A novel PAK1 variant causative of neurodevelopmental disorder with postnatal macrocephaly.

p21-activated kinases (PAKs) are protein serine/threonine kinases stimulated by Rho-family p21 GTPases such as CDC42 and RAC. PAKs have been implicated in several human disorders, with pathogenic variants in PAK3 associated with intellectual disability and several PAK members, especially PAK1 and PAK4, overexpressed in human cancer. Recently, de novo PAK1 variants were reported to be causative of neurodevelopmental disorder (ND) with secondary macrocephaly in three patients. We herein report a fourth patient with ND, epilepsy, and macrocephaly caused by a de novo PAK1 missense variant. Two previously reported missense PAK1 variants functioned as activating alleles by reducing PAK1 homodimerization. To examine the pathogenicity of the identified novel p.Ser110Thr variant, we carried out in silico structural analysis. Our findings suggest that this variant also prevents PAK1 homodimerization, leading to constitutive PAK1 activation.

Neurological results of the modified treatment of epilepsy by stimulation of the vagus nerve.

INTRODUCTION: The vagus nerve stimulation (VNS) is used for treatment of drug-resistant epilepsy but laryngeal side effects are common. We tried to improve VNS by modifying the implantation procedure. The aim was to reduce the rate of side effects that have prevented using VNS to its full capacity. METHODS: We operated on 74 pediatric patients for VNS device implantation using a modified surgical protocol incorporating lower neck incision for electrode placement and 36 patients who were operated by standard technique were used for control group. We retrospectively analyzed reduction in frequency of seizures, reduction in severity of seizures (assessed by the shortened Ictal/post-ictal subscale of the Liverpool Seizure Severity Scale that included falling to the ground, postictal headache and sleepiness, incontinence, tongue biting, and injury during attack). RESULTS: Using the new implantation technique, side effects related directly to VNS therapy occurred in six cases (8.1%) showing statistically sound improvement over the standard implantation technique (p Ë‚ 0.05). To achieve good results, the maximum stimulation (3.5 mA) was used in 24 patients (32.4%), with no laryngeal side effects detected. Twelve patients (16.2%) were seizure-free after the first year of VNS treatment. 74.3% of patients experienced a 50% reduction in seizure frequency and improved ictal or postictal activity. CONCLUSION: To minimize laryngeal complications in implantation surgery for VNS devices, the surgical technique may be modified, and lower neck incision could be used. A low rate of laryngeal side effects allows using the VNS device to its full electrical capacity.

Iron deficiency in children with attention deficit hyperactivity disorder.

BACKGROUND: Several studies have suggested that iron deficiency may be related to the pathophysiology of attention deficit hyperactivity disorder (ADHD) due to the role of iron in the production of dopamine and noradrenaline. OBJECTIVES: To evaluate the status of iron deficiency in ADHD children, using ferritin levels, a reliable measure of iron storage in body tissue, as an iron status marker, and to investigate a possible correlation between ferritin levels and the diagnosis of ADHD. METHODS: The study group included 113 newly referred ADHD children aged 5-15 years (mean age 8.8 +/- 2.7). RESULTS: Ferritin levels were below 20 ng/ml in 67 children (59%) and above 20 ng/ml in 46 (41%). There was a very low inverse statistical correlation between scores on Conners' Rating Scale and ferritin levels, probably without clinical significance. CONCLUSIONS: Our findings suggest that low iron stores may be related to ADHD pathophysiology; therefore, ferritin should be included in the overall evaluation of children with ADHD.

Prenatal diagnosis of sex chromosome abnormalities: the 8-year experience of a single medical center.

OBJECTIVE: To assess the indications for prenatal karyotyping of sex chromosomal abnormalities (SCAs) during pregnancy. METHODS: All singleton pregnancies interrupted in our institute because of SCAs (1998-2005) were categorized into subgroups of 45,XO (Turner syndrome), 47,XXY (Klinefelter syndrome), 47,XXX and 47,XYY. The indications for prenatal diagnostic testing were recorded. RESULTS: There were 67 SCAs pregnancies: 33% Turner syndrome, 28% Klinefelter syndrome, 21% 47,XXX and 18% 47,XYY. Maternal age was similar among the 4 groups (34 +/- 5, range 25-42 years). The main indications for fetal karyotyping were abnormal Down's syndrome (DS) screening or ultrasound findings, advanced maternal age (> or =35 years), and parental request. About 2/3 of the Turner and 47,XYY cases had either abnormal DS screening tests or sonographic findings, such as: increased nuchal translucency, mainly cystic hygroma and fetal hydrops. However, fetal karyotyping in more than 2/3 of the 47,XXX and 47,XXY cases was mainly performed because of advanced maternal age, and the diagnosis of fetal SCAs was coincidental (p <0.03). CONCLUSIONS: Our recent suggestion to expand the DS screening capacity to other chromosomal abnormalities including SCAs is further supported. Prenatal detection seems to be promising for Turner syndrome and possibly for 47,XYY syndrome, while other SCAs are less likely to be detected either by ultrasound or biochemical screening.

Chorioangioma and its severe infantile sequelae: case report.

OBJECTIVE: This case report describes a rare clinical presentation of chorioangioma diagnosed prenatally because of raised-maternal serum (MS) alpha-fetoprotein. METHODS: A thirty-year-old woman gravida 2, para 1 was referred to the ultrasound unit at 18 weeks of gestation because of abnormal MS triple-test results. This included AFP level of 14.9 MoM; hCG of 3.42 MoM and uE3 of 1.01 MoM. A detailed anomaly scan revealed a singleton fetus with no sonographically detectable malformations and normal amniotic fluid. The placenta was posterior. A well-circumscribed, rounded, predominantly hypoechoic lesion near the chorionic surface measuring 5 x 5 cm and protruding into the amniotic cavity was detected. Color Doppler sonogram showed no blood flow within the mass, but clear fetal waveforms in its periphery were demonstrated, and the diagnosis of chorioangioma was made. The pregnancy was followed uneventfully until 35 weeks of gestation when polyhydramnios and severe fetal cardiomegaly developed. Labor was therefore induced. RESULTS: A euploid female, who had multiple diffuse cutaneous and liver angiomatosis was born. She died at the age of one month because of cardiac failure and infection. CONCLUSIONS: The present case alerts to the interrelationship between placental and fetal angiomas. This may lead to severe infantile sequelae because of similar lesions.

Closure of patent ductus arteriosus with oral ibuprofen suspension in premature newborns: a pilot study.

OBJECTIVE: Patent ductus arteriosus (PDA), a common finding among premature infants, is conventionally treated by intravenous indomethacin. Intravenous ibuprofen was recently shown to be as effective and to have fewer adverse reactions in preterm infants. If equally effective, then oral ibuprofen for PDA closure would have several important advantages over the intravenous route. This study was designed to determine whether oral ibuprofen treatment is efficacious and safe in closure of a PDA in premature infants with respiratory distress syndrome. METHODS: Twenty-two preterm newborns (gestational age: 27.5 +/- 1.75 [range: 23.9-31 weeks]; weight: 979 +/- 266 [range: 380-1500 g]) with PDA and respiratory distress syndrome were studied prospectively. They received oral ibuprofen suspension 10 mg/kg/body weight for the first dose, followed at 24-hour intervals by 2 additional doses of 5 mg/kg each, if needed, starting on the second day of life. Echocardiography was performed before treatment and 24 hours after each dose. Every child underwent cranial ultrasonography before and after each ibuprofen dose. The rate of ductal closure, the need for additional treatment, side effects, complications, and the infants' clinical courses were recorded. RESULTS: Ductal closure was achieved in all newborns except for 1 (95.5%), in whom clinically nonsignificant ductal shunting persisted. No infant required surgical ligation of the ductus. There was no reopening of the ductus after closure had been achieved. Fourteen newborns were treated with 1 dose of ibuprofen, 6 were treated with 2 doses, and the remaining 2 were treated with 3 doses. The survival rate at 1 month was 86.4% (19 of 22). Three (13.6%) infants died from the following causes: 1 who was born at 24 weeks' gestation with a birth weight of 380 g died as a result of extreme prematurity complications, necrotizing enterocolitis, and low birth weight; 1 died as a result of Candida sepsis; and the third died as a result of Klebsiella sepsis. Intraventricular hemorrhage was observed in 7 infants. The classification was changed from grade 2 to grade 3 in 1 and from grade 0 to grade 1 or higher in 3 others. The rate of survival to discharge was 86.4% (19 of 22). No bronchopulmonary dysplasia was observed in the study group, and there was no case of tendency to bleed. There were no significant differences in the levels of serum creatinine before and after treatment with oral ibuprofen. CONCLUSIONS: Oral ibuprofen suspension may be an effective and safe alternative for PDA closure in premature infants with PDA. However, larger comparative studies are warranted.

Wiedemann-Beckwith syndrome: further prenatal characterization of the condition.

We describe three unrelated cases of Wiedemann-Beckwith syndrome (WBS). Two of them were diagnosed postnatally while the third was detected during pregnancy that resulted in elective termination. Amniotic karyotypes were normal in all. PCR amplification of polymorphic loci mapping to 11p15.5 region documented partial trisomy of 11p15.5 due to paternal translocation in one, and segmental and mosaic segmental unipaternal disomy (UPD) in the second and third cases, respectively. Based on findings documented in these cases and the literature, we tabulated the anomalies that might be detected prenatally by ultrasound and that may suggest the syndrome. Constant findings included fetal overgrowth, polyhydramios, enlarged placenta, and specifically a distended abdomen. As most described signs developed after 22 weeks of gestation, a careful follow-up should be carried on until late stages of pregnancy. An amniotic karyotype might not detect subtle chromosomal rearrangements. We therefore recommend utilizing PCR of polymorphic loci on 11p15.5, in addition to conventional cytogenetic analysis of the fetus and both parents to detect possible maternal deletions or inversions, paternal duplications, and UPD that may account for the largest subset of sporadic WBS reaching 25% of cases. An early diagnosis of WBS is important for counseling the parents concerning potential risk for developing embryonic tumors, selection of the mode of delivery due to potential adrenal cysts that might bleed during labor, and prevention of neonatal hypoglycemia.