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

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.

Liddle syndrome in a Serbian family and literature review of underlying mutations.

UNLABELLED: Severe and reproducible low-renin hypertension responsive to salt restriction and amiloride-thiazide therapy in a 13-year-old otherwise asymptomatic boy suggested Liddle syndrome. This assumption was strengthened by a positive family history of hypertension poorly responsive to conventional treatment or sudden deaths under 40 years of age in four generations. DNA analysis of the beta and gamma subunits of the epithelial sodium channel revealed a heterozygous mutation c.C1852T (p.Pro618Ser) in the SCNN1B gene in the patient and in both his hypertensive mother and uncle. A PubMed search revealed 21 different disease-causing mutations reported to date, all but two clustering in the cytoplasmic C-terminal regions of either beta (16 mutations) or gamma (5) subunit, leading to a three- to eightfold increase in the amiloride-sensitive sodium current. Inter- and intrafamilial variability in both hypertension and hypokalemia were disclosed, which may not be obligatory among the subjects carrying a Liddle mutation. CONCLUSION: Liddle syndrome should be considered as a cause of hypertension in children or adolescents particularly with suppressed renin activity. Early diagnosis and appropriately tailored treatment avoid complications of long-term unrecognized or inappropriately managed hypertension.

Recurrent left atrial myxomas in Carney complex: a genetic cause of multiple strokes that can be prevented.

BACKGROUND: Intracardiac myxomas in Carney complex are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. The genetic, clinical, and laboratory characteristics of Carney complex-related strokes from atrial myxomas have not been described. The regulatory subunit (R1A) of the protein kinase gene (PRKAR1A) is mutated in >60% of patients with Carney complex. METHODS: We studied patients with strokes and cardiac myxomas that were hospitalized in our institution and elsewhere; a total of 7 patients with 16 recurrent atrial myxomas and >14 episodes of strokes were identified. RESULTS: Neurologic deficits were reported; in 1 patient, an aneurysm developed at the site of a previous stroke. All patients were females, were also diagnosed with Cushing syndrome, and all had additional tumors or other Carney complex manifestations. Other than gender, although there was a trend for patients being overweight and hypertensive, no other risk factors were identified. A total of 5 patients (71%) had a PRKAR1A mutation; all mutations (c418_419delCA, c.340delG/p.Val113fsX15, c.353_365del13/p.Ile118fsX6, c.491_492delTG/p.Val164fsX4, and c.177+1G>A) were located in exons 3 to 5 and introns 2 to 3, and all led to a non-sense PRKAR1A mRNA. CONCLUSIONS: Female patients with Carney complex appear to be at a high risk for recurrent atrial myxomas that lead to multiple strokes. Early identification of a female patient with Carney complex is of paramount importance for the early diagnosis of atrial myxomas and the prevention of strokes.

Two cases of LEOPARD syndrome--RAF1 mutations firstly described in children.

. LEOPARD syndrome 2 (LS-2) (OMIM #611554) is a rare, dominantly inherited genetic disorder affecting multiple organ systems. We report two unrelated females of different ages whose phenotype fits best in the category of LEOPARD syndrome, both with proven mutations in the RAF1 gene not previouslyreported in pediatric patients. In our 10-year-old patient, who was negative in the PTPN11 gene analysis but involving the RAF1 gene in a complementary analysis, the sequence variant Ser257Leu (770C > T, exon 7) was detected, which previously had been reported in only one 35-year-old woman with LS. The second patient was a two-year-old female infant with Ser259Leu mutation in the same gene, described in several patients with Noonan syndrome (NS) but not in LS patients of any age. The first girl had ventricular and supraventricular extrasystoles, and the second had episodes of paroxysmal supraventricular tachycardia. Echocardiographic examination revealed biventricular obstructive hypertrophic cardiomyopathy in both patients.

Early recurrent left atrial myxoma in a teenager with de novo mutation of Carney complex.

We report a case of an extremely early recurrence of left atrial myxoma in a 13-year-old girl. On hospital admission, the clinical presentation was of cerebral embolism with noticeable spotty skin pigmentation and hypertelorism. The left atrial myxoma originated from the roof of the left atrium. The histology specimen showed typical finding of a myxoma. Six months later a new intracardial mass was evacuated, the postoperative result showing the same type of myxomatous tissue. Genetic investigations demonstrated Carney complex. The genetic analysis of the child's family was negative, demonstrating de novo mutation of this rare disorder.

An unusual presentation of cardiomyopathy in a patient with microcephaly-cardiomyopathy syndrome.

We report the case of a 15-year-old male patient with microcephaly, dilated cardiomyopathy, mental retardation, secondary hypopituitarism, and minor dysmorphic features: downward- slanting palpebral fissures, narrow palate, small and low-set ears, fifth finger clinodactyly, sandal gaps on both feet, and anal stenosis. He was admitted to the pediatric intensive care unit with signs of progressive cardiac failure. Lethal outcome occurred 25 days after admission. Most clinical features of the patient were similar to those of the four previously reported patients with microcephaly-dilated cardiomyopathy syndrome, but some of this patient's features, such as anal stenosis and secondary hypopituitarism, were unique.

Mowat-Wilson syndrome: growth charts.

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.

The usefulness of advanced lipid and oxidative stress testing for diagnosis and management of low HDL-cholesterol phenotype: A case report.

OBJECTIVE: Plasma high-density lipoprotein cholesterol (HDL-C) level is a strong inverse predictor of cardiovascular disease (CVD) development. Tangier disease, a consequence of mutations in the ATP binding cassette transporter 1 (ABCA1) gene, is associated with very low HDL-C levels. Still, the relationship between Tangier disease and CVD is not always evident. The study investigates usefulness of lipoprotein subfractions, oxidative stress and paraoxonase 1 (PON1) status assessment for evaluation and management of patient with low HDL-C phenotype. PATIENT AND METHODS: A 12-year-old boy was hospitalised due to hypertension. Laboratory evaluation revealed low HDL-C level, and subsequent molecular diagnostic confirmed Tangier disease. Lipoprotein subfractions were assessed by gradient-gel electrophoresis. Oxidative stress status was estimated by measuring total antioxidative status, total oxidative status, prooxidative-antioxidative balance, malondialdehyde and advanced oxidation protein products levels. Activity of paraoxonase 1 in serum and its distribution within HDL subclasses was also determined (ten healthy boys aged 13.1±3.4years served as the reference group). RESULTS: Analysis of oxidative stress status biomarkers revealed a state of prolonged prooxidants activity. In turn, serum PON1 activity was substantially reduced. The majority of PON1 activity was present on HDL 2 particles. CONCLUSION: Impaired antioxidative potential of HDL may point toward hidden cardiovascular risk in isolated low HDL-phenotype.

Determinants of job satisfaction of healthcare professionals in public hospitals in Belgrade, Serbia--Cross-sectional analysis.

INTRODUCTION: The quality of health care significantly depends on the satisfaction of the employees. OBJECTIVE: The objective of this study was to establish the level of professional satisfaction of healthcare professionals in state hospitals in Belgrade, Serbia, and to determine and to rank the factors which impact on their satisfaction or dissatisfaction. METHOD: Professional satisfaction survey was designed and conducted as a cross-sectional study in 2008. Completed questionnaires were returned by 6,595 healthcare professionals from Belgrade's hospitals. Statistical analysis was performed using the Student's t-test, χ² test and ANOVA. Factor analysis was applied in order to define determinants of professional satisfaction, i.e. dissatisfaction. RESULTS: This study showed that the degree of professional satisfaction of Serbian healthcare professionals was low. The main causes of professionals'dissatisfaction were wages, equipment, the possibility of continuous medical education/training and the opportunities for professional development. Healthcare professionals with university education were more satisfied with all the individual aspects of job satisfaction than those with secondary school and college education. CONCLUSION: There were significantly more healthcare professionals satisfied with their job among males, older than 60 years, in the age group 50-59 years, with managerial function, and with 30 or more years of service. Development strategy of human resources in the Serbian health care system would significantly improve the professional satisfaction and quality of the provided health care.

Health-related quality of life, anxiety, and depressive symptoms in children with primary immunodeficiencies.

INTRODUCTION: The aims of this study were to evaluate levels of health-related quality of life (HRQOL) and the presence of anxiety and depressive symptoms in children with primary immunodeficiency disease (PID) in Serbia. MATERIALS AND METHODS: Self- and parent-rated data from 25 children with PID were available. As controls, data from 50 children with juvenile idiopathic arthritis (JIA) and 89 healthy children were included. The Pediatric Quality of Life Inventory was used for HRQOL assessments. Anxiety symptoms were identified using the Screen for Child Anxiety-Related Emotional Disorders questionnaire, while depressive symptoms were identified using the Mood and Feeling Questionnaire. RESULTS: Children with PID had significantly lower Pediatric Quality of Life Inventory total scores compared to children with JIA and healthy children as child-rated (P=0.02) and parent-rated (P<0.001). Specifically, they had significantly lowered emotional functioning compared to children with JIA, and social functioning compared to both children with JIA and healthy children. School functioning was significantly lower among children with PID (parent-rated only). By parent-rated responses, six (24%) out of 25 children with PID had significant anxiety symptoms, while five (20%) children had significant depressive symptoms, which was statistically higher than among children with JIA and healthy controls (P=0.05). CONCLUSION: HRQOL could be significantly compromised in children with PID, particularly across such psychosocial domains as emotional, social, and school. These children were also found to be at an increased risk for suffering significant anxiety and depressive symptoms.

Differences in the clinical spectrum of two adolescent male patients with Alström syndrome.

Alström syndrome is a rare disorder typified by early childhood obesity, neurosensory deficits, cardiomyopathy, progressive renal and hepatic dysfunction, and endocrinological features such as severe insulin resistance, type 2 diabetes, hyperlipidemia, and hypogonadism. Widespread fibrosis leads to multiple organ failure. Mutations in ALMS1 cause Alström syndrome. Two age-matched, unrelated adolescent males of Serbian descent with Alström syndrome underwent an extensive workup of blood chemistries, and ophthalmological, audiological, and genetic evaluations. Although both showed typical features of Alström syndrome in childhood, several differences were observed that have not been reported previously. Patient 1 was first studied at the age of 13 years for multisystemic disease and re-evaluated at the age of 15.5 years. Patient 2 is a 15-year-old boy who presented at birth with epilepsy and psychomotor developmental delay and generalized tonic-clonic seizures with severe cognitive impairment, features not documented previously in this syndrome. Sequencing analysis indicated two novel ALMS1 mutations in exon 8: p.E1055GfsX4 and p.T1386NfsX15. Metabolic and physiological similarities were observed in both patients, including severe insulin resistance, and truncal obesity with fat loss suggestive of partial lipodystrophy, supporting evidence for a role for ALMS1 in adipose tissue function. The unusual phenotypes of clonic-tonic seizures and severe cognitive abnormalities and lipodystrophy-like adiposity pattern have not been documented previously in Alström syndrome and may be an under-reported abnormality.

[Adams-Oliver syndrome: case report].

INTRODUCTION: Adams-Oliver syndrome is characterized by congenital aplasia of the vertex skin of the skull in combination with skull and transverse limb defects. CASE OUTLINE: We presented a 5-month old female infant with Adams-Oliver syndrome manifested as cutis marmorata, dilated scalp veins and limb reduction defects. Clinical manifestation also included thumb hypoplasia and extreme hypoplasia of other fingers, with agenesis of all toes on both feet. Echocardiogram revealed foramen ovale apertum. Venography showed dilated malformed scalp and neck veins, predominantly on the right side. On the basis of the clinical features and extended investigation we confirmed Adams-Oliver syndrome in the presented patient. CONCLUSION: We recommended prenatal diagnosis in case of future pregnancies, ultrasound examination, and follow-up of foetal anomalies.

[Stenting aortic coarctation in children: immediate and mid-term results].

INTRODUCTION: Stent implantation, in patients with different forms of aortic coarctation, has significant theoretical advantages over primary balloon dilatation (BD). It can achieve over-dilatation of the coarcted segment with the rigid endoprothesis maintaining the increase in vessel diameter regardless of the intimal injury and, thus, reducing the likelihood of restenosis. Moreover, by preventing vascular recoil, stents can successfully expand long-segment tubular coarctations, hypoplastic isthmus and hypoplastic transverse aortic arch. Finally, by facilitating good apposition of the torn intima to the aortic wall, they can significantly reduce the incidence of aneurysm formation. OBJECTIVE: Evaluation of the immediate and mid-term results of stent implantation in patients with different forms of aortic coarctation. METHODS: Between February 2005 and March 2010 eleven stents were implanted in nine patients (two female and seven male) either with post surgical or post primary BD residual coarctation/recoarctation or with native aortic coarcatation. Mean age of our patients was 14 +/- 3 years (9.4-18.1 years) and mean body weight 54 +/- 18 kg (29-76 kg). RESULTS: Pressure gradient across the coarctation site was reduced from 24.9 +/- 12.4 mm Hg before to 3.9 +/- 5.0 mm Hg after stenting (p = 0.000). There were no complications. Mean followup was 2.0 +/- 1.5 years (range 0.1-5.2 years). In patients with localised aortic arch narrowing no restenosis or aneurysm formation was observed (residual pressure gradient 0-5 mm Hg). CONCLUSION: In properly selected children (body weight > 25 kg), adolescents and young adults stenting is the method of choice for patients with various forms of aortic arch obstruction.

[Assessment of health care quality in the tertiary level pediatric hospitals in Serbia].

BACKGROUND/AIM: It is necessary to improve the quality of health care for children. Assessment data would provide new insights into better treatment outcomes. The aim of this descriptive study was to estimate and to compare applied quality indicators in five pediatric in-patient tertiary level institutions in Serbia during the period from January 1st to December 31st 2008. METHODS: Quality data and indicators were collected in the Institute for Public Health of Serbia "Dr. Milan Jovanovid Batut". Descriptive statistics and chi-square test were used for data analysis. RESULTS: The average length of stay (ALOS) in pediatric departments was 7.51 + 1.30 days (5.88-8.91 days). In the same period, ALOS in pediatric surgery departments was 5.85 +/- 1.50 days (3.58-7.57 days). The average number of nurses per occupied bed was 0.76 +/- 0.20 and 1.09 +/- 0.36 in pediatric and in pediatric surgery departments, respectively. The number of operated patients per surgeon was in the range 51.0-160.5. The annual case fatality rate in pediatric departments was estimated to 0.72% +/- 0.20%, whereas in pediatric surgery departments it was 0.34% +/- 0.25%. The autopsy rate was estimated to 0.00%-63.16% in pediatric departments, and 37.14%-80.00% in pediatric surgery departments. There was statistically significant difference among the five hospitals regarding the following indicators of quality of work: total annual mortality rate of patients, autopsy rate, number of rate of patients, autopsy rate, number of patients referred to other institutions, both in pediatric and pediatric surgery departments. CONCLUSION: There is a significant difference among the five hospitals regarding indicators of quality of work. Obligatory set of quality indicators on the basis of legislative acts are the indicators of general quality of work in hospital. It is necessary to establish specific pediatric quality indicators and to define national standards related to these indicators.