Systematic Approach to Pediatric Macrocephaly.

Macrocephaly, defined as a head circumference greater than 2 standard deviations above the mean, is a relatively common presenting symptom in the pediatric population at routine well-child examinations and a common indication for neuroimaging. Multiple imaging modalities are complementary in evaluating macrocephaly, including US, CT, and MRI. The differential diagnosis for macrocephaly is broad, and many disease processes lead to macrocephaly only when the sutures are open. In patients with closed sutures, these entities instead lead to increased intracranial pressure, according to the Monroe-Kellie hypothesis, which states that there is an equilibrium between intracranial constituents due to the fixed intracranial volume. The authors describe a useful paradigm for classifying macrocephaly by identifying which of the four components of the cranium (ie, cerebrospinal fluid, blood and vasculature, brain parenchyma, or calvarium) has an increased volume. Patient age, additional imaging findings, and clinical symptoms are also useful features. Most cases in the pediatric population are due to increased cerebrospinal fluid spaces, such as benign enlargement of the subarachnoid space, which must be carefully distinguished from subdural fluid collections in patients with accidental or nonaccidental trauma. Other common causes of macrocephaly are discussed, including hydrocephalus secondary to an aqueductal web, hemorrhage, or a neoplasm. The authors also provide information on some of the rarer diseases for which imaging may provide the impetus for genetic testing (eg, overgrowth syndromes and metabolic disorders). ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Prevalence of Visible Subdural Spaces in Benign Enlargement of Subarachnoid Spaces in Infancy: A Retrospective Analysis Utilizing Magnetic Resonance Imaging.

OBJECTIVE: Benign Enlargement of the Subarachnoid Spaces in Infancy (BESSI) is a common finding during workup for progressive macrocephaly. BESSI has been associated with slightly higher prevalence of subdural (SD) spaces and a risk for developing subdural hematoma. This study utilizes fast brain magnetic resonance imaging (MRI) to investigate the prevalence of visible SD spaces in BESSI. METHODS: A retrospective review was performed for all pediatric patients who underwent brain MRI for macrocephaly. Patients with a diagnosis of BESSI were included in the study. A total of 109 patients met the inclusion criteria. Patient demographics were collected, and images were reviewed for size of subarachnoid, visible SD spaces, and ventricle size. Descriptive and inferential statistics were performed. RESULTS: The average age was 8 ± 4.6 months, 64 (59%) were male, and 55 patients had no previous medical history (50%). Sixty-seven percent of all patients were identified to have visible SD spaces. Eleven patients had confirmed SD hematomas; 1 patient was deemed to have abusive head trauma. Visible SD spaces were associated with younger age (6.9 months). Thirty-one patients with visible SD spaces had follow-up MRI, with complete resolution by 33 months. CONCLUSIONS: BESSI is a self-limiting pathology that has been associated with visible SD spaces and potential risk for SD hemorrhages. We report a high prevalence of visible SD spaces within BESSI through utilization of fast brain MRI. These spaces may contribute to the higher rate of incidental subdural hematoma in this population.

Head circumference at birth and intellectual disability: a nationwide cohort study.

BACKGROUND: Intellectual disability (ID) is a prevalent chronic disability affecting up to 1-3% of the general population. Small head circumference at birth, a surrogate measure of foetal cerebral growth, may be a risk factor for ID. We aimed to investigate the association between the full distribution of head circumference at birth and ID. METHODS: This cohort study was based on Danish nationwide registries and included all Danish singletons born alive from 1997 to 2013. Follow-up ended at October 2015. The data was analysed using a Cox proportional hazards regression model adjusted for a large number of potential confounders. RESULTS: The cohort comprised 986,909 infants. Neither microcephaly nor macrocephaly at birth was consistently associated with the risk of ID. Within the normal range of head circumference, larger head circumference was associated with a decreased risk of ID (HR per standard deviation increase in head circumference z score 0.85, 95% CI 0.81-0.88). The association detected within the normal range was consistent in all sensitivity analyses. CONCLUSIONS: Intrauterine brain growth restriction may be a risk factor for ID.

Overgrowth syndromes - clinical and molecular aspects and tumour risk.

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.

Clinical, radiological, and auxological characteristics of patients with cleidocranial dysplasia followed in a pediatric referral hospital in Argentina. / Características clínicas, radiológicas y auxológicas de pacientes con displasia cleidocraneal seguidos en un hospital pediátrico de referencia en Argentina.

Cleidocranial dysplasia is an autosomal dominant skeletal dysplasia caused by mutations in the RUNX2 gene; its prevalence has been estimated at 1/1 000 000 newborn infants. This study presents 37 patients (22 girls) assessed between 1992 and 2016 at the Skeletal Dysplasias Multidisciplinary Clinics of Hospital Garrahan, Argentina. FINDINGS: 35% of positive family history; median age at the time of diagnosis: 2.61 years old; positive radiological findings in the skull and pubis: 95%; in the clavicles: 100%. Dental and hearing complications were common. Auxology: boys had a median height of -1.81 SD (-3.26 to 0.2) and girls had a median height of -1.36 SD (-4.28 to 1.36). Five out of 13 patients were short for parental height. Adult height (median): 162.8 cm in boys and 149.2 cm in girls. No evident alterations were observed in the sitting height/height ratio. One patient had true macrocephaly; 12 (32%), relative macrocephaly. Intrafamily variability was described in terms of height.

La displasia cleidocraneal es una displasia esquelética autosómica dominante causada por mutaciones en el gen RUNX2, con una prevalencia estimada de 1/1 000 000 de recién nacidos. Se presentan 37 pacientes (22 mujeres) evaluados entre 1992 y 2016 en las clínicas de displasias esqueléticas, Hospital Garrahan, Argentina. Hallazgos: 35% de antecedentes familiares positivos; edad mediana al momento del diagnóstico: 2,61 años; características radiológicas positivas en el cráneo y el pubis: 95%; en las clavículas: 100%. Las complicaciones dentales y auditivas fueron comunes. Auxología: mediana de estatura de -1,81 (-3,26-0,2) DE en los varones, -1,36 (-4,28-1,36) DE en las mujeres. Cinco de trece pacientes fueron bajos para la estatura parental. Estatura adulta (mediana): 162,8 cm y 149,2 cm en los varones y las mujeres. No fueron evidentes alteraciones en la proporción estatura sentada/estatura. Un paciente presentó macrocefalia real; 12 (32%), macrocefalia relativa. Se describe variabilidad intrafamiliar de estatura.

Macrocephaly diagnosed during well child visits.

BACKGROUND: The measurement of head circumference (HC) provides valuable anthropometric data for a child's growth during well child visits. There are few studies on the characteristics of macrocephaly (MC) diagnosed during well child visits. The aim of this study was to identify the characteristics of children with MC diagnosed during the well-child visits. METHODS: This descriptive clinical study was carried out in the well child unit of a medical faculty hospital. The health records of all children who were followed up between 2004 and 2014 were reviewed. The records of children with the diagnosis of MC were evaluated. All children with MC had cranial ultrasonography, measurement of parental HC, and biochemistry. The HC measurements were carried out until 3 years of age in the unit. RESULTS: Ninety of 9,758 children (0.9%) had the diagnosis of MC. Of these children, 61% were male. Mean age at diagnosis was 2.7 months. The majority of children (63.3%) had familial MC. The other leading findings were isolated MC and hydrocephalus: two of eight children with hydrocephalus had delayed neuromotor development. CONCLUSION: MC was not rare in the present well child unit population. The evaluation of parental HC and cranial ultrasonography might be important for the differential diagnosis.

Wilms tumor screening in diffuse capillary malformation with overgrowth and macrocephaly-capillary malformation: A retrospective study.

BACKGROUND: CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies) syndrome is associated with regional bony and/or soft tissue overgrowth, capillary malformation, and an increased risk for Wilms tumor. OBJECTIVE: To evaluate the frequency of Wilms tumor in patients with 2 similar conditions: diffuse capillary malformation with overgrowth (DCMO) and macrocephaly-capillary malformation (M-CM). METHODS: Culling our Vascular Anomalies Center database, we retrospectively reviewed patients in whom DCMO and M-CM had been diagnosed and who were evaluated between 1998 and 2016 for possible development of Wilms tumor. Patients younger than 8 years of age at their last visit and not seen in more than 2 years were contacted for follow-up. RESULTS: The study comprised 89 patients: 67 with DCMO, 17 with M-CM, and 5 with an indeterminate diagnosis. No case of Wilms tumor was found in these groups. LIMITATIONS: Some patients were younger than 8 years of age at last follow-up visit and the sample size was small. CONCLUSION: Patients with DCMO do not appear to be at increased risk for Wilms tumor. Screening is probably unnecessary in DCMO unless there is associated hemihypertrophy. Although there were no cases in our cohort, there are 2 reports of M-CM associated with Wilms tumor in the literature.

Brief Report: Macrocephaly Phenotype and Psychiatric Comorbidity in a Clinical Sample of Mexican Children and Adolescents with Autism Spectrum Disorders.

Autism spectrum disorders (ASD) may present with macrocephaly. Few studies have analyzed the association with psychiatric comorbidity. Participants were 94 children with any ASD with an age range from 2 to 16 years (Mdn 6 years), 82% were boys. It was found that 20% of the sample had macrocephaly and 1% microcephaly. There was no association between the presence of macrocephaly and subtype of ASD. The most associated comorbidity was attention-deficit/hyperactivity disorder (ADHD) 54.2%, followed by specific phobia 34%, dysthimia 29.7%, oppositional defiant disorder 13.83% motor tics 11.7%, separation anxiety 9.5% and Gilles de la Tourette 8.5%. In conclusion, macrocephaly and psychiatric comorbidity in this clinical sample of children with ASD is similar to the international literature results.

Macrocephaly in infancy: benign enlargement of the subarachnoid spaces and subdural collections.

OBJECTIVE Benign enlargement of the subarachnoid spaces (BESS) is a common finding on imaging studies indicated by macrocephaly in infancy. This finding has been associated with the presence of subdural fluid collections that are sometimes construed as suggestive of abusive head injury. The prevalence of BESS among infants with macrocephaly and the prevalence of subdural collections among infants with BESS are both poorly defined. The goal of this study was to determine the relative frequencies of BESS, hydrocephalus, and subdural collections in a large consecutive series of imaging studies performed for macrocephaly and to determine the prevalence of subdural fluid collections among patients with BESS. METHODS A text search of radiology requisitions identified studies performed for macrocephaly in patients ≤ 2 years of age. Studies of patients with hydrocephalus or acute trauma were excluded. Studies that demonstrated hydrocephalus or chronic subdural hematoma not previously recognized but responsible for macrocephaly were noted but not investigated further. The remaining studies were reviewed for the presence of incidental subdural collections and for measurement of the depth of the subarachnoid space. A 3-point scale was used to grade BESS: Grade 0, < 5 mm; Grade 1, 5-9 mm; and Grade 2, ≥ 10 mm. RESULTS After exclusions, there were 538 studies, including 7 cases of hydrocephalus (1.3%) and 1 large, bilateral chronic subdural hematoma (0.2%). There were incidental subdural collections in 21 cases (3.9%). Two hundred sixty-five studies (49.2%) exhibited Grade 1 BESS, and 46 studies (8.6%) exhibited Grade 2 BESS. The prevalence of incidental subdural collections among studies with BESS was 18 of 311 (5.8%). The presence of BESS was associated with a greater prevalence of subdural collections, and higher grades of BESS were associated with increasing prevalence of subdural collections. After controlling for imaging modality, the odds ratio of the association of BESS with subdural collections was 3.68 (95% CI 1.12-12.1, p = 0.0115). There was no association of race, sex, or insurance status with subdural collections. Patients with BESS had larger head circumference Z-scores, but there was no association of head circumference or age with subdural collections. Interrater reliability in the diagnosis and grading of BESS was only fair. CONCLUSIONS The current study confirms the association of BESS with incidental subdural collections and suggests that greater depth of the subarachnoid space is associated with increased prevalence of such collections. These observations support the theory that infants with BESS have a predisposition to subdural collections on an anatomical basis. Incidental subdural collections in the setting of BESS are not necessarily indicative of abusive head injury.

De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism.

Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3ß)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.

Pre-schoolchildren with autism spectrum disorders are rarely macrocephalic: a population study.

Numerous clinical studies over the past decades have concluded that there is an association between autism spectrum disorders (ASD) and large head size. Lately, some studies have reported conflicting results. The present study was conducted with a view to assess the presence of macrocephaly in a community-representative group of pre-school children with ASD. The prevalence of ASD in this general population was 0.8%. Thirty-three children (5 girls, 28 boys) recruited after general population screening for ASD, and diagnosed with ASD (two-thirds not globally delayed) were assessed as regards growth parameters; height, weight, and head circumference (HC), at birth and at comprehensive medical-psychiatric diagnostic examinations at a mean age of 3 years. Macrocephaly in the present study was defined as HC above the 97th percentile, and ≥ 2 SD above recorded length/height. Only one of the 33 children (3%) had macrocephaly which is similar to the general population prevalence. Another 9% had a big but proportional head. None of the children were microcephalic. In this community-based study we found no evidence to support a strong link between a large head size and ASD. Conclusions must be guarded because of the relatively small number of ASD cases included.

How innocent is corpus callosum dysgenesis?

BACKGROUND/AIMS: We aimed to investigate the relationship between corpus callosum dysgenesis (CCD) and associated asymptomatic closed spinal dysraphisms (CSDs). METHODS: 2,840 pediatric patients who were referred to our outpatient clinic between the years 2005 and 2013 with the diagnosis of microcephaly, macrocephaly, congenital hydrocephaly, epilepsy, mental-motor retardation and suspicion of intracranial mass were evaluated. Eighty-five patients were identified with a CCD by cranial magnetic resonance imaging (MRI). The 85 patients with CCD were evaluated by whole spinal vertebral MRI for possible CSD and the results were evaluated. RESULTS: 31/85 (36.4%) patients (20 males, 11 females) were detected to have radiological findings of CSD. The most common radiological finding was a low-lying conus medullaris, either alone, or as part of a multiple pathology in 26 of the 31 patients, followed by diastematomyelia in 16 of 31 cases and spinal lipoma in 4 of the 31 cases. CONCLUSION: When the neuroaxis emerges as a whole, the structures of embryological ectodermal origin and cranial and spinal structures are not independent regions from each other and thus, asymptomatic CSDs have been demonstrated to accompany CCD. In diseases of neural origin in which early diagnosis is of the utmost importance, each case with dysgenesis, diagnosed incidentally or during differential diagnosis, should be evaluated for possible CSD and should be treated with a multidisciplinary approach before any neurological deficit appears.

Prevalence of subdural collections in children with macrocrania.

BACKGROUND AND PURPOSE: The relationship between enlarged subarachnoid spaces and subdural collections is poorly understood and creates challenges for clinicians investigating the etiology of subdural collections. The purpose of this study was to determine the prevalence of subdural collections on cross sectional imaging in children with macrocephaly correlating with subarachnoid space enlargement. MATERIALS AND METHODS: The radiology information system of a large pediatric medical center was reviewed for "macrocrania" and "macrocephaly" on reports of cranial MRI/CT examinations in children <24 months of age, over a 24-month period. Head circumference was obtained from the clinical record. Studies were reviewed blindly for subdural collection presence and subarachnoid space size. Children with prior cranial surgery, parenchymal abnormalities, hydrocephalus, or conditions predisposing to parenchymal volume loss were excluded. Chart review was performed on those with subdural collections. RESULTS: Imaging from 177 children with enlarged head circumference was reviewed. Nine were excluded, for a final cohort of 168 subjects (108 with enlarged subarachnoid space). Subdural collections were identified in 6 (3.6%), all with enlarged subarachnoid space (6/108, 5.6%). In 4, subdural collections were small, homogeneous, and nonhemorrhagic. In 2, the collections were complex (septations or hemorrhage). Two children were reported as victims of child abuse (both with complex collections). No definitive etiology was established in the other cases. CONCLUSIONS: The prevalence of subdural collections in imaged children with macrocrania was 3.6%, all occurring in children with enlarged subarachnoid space. Our results suggest that enlarged subarachnoid space can be associated with some subdural collections in this cohort. Despite this, we believe that unexpected subdural collections in children should receive close clinical evaluation for underlying causes, including abusive head trauma.

Poor postnatal head growth in very preterm infants is associated with impaired neurodevelopment outcome.

AIM: To examine the association between neurodevelopmental outcome and head circumference (HC) in a cohort of very preterm infants and in this context to investigate the relevance of suboptimal head size. METHODS: Somatometric data were obtained at birth, discharge and 3, 12 and 24 months for all infants born in Tyrol <32 weeks gestational age. Growth data are presented as z scores. HC was defined as microcephaly (>2 SD below mean), suboptimal (>1 SD below mean) or normal head size (<1 SD below mean). Neurodevelopmental outcome was quantified at 12 and 24 months using the Bayley Scales of Infant Development II. RESULTS: The percentage of infants with suboptimal head size increased until the age of 24 months and was related to adverse outcome. The association was strongest between HC at 3 months and psychomotor and mental outcome as quantified using the Bayley Scales of Infant Development. CONCLUSION: Poor postnatal head growth was common in our study cohort. Both microcephaly and suboptimal head size were associated with impaired neurodevelopmental outcome. Suboptimal head size at 3 months was found to be particularly associated with adverse neurodevelopmental outcome.

Risk of sensorineural hearing loss in infants with abnormal head size.

OBJECTIVE: The purpose was to determine the risk of sensorineural hearing loss (SNHL) in young infants with abnormal head sizes in a developing country. MATERIALS AND METHODS: A matched case-control study of two (hospital-based and community-based) cohorts of term infants who failed a two-stage hearing screening test with transient-evoked otoacoustic emissions and automated auditory brainstem response in Lagos, Nigeria. Abnormal head size (microcephaly or macrocephaly) was determined with World Health Organisation's growth standards for head circumference. The adjusted odds ratios for the risk of SNHL in microcephalic and macrocephalic infants were established through unconditional and conditional logistic regression analyses. RESULTS: Some 194 cases and 970 matched controls drawn from 8,872 term singletons 3 months or younger were studied. The median age of enrolment was 1 day in the hospital-based cohort and 17 days in the community-based cohort. Microcephalic infants in both cohorts were significantly at risk of SNHL while no significant risk was found among macrocephalic infants regardless of birth setting. CONCLUSIONS: Microcephalic infants should be routinely screened for potential hearing loss particularly where universal newborn hearing screening is not immediately practicable. Etiological investigation of abnormal head size in this and similar population is warranted. Routine screening and maternal immunization for congenital infections should also be considered.

Autism spectrum disorders: head circumference and body length at birth are both relative.

AIM: Although the body length and weight of an infant are related to head circumference, little research on ASDs has examined these factors. Our study compared the head circumferences of neonates who were later diagnosed with ASD with a control group. Additional comparisons on morphological disproportions at birth included the head circumference-to-height and head circumference-to-weight ratios. METHODS: We recruited 422 children with ASD and 153 typically developing children. Head circumference, body length and weight at birth were collected and standardized as percentile scores according to gestational age and gender. RESULTS: Our results revealed that genuine macrocephaly was significantly higher in children with other pervasive developmental disorders compared with the control group. This difference was not observed with regard to genuine microcephaly. Relative macrocephaly and relative microcephaly were significantly more frequent in children with autism disorder compared with the control group with regard to body length. CONCLUSIONS: The differences in relative macrocephaly and microcephaly, as well as in other parameters, between diagnostic subgroups suggest that the presence of several neurological mechanisms plays a role in the later expression of different phenotypes. An increased head circumference-to-body length ratio in newborns may be a factor to follow that could be related to ASD.

Israeli children with autism spectrum disorder are not macrocephalic.

The prevalence of macrocephaly in autism spectrum disorder is reported to be much higher than in the general population, 12% to 37%. Progressive macrocephaly is even considered a warning sign for the development of autism. We evaluated the prevalence of an abnormal head circumference in children with autism in Israel and compared it with the head circumferences of children with developmental language disorder and children with normal development. We did not find a higher prevalence of macrocephaly among Israeli children with autism spectrum disorder (4.4%). Although children with autism spectrum disorder had a significantly higher rate of a head circumference above the 75th percentile compared with children with developmental language disorder, it was not significantly different compared with normal controls. We conclude that there is no increased prevalence of macrocephaly in Israeli children with autism; this can be attributed to a different genetic background.

Macrocephaly in children with autism spectrum disorders.

Research indicates the presence of macrocephaly or abnormally large head circumferences in children with autism and spectrum-related disorders, compared with their typically developing peers. Previous research, however, centered on non-nationally representative, clinic-based samples of children and adults with autism spectrum disorders. Moreover, these samples were typically small. The present study represents results of a nationally representative, community-based sample of children with and without autism spectrum disorders, derived from the Early Childhood Longitudinal Study Birth Cohort. Results reveal statistically nonsignificant differences in the head circumferences of children with autism spectrum disorders across three time points, compared with children without autism spectrum disorders. These results may be considered highly generalizable, because they are derived from a nationally representative, community-based sample of children with and without autism spectrum disorders from the Early Childhood Longitudinal Study Birth Cohort.

Principal pathogenetic components and biological endophenotypes in autism spectrum disorders.

Autism is a complex neurodevelopmental disorder, likely encompassing multiple pathogenetic components. The aim of this study is to begin identifying at least some of these components and to assess their association with biological endophenotypes. To address this issue, we recruited 245 Italian patients with idiopathic autism spectrum disorders and their first-degree relatives. Using a stepwise approach, patient and family history variables were analyzed using principal component analysis ("exploratory phase"), followed by intra- and inter-component cross-correlation analyses ("follow-up phase"), and by testing for association between each component and biological endophenotypes, namely head circumference, serotonin blood levels, and global urinary peptide excretion rates ("biological correlation phase"). Four independent components were identified, namely "circadian & sensory dysfunction," "immune dysfunction," "neurodevelopmental delay," and "stereotypic behavior," together representing 74.5% of phenotypic variance in our sample. Marker variables in the latter three components are positively associated with macrocephaly, global peptiduria, and serotonin blood levels, respectively. These four components point toward at least four processes associated with autism, namely (I) a disruption of the circadian cycle associated with behavioral and sensory abnormalities, (II) dysreactive immune processes, surprisingly linked both to prenatal obstetric complications and to excessive postnatal body growth rates, (III) a generalized developmental delay, and (IV) an abnormal neural circuitry underlying stereotypies and early social behaviors.