Microcephaly

Angiotensin receptor blockers are potent antihypertensive drugs with very few side effects . No association has been documented between use of angiotensin receptor blockers during the first trimester of gestation and congenital defects. However, there are several reports of malformations and physiologic disturbances, mostly with lethal outcome, in infants exposed to these drugs during the second and third trimesters, as recently reviewed . We report the adverse long-term sequelae noted in an infant following maternal treatment with an angiotensin receptor blocker.

Wolf-Hirschhorn syndrome is caused by partial deletion of the short arm of chromosome 4 (4pϪ). Common features include developmental delay, microcephaly, seizures, craniofacial anomalies, mental retardation, and cardiac defects. This article further describes the ocular manifestations of this rare disorder. Methods: Charts of patients with 4pϪ from the University of Arkansas (n ϭ 3) and the University of Minnesota (n ϭ 7) were reviewed. Diagnosis was made by a geneticist and was confirmed by karyotype. Cytogenetic reports were available for review in eight patients. Results: Ten patients (six females and four males) aged 4 months to 11 years were included. Ophthalmic findings included exodeviation (9/10), nasolacrimal obstruction (6/10), shallow orbits (3/10), epicanthal folds (3/10), foveal hypoplasia (3/10), upper lid coloboma (2/10), optic disk anomalies (2/10), downslanting palpebral fissures (2/10), microcornea (2/10), hypertelorism (1/10), nystagmus (1/10), and chorioretinal coloboma (1/10). Eight patients with 4pϪ had break points ranging from band 4p14 to 4p16.3. Conclusions: This study expands on previous reports of the ophthalmic phenotype in 4pϪ and includes the additional findings of foveal hypoplasia, nystagmus, shallow orbits, epicanthal folds, and upper lid colobomas. Ophthalmic findings in 4pϪ are variable, likely related to the size of the deletion.

We report on five sibs affected by congenital microcephaly, growth retardation, sloping forehead, bitemporal grooving and micrognathia. Generalized tonic-clonic seizures started very early in life. Postnatal brain computerized tomography (CT) presented cortical band-like calcification, calcification of basal ganglia and brain stem while brain magnetic resonance imaging (MRI) revealed abnormal gyral pattern, marked loss of white matter, dysplastic ventricles, polymicrogyria, hypogenesis of corpus callosum and cerebellar hypoplasia. No abnormalities of the internal organs, eye, or skeleton were found to be associated with this syndrome. Fetal Magnetic resonance imaging helped reaching the diagnosis in utero in one patient. Three patients died in the first years of life while the others within days after birth preceded by high fever and status epilepticus. These patients present many overlapping features with pseudo TORCH syndrome, however, the imaging findings are quite different. We propose that the distinct pattern in these sibs constitutes genetic disorder of microcephaly, developmental brain malformation and intracranial calcification of likely autosomal recessive inheritance. © 2008 Wiley-Liss, Inc.

Earlier observations of the virtual endocast of LB1, the type specimen for Homo floresiensis, are reviewed, extended, and interpreted. Seven derived features of LB1's cerebral cortex are detailed: a caudallypositioned occipital lobe, lack of a rostrally-located lunate sulcus, a caudally-expanded temporal lobe, advanced morphology of the lateral prefrontal cortex, shape of the rostral prefrontal cortex, enlarged gyri in the frontopolar region, and an expanded orbitofrontal cortex. These features indicate that LB1's brain was globally reorganized despite its ape-sized cranial capacity (417 cm 3 ). Neurological reorganization may thus form the basis for the cognitive abilities attributed to H. floresiensis. Because of its tiny cranial capacity, some workers think that LB1 represents a Homo sapiens individual that was afflicted with microcephaly, or some other pathology, rather than a new species of hominin. We respond to concerns about our earlier study of microcephalics compared with normal individuals, and reaffirm that LB1 did not suffer from this pathology. The intense controversy about LB1 reflects an older continuing dispute about the relative evolutionary importance of brain size versus neurological reorganization. LB1 may help resolve this debate and illuminate constraints that governed hominin brain evolution.

A de novo supernumerary marker chromosome (SMC) was identified in a 13month-old girl who presented with microcephaly and mild mental retardation. On further characterization by oligo-nucleotide array-comparative genomic hybridization [array-CGH], the SMC was confirmed to be 18p.

Two families and three sporadic cases have been described so far with the combination of radio-ulnar synostosis and microcephaly as main features. Some authors have discussed whether the first family reported by Giuffrè et al. [1994] and the second family described by Tsukahara et al. [1995] had the same syndrome. Although there is phenotypic variability among the described cases (especially with respect to facial dysmorphisms and mental retardation), the clinical patterns do not seem to be clearly distinguishable from each other. We describe another family with apparent X-linked semi-dominant inheritance with milder features in the female patient due to skewed X-inactivation. From a clinical synopsis, we consider the Giuffrè–Tsukahara syndrome as one genetic entity, which is characterized by the association of microcephaly and radio-ulnar synostosis, mental retardation in male patients and variable minor features. Patients with the Giuffrè–Tsukahara syndrome do not present with a characteristic pattern of facial features. © 2008 Wiley-Liss, Inc.

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain vol...

We report on a girl with Giuffrè–Tsukahara syndrome manifesting microcephaly, mental retardation, radio-ulnar synostosis, short stature and scoliosis. Skewed X-inactivation was not observed in our patient. We reviewed previous reports and provide evidence in support of X-linked dominant inheritance of this condition. © 2010 Wiley-Liss, Inc.

A growing body of health officials in Brazil are doubting that the Zika " virus " is responsible for the rise in birth defects in parts of that country. Zika, along with yellow fever, has been tossed into the family Flaviviruses; the Latin " flavus " meaning yellow. But unlike yellow fever, the vast majority of Zika's symptoms for the last 70 years have been mild to non-existent. Despite disseminations by the lay and scientific press, there are serious questions whether Zika causes microcephaly at all. If by March, 2016 the Brazilian Ministry of Health reported 2,197 suspected cases of microcephaly, only 11.48% of these were Zika-positive. Zika is widespread throughout Brazil and South and Central America, yet the bulk of microcephaly cases are confined to the costal tip of Northeastern Brazil. Furthermore, despite extensive testing, no known mosquito-borne arbovirus or any other virus has to this point been proven to cause Brazilian microcephaly. While Zika was being portrayed as " the most alarming health crisis to hit Brazil in decades " , tuberculosis and its related mycobacteria were quietly gaining a stranglehold and building an ecologic niche in the very Northeastern region being hit by epidemic microcephaly. Why was this important? With NE Brazilian microcephaly/Zika we are probably dealing with a mosquito-fuelled environmental zoonosis ― a disease that can be transmitted from animals to humans ― such as primates, and to a lesser extent birds (Mycobacterium avium), and rodents (Mycobacterium microti) , all mentioned in the Zika literature. Add to this the penchant of Brazilian's to illegally capture and keep mycobacterial-laden wild monkeys and exotic birds as pets or for revenue, and you have a potential zoonotic time-bomb ready to explode once the proper vectors presents themselves. Three mosquito vectors have been steadily populating Northeastern Brazil: namely Culex quinquefasciatus, the Aedes aegypti and the Aedes albopictus ― all of which have the capacity to transmit viral-like forms of the mycobacteria associated with HIV and through direct laboratory investigation with microcephaly. Perhaps it is time to rethink what's really behind Brazilian Microcephaly and other symptomatology from the " Zika " agent.

Microcephaly results from inadequate brain growth during development. It may develop in utero, and therefore be present at birth, or may develop later as a result of perinatal events or postnatal conditions. The aetiology of microcephaly may be congenital (secondary to cerebral malformations or metabolic abnormalities) or acquired, most frequently following an ischaemic insult. This distinct radiological and pathological entity is reviewed with a specific focus on aetiology.

IMPORTANCE Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects. OBJECTIVE To describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil. DESIGN, SETTING, AND PARTICIPANTS We observed 11 infants with congenital ZIKV infection from gestation to 6 months in the state of Paraíba, Brazil. Ten of 11 women included in this study presented with symptoms of ZIKV infection during the first half of pregnancy, and all 11 had laboratory evidence of the infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by magnetic resonance imaging. Histopathological analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis. MAIN OUTCOMES AND MEASURES Description of the major lesions caused by ZIKV congenital infection. RESULTS Of the 11 infants, 7 (63.6%) were female, and the median (SD) maternal age at delivery was 25 (6) years. Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and brain). Phylogenetic analyses showed an intrahost virus variation with some polymorphisms in envelope genes associated with different tissues. CONCLUSIONS AND RELEVANCE Combined findings from clinical, laboratory, imaging, and pathological examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported. The term congenital Zika syndrome is preferable to refer to these cases, as microcephaly is just one of the clinical signs of this congenital malformation disorder.

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to antiepileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During followup, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.

We report on a child with blepharophimosis, ptosis, and epicanthus inversus (BPES), developmental delay and an interstitial deletion of band q22 of chromosome 3. A review of chromosome 3q anomalies associated with eye abnormalities, specifically blepharophimosis and ptosis, strongly suggests that a locus for eyelid development is present at the interface of bands 3q22.3 and 3q23. o 1993 Wiley-Liss, Inc.

Several studies have recently shown that germline mutations in RTEL1, an essential DNA helicase involved in telomere regulation and DNA repair, cause Hoyeraal-Hreidarsson syndrome (HHS), a severe form of dyskeratosis congenita. Using original new softwares, facilitating the delineation of the different domains of the protein and the identification of remote relationships for orphan domains, we outline here that the C-terminal extension of RTEL1, downstream of its catalytic domain and including several HHS-associated mutations, contains a yet unidentified tandem of harmonin-N-like domains, which may serve as a hub for partner interaction. This finding highlights the potential critical role of this region for the function of RTEL1 and gives insights into the impact that the identified mutations would have on the structure and function of these domains.

The proposed new hominid ''Homo floresiensis'' is based on specimens from cave deposits on the Indonesian island Flores. The primary evidence, dated at $ 18,000 y, is a skull and partial skeleton of a very small but dentally adult individual (LB1). Incomplete specimens are attributed to eight additional individuals. Stone tools at the site are also attributed to H. floresiensis. The discoverers interpreted H. floresiensis as an insular dwarf derived from Homo erectus, but others see LB1 as a small-bodied microcephalic Homo sapiens. Study of virtual endocasts, including LB1 and a European microcephalic, purportedly excluded microcephaly, but reconsideration reveals several problems. The cranial capacity of LB1 ($ 400 cc) is smaller than in any other known hominid < 3.5 Ma and is far too small to derive from Homo erectus by normal dwarfing. By contrast, some associated tools were generated with a prepared-core technique previously unknown for H. erectus, including bladelets otherwise associated exclusively with H. sapiens. The single European microcephalic skull used in comparing virtual endocasts was particularly unsuitable. The specimen was a cast, not the original skull (traced to Stuttgart), from a 10-year-old child with massive pathology. Moreover, the calotte does not fit well with the rest of the cast, probably being a later addition of unknown history. Consideration of various forms of human microcephaly and of two adult specimens indicates that LB1 could well be a microcephalic Homo sapiens. This is the most likely explanation for the incongruous association of a small-brained recent hominid with advanced stone tools.

Pericentric inversion of chromosome 19 appears to be a rare abnormality with only a few families reported. As far as we are aware, none of them were ascertained because of a recombinant individual. We describe the first identified case due to an affected patient, with duplication deficiency for chromosome 19 arising from a maternal inversion confirmed by FISH and CGH. His features included prenatal growth retardation, microcephaly, dysmorphic facies, congenital heart defect, hypoplasia of corpus callosum and psychomotor delay. The identification of recombinant individuals contribute to calculate a precise risk for inv (19) carriers and to provide a more accurate genetic counselling.

Two unrelated girls presented with multiple disseminated, paired, small café-au-lait spots and hypopigmented macules, suggesting didymosis (twin spotting). The girls also had growth retardation, microcephaly, hypertelorism, triangular facies, and a 46,XY, r(15) karyotype. The term cutis tricolor parvimaculata has been proposed to describe a twin spot phenomenon characterized by small, paired hypochromic and hyperchromic macules on a background of normal intermediate-pigmented skin. It has been hypothesized that the underlying gene locus of this phenomenon is a hot spot for postzygotic recombination, resulting in multiple pigmentary twin spots. Future clinical research may show whether analogous ''simple'' twinspot phenotypes in the form of cutis tricolor parvimaculata may be considered a further cutaneous sign of the ring chromosome 15 syndrome.

We ascertained a patient with the full-blown phenotype of isolated sulfite oxidase deficiency in a consanguineous Arab family. The proband's phenotype included the presence of intractable seizures in the neonatal period, some dysmorphic features, neuroradiologic findings reminiscent of hypoxic ischemic encephalopathy and rapidly progressive brain destruction leading to severe neurodevelopmental impairment. Biochemically, the patient excreted a large amount of S-sulfocysteine with normal amounts of xanthene and hypoxanthine and had normal plasma uric acid, which was consistent with isolated sulfite oxidase deficiency. We report the identification of the first Arab mutation in SUOX, the gene for sulfite oxidase enzyme, in the ascertained family. The newly identified Arab mutation in the SUOX gene (a single nucleotide deletion, del G1244) is predicted to cause a frame shift at amino acid 117 of the translated protein with the generation of a stop codon and total truncation of the molybdo-pterinand the dimerizing-domain(s) of SUOX protein expressed from the mutant allele. The identification of this new Arab SUOX mutation should facilitate pre-implantation genetic diagnosis and selection of unaffected embryos for future pregnancy in the ascertained family with the mutation and related families with the same mutation.

BACKGROUND The risk of congenital neurologic defects related to Zika virus (ZIKV) infection has ranged from 6 to 42% in various reports. The aim of this study was to estimate this risk among pregnant women with symptomatic ZIKV infection in French territories in the Americas. METHODS From March 2016 through November 2016, we enrolled in this prospective cohort study pregnant women with symptomatic ZIKV infection that was confirmed by polymerasechain-reaction (PCR) assay. The analysis included all data collected up to April 27, 2017, the date of the last delivery in the cohort. RESULTS Among the 555 fetuses and infants in the 546 pregnancies included in the analysis, 28 (5.0%) were not carried to term or were stillborn, and 527 were born alive. Neurologic and ocular defects possibly associated with ZIKV infection were seen in 39 fetuses and infants (7.0%; 95% confidence interval, 5.0 to 9.5); of these, 10 were not carried to term because of termination of pregnancy for medical reasons, 1 was stillborn, and 28 were live-born. Microcephaly (defined as head circumference more than 2 SD below the mean for sex and gestational age) was detected in 32 fetuses and infants (5.8%), of whom 9 (1.6%) had severe microcephaly (more than 3 SD below the mean). Neurologic and ocular defects were more common when ZIKV infection occurred during the first trimester (24 of 189 fetuses and infants [12.7%]) than when it occurred during the second trimester (9 of 252 [3.6%]) or third trimester (6 of 114 [5.3%]) (P = 0.001). CONCLUSIONS Among pregnant women with symptomatic, PCR-confirmed ZIKV infection, birth defects possibly associated with ZIKV infection were present in 7% of fetuses and infants. Defects occurred more frequently in fetuses and infants whose mothers had been infected early in pregnancy. Longer-term follow-up of infants is required to assess any manifestations not detected at birth.

Clubfoot is a common birth deformity, and agenesis of the corpus callosum is one of the most prevalent brain malformations. We describe three sibs of Arab origin, who were born with clubfeet, agenesis of corpus callosum, and minor anomalies. Two of them were born with microcephaly. This phenotype may represent a novel autosomal recessive genetic condition.

In recent years, several patients with microcephaly, lymphedema and chorioretinal dysplasia have been described. We have studied two additional patients with similar findings. The question of whether microcephaly with lymphedema and microcephaly with chorioretinal dysplasia and lymphedema are distinct entities remains unanswered. Identification of other patients in the future may provide additional information.

INTRODUCTION With the global outbreak of Zika virus and its association with microcephaly, an up-to-date fetal head circumference (HC) nomogram is crucial to offer a reference standard in order to make an accurate diagnosis. This study was conducted to revise the local fetal HC nomogram. MATERIALS AND METHODS In this retrospective study, ultrasound data was used for construction of the fetal HC nomogram from a total of 6155 pregnancies in the ethnic Chinese population with low risk profile at KK Women&#39;s and Children&#39;s Hospital over a 10-year period. Regression model was fitted to calculate the mean and standard deviation of HC at each gestational age (GA). Comparison of HC between ethnic groups (no significant differences) and genders were made. The revised chart was compared with another commonly used reference chart (Hadlock). In an independent test population, different reference charts were used to estimate number of cases with microcephaly. RESULTS A statistically signi...

In a recent review of lissencephaly syndromes [Dobyns, 19841, the name "Norman-Roberts syndrome" was proposed for a single patient with lissencephaly originally reported by Norman et al. [1976]. We wish to present a patient initially diagnosed as having Norman-Roberts syndrome, based on striking similarity to Dr. Roberts' patient. However, autopsy findings differed substantially, leading us to conclude that the clinical manifestations of Norman-Roberts syndrome are not unique to it. CLINICAL REPORT This 3-month-old Caucasian boy, son of nonconsanguineous parents was seen by us for evaluation of microcephaly. His 16-year-old mother smoked during pregnancy but did not consume alcohol or drugs. At 16 wk gestation, she was in a car accident and was "tossed around a lot," but did not sustain any obvious injuries. At about the same time she developed a sore throat with cervical lymph node swelling. The infant was born 3 wk post-term by cesarean section, done for face presentation. Microcephaly was noted at birth. At the time of evaluation, head circumference was below the third centile, while length and weight were normal. As seen in Figure la, b, he had a sloping forehead, prominent occiput, nearly closed sutures with ridging, bitemporal grooving, posteriorly angulated ears, micrognathia, and prominent nasal bridge with wide-set eyes. No other systemic abnormalities were present. Neurologically, the infant was severely delayed in psychomotor development, unable to see or hear, had optic atrophy, feeding problems, spasticity of all limbs, and episodes of opisthotonic arching and infantile spasms. Skull films confirmed that most of the sutures were closed. CT scan showed reduced number of sulci and gyri, with failure of opercularization of the insula and partial absence of the septum pellucidum. Calcification was noted in the periventricular region. A burst-suppression pattern was seen on EEG. Results of high-resolution chromosome studies and thyroid and adrenal function tests were normal. He had chronic hyponatremia, which was considered to be due to osmoregulator dysfunction. Spinal fluid examination, serology, and TORCH titers were normal.

Background: Despite multiple risk factors for neurodevelopmental vulnerability, few studies have assessed neurodevelopmental performance of Australian Aboriginal children. An important risk factor for neurodevelopmental vulnerability is prenatal alcohol exposure (PAE), which places children at risk for Fetal Alcohol Spectrum Disorder (FASD).
Aims: This study assesses neurodevelopment outcomes in a population of Australian Aboriginal children with and without PAE.
Methods and procedures: Children born in 2002/2003, and living in the Fitzroy Valley, Western Australia between April 2010 and November 2011, were eligible (N = 134). Sociodemographic and antenatal data, including PAE, were collected by interview with 127/134 (95%) consenting parents/caregivers. Maternal/child medical records were reviewed. Neurodevelopment was assessed by clinicians blinded to PAE in 108/134 (81%) children and diagnoses on the FASD spectrum were assigned.
Outcomes and results: Neurodevelopmental disorder was documented in 34/108 children (314.8 per 1000). Any diagnosis on the FASD spectrum was made in 21/108 (194.4 per 1000) children (95% CI = 131.0–279.0).
Conclusions and implications: Neurodevelopmental impairment with or without PAE is highly prevalent among children in the Fitzroy Valley. Rates of diagnoses on the FASD spectrum are among the highest worldwide. Early intervention services are needed to support developmentally vulnerable children in remote communities.

Centrosome amplification is a hallmark of human tumours. In flies, extra centrosomes cause spindle position defects that result in the expansion of the neural stem cell (NSC) pool and consequently in tumour formation. Here we investigated the consequences of centrosome amplification during mouse brain development and homeostasis. We show that centrosome amplification causes microcephaly due to inefficient clustering mechanisms, where NSCs divide in a multipolar fashion producing aneuploid cells that enter apoptosis. Importantly, we show that apoptosis inhibition causes the accumulation of highly aneuploid cells that lose their proliferative capacity and differentiate, thus depleting the pool of progenitors. Even if these conditions are not sufficient to halt brain development, they cause premature death due to tissue degeneration. Our results support an alternative concept to explain the etiology of microcephaly and show that centrosome amplification and aneuploidy can result in tissue degeneration rather than overproliferation and cancer.