True Microcephaly Research Articles

Whole exome sequencing identifies a novel homozygous frameshift mutation in the ASPM gene, which causes microcephaly 5, primary, autosomal recessive

Microcephaly is a genetically heterogeneous disorder and is one of the frequently notable conditions in paediatric neuropathology which exists either as a single entity or in association with other co-morbidities. More than a single gene is implicated in true microcephaly and the list is growing with the recent advancements in sequencing technologies. Using massive parallel sequencing, we identified a novel frame shift insertion in the abnormal spindle-like microcephaly-associated protein gene in a client with true autosomal recessive primary microcephaly. Exome sequencing in the present case helped in identifying the true cause behind the disease, which helps in the premarital counselling for the sibling to avoid future recurrence of the disorder in the family.

Whole exome sequencing identifies a novel homozygous frameshift mutation in the ASPM gene, which causes microcephaly 5, primary, autosomal recessive.

Microcephaly is a genetically heterogeneous disorder and is one of the frequently notable conditions in paediatric neuropathology which exists either as a single entity or in association with other co-morbidities. More than a single gene is implicated in true microcephaly and the list is growing with the recent advancements in sequencing technologies. Using massive parallel sequencing, we identified a novel frame shift insertion in the abnormal spindle-like microcephaly-associated protein gene in a client with true autosomal recessive primary microcephaly. Exome sequencing in the present case helped in identifying the true cause behind the disease, which helps in the premarital counselling for the sibling to avoid future recurrence of the disorder in the family.

A quality assessment of reporting sources for microcephaly in Utah, 2003 to 2013.

Obtaining accurate microcephaly prevalence is important given the recent association between microcephaly and Zika virus. Assessing the quality of data sources can guide surveillance programs as they focus their data collection efforts. The Utah Birth Defect Network (UBDN) has monitored microcephaly by data sources since 2003. The objective of this study was to examine the impact of reporting sources for microcephaly surveillance. All reported cases of microcephaly among Utah mothers from 2003 to 2013 were clinically reviewed and confirmed. The UBDN database was linked to state vital records and hospital discharge data for analysis. Reporting sources were analyzed for positive predictive value and sensitivity. Of the 477 reported cases of microcephaly, 251 (52.6%) were confirmed as true cases. The UBDN identified 94 additional cases that were reported to the surveillance system as another birth defect, but were ultimately determined to be true microcephaly cases. The prevalence for microcephaly based on the UBDN medical record abstraction and clinical review was 8.2 per 10,000 live births. Data sources varied in the number and accuracy of reporting, but a case was more likely to be a true case if identified from multiple sources than from a single source. While some reporting sources are more likely to identify possible and true microcephaly cases, maintaining a multiple source methodology allows for more complete case ascertainment. Surveillance programs should conduct periodic assessments of data sources to ensure their systems are capturing all possible birth defects cases. Birth Defects Research (Part A) 106:983-988, 2016. © 2016 Wiley Periodicals, Inc.

348: The accuracy of prenatal ultrasound in the diagnosis of true microcephaly

in the diagnosis of true microcephaly Jennifer Wong, Casey Howe, Angela Bianco, Robert Green, Joanne Stone Mount Sinai School of Medicine, Maternal Fetal Medicine, New York, NY, Mount Sinai School of Medicine, Department of Obstetrics and Gynecology, New York, NY, Department of Pediatrics, New York, NY OBJECTIVE: To determine the accuracy of prenatal ultrasound in detection of microcephaly, defined as birth head circumference (HCbirth) 10%ile. STUDY DESIGN: This was a retrospective chart review of fetuses identified prenatally with a head circumference (HCfetal) of 3%ile. HCbirth were abstracted from the newborn medical chart, and Z-scores calculated for both. Sensitivity, specificity, false positive (FP) and false negative (FN) rates were calculated for HCfetal. An ROC curve was calculated to determine the accuracy of HCfetal in the detection of microcephaly. RESULTS: An ultrasound database search from Jan 2005 to July 2011 for HC 3% identified 730 ultrasounds of 455 fetuses in 433 patients. There were 375 live births in this group. Median Z-scores were similar between fetal and neonatal groups ( 1.16 [ 1.6, 0.9] and 1.2 [ 1.8, 0.7], respectively). The overall prevalence of microcephaly was similar in both groups using an HCfetal Z-score cutoff of 1.3 (40.1% and 49.6% respectively). A Z-score of 1.3 had 44.6% sensitivity, 35.1% specificity, 44.9% FP rate, and 45.9% FN rate for detection of microcephaly (p 0.08). Using a HCfetal Z-score cutoff of 1.7 yielded 28.8% sensitivity, 21% specificity, 62.6% FP and 28.2% FN rate (p 0.09). The area under the ROC curve was 0.6, indicating that HCfetal is an inaccurate test for microcephaly. Gestational age at time of ultrasound was not significantly associated with microcephaly (95% CI 0.27-0.01). CONCLUSION: Prenatal ultrasound was able to detect a population at risk for microcephaly as evidenced by the high prevalence in this group at birth; however, the ability of prenatal ultrasound to predict a specific HCbirth for an individual is poor. Sensitivity and specificity for prenatal ultrasound are low, and FP and FN rates are high. Factors which contribute to the inaccuracy of prenatal ultrasound include the variability of the microcephaly phenotype, heterogeneous etiologies, lack of consensus regarding the definition of microcephaly, high rate of concurrent growth restriction, and lack of genderor race-specific fetal growth curves. 349 Antenatal ultrasonographic findings to predict esophageal atresia in cases with visible stomach bubble Jeong Woo Park, Yeo rang Kim, Seung Mi Lee, Chan-Wook Park, Joong Shin Park, Jong Kwan Jun, Hee Chul Shin Seoul National University College of Medicine, Deptartment of Obstetrics and Gynecology, Seoul, Korea, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Obstetrics and Gynecology, Seoul, Korea, Seoul National University College of Medicine, Department of Obstetrics and Gynecology, Seoul, Korea OBJECTIVE: Becauses fetuses with esophageal atresia need an early postnatal surgery, they should be delivered in a tertiary center. However, prenatal diagnosis of esophageal atresia sometimes challenging. The aim of this study was to determine the antenatal ultrasonographic findings which offer the best diagnostic accuracy in fetal esophageal atresia with or without tracheoesophageal fistula (EA/TEF) with moderate to severe polyhydramnios and visible stomach bubble. STUDY DESIGN: We performed a retrospective analysis of 121 pregnant women who presented polyhydramnios (AFI 24) between March 1996 and April 2011. Of these, 3 cases in whom EA was suspicious but delivered stillbirth without autopsy, and those who were diagnosed as having other fetal gastrointestinal obstructions (e.g. duodenal atresia, jejunal atresia, or ileal atresia), hydrops fetalis, or congenital diaphragmatic hernia were excluded. A total of 87 cases were enrolled. Ultrasonographic findings evaluated were (1) small abdominal circumference (AC) less than 10 percentile for gestational age, (2) upper pouch sign, and (3) tiny stomach bubble. Predictive value of an individual sonographic marker was calculated. RESULTS: Of a total of 87 cases with polyhydramnios, 2 cases had upper neck pouch sign. Of these 85 cases, 8 cases showed absent stomach bubble. The remaining 77 cases were analysed. In the setting of polyhydramnios and visible stomach bubble (77 cases), the prevalence of EA/TEF was 6.5% (5/77). Small AC had higher sensitivity compared to tiny stomach bubble. Small AC and tiny stomach bubble were statistically significant sonographic findings for diagnosing esophageal atresia antenatally. After adjusting possible confounders, only small AC was remained significant (P 0.05). CONCLUSION: In polyhydramnios and visible fetal stomach bubble, small AC as an antenatal sonographic finding suggests that the fetus has EA/TEF. Clinicians should measure AC in this setting. Poster Session II Diabetes, Labor, Medical-Surgical-Disease, Obstetric Quality & Safety, Prematurity, Ultrasound-Imaging www.AJOG.org

Neurologic Presentation in Children with Ataxia-Telangiectasia: Is Small Head Circumference a Hallmark of the Disease?

To define the neurologic characteristics and course of ataxia-telangiectasia (A-T). Retrospective cross-sectional chart study of 57 children (ages 2 to 19 years) followed at an A-T clinic. Cerebellar and extracerebellar symptoms were graded according to degree of functional impairment. Head circumferences were plotted from the charts and z-scores were calculated and compared with that of family members. Ataxia was present in 87.7%, followed by dysarthria (82.1%), dysmetria (75.4%), bradykinesia (69.2%), hyperkinetic movements (58.9%), and dystonia (15.8%). All features aggravated with age. The most striking clinical observation in our patients was low head circumference (z-score below 1), which was present in 60.9%; 17% had true microcephaly (z-score below 2). Microcephaly appeared postnatally, was proportionate to height and weight, and did not correlate with severity of ataxia or genotype. In addition to cerebellar ataxia, extrapyramidal symptoms, especially bradykinesia, were frequent and disabling. Microcephaly is an integral part of A-T; understanding its pathogenesis may shed light on the mechanism by which ATM mutation causes dysfunction in the nervous system.

Nonsyndromic Microcephaly: An Overview

Microcephaly is the term customarily used by clinicians to refer to a patient’s head size significantly below the mean for ageand sex-appropriate reference values for occipitofrontal circumference (OFC). It is not a specific diagnosis but merely a clinical sign, a finding on physical examination, which is causally very heterogeneous. Microcephaly is rarely a parental complaint, and it is often unrecognized by the physician, as clinical inspection may be misleading and objective measurements are, unfortunately, commonly omitted. Microcephaly is either the consequence of different developmental anomalies or inborn errors of metabolism that adversely affect the intracranial central nervous system (CNS), or of its disruption by various environmental factors. Irrespective of its cause and pathogenesis, microcephaly results from lack of expansive growth of the brain. The normal prenatal and postnatal increase in size of the human skull is in part a component of normal skeletal growth, but most importantly, a phenomenon dependent on intensive brain growth in infancy and early childhood. Usually, microcephaly is associated with moderate to severe mental retardation (MR) and often with other CNS dysfunctions. Paradoxically, only about one quarter of patients with MR, irrespective of associated CNS dysfunction, have true microcephaly. Because of its complex etiology, micro-

On the nosology of the “primary true microcephaly, chorioretinal dysplasia, lymphoedema” association

We describe a male child with prenatal growth retardation, true microcephaly, pedal lymphoedema and characteristic ocular anomalies. Ophthalmological examination revealed remnants of the posterior hyaloidea, more pronounced in the right eye where a retinal fold extended from the papilla into the vitreum, chorioretinal dysplasia with narrow retinal vessels, multiple large round areas of chorioretinal atrophy and atrophic papillae. The associations "Microcephaly-chorioretinal dysplasia", "Microcephaly-retinal folds" and "Microcephaly-lymphoedema" have been reported as separate autosomal dominant conditions. The findings in the present child suggest that these associations could be variable expressions of the same autosomal dominant condition.

Identical syndromes of cerebral palsy in the same family.

SummaryFamilial cases of cerebral palsy were traced all over Sweden. Fortythree families were collected, in 30 of which the patients were siblings. The families were divided into three groups: (1) 16 families with cases of identical syndromes and a history of normal pregnancy, delivery and perinatal period; (2) 3 families with cases of identical syndromes but an abnormal perinatal period; (3) 24 families with non‐identical syndromes.Within the first group, which is of main genetic importance, 10 families were found with 2‐3 siblings affected with congenital non‐progressive ataxia and mental retardation, the mode of inheritance with all probability being autosomal recessive. Three families showed ataxic diplegia, two of them only in siblings, the third with affected members of both sexes represented in three generations. Surprisingly enough, pure spastic diplegia was only revealed in one family, viz. a grandfather and his grandson. Spastic tetraplegia was found in two mentally retarded siblings in an otherwise healthy sibship of 11 members. True microcephaly combined with a dystonic tetraplegic cerebral palsy was seen in one family and was thought to have an autosomal recessive inheritance as in similar cases reported in the literature.Chromosome studies and laboratory screening tests revealed no abnormalities indicating particular aetiological mechanisms.