Anita Horodnicka-Józwa

Possible counter effect in newborns of 1936A>G (I646V) polymorphism in the AKAP10 gene encoding A-kinase-anchoring protein 10.

Objective:Cyclic adenosine monophosphate/protein kinase A (PKA) is important in embryonic development. The human AKAP10 gene is polymorphic: 1936A>G results in changes to a PKA-binding domain and increased targeting to mitochondria. Previous studies found G1936 as ‘deleterious’ in adults, and this study investigates whether this holds true in preterm birth.Study Design:Study group consisted of 80 preterm newborns (PTNs) born before the 38th gestation week. Control group consisted of 123 full-term healthy newborns born after the 37th gestation week with uncomplicated pregnancies. Genomic DNA was extracted from umbilical blood and AKAP10 genotypes were identified by PCR/restriction enzyme.Result:Significant differences in frequencies of 1936A>G genotypes/alleles between both groups were found. PTNs had increased frequency (55%) of AA homozygotes (odds ratio, AA versus AG+GG: 2.63 (95% confidence interval: 1.33 to 5.20), P=0.006) after adjustments: mothers with previous PTNs, smoking, first pregnancy, first delivery and Cesarean section.Conclusion:Results suggest G1936 is preventative factor against preterm birth, in contrast with previously asserted negative effects in adults.

Familial distal monosomy 3p26.3-pter with trisomy 4q32.2-qter, presenting with progressive ataxia, intellectual disability, and dysmorphic features.

We present a boy diagnosed with partial 3p monosomy and partial 4q trisomy. The patient was 9 years of age with intellectual disability, dysmorphic features, and ataxia. A family history and medical evaluation showed that the father manifested similar facial dysmorphic features, intellectual disability, quadriparesis, and progressive cerebrospinal ataxia. The chromosomal aberration found in the proband was inherited from his father who was found to have a balanced reciprocal translocation of chromosomes 3p and 4q, which was in turn inherited from the paternal grandfather. The final cytogenetic diagnosis according to microarray was 46,XY,der(3)t(3;4)(p26.1;q32.2)arr 3p26.1(39,066–5,363,502)x1,4q32.2q35.2(162,555,236–191,173,881)x3. We describe the cytogenetic investigations that led to the identification of the breakpoints. In addition, we present an overview of the clinical features found in patients with partial 3p monosomies and partial 4q trisomies as reported in the literature.

Association of functional genetic variants of A-kinase anchoring protein 10 with QT interval length in full-term Polish newborns.

Introduction A-Kinase Anchoring Proteins (AKAPs) coordinate the specificity of protein kinase A signaling by localizing the kinase to subcellular sites. The 1936G (V646) AKAP10 allele has been associated in adults with low cholinergic/vagus nerve sensitivity, shortened PR intervals in ECG recording and in newborns with increased blood pressure and higher cholesterol cord blood concentration. The aim of the study was to answer the question of whether 1936A > G AKAP10 polymorphism is associated with the newborn electrocardiographic variables. Material and methods Electrocardiograms were recorded from 114 consecutive healthy Polish newborns (55 females, 59 males), born after 37 gestational weeks to healthy women with uncomplicated pregnancies. All recordings were made between 3rd and 7th day of life to avoid QT variability. The heart rate per minute and duration of PR, QRS, RR and QT intervals were usually measured. The ECGs were evaluated independently by three observers. At birth, cord blood of neonates was obtained for isolation of genomic DNA. Results The distribution of anthropometric and electrocardiographic variables in our cohort approached normality (skewness < 2 for all variables). No significant differences in anthropometric variables and electrocardiographic traits with respect to AKAP10 genotype were found. Multiple regression analysis with adjustment for gender, gestational age and birth mass revealed that QTc interval in GG AKAP10 homozygotes was significantly longer, but in range, when compared with A alleles carriers (AA + AG, recessive mode of inheritance). No rhythm disturbances were observed. Conclusions Results demonstrate possible association between AKAP10 1936A > G variant and QTc interval in Polish newborns.

Monogenic diabetes prevalence among Polish children—Summary of 11 years-long nationwide genetic screening program

Estimated monogenic diabetes (MD) prevalence increases as screening programs proceeds.

Association of 1936A > G in AKAP10 (A-kinase anchoring protein 10) and blood pressure in Polish full-term newborns

Abstract Objective. The 1936G AKAP10 allele is associated with increased adult basal heart rate (HR) and decreased variability, markers of low cholinergic/vagus sensitivity associated with hypertension. Blood pressure (BP) values in newborns are important measurable markers of cardiovascular risk later in life. The question was whether decreased vagal function-related 1936A > G AKAP10 is associated with newborn BP. Study design. 114 healthy Polish newborns born after 37th gestational week to healthy women with uncomplicated pregnancies. At birth, newborn cord blood obtained for isolation of genomic DNA. BP and HR measured on days 1 and 3 after delivery. Results. Diastolic BP on day 3 and absolute and relative differences between diastolic BP values, as well as between mean BP values on day 3 and on day 1 after birth, in carriers of 1936G AKAP10 allele, were significantly higher as compared with wild-type homozygotes. Conclusion. Results demonstrate possible association between 1936G AKAP10 variant and BP in Polish newborns.

Treatment of severe primary IGF-1 deficiency using rhIGF-1 preparation – first three years of Polish experience

INTRODUCTION The objective of this study was to analyse the effects of the first three years of treatment with recombinant human insulinlike growth factor 1 (rhIGF-1) in patients from the Polish population. MATERIAL AND METHODS Twenty-seven children (22 boys and five girls) aged 2.8 to 16.0 years old were qualified for treatment with rhIGF-1 (mecasermin) in different treatment centres, according to Polish criteria: body height below -3.0 SD and IGF-1 concentration below percentile 2.5 with normal growth hormone (GH) levels. Mecasermin initial dose was 40 μg/kg bw twice a day and was subsequently increased to an average of 100 μg/kg bw twice a day. Body height, height velocity, weight, body mass index (BMI), and adverse events were measured. RESULTS Mecasermin treatment resulted in a statistically significant increase in body height (1.45 ± 1.06 SD; p < 0.01) and height velocity in comparison with pre-treatment values. The biggest change in height velocity happened during the first year and diminished during subsequent years. Body weight and BMI also increased significantly after treatment (1.16 ± 0.76 SD and 0.86 ± 0.75 SD, respectively; p < 0.01). Eight patients reported adverse events. These were mild and temporary and did not require treatment modification except in two patients. CONCLUSIONS Treatment with rhIGF-1 was effective and safe in Polish patients with primary IGF-1 deficiency. It had a clear beneficial effect on the height of the patients and significantly accelerated the height velocity, particularly in the first year of treatment.

The Prognostic Value of The Growth Hormone Secretion Stimulating Tests withl-dopa and clonidine in Children with Growth Hormone Deficiency Treated with Recombinant Human Growth Hormone in Western Pomeranian Region

Introduction. The detailed interview with auxological parameters and additional examinations including growth hormone secretion stimulating test are obligatory to establish the diagnosis of growth hormone deficiency. The aim. The aim of the study was to estimate the prognostic value of the growth hormone secretion stimulating test with clonidine and L-dopa. Material and methods. Medical records of 149 children, including 103 (69.1%) boys and 46 (30.9%) girls from the Western Pomeranian region treated with rhGH (mean dose 0.031mg/kg/d) in the Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology Developmental Age, PUM, in Szczecin between 2000 and 2010 were analyzed. All patients were qualified for the therapy and withdrawn according to agreed criteria; children with chronic illnesses, genetic disorders and malformations influencing growth pattern were excluded.Based on the results of GH secretion stimulating tests with clonidine and L-dopa the severe GHD group (sGHD – peak GH under 5 ng/ ml in both tests) and the partial GHD group (pGHD Klinika Pediatrii, Endokrynologii, Diabetologii, Chorób Metabolicznych i Kardiologii Wieku Rozwojowego Pomorskiego Uniwersytetu Medycznego w Szczecinie The prognostic value of the growth hormone secretion stimulating tests with L-dopa and clonidine in children with growth hormone deficiency treated with recombinant human growth hormone in Western Pomeranian region Clinic of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age Pomeranian Medical University, Szczecin, Poland

[Assessment of selected anthropometric parameters in children exposed to gestational diabetes in utero - preliminary results].

INTRODUCTION Current studies show uncreased risk of obesity cardiovascular diseases and diabetes mellitus in children exposed to gestational diabetes in utero. AIM The aim of this study was to assess the selected anthropometric parameters in children exposed to gestational diabetes in utero. MATERIAL AND METHODS 43 children, 7-15 years of age, exposed to gestational diabetes in utero were included in the study. Data including mothers pregestational anthropometric parameters, the course of pregnancy and anthropometric parameters of a newborn were obtained from the interview and medical records. Pediatric physical examination with Tanner assessment of pubertal development was conducted. In children and mothers the height and body mass were measured, and body mass index (BMI) was calculated. In participants of the study waist and hip circumferences were measured. RESULTS Higher birth weight (p=0.02), head and chest circumferences (p=0,02 and p=0.03) were observed in newborns of mothers with pregestational overweight and obesity. The analysis of newborns growth parameters and type of gestational diabetes did not show a significant difference. Obesity (BMI z 95th percentile) was diagnosed in 9 children (20.9 %) and overweight (BMI between 85th and 94th percentile) in 6 participants (13.9%). Higher body mass (p=0.02), BMI (p=0.02) and waist circumference (p-0.03) were observed in children who reached III-V Tanner stage, comparing to participants in Tanner Ml. Higher body mass, BMI, waist and hip circumferences were observed in the offspring of mothers with pregestational overweight and obesity. Mothers of children with BMI > 90th percentile currently show higher body mass and BMI in comparison to mothers of slimmer participants. CONCLUSIONS Excessive body weight before pregnancy in mothers with gestational diabetes can influence not only the anthropometric parameters of newborns and lead to fetal macrosomy, but also can be a predisposing factor for overweight and obesity in later childhood.

Aspekty endokrynne zespołu Pradera i Williego u dzieci i młodzieży

Zespol Pradera i Williego [PW] jest genetycznie uwarunkowaną chorobą, ktora wystepuje z czestością 1: 10 000–25 000 zywo urodzonych noworodkow. Choroba ta charakteryzuje sie: niedoborem wysokości ciala, zmniejszoną ilością beztluszczowej masy ciala, obnizonym napieciem mieśniowym, opoźnieniem rozwoju intelektualnego, zaburzeniami zachowania, cechami dysmorfii. Cechą stalą są rowniez zaburzenia laknienia, czesto prowadzące do otylości olbrzymiej. Spośrod poznanych zaburzen endokrynnych u pacjentow z zespolem PW opisuje sie zmniejszone wydzielanie hormonu wzrostu oraz hipogonadyzm hipogonadotropowy, co moze sugerowac dysfunkcje osi podwzgorzowo-przysadkowej. Przebieg dojrzewania u dzieci jest zazwyczaj nieprawidlowy i opoźniony. U pacjentow stwierdzono zarowno obnizone spontaniczne wydzielanie GH, obnizone stezenie IGF-1, jak i niezadowalające wyrzuty GH w testach stymulacyjnych. U pacjentow dotknietych zespolem znamiennie cześciej, prawdopodobnie wtornie do otylości i insulinooporności, wystepują zaburzenia tolerancji glukozy oraz cukrzyca typu 2. Zastepcza terapia rekombinowanym hormonem wzrostu i/lub hormonami plciowymi moze zatem przynieśc korzyści pacjentom dotknietym tą chorobą. Do korzystnych efektow leczenia hormonem wzrostu zaliczyc nalezy: poprawe tempa wzrastania, zwiekszenie beztluszczowej masy ciala i redukcje ilości tkanki tluszczowej. Jednakze odlegle skutki leczenia rekombinowanym hormonem wzrostu w zespole PW są dotychczas nieznane i wymagają dalszych obserwacji.

Współwystępowanie wad wrodzonych serca, rozszczepu podniebienia i innych cech dysmorficznych u dzieci jako przesłanka diagnostyczna poszukiwania zespołów delecji 22q11.2

Dotychczas opisano ok. 180 cech dysmorficznych i wad charakteryzujących z rozną czestością wystepowania zespoly delecji 22q11.2. Za najbardziej istotne uwaza sie wady wrodzone serca (glownie dotyczące podzialu stozka i pnia naczyniowego), cechy dysmorficzne twarzy i rozszczep podniebienia. Cechy te nie tworzą jednak na tyle jednoznacznego obrazu klinicznego, aby umozliwic z wysokim prawdopodobienstwem rozpoznanie na poziomie fenotypu i wysoką czestośc potwierdzen w dalszej diagnostyce cytogenetycznej i molekularnej. Przeprowadziliśmy analize 41 pacjentow (i ich rodzicow) prezentujących rozne polączenia powyzszych cech diagnostycznych. Pacjentow kwalifikowano do grup: A. wada serca + dysmorfia twarzy = 18 pacjentow, B. rozszczep podniebienia + dysmorfia twarzy = 1 pacjent, C. wada serca + rozszczep podniebienia = 17 pacjentow, D. tylko charakterystyczne dysmorfie twarzy = 5 pacjentow. U wszystkich probandow wykonano badanie kariotypu o wysokiej rozdzielczości i badanie FISH (sondy N25, TUPLE1), u 4 (9,7%) wykryto delecje w obszarze 22q11.2, a u 37 jej nie znaleziono. Analiza kariotypu w siedmiu przypadkach (17%) wykazala istnienie innych, liczbowych i strukturalnych aberracji chromosomowych. Wspolwystepowanie wady serca, rozszczepu podniebienia, dysmorfii twarzy oraz kwalifikacja na tej podstawie do badan cytogenetycznych i molekularnych nie wplywa na czestośc rozpoznawania zespolu delecji 22q11.2. Obrazuje to znaczne trudności w diagnostyce fenotypowej tych zespolow. U pacjentow z ujemnymi wynikami badania techniką FISH wskazana jest dalsza analiza technikami molekularnymi (CGH, badanie markerow polimorficznych – STRP), zarowno w celu wykrycia mozliwych uwarunkowan rodzinnych, jak i poszukiwania innych anomalii kariotypu.