Correlation analysis of maternal condition during pregnancy with head circumference and autism spectrum disorder: A propensity score-matched study.

To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study included 41 Han children with ASD who visited the Children's Health Clinic of the Second Hospital of Shandong University between March 2018 and February 2019, and 264 Han children with typical development (TD) who visited the clinic during the same period. Physical measurements were performed on the children. The questionnaire obtained information on maternal risk factors that may be related to the increased risk of ASD and folic acid (FA) supplementation. We designed an observational case-control study using propensity score matching and multivariate logistic regression analysis. The incidence of macrocephaly in the ASD group was 22.0%, significantly higher than that in the TD group (1.8%). The incidence of microcephaly in the ASD group was 17.1% (n = 7), significantly higher than that in the TD group (1.8%). The differences between the comparisons were statistically significant. Maternal FA supplementation during pregnancy was significantly associated with ASD (P < .05), with an odds ratio (95% confidence interval of 3.69 (1.76, 7.76)). Also was associated with macrocephaly (P < .05), odds ratio (95% confidence interval) were 8.13 (1.63, 40.61) and 4.16 (1.18, 14.60), respectively. The incidence of abnormal HC was higher in the ASD group than that in the TD group. Maternal FA supplementation during pregnancy may be negatively associated with the occurrence of ASD and abnormal HC in the offspring. Further examination of the role of maternal health status in the etiology of ASD is recommended.

Subdural Hemorrhage as an Early Presentation in a Case of Sotos Syndrome.

Subdural hemorrhages (SDHs) in the pediatric population are associated with a high mortality and morbidity and may present in the context of abusive head trauma. Diagnostic investigations for such cases often include evaluation for rare genetic and metabolic disorders that can have associated SDH. Sotos syndrome is an overgrowth syndrome associated with macrocephaly and increased subarachnoid spaces and rarely with neurovascular complications. Here, we report two cases of Sotos syndrome, one with SDH during infancy who underwent repeated evaluation for suspected child abuse prior to the Sotos syndrome diagnosis and the other with enlarged extra-axial cerebrospinal fluid spaces, demonstrating a possible mechanism for SDH development in this setting. These cases suggest that some individuals with Sotos syndrome may be at elevated risk of developing SDH in infancy and that Sotos syndrome should be on the differential diagnosis during a medical genetics evaluation in cases of unexplained SDH, especially in the setting of macrocephaly.

Syndrome of megalencephaly, mega corpus callosum, and complete lack of motor development: an unusual case and a literature review.

The syndrome of megalencephaly, mega corpus callosum (MEG-MegaCC) accompanied by complete lack of motor development is a rare condition with only few sporadic cases having been reported in the literature. In this paper, we describe a child from non-consanguineous parents presenting with MegaCC, psychomotor retardation, and language impairment linked to MEG-MegaCC syndrome. Genetic analysis, radiological findings, and detailed neurological phenotype of MEG-MegaCC syndrome with its overlapping syndromes would allow for a better classification of the disease spectrum.

Acquisition and Loss of Developmental Milestones and Time to Disease-Related Outcomes in Cerebral Alexander Disease.

Objective: To determine the ages at acquisition of developmental milestones, loss of motor function, and clinical symptoms in Alexander disease. Methods: Patients with confirmed cerebral Alexander disease were included. Data abstraction of developmental and disease-specific milestones was performed from medical records, physical exams, and questionnaires. Mixed effects logistic regression was used to determine if key clinical features were associated with milestone achievement, controlling for patient age. Results: 51 patients with cerebral/infantile Alexander disease were evaluated at a mean age of 10.96 years (range 2.29-31.08 years). Developmental milestones in Alexander disease were often achieved but delayed. Ambulation was achieved in 44 subjects (86%); 34 (67%) subjects walked independently (mean age 1.9 years, range 0.91-3.25 years) and an additional 10 (20%) subjects walked with assistance (mean age 3.9 years, range 1.8-8 years) but did not progress to independent ambulation. Developmental delay was the earliest and most prevalent symptom (N = 48 [94%], mean age 0.58 years), compared to an initial seizure (N = 41 [80%], mean age 2.80 years), and macrocephaly (N = 28 [55%], mean age 4.04 years), P < .0001 between these ages of onset. Loss of independent ambulation occurred in 11 of the 34 (32%) children who had acquired ambulation (range 3.41-15.10 years). Presence of seizures or macrocephaly did not predict the achievement or loss of ambulation. Conclusions: The clinical triad of developmental delay, seizures, and macrocephaly are not universally present in cerebral Alexander disease. Clinicians should have a high index of suspicion for Alexander disease in patients with mild delays and a first seizure.

Abordaje diagnóstico de la macrocefalia / Diagnostic management of macrocephaly

La macrocefalia, definida como un aumento del perímetro occipitofrontal o craneal por encima de 2 desviaciones estándar para la edad, sexo y edad gestacional, es un hallazgo potencial en las exploraciones habituales en Pediatría en Atención Primaria y en otros ámbitos. Se trata de una situación que refleja una posible alteración en el neurodesarrollo, en el crecimiento del niño o una situación puramente benigna. Dado que no es indicativo de una patología concreta, es necesario aplicar un abordaje diagnóstico adecuado, distinguiendo entre cuadros que requieren estudios más profundos y aquellos que no precisan intervención por nuestra parte. En este artículo se analizarán los elementos de la historia clínica y la exploración física que permitirán orientar este hallazgo (AU)

Macrocephay, defined as an increase of the occipitofrontal or cranial perimeter over 2 standard deviation for a determined age, sex or gestational age; is a potential finding in the usual physical exploration in Paediatrics in Primary Care and other areas. It is a situation that may show a potential neurodevelopmental or growth disorder or a completely benign condition. Since it is not an indicative of a specific disease, it is necessary to resort to a proper diagnostic management, distinguishing between clinical presentations that require a deeper study and those that do not require an intervention on our part. Elements of the medical record and physical exploration that allow to guide the diagnosis will be analysed in this article. (AU)

Cranial vault reduction cranioplasty for severe macrocephaly due to holoprosencephaly and subdural hygroma: a case report.

BACKGROUND: Severe macrocephaly can still be found in developing countries. This condition is usually caused by neglected hydrocephalus and can cause a lot of morbidities. Cranial vault reconstruction cranioplasty is the main treatment option for severe macrocephaly. Holoprosencephaly is often seen with features of microcephaly. Hydrocephalus should be considered as the main cause in HPE patients with features of macrocephaly. In this report, we present a rare case of cranial vault reduction cranioplasty procedure in patient with severe macrocephaly due to holoprosencephaly and subdural hygroma. CASE DESCRIPTION: A 4-year-10-month-old Indonesian boy was admitted with head enlargement since birth. He had a history of VP shunt placement when he was 3 months old. But the condition was neglected. Preoperative head CT showed massive bilateral subdural hygroma that compressed brain parenchyma caudally. From the craniometric calculation, the occipital frontal circumference was 70.5 cm with prominent vertex expansion, the distance between nasion to inion was 11.91 cm and the vertical height was 25.59 cm. The preoperative cranial volume was 24.611 cc. The patient underwent subdural hygroma evacuation and cranial vault reduction cranioplasty. The postoperative cranial volume was 10.468 cc. CONCLUSION: Subdural hygroma can be a rare cause of severe macrocephaly in holoprosencephaly patients. Cranial vault reduction cranioplasty and subdural hygroma evacuation is still the main treatment option. Our procedure successfully reduces significant cranial volume (57.46% volume reduction).

Clinical and genetic diagnosis of Cowden syndrome: A case report of a rare PTEN germline variant and diverse clinical presentation.

INTRODUCTION: Cowden syndrome is a rare autosomal dominant disease characterized by the development of hamartomas and increased risks of other tumors, including breast, thyroid, and uterine cancers. Most patients with Cowden syndrome show mutations of the phosphatase and tensin homolog (PTEN) gene on chromosome 10; however, some patients with mutations do not show clinical symptoms, while patients with clinical symptoms may not have detectable PTEN mutations. CASE PRESENTATION: A 39-year-old woman with macrocephaly had previously been diagnosed with Cowden syndrome at another hospital, when she presented with the onset of breast cancer. A wide variety of complications were detected, including cerebellar tumors treated by resection, hydrocephalus, and multiple polyps in the stomach and large intestine. She was further diagnosed with adult-onset Lhermitte-Duclos disease as a complication of Cowden syndrome. She subsequently developed a dural arteriovenous fistula treated by transvenous embolization. After transfer to our hospital, she developed adenomatous goiter treated by resection, recurrent breast cancer treated with hormonal therapy, and multifocal oral mucosal papillomatosis. Her older sister had previously been diagnosed with Cowden syndrome and her father was undiagnosed but had macrocephaly, hydrocephalus, and multifocal oral mucosal papillomatosis, suggestive of Cowden syndrome. After consultation with a genetic specialist, analysis of the PTEN gene showed a rare but likely pathogenic germline c.801 + 2T>A variant located at the splice donor site of intron 7. The patient's clinical diagnosis of Cowden syndrome was accordingly confirmed by the genetic findings. Appropriate surveillance procedures were put in place to detect any further tumors. CONCLUSIONS: The clinical symptoms of Cowden syndrome do not always correlate with the genetic results. However, recent improvements in genetic testing suggest the importance of diagnosing this disease using both clinical and genetic approaches, in collaboration with genetic experts, to ensure an accurate diagnosis and appropriate surveillance for malignant tumors.

The PTEN hamartoma tumor syndrome: how oral clinicians may save lives.

INTRODUCTION: Patients with the PTEN hamartoma tumor syndrome (PHTS) have an 81%-90% cumulative lifetime risk of developing cancer. Around 90% of these patients have recognizable oral features. Receiving a diagnosis may save these patients' lives. This is the first presentation of a family with the PHTS diagnosis with focus on the oral and periodontal findings and treatments. CASE PRESENTATION: All three children (one son and two daughters) inherited the same heterozygous variant in the PTEN gene from their father. Gingival overgrowth was observed in all patients in addition to macrocephaly. Other findings included fissured tongue, high arched palate, papules, and trichilemmomas. The father had experienced severe tooth loss. Surgery was performed to treat the gingival overgrowth and periodontal pockets; however, the treatment was characterized by multiple recurrences of the overgrowth. CONCLUSIONS: Oral changes, macrocephaly, tumors, and/or a family history of benign or malignant lesions are important features that oral clinicians should be aware of for a possible PHTS diagnosis. Patients suspected of having PHTS should be referred to a medical practitioner, specifically a geneticist, for further diagnostic investigations. The periodontal problems seemed to be difficult to control for these patients. They will likely need an active and frequent maintenance therapy to control the persistent inflammation and gingival overgrowth. In addition, they need a thorough monitoring for benign or malignant changes in the orofacial regions. Why are these cases new information? Oral features are found in 90% of the cases with the PHTS diagnosis. The periodontal findings showed a persistent recurrence of gingival overgrowth with a strong probability of serious periodontal diseases. What are the keys to successful management of these cases? A suspicion of a PHTS diagnosis with a referral to a medical practitioner, specifically a geneticist, for complete workup may help save these patients' lives. Close monitoring during maintenance therapy with re-treatment as needed to prevent further periodontal complications. Continued monitoring and treatment throughout the patient's lifetime for development of recurrent or new, benign or malignant lesions at relevant sites. What are the primary limitations to success in these cases? A failure to identify the PHTS syndrome with the accompanying oral and periodontal complications. Complications may lead to a delay in appropriate treatment. Inability to control the persistent gingival overgrowth and a deteriorating periodontal condition. A failure to discover benign and malignant lesions in the orofacial region.

Surgical management of Chiari malformation type 1 associated to MCAP syndrome and study of cerebellar and adjacent tissues for PIK3CA mosaicism.

BACKGROUND: Subjects with Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP) can present with a Chiari Malformation Type 1 and resulting alterations in cerebrospinal fluid (CSF) dynamics, which may require surgical treatment. The aim of this paper is to describe the features of children with MCAP who underwent surgical decompression for CM1, and to explore the PIK3CA variant allele frequency (VAF) identified in cerebellar parenchyma and other adjacent structures. METHODS: This study reviewed two cases of children with CM1 and MCAP who underwent surgical decompression treatment. These two cases were part of a national cohort of 12 MCAP patients who had CM1, due to their surgical eligibility. Tissue samples were obtained from the cerebellar tonsils and adjacent anatomical structures during the surgical procedures. Samples were then subsequently analyzed for PIK3CA postzygotic variants. RESULTS: In both cases, alterations in CSF dynamics, specifically hydrocephalus and syringomyelia, were observed and required surgical treatment. PIK3CA targeted sequencing determined the VAF of the postzygotic variant in both cerebellar and adjacent bone/connective tissues. DISCUSSION: The recognition of a CM1 comorbidity in MCAP patients is of paramount importance when considering personalized treatment options, especially because these patients are at higher risk of developing complications during surgical decompression surgery. The variable PIK3CA VAF identified in the different analyzed tissues might help explain the heterogeneous nature and severity of anomalies observed in the volume of the posterior fossa structures in MCAP patients and associated CSF and venous disorders.

Prenatal diagnosis and delivery of megalencephaly-capillary malformation syndrome.

Hemimegalencephaly (HME) is a rare neurological diagnosis defined as hamartomatous overgrowth of one cerebral hemisphere. The hypothesised pathogenesis is due to an increased number or size of neural cells; however, the exact mechanism can vary widely, depending on the underlying aetiology. We report a case outlining the prenatal diagnostic process and obstetric considerations for delivering an infant with HME secondary to megalencephaly-capillary malformation syndrome. After diagnosis, our patient was induced and delivered at 37 weeks of gestation via operative vaginal delivery. To our knowledge, this is the first report describing the course from prenatal diagnosis through delivery of a fetus with HME.

Somatic Development Disorders in Children and Adolescents Affected by Syndromes and Diseases Associated with Neurodysfunction and Hydrocephalus Treated/Untreated Surgically.

Background: This study was conducted to evaluate the co-occurrence of hydrocephalus treated/untreated surgically and congenital nervous system disorders or neurological syndromes with symptoms visible since childhood, and with somatic development disorders, based on significant data obtained during admission to a neurological rehabilitation unit for children and adolescents. Methods: The study applied a retrospective analysis of data collected during hospitalization of 327 children and adolescents, aged 4−18 years, all presenting congenital disorders of the nervous system and/or neurological syndromes associated with at least one neurodysfunction that existed from early childhood. To allow the identification of individuals with somatic development disorders in the group of children and adolescents with hydrocephalus treated/untreated surgically, the adopted criteria considered the z-score values for body height, body weight, head circumference, body mass index, and head circumference index. Results: Treated/untreated hydrocephalus was observed in the study group at the rates of 8% and 0.9%, respectively. Among 239 patients with cerebral palsy, 9 (3.8%) had surgically treated hydrocephalus, 17 (70.8%) of 24 patients with neural tube defects also had hydrocephalus treated with surgery, and 3 (12.5%) of 24 patients with neural tube defects had untreated hydrocephalus. This medical condition was a more frequent comorbidity in subjects with neural tube defects compared with those with cerebral palsy (p < 0.001). Subjects with untreated hydrocephalus most frequently presented macrocephaly (p < 0.001), including absolute macrocephaly (p = 0.001), and with tall stature (p = 0.007). Excessive body mass co-occurred more frequently with surgically untreated hydrocephalus, but the relationship was not statistically significant (p = 0.098). Conclusions: Surgically treated hydrocephalus occurred in patients with cerebral palsy and neural tube defects, and untreated hydrocephalus was present only in patients with neural tube defects. Untreated hydrocephalus negatively changed the course of individual development in the studied group of children, in contrast to surgically treated hydrocephalus.

Megalencephalic leukoencephalopathy with subcortical cysts: the importance of early diagnosis.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts is a rare type of leukodystrophy associated with mutations in the MLC1 and GlialCAM genes. The classic form is characterized by macrocephaly, early or delayed normal neurodevelopment followed by a period of slow motor skill loss, with cerebellar ataxia and spasticity; some patients develop movement disorders and seizures. Magnetic resonance imaging shows widespread diffuse white matter involvement with edema and subcortical cysts. CASE REPORT: We describe the case of two sisters aged 6 and 10 years, consanguineous parents, with a history of psychomotor delay and macrocephaly. The older sister presented with seizures at the age of 4 years and spasticity without loss of gait; the younger sister had a similar clinical picture. Magnetic resonance imaging showed diffuse alteration of the white matter and subcortical cysts in the temporal lobes. Electroencephalogram detected focal epileptiform activity. Seizure control was achieved upon initiation of carbamazepine treatment. By sequencing, a homozygous variant of the MLC1 gene was found in exon 3: c.255T>G (p.Cys85Trp). CONCLUSIONS: Leukodystrophies are rare diseases that represent a diagnostic challenge. Clinical, radiological, and molecular findings allow diagnostic certainty, the appropriate direction of interventions, and adjustment to the prognosis of each entity. The c.255T>G mutation was previously described in a South American patients, suggesting that it is a specific variant to Latin populations.

INTRODUCCIÓN: La leucoencefalopatía megalencefálica con quistes subcorticales es una leucodistrofia poco frecuente, asociada con mutaciones en los genes MLC1 y GlialCAM. La forma clásica se caracteriza por macrocefalia, neurodesarrollo temprano normal o con retraso seguido por un periodo de pérdida lenta de habilidades motoras, con ataxia cerebelosa y espasticidad; algunos pacientes desarrollan trastornos del movimiento y crisis convulsivas. La resonancia magnética muestra afección difusa generalizada de la sustancia blanca con edema y quistes subcorticales. CASO CLÍNICO: Se presenta el caso de dos hermanas de 6 y 10 años con historia de retraso psicomotor y macrocefalia, hijas de padres consanguíneos. La mayor inició con crisis convulsivas a los 4 años y espasticidad sin pérdida de la marcha autónoma; la menor presentó un cuadro clínico similar. La resonancia magnética mostró una alteración difusa de la sustancia blanca y quistes subcorticales en los lóbulos temporales. El electroencefalograma detectó actividad epileptiforme focal. Se logró el control de las crisis convulsivas al iniciar el tratamiento con carbamazepina. Por secuenciación, se encontró una variante homocigota del gen MLC1 en el exón 3: c.255T>G (p.Cys85Trp). CONCLUSIONES: Las leucodistrofias son enfermedades raras que representan un desafío para su diagnóstico. Los hallazgos clínicos, radiológicos y moleculares permiten la certeza del diagnóstico, la dirección adecuada de las intervenciones y el ajuste al pronóstico de cada una. La mutación c.255T>G fue descrita previamente en pacientes sudamericanos, lo que sugiere que podría tratarse de una variante específica de poblaciones latinas.

Megalencephaly-capillary malformation syndrome and associated hydrocephalus: treatment options and revision of the literature.

PURPOSE: We describe our series of 4 patients with megalencephaly-capillary malformation syndrome (MCAP) and review the literature in order to assess the optimal treatment for the associated hydrocephalus. METHODS: We review our institutional series of hydrocephalus associated with MCAP and review the literature, analyzing the causes that could originate the hydrocephalus and the different types of treatments proposed for them. RESULTS: Of our patients treated with ventriculoperitoneal (VP) shunt, one suffered a surgical revision of the shunt and died due to a cranial trauma unrelated to her syndrome or the previous shunt surgery, and the other did not undergo surgical revisions until the end of her follow-up. Our patients treated with endoscopic third ventriculostomy (ETV) have improved their symptomatology and have not suffered of any complications related to the hydrocephalus after the ETV surgery. CONCLUSIONS: We update the treatment of MCAP-associated hydrocephalus and propose ETV as a valid treatment, as it seems a safe procedure with a low rate of complications.

Clinical characterization of individuals with the distal 1q21.1 microdeletion.

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.

Leukoencephalopathy in RIN2 syndrome: Novel mutation and expansion of clinical spectrum.

RIN2 syndrome also known as MACS syndrome is a rare autosomal recessive connective tissue disorder caused by RIN2 mutations and is accompanied by following clinical features: macrocephaly, coarsening of facial features, downward slanting palpebral fissures, Puffy droopy eyelids, full everted lips, soft redundant skin especially in face, gum hypertrophy, irregular dentition, sparse scalp hair, skeletal problems, joint hypermobility and scoliosis. RIN2 gene encodes the RAS and RAB interactor 2 and biallelic mutations in this gene cause cell trafficking dysfunction. Here we reported the eleventh patient of RIN2 syndrome in a 4 yr-old boy, from Tehran, Iran as the youngest reported patient so far. Whole exome sequencing revealed a novel frameshift homozygous variant of NM_001242581.1: c.2251dup; p.(Leu751Profs*9) in RIN2 gene. In addition to the previously reported symptoms for the RIN2 syndrome, white matter abnormalities in his brain MRI were noticed. Our findings expand the clinical spectrum of MACS syndrome due to mutation in RIN2 gene.

Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.

The genotype-first approach has been successfully applied and has elucidated several subtypes of autism spectrum disorder (ASD). However, it requires very large cohorts because of the extensive genetic heterogeneity. We investigate the alternate possibility of whether phenotype-specific genes can be identified from a small group of patients with specific phenotype(s). To identify novel genes associated with ASD and abnormal head circumference using a phenotype-to-genotype approach, we performed whole-exome sequencing on 67 families with ASD and abnormal head circumference. Clinically relevant pathogenic or likely pathogenic variants account for 23.9% of patients with microcephaly or macrocephaly, and 81.25% of those variants or genes are head-size associated. Significantly, recurrent pathogenic mutations were identified in two macrocephaly genes (PTEN, CHD8) in this small cohort. De novo mutations in several candidate genes (UBN2, BIRC6, SYNE1, and KCNMA1) were detected, as well as one new candidate gene (TNPO3) implicated in ASD and related neurodevelopmental disorders. We identify genotype-phenotype correlations for head-size-associated ASD genes and novel candidate genes for further investigation. Our results also suggest a phenotype-to-genotype strategy would accelerate the elucidation of genotype-phenotype relationships for ASD by using phenotype-restricted cohorts.

Differential Altered Auditory Event-Related Potential Responses in Young Boys on the Autism Spectrum With and Without Disproportionate Megalencephaly.

Autism spectrum disorder (ASD), characterized by impairments in social communication and repetitive behaviors, often includes altered responses to sensory inputs as part of its phenotype. The neurobiological basis for altered sensory processing is not well understood. The UC Davis Medical Investigation of Neurodevelopmental Disorders Institute Autism Phenome Project is a longitudinal, multidisciplinary study of young children with ASD and age-matched typically developing (TD) controls. Previous analyses of the magnetic resonance imaging data from this cohort have shown that ∼15% of boys with ASD have disproportionate megalencephaly (DM) or brain size to height ratio, that is 1.5 standard deviations above the TD mean. Here, we investigated electrophysiological responses to auditory stimuli of increasing intensity (50-80 dB) in young toddlers (27-48 months old). Analyses included data from 36 age-matched boys, of which 24 were diagnosed with ASD (12 with and 12 without DM; ASD-DM and ASD-N) and 12 TD controls. We found that the two ASD subgroups differed in their electrophysiological response patterns to sounds of increasing intensity. At early latencies (55-115 ms), ASD-N does not show a loudness-dependent response like TD and ASD-DM, but tends to group intensities by soft vs. loud sounds, suggesting differences in sensory sensitivity in this group. At later latencies (145-195 ms), only the ASD-DM group shows significantly higher amplitudes for loud sounds. Because no similar effects were found in ASD-N and TD groups, this may be related to their altered neuroanatomy. These results contribute to the effort to delineate ASD subgroups and further characterize physiological responses associated with observable phenotypes. Autism Res 2019, 12: 1236-1250. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Approximately 15% of boys with ASD have much bigger brains when compared to individuals with typical development. By recording brain waves (electroencephalography) we compared how autistic children, with or without big brains, react to sounds compared to typically developing controls. We found that brain responses in the big-brained group are different from the two other groups, suggesting that they represent a specific autism subgroup.

Familial Intracranial Hypertension in 2 Brothers With PTEN Mutation: Expansion of the Phenotypic Spectrum.

PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppressor protein that antagonizes the PI3 K signaling pathway and alters the MTOR pathway. Mutations in PTEN have been described in association with a number of syndromes including PTEN hamartoma-tumor syndrome, macrocephaly/autism, and juvenile polyposis of infancy. Although there is a wide variability in the clinical and radiologic presentations of PTEN-related phenotypes, the most consistent features include macrocephaly and increased tumorigenesis. Intracranial hypertension may be idiopathic or secondary to multiple etiologies. We describe 2 siblings harboring a PTEN mutation who presented with macrocephaly and intracranial hypertension. Repeat brain MRIs were normal in both. Acetazolamide treatment normalized intracranial pressure, but several trials of medication tapering led to recurrence of intracranial hypertension symptoms. The clinical presentation of our patients expands the PTEN-related phenotypes. We discuss the possible pathophysiology in view of PTEN function.