Relative Microcephaly Research Articles

The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability

MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.

ANKLE2-related microcephaly: A variable microcephaly syndrome resembling Zika infection.

ObjectiveThis study delineates the clinical and molecular spectrum of ANKLE2‐related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus.MethodsWe identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster.ResultsAll individuals had MIC (z‐score ≤ −3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra‐axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of ANKLE2 including hyper‐ and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial‐loss‐of‐function variants, whereas the c.1421‐1G>C splicing variant demonstrated a strong loss‐of‐function effect.InterpretationDeleterious variants in the ANKLE2 gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between ANKLE2‐related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC.

The Characterisation of the Craniofacial Morphology of Infants Born With Zika Virus; Innovative Approach for Public Health Surveillance and Broad Clinical Applications.

Background: This study was carried out in response to the Zika virus epidemic, which constituted a public health emergency, and to the 2019 WHO calling for strengthened surveillance for the early detection of related microcephaly. The main aim of the study was to phenotype the craniofacial morphology of microcephaly using a novel approach and new measurements, and relate the characteristics to brain abnormalities in Zika-infected infants in Brazil to improve clinical surveillance.Methods: 3D images of the face and the cranial vault of 44 Zika-infected infants and matched healthy controls were captured using a 3D stereophotogrammetry system. The CT scans of the brain of the infected infants were analysed. Principal component analysis (PCA) was applied to characterise the craniofacial morphology. In addition to the head circumference (HC), a new measurement, head height (HH), was introduced to measure the cranial vault. The level of brain abnormality present in the CT scans was assessed; the severity of parenchymal volume loss and ventriculomegaly was quantified. Student's t-test and Spearman's Rho statistical test have been applied.Findings: The PCA identified a significant difference (p < 0.001) between the cranial vaults and the face of the Zika infants and that of the controls. Spearman's rank-order correlation coefficients show that the head height (HH) has a strong correlation (0.87 in Zika infants; 0.82 in controls) with the morphology of the cranial vaults, which are higher than the correlation with the routinely used head circumference (HC). Also, the head height (HH) has a moderate negative correlation (−0.48) with the brain abnormalities of parenchymal volume loss.Interpretation: It is discovered that the head height (HH) is the most sensitive and discriminatory measure of the severity of cranial deformity, which should be used for clinical surveillance of the Zika syndrome, evaluation of other craniofacial syndromes and assessment of various treatment modalities.

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum.

Background(Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes.Subjects and MethodsTo clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis.ResultsThese 249 patients with SGA-SS were classified into the “SRS-compatible group” (n = 148), the “non-SRS with normocephaly or relative macrocephaly at birth group” (non-SRS group) (n = 94), or the “non-SRS with relative microcephaly at birth group” (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the “SRS-compatible group,” 21.3% of patients in the “non-SRS group,” and 14.3% in the “non-SRS with microcephaly group” had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the “SRS-compatible group” and in 13.8% of patients in the “non-SRS group.”ConclusionWe clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.

Abnormal Head Size in Children and Adolescents with Congenital Nervous System Disorders or Neurological Syndromes with One or More Neurodysfunction Visible since Infancy.

The current study was designed to investigate co-occurrence of absolute/relative microcephaly, absolute/relative macrocephaly and congenital nervous system disorders or neurological syndromes with symptoms visible since infancy, based on fundamental data acquired during the admission procedure at a neurological rehabilitation ward for children and adolescents. The study applied a retrospective analysis of data collected during the hospitalization of 327 children and adolescents, aged 4–18 years, affected since infancy by congenital disorders of the nervous system and/or neurological syndromes associated with a minimum of one neurodysfunction. To identify subjects with absolute/relative microcephaly, absolute/relative macrocephaly in the group of children and adolescents, the adopted criteria took into account z-score values for head circumference (z-score hc) and head circumference index (z-score HCI). Dysmorphological (x+/−3s) and traditional (x+/−2s) criteria were adopted to diagnose developmental disorders of head size. Regardless of the adopted criteria, absolute macrocephaly often coexists with state after surgery of lumbar myelomeningocele and hydrocephalus, isolated hydrocephalus, hereditary motor and sensory polyneuropathy, and Becker’s muscular dystrophy (p < 0.001, p = 0.002). Absolute macrocephaly is often associated with neural tube defects and neuromuscular disorders (p = 0.001, p = 0.001). Relative microcephaly often occurs with non-progressive encephalopathy (p = 0.017, p = 0.029). Absolute microcephaly, diagnosed on the basis of traditional criteria, is often associated with epilepsy (p = 0.043). In children and adolescents with congenital nervous system disorders or neurological syndromes with one or more neurodysfunction visible since infancy, there is variation in abnormal head size (statistically significant relationships and clinical implications were established). The definitions used allowed for the differentiation of abnormal head size.

A Novel Mutation in Aicardi–Goutières' Syndrome: A Case Report

AbstractAicardi–Goutières' syndrome (AGS) is a rare heterogeneous genetic disorder characterized by encephalopathy and may bear resemblance to congenital infections. The prevalence of AGS is estimated at more than 4,000 worldwide. Mutations in TREX1 gene are present in ∼22% of patients. We present the case of a 2-year-old boy who came to the Biogene laboratory (Tehran, Iran) with a constellation of congenital disorders but no clear diagnosis. His clinical phenotype consisted of neonatal jaundice, relative microcephaly with diffuse cerebral atrophy in both hemispheres, developmental delay, hypotonia, and nystagmus. There was history of parental consanguineous marriage and prematurity. In our study, a homozygous potentially pathogenic mutation in TREX1 gene associated with AGS1 was detected. This mutation has not been reported in the other patients with AGS. A novel frameshift homozygous potentially pathogenic mutation in TREX1 is postulated to be the cause of disease in our patient.

Small head circumference at birth: an 8-year retrospective cohort study in China

ObjectiveHead circumference is considered a reliable assessment of the volume of the underlying brain. We sought to identify risk factors (maternal factors or antenatal antecedents) for microcephaly and to assess...

P24.10: The first case of Zika virus related microcephaly in the Netherlands

P24.10: The first case of Zika virus related microcephaly in the Netherlands

Alcohol and thiamine deficiency trigger differential mitochondrial transition pore opening mediating cellular death.

Accumulating evidence has shown that binge-type alcohol intake in mothers interferes with thiamine deficiency (TD) to promote the fetal alcohol syndrome (FAS). Developmental alcohol or TD exposures act either synergistically or separately to reproduce FAS features e.g. intrauterine growth retardation and related microcephaly characterized by extensive cellular death induced by one another neurotoxicant. However molecular and cellular mechanisms underlying apoptosis in both alcohol and TD toxicities are unknown. The current review addresses mechanisms of apoptosis underlying alcohol and TD toxicities for further understanding FAS pathology. This study indicates two different mitochondria pathways regulating cellular death: The first mechanism may engage alcohol which activates the c-subunit ring of the F0-ATP synthase to form MPT pore-dependent apoptosis; following the second mechanism, TD activates CyP-D translocation from mitochondrial matrix towards the mitochondrial inner membrane to form MPT pore-dependent necrosis. These studies shed light upon molecular and cellular mechanisms underlying apoptosis and necrosis in developemental brain disorders related to alcohol and thiamine deficiency, in hopes of developing new therapeutic strategies for FAS medication.

Ophthalmic Manifestations of Congenital Zika Syndrome in Colombia and Venezuela

The ocular manifestations and sequelae of Zika virus infection are not well known. Recently, the World Health Organization changed the declaration of Zika as a public health emergency and designated the viral outbreak and related microcephaly clusters as a long-term program of work. This change indicates the urgent need to evaluate and document ophthalmic manifestations in patients for timely management of this disease. In addition, confirmation whether the public health problem in Brazil extends to other regions in South America is needed. To report the ocular manifestations of congenital Zika syndrome with microcephaly in Colombia and Venezuela. This prospective case series included 43 patients from 2 ophthalmic centers in Colombia and Venezuela who underwent evaluation from October 1, 2015, through June 30, 2016, and were clinically diagnosed with congenital Zika syndrome. Twenty patients were Hispanic; 13, African; 8, white; and 2, Native American. Ophthalmic and systemic evaluations and serologic testing were performed on all infants. Patients underwent external ocular examination and dilated ophthalmoscopy. Serologic testing ruled out toxoplasmosis, rubella, cytomegalovirus, syphilis, and human immunodeficiency virus. Ophthalmic manifestations of congenital Zika syndrome. Of the 43 patients included in this series (28 female and 15 male), the mean (SD) age at examination was 2.1 (1.5) months. The mothers of all the children had no ophthalmic findings and did not report ocular symptoms during pregnancy. All patients had bilateral ophthalmic manifestations. Optic nerve findings included hypoplasia with the double-ring sign, pallor, and increased cup-disc ratio in 5 patients (11.6%). Macular abnormalities included mild to severe pigment mottling in 27 patients (63%) and lacunar maculopathy in 3 (6.9%). Chorioretinal scarring was present in 3 patients (7%). Eleven patients (26%) had a combination of lesions in the posterior pole. Five patients (12%) were diagnosed with congenital glaucoma, characterized by the clinical triad of epiphora, photophobia, and blepharospasm; increased intraocular pressure; corneal clouding at birth; and buphthalmos. These data reveal that 12% (95% CI, 5%-24%) of cases of congenital Zika with microcephaly had anterior segment abnormalities and 88% (95% CI, 76%-94%) had important macular and optic nerve abnormalities. The visual sequelae of these ophthalmic manifestations remain unknown. Congenital Zika syndrome in the current study had severe ocular abnormalities, and all patients had bilateral involvement. Ocular findings were focal macular pigment mottling, chorioretinal atrophy with a predilection for the macular area, congenital glaucoma and optical nerve hypoplasia, and optic disc abnormalities. Ophthalmic examination is recommended in patients with congenital Zika syndrome.

Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study

Objective To report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika...

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

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. 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. 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. 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.

Clinical, Biochemical, and Neuroimaging Findings Predict Long-Term Neurodevelopmental Outcome in Symptomatic Congenital Cytomegalovirus Infection

To evaluate clinical, biochemical, and neuroimaging findings as predictors of neurodevelopmental outcome in patients with symptomatic congenital cytomegalovirus (CMV). The study cohort comprised 26 patients with symptomatic congenital CMV born between 1993 and 2009 in a single center. Absolute and weight deficit-adjusted head circumference were considered. Cerebrospinal fluid (CSF) investigations included standard cytochemical analysis, determination of beta2-microglobulin (β2-m), neuron-specific enolase, and CMV DNA detection. Neuroimaging was classified according to a validated scoring system comprising calcifications, ventriculomegaly, and atrophy, with findings graded from 0 to 3. Systematic long-term neurodevelopmental assessment included motor function, cognition, behavior, hearing, vision, and epilepsy. Sequelae were graded as mild/absent, moderate, or severe; adverse outcome was defined as death or moderate to severe disability. Three children died. The mean age at follow-up of the survivors was 8.7 ± 5.3 years (range, 19 months to 18.0 years). Neonatal findings showing a significant association with adverse outcome were relative microcephaly, CSF β2-m concentrations, and grade 2-3 neuroimaging abnormalities (P < .05). Receiver operator characteristic curve analysis indicated that the most accurate single factor for predicting unfavorable outcome was CSF β2-m>7.9 mg/L (area under the curve, 0.84 ± 0.08; sensitivity, 69%; specificity, 100%). The combination of CSFβ2-m >7.9 mg/L and moderate-severe neuroimaging alterations improved predictive ability (area under the curve, 0.92 ± 0.06; sensitivity, 87%; specificity, 100%). Adjusted head circumference, CSF β2-m level, and neuroimaging studies have prognostic significance for neurodevelopmental outcome in newborns with congenital CMV. A combination of early findings improves the predictive value.

Angelman syndrome: Mutations influence features in early childhood.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by a lack of expression of the maternal copy of UBE3A. Although the "classic" features of AS are well described, few large-scale studies have delineated the clinical features in AS. We present baseline data from 92 children with a molecular diagnosis of AS between 5 and 60 months old who are enrolled in the National Institutes of Health Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study from January 2006 to March 2008. Seventy-four percent of participants had deletions, 14% had either uniparental disomy (UPD) or imprinting defects, and 12% had UBE3A mutations. Participants with UPD/imprinting defects were heavier (P = 0.0002), while those with deletions were lighter, than the general population (P < 0.0001). Twenty out of 92 participants were underweight, all of whom had deletions or UBE3A mutations. Eight out of 92 participants (6/13 (46%) with UPD/imprinting defects and 2/11 (18%) with UBE3A mutations) were obese. Seventy-four out of 92 participants (80%) had absolute or relative microcephaly. No participant was macrocephalic. The most common behavioral findings were mouthing behavior (95%), short attention span (92%), ataxic or broad-based gait (88%), history of sleep difficulties (80%), and fascination with water (75%). Frequent, easily provoked laughter was observed in 60%. Clinical seizures were reported in 65% of participants but all electroencephalograms (EEGs) were abnormal. We conclude that the most characteristic feature of AS is the neurobehavioral phenotype, but specific EEG findings are highly sensitive for AS. Obesity is common among those with UPD/imprinting defects.

Developmental delay and facial dysmorphism in a child with an 8.9 Mb de novo interstitial deletion of 3q25.1–q25.32: Genotype–phenotype correlations of chromosome 3q25 deletion syndrome

Interstitial deletions of the long arm of chromosome 3 are rare and detailed genotype–phenotype correlations are not well established. We report on the clinical, cytogenetic and molecular findings of a 5-year-old patient with a de novo interstitial deletion from 3q25.1 to 3q25.32. Clinical features include relative microcephaly, developmental delay and facial dysmorphism with a coarse face, ptosis, synophrys, epicanthic folds, broad nasal bridge, long philtrum, large mouth with full lips, dysplastic and low-set ears. Revealed by conventional banding techniques, the deleted region of 8.9 Mb was confirmed by fluorescent in situ hybridization (FISH) analyses and array comparative genomic hybridization (array-CGH). To our knowledge, this is the smallest interstitial deletion reported in the 3q25 region. The phenotype of our patient is compared with the 10 previously reported cases implicating the 3q25 region.

Clinical and molecular characterization of two patients with overlapping de novo microdeletions in 2p14-p15 and mild mental retardation

Here, we present two patients with overlapping de novo microdeletions in chromosome 2p14-p15, mild mental retardation concerning especially language development, as well as mild dysmorphic features. Patient 1 also presented with generalized seizures, sensorineural hearing loss, and relative microcephaly. In patient 1, molecular karyotyping detected a 2.23-Mb deletion in chromosome 2p14-p15 including 11 known genes. The second patient, with a 2.84-Mb microdeletion containing 15 genes, was identified in the DECIPHER database. The two deleted regions overlap by a stretch of 1.6 Mb that contains 10 genes, several of which have functions in neuronal development. This report illustrates the power of databases such as DECIPHER and MRNET in assessing the pathogenicity of copy-number variations (CNVs).

Microduplication of Xp11.23p11.3 with effects on cognition, behavior, and craniofacial development

We report an ~1.3 Mb tandem duplication at Xp11.23p11.3 in an 11-year-old boy with pleasant personality, hyperactivity, learning and visual-spatial difficulties, relative microcephaly, long face, stellate iris pattern, and periorbital fullness. This clinical presentation is milder and distinct from that of patients with partially overlapping Xp11.22p11.23 duplications which have been described in males and females with intellectual disability, language delay, autistic behaviors, and seizures. The duplicated region harbors three known X-linked mental retardation genes: FTSJ1, ZNF81, and SYN1. Quantitative polymerase chain reaction from whole blood total RNA showed increased expression of three genes located in the duplicated region: EBP, WDR13, and ZNF81. Thus, over-expression of genes in the interval may contribute to the observed phenotype. Many of the features seen in this patient are present in individuals with Williams-Beuren syndrome (WBS). Interestingly, the SYN1 gene within the duplicated interval, as well as the STX1A gene, within the WBS critical region, co-localize to presynaptic active zones, and play important roles in neurotransmitter release.

Clavicular pseudoarthrosis, anomalous coronary artery and extra crease of the fifth finger-previously unreported features in individuals with class II 1q21.1 microdeletions

Submicroscopic deletions of two adjacent regions within chromosomal band 1q21.1 were recently associated with two distinct phenotypes: A deleted region of 200–500 kb was found in individuals with Thrombocytopenia Absent Radius syndrome (TAR). Deletion in another region of about 1.25 Mb that is located just telomeric of the TAR region, referred to as distal 1q21.1 region, was found to be associated with a phenotype of cognitive impairment, congenital heart defects and other variable manifestations. A significant proportion of individuals with either of the two deletions did not have phenotypic abnormalities. More than 40 individuals with distal 1q21.1 deletions have been reported to-date. A proportion of them (9 reported individuals) had larger (>2 Mb) deletions involving both the TAR and the distal 1q21.1 regions, referred to as class II deletions. We describe here four additional individuals from two families with such class II deletions, who presented with previously unreported manifestations: clavicular pseudoarthrosis and anomalous origin of the coronary artery in the proband of the first family; an extra transverse crease of the fifth finger, segregating in two of the three deletion carriers in the second family. Previously reported features, associated with such microdeletions – absolute or relative microcephaly, cognitive impairment and short stature, were variably observed in the reported individuals. This report expands the phenotypic spectrum associated with class II 1q21.1 deletions, and demonstrates striking phenotypic variability even within the same family.

Duplication of the Rubinstein–Taybi region on 16p13.3 is associated with a distinctive phenotype

We report on a 16-year-old girl with a multiple congenital anomalies/mental retardation condition, in which a 1.7 Mb tandem duplication of chromosome region 16p13.3 was detected by array-CGH. Mental retardation was moderate (IQ 45), with very limited speech. She had tall stature with relative microcephaly. Clinical manifestations included distinctive facial appearance with deep set eyes, narrow palpebral fissures, wide nasal bridge, long philtrum, rounded nasal tip, thin upper lip, protruding mandible and abnormal auricles, hand and foot anomalies. The causal 16p13.3 duplication is one of the smallest reported so far, and includes the CBP gene, whose haploinsufficiency is responsible for the Rubinstein-Taybi syndrome. By comparing clinical manifestations of our patient with those of patients carrying similar rearrangements, we could infer that 16p13.3 microduplications encompassing the Rubinstein-Taybi region result in a recognizable clinical condition, most likely representing a single gene disorder.

Distinct facial appearance with nasal hypoplasia, constipation, severe mental retardation and hypotonia in two unrelated young males

In this report we describe two unrelated young males with severe mental retardation, persisting hypotonia, and constipation. A maternal uncle of one of these two boys died at the age of 18 months and presented the same clinical symptoms. The triad mental retardation, hypotonia, constipation is a characteristic finding in the FG syndrome, an X-linked mental retardation syndrome. At the present time, there is increasing evidence that the FG syndrome-phenotype may be present in different XLMR conditions, e.g. the fragile X syndrome. In addition to the triad severe mental retardation, hypotonia, constipation, the present two male index patients had a characteristic facial appearance with nasal hypoplasia, relative microcephaly and pre- and postnatal overgrowth. The question is raised whether the present two males are examples of a specific entity within the FG-syndrome-like phenotype.