BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening.

There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Double Extrahepatic Biliary Duct.

We report a 39-year-old male patient diagnosed with double extrahepatic biliary ducts by magnetic resonance cholangiopancreatography. Respiratory-triggered 3-dimensional magnetic resonance cholan - giopancreatography was performed during free breathing. Two extrahepatic biliary ducts, an anomalous union of accessory extrahepatic biliary duct with pancreatic duct, and a unique com - munication channel between 2 extrahepatic biliary ducts were determined on maximum intensity projection and 3-dimensional magnetic resonance cholangiopancreatography volume rendering. This case illustrates the utility of 3-dimensional magnetic resonance cholangiopancreatography for diagnosis of pancreatobiliary ductal system developmental anomalies. Also, we reviewed embryology of the hepatobiliary system and the current classifications of the double extrahepatic biliary ducts and have proposed a new variant of existing classifications.

Evaluation of clinical, endocrine and metabolic findings in obese children with and without hepatosteatosis.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common obesity-related comorbidity in childhood. In this study, we aimed to evaluate predictors of NAFLD by comparing clinical, endocrine and metabolic findings in obese children with and without hepatosteatosis. METHODS: Two hundred and eight obese children aged 6-18 years were included. The patients were divided into group 1 (patients with NAFLD, n=94) and group 2 (patients without NAFLD, n=114). Anthropometric measurements, pubertal stage, lipid profiles, fasting glucose and insulin, homeostatic model of assessment for insulin resistance (HOMA-IR), uric acid, total bilirubin, alanine aminotransferase (ALT), blood urea nitrogen, thyroid-stimulating hormone and free thyroxine parameters were compared retrospectively. RESULTS: The mean body weight, body mass index (BMI), height, tri-ponderal mass index (TMI), insulin, HOMA-IR, triglyceride, ALT and uric acid values were significantly higher, while high-density lipoprotein-cholesterol (HDL-C) values were significantly lower in group 1. The 70.7% of obese children with hepatosteatosis and 83.9% of those without hepatosteatosis were correctly estimated by parameters including age, gender, ALT, HDL-C, fasting insulin and uric acid values. CONCLUSIONS: Since obesity-associated hepatosteatosis induces various long-term metabolic impacts in children, early detection is of critical importance. Age, gender, TMI, BMI, ALT, HDL-C, fasting insulin and uric acid values may help to predict the risk of hepatosteatosis. Besides, we assessed whether TMI compared to BMI does not have a better utility in estimating obesity-induced hepatosteatosis in children. This is the first study to show the association between TMI and hepatosteatosis in children.

Clinical Importance of Main Portal Vein and Right Portal Vein Variations: A Prevalence Study With 128-Slice Multidetector Computed Tomography.

OBJECTIVES: The portal vein variation type significantly affects the outcome of transplant surgery, hepatectomies, and interventional radiological procedures. To reveal variation types, especially rare types, we used high-technology multidetector computed tomography. MATERIALS AND METHODS: We evaluated multiphase abdominal multidetector computed tomography scans of 278 consecutive patients. Multidetector computed tomography scans were processed for axial, coronal, and axial-oblique multiplane reformation and for maximum intensity projection. Variations of the main portal vein and right portal vein were simulta-neously analyzed by 2 radiologists. Prevalence of each variation and differences in sexes were investigated. RESULTS: Variant anatomy was detected in 29.5% of main portal veins and 20.9% of right portal veins. There was no statistical difference between sexes. Type 3 was reported as the most frequent variant of main portal vein, whereas type 4 was the most frequent variant of right portal vein. Some miscellaneous types were also ascertained. CONCLUSIONS: Different types of anatomic variations may adversely affect the course of surgery and interventional radiological procedures. Fortunately, radiologists can now discover the critical types by using the new generation multidetector computed tomography with 3-dimensional reconstruction techniques. This information should be included in the radiology reports of patients who are scheduled for major surgery.

Lipid accumulation product is a predictor of nonalcoholic fatty liver disease in childhood obesity.

BACKGROUND: Lipid accumulation product (LAP) is associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults. PURPOSE: Here we evaluated the ability of LAP to predict NAFLD in obese children. METHODS: Eighty obese children (38 girls; age 6-18 years) were included. Anthropometric measurements and biochemical values were obtained from the patients' medical records. LAP was calculated as [waist circumference (WC) (cm) - 58]×triglycerides (mmol/L) in girls; [WC (cm) - 65]×triglycerides (mmol/ L) in boys. The minLAP and adjLAP were described (3% and 50% of WC values, respectively) and the total/high-density lipoprotein cholesterol index (TC/HDL-C) was calculated. NAFLD was observed on ultrasound, and patients were divided into 3 groups by steatosis grade (normal, grade 0; mild, grade 1; moderate-severe, grade 2-3). The area under the curve (AUC) and appropriate index cutoff points were calculated by receiver operator characteristic analysis. RESULTS: LAP was positively correlated with puberty stage (rho=0.409; P<0.001), fasting insulin (rho= 0.507; P<0.001), homeostasis model assessment of insulin resistance (rho=0.470; P<0.001), uric acid (rho=0.522; P<0.001), and TC/HDL-C (rho=0.494; P<0.001) and negatively correlated with HDL-C (rho=-3.833; P<0.001). LAP values could be used to diagnose hepatosteatosis (AUC=0.698; P=0.002). The LAP, adjLAP, and minLAP cutoff values were 42.7 (P=0.002), 40.05 (P=0.003), and 53.47 (P= 0.08), respectively. For LAP, the differences between the normal and mild groups (P=0.035) and the normal and moderate-severe groups were statistically significant (P=0.037), whereas the difference between the mild and moderate-severe groups was not (P>0.005). There was a statistically significant difference between the normal and mild groups for adjLAP (P=0.043) but not between the other groups (P>0.005). There was no significant intergroup difference in minLAP (P>0.005). CONCLUSION: LAP is a powerful and easy tool to predict NAFLD in childhood. If LAP is ≥42.7, NAFLD should be suspected. This is the first study to assess LAP diagnostic accuracy for childhood obesity.

Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort.

PURPOSE: Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES). METHODS: After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes. RESULTS: We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects. CONCLUSION: We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371.

Evidence for genotype-phenotype correlation for OTOF mutations.

OBJECTIVES: The aim of this study is to evaluate the auditory phenotype in subjects with OTOF gene mutations to describe genotype-phenotype correlations. METHODS: Twenty-two affected members from three families with homozygous OTOF mutations were included. Nine subjects were evaluated audiologically with otoscopic examination, pure-tone audiometry, tympanometry with acoustic reflex testing, auditory brain stem responses, and otoacoustic emission tests. RESULTS: Homozygous c.4718T>C (p.Ile1573Thr) mutation was associated with the auditory neuropathy/auditory dys-synchrony (AN/AD) phenotype and with progressive sensorineural hearing loss in four siblings in one family, while homozygous c.4467dupC (p.I1490HfsX19) was associated with severe to profound sensorineural hearing loss without AN/AD in four relatives in another family. Homozygous c.1958delC (p.Pro653LeufsX13) mutation was associated with moderate sensorineural hearing loss without AN/AD in one affected person in an additional family. CONCLUSIONS: The audiological phenotype associated with different OTOF mutations appears to be consistently different suggesting the presence of a genotype-phenotype correlation.

Recurrent and private MYO15A mutations are associated with deafness in the Turkish population.

The identities and frequencies of MYO15A mutations associated with hearing loss in different populations remained largely unknown. We screened the MYO15A gene for mutations in 104 unrelated multiplex and consanguineous Turkish families with autosomal recessive nonsyndromic sensorineural hearing loss using autozygosity mapping. The screening of MYO15A in 10 families mapped to the DFNB3 locus revealed five previously unreported mutations: p.Y289X (1 family), p.V1400M (1 family), p.S1481P (1 family), p.R1937TfsX10 (3 families), and p.S3335AfsX121 (2 families). Recurrent mutations were associated with conserved haplotypes suggesting the presence of founder effects. Severe to profound sensorineural hearing loss was observed in all subjects with homozygous mutations except for two members of a family who were homozygous for the p.Y289X mutation in the N-terminal extension domain and had considerable residual hearing. We estimate the prevalence of homozygous MYO15A mutations in autosomal recessive nonsyndromic deafness in Turkey as 0.062 (95% confidence interval is 0.020-0.105).

Double outlet right ventricle with giant pulmonary artery aneurysm and severe aortic coarctation: diagnosis with multislice CT.

Complex cardiovascular pathologies in the pediatric population are usually evaluated with echocardiography and catheter angiography as initial and advanced imaging of choice, respectively. Echocardiography may pose some difficulties in the diagnosis of complex cardiovascular pathologies. Due to short acquisition times, detailed imaging by the use of post-processing techniques, reduced radiation exposure compared to catheter angiography, and additional information obtained on lung parenchyma, multi-slice computed tomography (CT) is the advanced imaging method of choice in selected cases. The present report describes a 14-year-old symptomatic case with complex cardiovascular pathology, whose vascular architecture could be properly demonstrated by multi-slice CT.

Mutations in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss: a report of five novel mutations.

Genome wide homozygosity mapping using Affymetrix 10K arrays revealed the DFNB7/11 locus including the TMC1 gene in 5 of 35 Turkish families with autosomal recessive nonsyndromic severe to profound congenital or prelingual-onset sensorineural hearing loss (SNHL). Additional 51 families were later screened for co-segregation of the locus with the phenotype using microsatellite markers. GJB2 and mtDNA A1555G mutations were negative in probands from each family. Mutation analysis was performed in families showing co-segregation of autosomal recessive SNHL with haplotypes at the DFNB7/11 locus. A total of six different mutations in seven families were identified, including novel missense alterations, p.G444R (c.1330G>A), p.R445C (c.1333C>T), and p.I677T (c.2030T>C), one novel splice site mutation IVS6+2 T>A (c.64+2T>A), and a novel large deletion of approximately 31kb at the 3' region of the gene including exons 19-24, as well as a previously reported nonsense mutation, p.R34X (c.100C>T). All identified mutations co-segregated with autosomal recessive SNHL in all families and were not found in Turkish hearing controls. These results expand the mutation spectrum of TMC1 with five novel mutations and provide data for the significant contribution of TMC1 mutations in hearing loss.

A rare cause of hyperbilirubinemia in a newborn: bilateral adrenal hematoma.

Hyperbilirubinemia is an important health problem in newborns. The most common causes are Rh and ABO incompatibility, hemolytic anemias, enzyme deficiencies, sepsis, hypothyroidism, pyloric stenosis and breast-milk jaundice. Adrenal hemorrhage is a rare cause of hyperbilirubinemia in the neonate. We present a six-day-old newborn with hyperbilirubinemia and suprarenal hematoma who was born at home without assistance of healthcare personnel. Adrenal hematoma should also be considered in the differential diagnosis of hyperbilirubinemia, particularly in newborns that experienced a difficult delivery.

[Broken Racz catheter during application (case report)]. / Uygulama esnasinda kopan Racz kateter (olgu sunumu).

The most important complication of lumber disc hernia operations is Failed Back Surgery Syndrome (FBSS), which goes with fibrotic adhesions at the surgical site. The primary treatment applied to the cases that develop FBSS is the placement of Racz catheter under floroscopy and application of epidural neuroplasty which is a three-day procedure. However, this intervention, from which patients benefit a great deal, has some important complications during and after the application. One of these complications is that some pieces of Racz catheter may be broken out and retain at some levels of epidural space and subcutaneous tissue during placement and removal. General approach is to remove the retaining piece surgically. However, there is a less common view that, instead of removing the retaining piece, the patient should be followed up strictly and regularly in terms of neurologic complications. In our case, we decided to perform epidural neuroplasty to the patient diagnosed as FBSS. However, during the placement of the catheter, it was trapped in the left side of L5-S1 foramen by accident due to dense fibrotic tissues, and the subcutaneus part retained in the epidural space. Monthly follow-ups for 12 month were proposed to the patient, while surgery was not recommended. At the end of this period, no sign of infection was observed and neurologic and radiologic findings of the patient did not worsen. It is also interesting that a remarkable recovery was observed in the patient's clinical situation.