. Initial investigations with an ultrasound did not prove to be helpful and so a plan was made to surgically explore the lump. The appendiceal tip was incarcerated within the hernial sac. The appendix was removed using an open inguinal incision with repair of the defect using a light weight partially absorbable mesh. It is important to consider the possibility of a De Garangeot's Hernia as a differential diagnosis for patients presenting with a groin lump.
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http://dx.doi.org/10.1093/jscr/rjab291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272393PMC
July 2021

Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples.

Genes (Basel) 2021 Jun 24;12(7). Epub 2021 Jun 24.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.
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http://dx.doi.org/10.3390/genes12070962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303193PMC
June 2021

Isolated perforated jejunal diverticulitis: a case report.

J Surg Case Rep 2021 Jan 31;2021(1):rjaa587. Epub 2021 Jan 31.

Department of Surgery, Wexford General Hospital, Newtown Rd, Carricklawn, Wexford Y35 Y175, Ireland.

Jejunal diverticulosis is a rare phenomenon often identified either incidentally on imaging or intra-operatively. Complications of jejunal diverticulosis are associated with high rates of mortality. For this reason, it remains important that this pathology is considered amongst differentials for an acute abdomen. A 78-year old gentleman presented with a short history of generalized lower abdominal pain. Computer tomography scan revealed a large inflammatory abscess relating to a perforated jejunal diverticulum. The patient was taken to theatre where he underwent small bowel resection with primary anastomosis. Early cross sectional imaging is vital to allow early diagnosis and prompt management of this pathology. Small bowel resection with primary anastomosis was associated with an excellent clinical outcome.
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http://dx.doi.org/10.1093/jscr/rjaa587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852602PMC
January 2021

An obturator hernia of the Richter type - a video vignette.

Colorectal Dis 2021 May 22;23(5):1284-1285. Epub 2021 Feb 22.

Wexford General Hospital, Wexford, Ireland.

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http://dx.doi.org/10.1111/codi.15574DOI Listing
May 2021

Obturator hernia of Richter type: a diagnostic dilemma.

BMJ Case Rep 2020 Dec 28;13(12). Epub 2020 Dec 28.

General Surgery, Wexford General Hospital, Wexford, Ireland.

An 85-year-old malnourished woman presented with symptoms of small bowel obstruction of uncertain aetiology. She had presented numerous times over the previous 2 years with symptoms of left groin and thigh pain, vomiting and abdominal distension. A CT of her abdomen and pelvis ultimately revealed a left-sided pelvic hernia, between the obturator internus and pectineal muscles. This was consistent with an obturator hernia. Diagnostic laparoscopy confirmed an obturator hernia of Richter type, incarcerated within the left obturator canal. Reduction revealed a hernia sac containing viable small bowel. A primary repair was performed using a double-layer suture technique to both close and plug the hernia defect. The patient rapidly recovered following hernia repair, with resolution of all previous long-standing symptoms. This case exemplifies the typical presentation of an obturator hernia and the diagnostic challenge it poses to clinicians.
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http://dx.doi.org/10.1136/bcr-2020-238252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772305PMC
December 2020

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.
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http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

Lights and darks of neuroendocrine tumors of the appendix.

Minerva Endocrinol 2020 Dec 23;45(4):381-392. Epub 2020 Jul 23.

Department of Surgery, Wexford General Hospital, Wexford, Ireland.

Introduction: Neuroendocrine tumors of the appendix are a relatively frequent type of neuroendocrine tumor, usually detected incidentally after appendectomy. Almost all small slow-growing G1 tumors with no risk factors are cured with appendectomy while the rare and aggressive G3 carcinomas may represent a challenge in terms of management and often lead to a poor outcome. In the middle of the spectrum, a number of tumors present with in-between features and sometimes no clear-cut guidance emerges from the literature for directing the management and follow-up of these patients.

Evidence Acquisition: A meticulous review of the literature on neuroendocrine tumors of the appendix, including the recommendations published by the relevant international societies.

Evidence Synthesis: The literature on the neuroendocrine tumors of the appendix appears to be inhomogeneous. Likely this occurs as a consequence of a number of factors, including the mostly retrospective nature of the available data, the heterogeneous records of the same, and some peculiar aspects of the appendiceal neuroendocrine tumors, with evidence of considerable biological and clinical differences in terms of epidemiology, management, and prognosis from the less aggressive tumors to the most aggressive cancers. In particular, some situations concerning tumors in the middle of the biological and clinical spectrum are still poorly defined.

Conclusions: There are some persisting "grey areas" with regard to the characterization and the clinical management of neuroendocrine tumors of the appendix. An increasing awareness of the biological and clinical aspects of this disease and new, ideally prospective, focused studies might help and clarify some relevant issues that are not fully elucidated yet and could increase the solidity of the guidance for the management and the follow-up of the patients.
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http://dx.doi.org/10.23736/S0391-1977.20.03206-XDOI Listing
December 2020

Mowat-Wilson syndrome: growth charts.

Orphanet J Rare Dis 2020 06 15;15(1):151. Epub 2020 Jun 15.

ATS Bergamo, Brembana Valley district, Bergamo, Italy.

Background: Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.

Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build.

Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.
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http://dx.doi.org/10.1186/s13023-020-01418-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294656PMC
June 2020

Predictive value of CRP/albumin ratio in major abdominal surgery.

Ir J Med Sci 2020 Nov 2;189(4):1465-1470. Epub 2020 May 2.

Wexford General Hospital, Co. Wexford, Ireland.

Introduction: Surgical site infection (SSI) is a major cause of morbidity, resulting in significant healthcare and economic implications. The ability to predict patients at high risk of SSI may enable targeted follow-up and management. This study sought to examine the relationship between the CRP/albumin ratio in the prediction of SSI in patients undergoing emergency major abdominal surgery.

Methods: A retrospective study of all patients who underwent emergency major abdominal surgery in our institution over 2 years was performed. Patients were identified from a prospectively maintained database of SSI's and cross-referenced with hospital records. Patient demographics including age, gender, ASA grade, and wound classification (clean, clean/contaminated, contaminated, and dirty) were collated.

Results: CRP preoperatively of greater than 5 was statistically significant in predicting an SSI (P < 0.05). In addition, preoperative serum albumin of < 32 was also significant in predicting a superficial site infection. Interestingly, preoperative CRP/albumin ratio did not predict SSI, but postoperative CRP/albumin ratio was predictive at both 24 and 48 hour time points (P < 0.05). Median length of stay in the SSI group was statistically significantly longer at 27.88 days (range 7-76) versus 18.32 days (1-56) (P < 0.01).

Conclusions: Though CRP and albumin have merit in isolation in preoperative identification of patients at risk of SSI, CRP/albumin ratio is a useful postoperatively adjunct in predicting SSI postoperatively at 24 and 48hrs postoperatively.
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http://dx.doi.org/10.1007/s11845-020-02238-yDOI Listing
November 2020

Diaphragmatic hernia following esophagectomy for esophageal cancer: A systematic review.

J BUON 2019 Sep-Oct;24(5):1793-1800

Department of Surgery, Mercy University Hospital, Cork, Ireland.

Purpose: Diaphragmatic hernia following an esophagectomy for esophageal cancer (EC) can be both an early and late complication. The esophageal hiatus within the diaphragm is disrupted during the operation. However, the incidence of Post-Esophagectomy Diaphragmatic Hernia (PEDH) is unknown. PEDH can be life-threatening and surgical treatment is challenging. However, all PEDH do not require surgery. The rate of EC diagnosis is rising. Therefore, esophageal surgery, particularly esophagectomy, is gradually increasing. Undoubtedly, the numbers of PEDH increase as well.

Methods: This review describes the presentation and diagnosis of PEDH after surgery for esophageal malignancy, as well as the management options for PEDH.

Results: Fifteen papers regarding PEDH have been published. There are many different surgical approaches to complete an esophagectomy, while there are different approaches to repair PEDH.

Conclusion: Upper GI surgeons need to have an index of suspicion for PEDH. They must investigate and operate these patients if this complication develops, since an immediate surgery has a high mortality and poor outcome.
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April 2020

Alazami syndrome: the first case of papillary thyroid carcinoma.

J Hum Genet 2020 Jan 28;65(2):133-141. Epub 2019 Oct 28.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.
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http://dx.doi.org/10.1038/s10038-019-0682-5DOI Listing
January 2020

Severe Peripheral Joint Laxity is a Distinctive Clinical Feature of Spondylodysplastic-Ehlers-Danlos Syndrome (EDS)- and Spondylodysplastic-EDS-.

Genes (Basel) 2019 10 12;10(10). Epub 2019 Oct 12.

Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS of Reggio Emilia, 42122 Reggio Emilia, Italy.

Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related to mutations in genes and (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of and -related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.
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http://dx.doi.org/10.3390/genes10100799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826576PMC
October 2019

Over-admission and over-treatment of patients with cellulitis: a 5-year audit against international guidelines.

Ir J Med Sci 2020 Feb 14;189(1):245-249. Epub 2019 Aug 14.

Department of Surgery, Wexford General Hospital, Wexford, Ireland.

Background/aims: Application of evidence-based guidelines in the management of cellulitis is poorly studied in Ireland and it is observed that current admission and prescription practices in this country vary widely from internationally accepted standards of care. We aimed to examine the management of cellulitis with regard to hospital admission and initial antibiotic therapy.

Methods: A retrospective audit of patients admitted with cellulitis from 2013 to 2017 in an Irish district general hospital. Exclusion criteria included specialist regions of the body and surgical site infections. Appropriateness of admission and management was compared against international guidelines (Clinical Research Efficiency Support Team (CREST) and Infectious Disease Society of America (IDSA)).

Results: Five hundred twenty emergency admissions with cellulitis were analysed. Thirty-five percent (n = 182) were deemed inappropriate admissions compared with CREST and IDSA guidelines, with an estimated cost of €152,203 per annum. Ninety-six percent (n = 501) of patients with cellulitis were treated with a combination of flucloxacillin and benzylpenicillin, despite level 1 evidence showing combination therapy to provide no benefit over appropriate monotherapy.

Conclusions: There is a significant discrepancy between current clinical practice and international guidelines for the management of cellulitis in Ireland; local guidelines are not in keeping with newer evidence and there is a lack of national guidelines for this common condition. Closer adherence to international guidelines would significantly reduce costs by reducing unnecessary admissions and initial monotherapy would improve antibiotic stewardship. This study shows a clear need for local institutions to re-examine antibiotic guidelines to ensure the HSE provides effective evidence-based treatment in the correct setting.
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http://dx.doi.org/10.1007/s11845-019-02065-wDOI Listing
February 2020

Do the vaccines harm?

J Trace Elem Med Biol 2019 09 12;55:107-109. Epub 2019 Jun 12.

Faculty of Medicine, University of Belgrade, 8 Dr Subotića str., Belgrade, 11000, Serbia. Electronic address:

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http://dx.doi.org/10.1016/j.jtemb.2019.06.006DOI Listing
September 2019

Sleep in Mowat-Wilson Syndrome: a clinical and video-polysomnographic study.

Sleep Med 2019 09 26;61:44-51. Epub 2019 Apr 26.

Child Neurology and Psychiatry Unit, Department of Medical and Surgical Sciences (DIMEC), S. Orsola Hospital, University of Bologna, Italy. Electronic address:

Objective: Sleep disturbances are frequently reported in Mowat-Wilson Syndrome (MWS). The current study aimed to evaluate clinical and video-polysomnographic (VPSG) characteristics of the sleep architecture and abnormal electroencephalogram (EEG) patterns during sleep in MWS.

Methods: Sixteen individuals with MWS (range 16 months-25 years), attending the Department of Child Neurology and Psychiatry of the University of Bologna, were included. The "Sleep Disturbances Scale for Children (SDSC)" questionnaire was administered to all parents of MWS patients, and all patients underwent a VPSG recording.

Results: The analysis of the SDSC questionnaire revealed disturbances mainly at the sleep-wake transition and in initiating and maintaining sleep. Evaluation of sleep structure in MWS patients showed a significant reduction of total sleep time, an increase of wake after sleep onset and arousal index as compared to normal controls. An EEG pattern characterized by slowing of background activity and poverty of physiological sleep characterisitcs was observed in all patients. Moreover, in patients aged >7 years, anteriorly predominant spike and waves were observed, markedly activated by sleep configuring a sub-continuous or continuous activity.

Conclusion: Our data (both clinical and VPSG) documented the presence of significant and clinically relevant sleep disturbances in MWS patients. Moreover, we identified a characteristic age-dependent sleep EEG pattern that could provide a new element to assist in the management of MWS.
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http://dx.doi.org/10.1016/j.sleep.2019.04.011DOI Listing
September 2019

PEDIA: prioritization of exome data by image analysis.

Genet Med 2019 12 5;21(12):2807-2814. Epub 2019 Jun 5.

National Research and Applied Medicine Centre 'Mother and Child'', Minsk, Belarus.

Purpose: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists.

Methods: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds.

Results: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene.

Conclusion: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.
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http://dx.doi.org/10.1038/s41436-019-0566-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892739PMC
December 2019

Appendiceal adenocarcinoma-Two unique cases of adenocarcinoma ex-goblet cell carcinoid.

Clin Case Rep 2019 Apr 14;7(4):806-808. Epub 2019 Mar 14.

Department of Surgery Wexford General Hospital Wexford Ireland.

We describe the different clinical presentations, radiology, histology and management of this unique, highly aggressive disease. Clinical presentation of appendicitis may not just be appendicitis. Appendiceal tumors must always be considered in the differential diagnosis. Dedicated radiology and histological examination in addition to aggressive surgical and oncological input improve outcome.
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http://dx.doi.org/10.1002/ccr3.2078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452524PMC
April 2019

Aluminium in brain tissue in autism.

J Trace Elem Med Biol 2019 Jan 13;51:138-140. Epub 2018 Oct 13.

Medical Faculty University of Belgrade, 8 Dr Subotića str, Belgrade, 11000, Serbia. Electronic address:

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http://dx.doi.org/10.1016/j.jtemb.2018.10.013DOI Listing
January 2019

Prominent and elongated coccyx, a new manifestation of KBG syndrome associated with novel mutation in ANKRD11.

Am J Med Genet A 2018 09 8;176(9):1991-1995. Epub 2018 Aug 8.

Medical Genetics Unit, Maternal and Child Health Department, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy.

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon-intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx.
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http://dx.doi.org/10.1002/ajmg.a.40386DOI Listing
September 2018

Van Maldergem syndrome and Hennekam syndrome: Further delineation of allelic phenotypes.

Am J Med Genet A 2018 05;176(5):1166-1174

Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n = 11) and Hennekam syndrome (HS) (n= 40). Both conditions are characterized by a typical facial gestalt and mild to moderate intellectual disability, but differ in the occurrence of neonatal hypotonia and feeding problems, hearing loss, tracheal anomalies, and osteopenia in VMS, and lymphedema in HS. VMS can be caused by autosomal recessive variants in DCHS1 as well, and HS can also be caused by autosomal recessive variants in CCBE1 and ADAMTS3. Here we report two siblings with VMS and one girl with HS, all with FAT4 variants, and provide an overview of the clinical findings in all patients reported with FAT4 variants. Our comparison of the complete phenotypes of patients with VMS and HS indicates a resemblance of several signs, but differences in several other main signs and symptoms, each of marked importance for affected individuals.
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http://dx.doi.org/10.1002/ajmg.a.38652DOI Listing
May 2018

Complex cranio-vertebral malformation: disruption sequence or iniencephaly?

Clin Dysmorphol 2018 Jul;27(3):105-108

Department of Pediatrics, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland.

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http://dx.doi.org/10.1097/MCD.0000000000000218DOI Listing
July 2018

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

Genet Med 2018 09 4;20(9):965-975. Epub 2018 Jan 4.

Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.

Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.

Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.

Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
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http://dx.doi.org/10.1038/gim.2017.221DOI Listing
September 2018

Metabolically based liver damage pathophysiology in patients with urea cycle disorders - A new hypothesis.

World J Gastroenterol 2017 Nov;23(44):7930-7938

School of Medicine University of Belgrade, Belgrade 11000, Serbia.

The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism.

Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.
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http://dx.doi.org/10.3748/wjg.v23.i44.7930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703922PMC
November 2017

Endocrinological Abnormalities Are a Main Feature of 17p13.1 Microduplication Syndrome: A New Case and Literature Review.

Mol Syndromol 2016 Nov 14;7(6):337-343. Epub 2016 Oct 14.

Clinical Genetics Unit, Università degli Studi di Parma, Parma, Italy.

To date, 5 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability was reported as the core feature, together with minor facial dysmorphisms and obesity, but a characteristic phenotype for 17p13.1 microduplication has not been delineated. Here, we describe a patient with a 1.56-Mb de novo duplication in 17p13.1, affected by mild intellectual disability, facial dysmorphisms, obesity, and diabetes. By comparing the different phenotypes of currently described cases, we delineated the main clinical features of 17p13.1 microduplication syndrome. All patients described to date had variable facial dysmorphisms; therefore, it was difficult to define a common facial gestalt. Furthermore, we stress endocrinological abnormalities as important features and the need to monitor these over time.
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http://dx.doi.org/10.1159/000450718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131335PMC
November 2016

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

Genet Med 2017 06 10;19(6):691-700. Epub 2016 Nov 10.

Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.

Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.

Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.

Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.
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http://dx.doi.org/10.1038/gim.2016.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438871PMC
June 2017

Natural history and life-threatening complications in Myhre syndrome and review of the literature.

Eur J Pediatr 2016 Oct 25;175(10):1307-15. Epub 2016 Aug 25.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Unlabelled: Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients.

Conclusion: Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity.

What Is Known: • The clinical and radiological signs of the disease in children older than 7-8 years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.
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http://dx.doi.org/10.1007/s00431-016-2761-3DOI Listing
October 2016

RIN2 syndrome: Expanding the clinical phenotype.

Am J Med Genet A 2016 09 8;170(9):2408-15. Epub 2016 Jun 8.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37789DOI Listing
September 2016

Mitotic crossover promotes leukemogenesis in children born with TEL-AML1 via the generation of loss of heterozygosity at 12p.

Pediatr Med Chir 2015 Jun 30;37(2):pmc.2015.112. Epub 2015 Jun 30.

School of Medicine, University of Belgrade, Serbia; Struttura Semplice Dipartimentale di Genetica Clinica, Dipartimento Ostetrico-Ginecologico e Pediatrico, Istituto di Ricovero e Cura a Carattere Scientifico Arcispedale S. Maria Nuova, Reggio Emilia.

TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia bottleneck phenomenon. In most cases of TEL-AML1+ leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene, i.e. loss of heterozygosity at 12p, occurs postnatally during the mitotic proliferation of TEL-AML1+ cell in the mitotic crossing over process. Mitotic crossing over is a very rare event with a frequency rate of 10-6 in a 10 kb region. The exploration and identification of the environmental exposure(s) that cause(s) proliferation of the TELAML1+ cell in which approximately 106 mitoses are generated to cause 12p loss of heterozygosity, i.e. TEL gene deletion, may contribute to the introduction of preventive measures for leukemia.
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http://dx.doi.org/10.4081/pmc.2015.112DOI Listing
June 2015

Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma.

Am J Med Genet A 2015 Aug 5;167A(8):1902-7. Epub 2015 Apr 5.

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.
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http://dx.doi.org/10.1002/ajmg.a.37082DOI Listing
August 2015
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