To examine head growth in macrocephalic infants with benign expansion of subarachnoid spaces (BESS) relative to those without imaging abnormalities and World Health Organization (WHO) standard curves. Patients with macrocephaly who underwent intracranial imaging at St. Louis Children's Hospital between 2012 and 2022 were identified via radiology records search. Records were retrospectively reviewed to identify patients with isolated macrocephaly (without intracranial abnormalities) and BESS (defined by macrocephaly and concurrent imaging diagnosis of BESS by neuroradiology). Nonlinear least-squares regression of head circumference (HC) by cohort and gender was performed and compared with WHO curves. Infants with macrocephaly and BESS (n = 159, 29% female) and macrocephaly without BESS (n = 152, 28% female) were included. Infants with BESS have larger HCs than the WHO 97th-percentile curve (male: P = .0032, female: P < .001) as well as infants with isolated macrocephaly (male: P = .0095, female: P < .001). Ventricle size (estimate: 1.751; 95% CI -0.728-4.230, P = .102), but not subarachnoid space (estimate: -0.057; 95% CI -0.697-0.583, P = .861), appeared to be positively associated with HC z-score, but was not significant. HC rate of change >0.043 cm/day at 5-7 months of age was 82% specific (95% CI 70.0-92.0) for BESS. Infants with BESS have different head growth trajectories compared infants with isolated macrocephaly as well as WHO curves. This study provides preliminary insights into head growth in BESS and may help identify patients more likely to have BESS among those presenting with macrocephaly.

The Succinate Dehydrogenase (SDH) enzyme is known as Complex-II in the electron transport chain. This study reports the clinical and molecular investigations of three pediatric patients (two of whom are siblings), with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to SDH gene mutations. The patients presented with severe hypotonia, developmental delay, spasticity, macrocephaly, and megalencephaly. Magnetic Resonance Imaging (MRI) revealed signal changes in the frontal, temporal, parietal, occipital cerebral, and cerebellar white matter, corpus striatum, thalamus, substantia nigra, inferior olivary nucleus, pyramidal tracts at the level of the pons and posterior limb of the internal capsule. Other typical findings involved a high succinate peak at 2.42 ppm and lactate peak at 1.3 ppm in Magnetic Resonance Spectroscopy (MRS). The siblings presented due to compound heterozygous c.143A>T (p. Asp48Val) and c.308T>C (p. Met103Thr) SDHB mutations, while the other patient presented due to compound heterozygous c.1754G>A (p. Arg585Gln) and c.1786G>C (p. Asp596His) SDHA mutation. The demonstration of succinate peak, particularly MRS, is highly diagnostic regarding SDH deficiency. MRS should be a standard part of routine radiological exams when there is a suspicion of a neurometabolic disease, especially mitochondrial disorders. Additionally, employing Next-Generation Sequencing (NGS) is advisable for patients as it allows for accurate diagnosis without requiring invasive procedures like muscle biopsies.

To assess the diagnostic utility of exome sequencing (ES) in macrocephalic fetuses. Fetuses with macrocephaly (head circumference (HC) ≥ +2 SD) and negative chromosomal microarray results were included, who had available trio-ES data. Molecular diagnoses were systematically analyzed. Subgroup analyses were performed on the ES diagnostic yield based on gestational age, HC Z-scores, associated anomalies, and growth parameters. Molecular diagnoses were established in 34 out of 87 macrocephalic fetuses (39.1%) through trio-ES. These diagnoses revealed that the variants predominantly affect key signaling pathways, including mTOR, RASopathies and Sotos syndrome. The detection rate was significantly higher in non-isolated compared to isolated macrocephaly cases (65.0%, 26/40 vs. 17.0%, 8/47; p < 0.001). The most frequent anomalies associated with genetic diagnoses included micromelia (100.0%, 14/14), megalencephaly (100.0%, 2/2), and ventriculomegaly (60.0%, 6/10). Subgroup analysis identified higher diagnostic yields in fetuses diagnosed before 32 gestational weeks, with HC Z-scores ≥ +3 SD, micromelia, and absence of large-for-gestational-age (LGA). Exome sequencing significantly enhances the detection of monogenic disorders in macrocephalic fetuses compared with CMA, irrespective of isolated or non-isolated cases. These clinical features and phenotypes are essential for assessing monogenic disorders and for prenatal counseling and evaluations of macrocephalic fetuses.

Macrocephaly is a clinical observation denoted as an occipitofrontal head circumference exceeding two standard deviations above same age and sex norms. By its definition, macrocephaly occurs in approximately 3% of the population. Descriptive epidemiologic evaluations of macrocephaly are lacking in the literature. The primary objective of this study was to describe the prevalence of macrocephaly captured by the Texas Birth Defects Registry (TBDR) by infant sex, rural/urban residence, and select maternal characteristics. Cases of TBDR between 1999 and 2019 with a six-digit Centers for Disease Control modified-British Pediatric Association (BPA) code of 742.400 (enlarged brain/head, large head, macrocephaly, megalencephaly) were identified. All pregnancy outcomes and diagnostic certainties were included. Prevalence (per 10,000 live births) and 95% confidence intervals (CIs) were calculated using a Poisson table by rural/urban residence, infant sex, maternal age, education, race/ethnicity, history of diabetes, and body mass index (BMI). Prevalence calculations were repeated across multiple sensitivity analyses including (1) definite, isolated cases excluding those with indication of being either "benign" or "familial", (2) definite, non-isolated cases, (3) definite non-isolated cases excluding chromosomal and syndromic cases, and (4) definite, proportionate (at birth) cases. A secondary objective was to describe the most common co-occurring congenital defects among definite, non-isolated cases. Overall, between 1999 and 2019, 14,637 cases of macrocephaly were identified in the TBDR resulting in a prevalence of 18.12/10,000 live births (95% CI: 17.83-18.42). Most cases were live born (99%), had a definite diagnosis (87%), and were non-isolated (57%). Prevalence was significantly higher among males, among those with an urban residence, and among mothers who were older, Non-Hispanic White, who had greater than high school education, who had a history of diabetes, and who were obese. Prevalence patterns remained consistent across all sensitivity analyses. The most common co-occurring congenital defects among definite, non-isolated cases were minor and primarily included skull and facial bone anomalies (e.g., plagiocephaly [18%]). To our knowledge, this is the first epidemiologic evaluation of macrocephaly in a birth defects registry. The long-term clinical impact of isolated macrocephaly is not well understood and should be the focus of future investigations.

Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.