Cranio-Facial Characteristics in Autism Spectrum Disorder: A Scoping Review.

Autism spectrum disorders (ASD) consist of a complex group of neurodevelopmental disorders characterised by qualitative impairments of social interactions, communication abilities, and a limited, stereotyped, and repetitive selection of interests and activities. In light of the imperative to identify a possible biomarker for ASD, it has been determined that craniofacial anomalies serve as significant risk factors for neurodevelopmental disorders. The aim of this scoping review is to deepen the knowledge of the scientific literature related to cranio-facial characteristics in individuals with ASD, with a particular focus on recent research advancements. The review was performed by employing the search strings (("Autism Spectrum Disorder" OR autism OR ASD OR "Autism Spectrum") AND ("facial morphology" OR "facial phenotype")) on the databases PubMed/MEDLINE, Scopus, and ERIC as of March 9, 2023. The review comprised seven studies whose findings were obtained through quantitative analysis of Euclidean distances between anatomical landmarks. The examination of facial abnormalities represents a possible reliable diagnostic biomarker that could aid in the timely identification of ASD. Phenotypic characteristics that may serve as predictive indicators of the severity of autistic symptoms can be observed in certain individuals with ASD by applying anthropometric and instrumental measurements. The presence of a phenotype characterised by an increased intercanthal distance and a reduced facial midline height appears to be associated with a higher degree of severity in autistic symptoms. In addition, it is worth noting that facial asymmetry and facial masculinity can be considered reliable indicators for predicting a more severe manifestation of symptoms.

Evolution of Pediatric Migraine Patients Admitted at an Emergency Department after a 10-Year Follow-Up.

BACKGROUND: Despite its high prevalence, the clinical course of pediatric migraine has not been fully understood, and previous studies present conflicting results. We present here the findings of a 10-year follow-up study involving children with severe migraine pain admitted to our emergency department. Furthermore, all studies were carried out on selected outpatient clinical case studies. Our aim was to evaluate a population of migraine children admitted to an emergency department because of increased severity or frequency of pain or even because of very anxious parents concerning their child's headache in order to describe their long-term outcomes, whether it differed from that of outpatient populations and to identify possible predictors of prognosis. METHODS: We recruited 80 subjects with migraine headaches (mean age 8 years with a range of 4-14 years, 50% females), attending the baseline examination of a population admitted for a headache to the Emergency Department in the first half year of 2012. Of the 80 subjects, 48 (60%) were eligible for follow-up in 2022. We included in our study only patients diagnosed with migraine, according to the diagnostic criteria of the International Classification of Headache Disorders. All were contacted by telephone, and a semi-structured questionnaire was provided to them by email. The association between several possible prognostic factors (gender, familiar neurologic disorders, prenatal and perinatal disorders, social activities, sleep disorders, etc.) and the long-term persistence of migraine headaches were explored using logistic regression analysis. RESULTS: Of 48 subjects with migraine headaches at baseline, 31 (65%) had persistent migraine, and 17 (35%) experienced remission. The preliminary results showed that the presence of neurologic disorders in parents (p < 0.01-odds ratio 9.34 (2.53-41.64) and sleep disorders (p < 0.01-odds ratio 13.18 (2.25-252.74) significantly predicted the 10-year persistence of migraine headaches, while the other considered predictors were found not to influence prognosis. CONCLUSIONS: To our knowledge, this was the first study conducted on a selected pediatric population upon admission to the emergency room. Our study suggests that a population of pediatric migraine selected for admission to the emergency department also shows a favorable long-term prognosis, like the studies conducted in the outpatient sample. Familial neurological comorbidity and sleep disorders were unfavorable factors for predicting good outcomes.

Idiopathic Non-Dental Facial Pain Syndromes in Italian Children: A Clinical Case Series.

BACKGROUND: The orofacial pain syndromes (OFPs) are a heterogeneous group of syndromes characterized by painful attacks involving the orofacial structures. They may be summarily subdivided into two great categories: (1) orofacial pain mainly attributed to dental disorders such as dentoalveolar and myofascial orofacial pain or temporomandibular joint (TM) pain; (2) orofacial pain mainly attributed to non-dental pain as neuralgias, facial localization of primary headaches or idiopathic orofacial pain. The second group is uncommon, often described by single case reports, can often show overlapping symptoms with the first group, and represents a clinical challenge, carrying the risk of undervaluation and possibly invasive odontoiatric treatment. We aimed to describe a clinical pediatric series of non-dental orofacial pain and better to underline some topographic and clinical features associated with them. We retrospectively collected the data of children admitted to our headache centers (Bari, Palermo, Torino) from 2017 to 2021. Our inclusion criterion was the presence of non-dental orofacial pain following the topographic criteria of 3° International Classification of Headache Disorders (ICHD-3), and exclusion criteria included the pain syndromes attributed to the dental disorders and pain syndromes due to the secondary etiologies Results. Our sample comprised 43 subjects (23/20 M/F, in the range of ages 5-17). We classified them int: 23 primary headaches involving the facial territory during attacks, 2 facial trigeminal autonomic cephalalgias, 1 facial primary stabbing headache, 1 facial linear headache, 6 trochlear migraines, 1 orbital migraine 3 red ear syndrome and 6 atypical facial pain. All patients described debilitating pain for intensity (moderate/severe), 31 children had episodic attacks, and 12 had continuous pain. Almost all received drugs for acute treatment (less than 50% were satisfied), and some received non-pharmacological treatment associated with drug therapy Conclusion. Although rare OFP can occur in pediatric age, it can be debilitating if unrecognized and untreated, affecting the psychophysical well-being of young patients. We highlight the specific characteristics of the disorder for a more correct and earlier identification during the diagnostic process, already difficult in pediatric age, and to define the approach and possible treatment to prevent negative outcomes in adulthood.

The Quality of Life among Siblings of Autistic Individuals: A Scoping Review.

Autism spectrum disorders are a heterogeneous group of neurodevelopmental disorders presenting at a tender age, defined by qualitative deficits in social interactions and communication, thus having a substantial influence on the subject's family unit. Quality of life (QoL) refers to a person's perspective of their life situation, cultural and value background, objectives, expectations, and standards. When focusing on childhood and adolescence, age-related changes should be considered. For this scoping review, the authors used three peer-review literature database sources (PubMed/MEDLINE, Scopus, and ERIC) to delve deeper into components of the QoL of non-autistic siblings of autistic individuals. At the completion of the eligibility phase, 9 studies were included out of the 96 initial records. A total of 4/9 articles (45%) compared the non-autistic siblings of autistic individuals to the siblings of non-autistic people, while 3/9 articles (33%) compared the first group to the non-autistic siblings of patients with other chronic diseases. A total of 5/9 studies adopted specific questionnaires to evaluate QoL. Results from 6/9 articles revealed that the autism condition has varying effects on non-autistic siblings' QoL. According to the considered research, non-autistic siblings of autistic individuals experienced decreased psychological well-being, less perceived social support, increased aggressiveness and conflict-proneness, and higher levels of anxiety and stress impacting their QoL. The present findings provide important implications for additional and more punctual studies in this sector. Furthermore, as being a non-autistic sibling of an autistic individual is commonly undervalued, this review advocates the need to organize and improve support services for siblings.

A Preliminary Study on Photic Driving in the Electroencephalogram of Children with Autism across a Wide Cognitive and Behavioral Range.

Intermittent photic stimulation (IPS) is a useful technique in electroencephalography (EEG) to investigate the neurophysiological anomalies of brain activity. Although not an active task, IPS has also been explored in ASD; it is thought to capture local potential oscillators at specific frequencies and perhaps tap into rhythmic activity in a way that general resting-state recordings cannot. Previous studies suggest that individuals with ASD showed photic driving reactivity predominantly at lower frequencies of stimulation. In our study we used IPS to measure rhythmic oscillatory activity in a sample of 81 ASD children. We found a significant correlation linking ASD children with photic driving activation only at low frequencies (δθ band) and increased severity of "restricted behavior". This suggests that ASD children with higher severity of restricted behaviors could have a hypersynchronous θ power and an impaired resonance synchronization at middle-ranged frequencies (α). Furthermore, we found some evidence of hemispherical oscillatory asymmetry linked particularly to behavioral impairments. This result is in line with the EEG pattern model indicating a "U-shaped profile" of electrophysiological power alterations with excess power in low- and high-frequency bands and a reduction of power in the middle-ranged frequencies. IPS technique in electroencephalography is confirmed to reveal EEG biomarkers in autistic children, with a focus on spectral power, coherence, and hemisphere asymmetries.

A Preliminary Study on Cranio-Facial Characteristics Associated with Minor Neurological Dysfunctions (MNDs) in Children with Autism Spectrum Disorders (ASD).

Background. Craniofacial anomalies and minor neurological dysfunction (MNDs) have been identified, in literature, as risk factors for neurodevelopmental disorders. They represent physical indicators of embryonic development suggesting a possible contributory role of complications during early, even pre-conceptional, phases of ontogeny in autism spectrum disorders (ASD). Limited research has been conducted about the co-occurrence of the two biomarkers in children with ASD. This study investigates the associative patterns of cranio-facial anomalies and MNDs in ASD children, and whether these neurodevelopmental markers correlate with intensity of ASD symptoms and overall functioning. Methods. Caucasian children with ASD (n = 33) were examined. Measures were based on five anthropometric cranio-facial indexes and a standardized and detailed neurological examination according to Touwen. Relationships between anthropometric z-scores, MNDs and participant characteristics (i.e., age, cognitive abilities, severity of autistic symptoms measured using the Childhood Autism Rating Scale (CARS) checklist) were assessed. Results. With respect to specific MNDs, significant positive correlations were found between Cephalic Index and Sensory deficits (p-value < 0.001), which did not correlate with CARS score. Importantly, CARS score was positively linked with Intercanthal Index (p-value < 0.001), and negatively associated with posture and muscle tone (p-value = 0.027) and Facial Index (p-value = 0.004). Conclusion. Our data show a link between a specific facial phenotype and anomalies in motor responses, suggesting early brain dysmaturation involving subcortical structures in cerebro-craniofacial development of autistic children. This research supports the concept of a "social brain functional morphology" in autism spectrum disorders.

Incomplete Gestation has an Impact on Cognitive Abilities in Autism Spectrum Disorder.

Extreme prematurity is known as a risk factor for autism spectrum disorder (ASD). However, the association between prematurity and ASD, for children born moderately and late preterm (MLPT) and those born early term (ET), is less established. This retrospective study aimed to characterize the phenotypic characteristics (i.e. behavioral profile and cognitive abilities) of 254 children with ASD, between 3 and 15 years of age, born MLPT (19 children), ET (60 children) and full term (175 children). MLPT and ET births do not modify ASD symptomatology, but modify cognitive development. The results highlight that incomplete gestation, i.e., MLPT or ET, has a negative impact on both verbal and nonverbal cognitive abilities, in children with neurodevelopmental vulnerability.

Cranio-Facial Characteristics in Children with Autism Spectrum Disorders (ASD).

Background: Cranio-facial anomalies frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm. The identification of differences in the facial phenotype of children with Autism Spectrum Disorders (ASD) may reflect alterations in embryologic brain development in children with ASD. Methods: we evaluated 33 caucasian children with ASD using a 2D computerized photogrammetry. Anthropometric euclidean measurements and landmarks located on the soft tissue of the face and head, were based on five cranio-facial indexes. Relationships between anthropometric z-scores and participant characteristics (i.e., age, Global IQ, severity of autistic symptoms measured using the CARS checklist) were assessed. Results: Cephalic index z-score differed significantly from 0 in our ASD group (p = 0.019). Moreover, a significant negative correlation was found between Facial Index z-score and CARS score (p = 0.003); conversely, a positive correlation was found between Interchantal Index z-score and CARS score (p = 0.028). Conclusion: our measurements shows a dolichocephalic head shape which is not correlated with autism severity. Importantly, two craniofacial markers were significantly correlated with autism severity: increased orbital hyperthelorism and decrease of height of the facial midline. These data support previous findings of craniofacial anomalies in autism spectrum disorder suggesting an "ASD facial phenotype" that could be used to improve ASD diagnoses.

Autism is a prenatal disorder: Evidence from late gestation brain overgrowth.

This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum disorder (ASD) using prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms.

Sympathetic, Metabolic Adaptations, and Oxidative Stress in Autism Spectrum Disorders: How Far From Physiology?

Autism spectrum disorders (ASD) is a complex and multifaceted neurobehavioral syndrome with no specific cause still identified, despite the worldwide increasing (prevalence for 1,000 children from 6.7 to 14.6, between 2000 and 2012). Many biological and instrumental markers have been suggested as potential predictive factors for the precocious diagnosis during infancy and/or pediatric age. Many studies reported structural and functional abnormalities in the autonomic system in subjects with ASD. Sleep problems in ASD are a prominent feature, having an impact on the social interaction of the patient. Considering the role of orexins (A and B) in wake-sleep circadian rhythm, we could speculate that ASD subjects may present a dysregulation in orexinergic neurotransmission. Conversely, oxidative stress is implicated in the pathophysiology of many neurological disorders. Nonetheless, little is known about the linkage between oxidative stress and the occurrence or the progress of autism and autonomic functioning; some markers, such as heart rate (HR), heart rate variability (HRV), body temperature, and galvanic skin response (GSR), may be altered in the patient with this so complex disorder. In the present paper, we analyzed an autism case report, focusing on the rule of the sympathetic activity with the aim to suggest that it may be considered an important tool in ASD evaluation. The results of this case confirm our hypothesis even if further studies needed.

Minor Neurological Dysfunctions (MNDs) in Autistic Children without Intellectual Disability.

BACKGROUND: Children with autism spectrum disorder (ASD) require neurological evaluation to detect sensory-motor impairment. This will improve understanding of brain function in children with ASD, in terms of minor neurological dysfunctions (MNDs). METHODS: We compared 32 ASD children without intellectual disability (IQ ≥ 70) with 32 healthy controls. A standardized and age-specific neurological examination according to Touwen was used to detect the presence of MNDs. Particular attention was paid to severity and type of MNDs. RESULTS: Children with ASD had significantly higher rates of MNDs compared to controls (96.9% versus 15.6%): 81.3% had simple MNDs (p < 0.0001) and 15.6% had complex MNDs (p = 0.053). The prevalence of MNDs in the ASD group was significantly higher (p < 0.0001) than controls. With respect to specific types of MNDs, children with ASD showed a wide range of fine manipulative disability, sensory deficits and choreiform dyskinesia. We also found an excess of associated movements and anomalies in coordination and balance. CONCLUSIONS: Results replicate previous findings which found delays in sensory-motor behavior in ASD pointing towards a role for prenatal, natal and neonatal risk factors in the neurodevelopmental theory of autism.

The Rorschach Test Evaluation in Chronic Childhood Migraine: A Preliminary Multicenter Case-Control Study.

OBJECT: About 1.2-3.2% of children at 7 years of age with increasing age up to 4-19% in adolescents are suffering from migraine without aura (MwA). The aim of the present study is investigating the personality style associated with children and adolescents affected by MwA, administrating the Rorschach test, and comparing with typical developing healthy controls (TD). METHODS: 137 patients (74 males), aged 7.3-17.4 years (mean age 11.4, SD 3.02 years), affected by MwA according to the IHs-3 criteria. The Rorschach variables were treated as numerical variables and statistically tested with t-Student's analysis. RESULTS: No statistical differences were found between the MwA and TD for age (p = 0.55), and gender (p = 0.804). From the comparison between the two samples, MwA group shows lower W responses (p < 0.001), good quality W responses (p < 0.001), high frequency of detailed responses (p < 0.001), the presence of even minor form of good quality responses (p < 0.001), increased presence of animals answers (A%) (p < 0.001), more frequent trivial answers (Ban%) (p < 0.001). DISCUSSION: Rorschach interpretation pinpointed many interesting and, perhaps, peculiar aspects in our MwA population such as a trend predisposition for: analytical reasoning rather than synthetic, ease/practicality rather than creativity, oppositionality rather than external adaptation to the environment that may be interpreted as effect of general maladaptivity.

Metabolomics Study of Urine in Autism Spectrum Disorders Using a Multiplatform Analytical Methodology.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with no clinical biomarker. The aims of this study were to characterize a metabolic signature of ASD and to evaluate multiplatform analytical methodologies in order to develop predictive tools for diagnosis and disease follow-up. Urine samples were analyzed using (1)H and (1)H-(13)C NMR-based approaches and LC-HRMS-based approaches (ESI+ and ESI- on HILIC and C18 chromatography columns). Data tables obtained from the six analytical modalities on a training set of 46 urine samples (22 autistic children and 24 controls) were processed by multivariate analysis (orthogonal partial least-squares discriminant analysis, OPLS-DA). The predictions from each of these OPLS-DA models were then evaluated using a prediction set of 16 samples (8 autistic children and 8 controls) and receiver operating characteristic curves. Thereafter, a data fusion block-scaling OPLS-DA model was generated from the 6 best models obtained for each modality. This fused OPLS-DA model showed an enhanced performance (R(2)Y(cum) = 0.88, Q(2)(cum) = 0.75) compared to each analytical modality model, as well as a better predictive capacity (AUC = 0.91, p-value = 0.006). Metabolites that are most significantly different between autistic and control children (p < 0.05) are indoxyl sulfate, N-α-acetyl-l-arginine, methyl guanidine, and phenylacetylglutamine. This multimodality approach has the potential to contribute to find robust biomarkers and characterize a metabolic phenotype of the ASD population.

Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study.

The aromatic compound p-cresol (4-methylphenol) has been found elevated in the urines of Italian autistic children up to 8 years of age. The present study aims at replicating these initial findings in an ethnically distinct sample and at extending them by measuring also the three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol. Total urinary p-cresol, p-cresylsulfate and p-cresylglucuronate were significantly elevated in 33 French autism spectrum disorder (ASD) cases compared with 33 sex- and age-matched controls (p < 0.05). This increase was limited to ASD children aged ≤8 years (p < 0.01), and not older (p = 0.17). Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p < 0.05), although not with overall autism severity. These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism.

West syndrome followed by juvenile myoclonic epilepsy: a coincidental occurrence?

BACKGROUND: West syndrome is an age-dependent epilepsy with onset peak in the first year of life whose aetiology may be symptomatic or cryptogenic. Long-term cognitive and neurological prognosis is usually poor and seizure outcome is also variable. Over the past two decades a few patients with favourable cognitive outcome and with total recovery from seizures were identified among the cryptogenic group suggesting an idiopathic aetiology. Recent research has described two children with idiopathic WS who later developed a childhood absence epilepsy. CASE PRESENTATION: We reviewed the medical records of patients with West syndrome admitted to the our Child Neuropsychiatry Unit in the last 15 years in order to know the clinical evolution of infantile spasms.We report a child with West syndrome with onset at 8 months of age followed by some clusters of bilateral, arrhythmic myoclonic jerks of the upper limbs, mainly on awakening, synchronous with the generalized discharges of 4 Hz spike-wave occurring at 12 years of age and by co-occurrence of a later generalized tonic-clonic seizure at 14 years and four months, both sensitive to Levetiracetam suggesting a juvenile myoclonic epilepsy. CONCLUSIONS: This unusual evolution, never previously reported, suggests that both electroclinical features mentioned above may share some pathophysiological processes genetically determined which produce a susceptibility to seizure and emphasizes that the transition between different age-related epileptic phenotypes may involve also the West syndrome.

Minor physical anomalies in children with autism spectrum disorder.

AIM: To investigate the rate and topological profile of minor physical anomalies (MPAs) (prenatal errors of morphogenesis) in a group of children with Autism Spectrum Disorder (ASD), in order to better set a temporal framing of embryological factors involved in the neurodevelopmental etiology. METHOD: A new modified Waldrop scale and a mixed approach of computerized photogrammetry and classic anthroposcopy was used to detect the presence or absence of 41 MPAs in 24 children (mean age: 7 years; sex ratio: 22M:2F) with ASD and 24 healthy comparison subjects (mean age: 7 years; sex ratio: 19M:5F) selected with DSM IV and CARS. RESULTS: We found that children with ASD presenting MPAs (n=23; 96%) had significantly higher rates of MPAs in four body areas (head, ears, mouth, hands); interestingly three of 41 MPAs best discriminated ASD groups from comparison subjects: abnormal head circumference, abnormal cephalic index, abnormal palate. Moreover, our results suggest that most MPAs occur predominantly after the first trimester of pregnancy. CONCLUSIONS: These results support a prenatal neurodevelopmental model of the autism spectrum disorder.