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PubMed2005

Prenatal diagnosis of 13q-syndrome in a fetus with Dandy-Walker malformation.

BACKGROUND: Partial deletion of the long arm of the chromosome 13 is a rare chromosomal aberration and may present with microcephaly, colobomata, microphthalmia, distal limb and digital anomalies, cardiac defects, brain and urogenital malformations, anal atresia and growth restriction. CASE: We report such a case in 25th week of gestation referred for sonographic examination which revealed growth restriction, microcephaly, Dandy-Walker malformation, right microphthalmia, micrognathia, marked nuchal edema, four fingers-oligodactyly in feet and in hands with thumb aplasia and ambiguous genitalia. Chromosome analysis identified chromosome 13q deletion [46 XY del (13) (13q31.2/q32.1 --> qter)]. Postmortem examination confirmed prenatal findings and showed aniridia, low-set ears, cryptorchidism, and anal atresia. CONCLUSION: Detection of Dandy-Walker malformation, microphthalmia, oligodactyly with thumb aplasia and growth restriction during prenatal ultrasonography should be a reminder of deletion of chromosome 13q and warrant cytogenetic analysis.

Abnormalities, Multiple↗

PubMed2006

Deletion of chromosome 21 disturbs human brain morphogenesis.

PURPOSE: Humans with small deletions of chromosome 21 provide important models for understanding the role of dosage-sensitive genes in brain morphogenesis. To identify chromosome 21 genes responsible for defects of the central nervous system, we determined the deleted regions and brain malformations in three unrelated individuals with overlapping partial deletions of chromosome 21. METHODS: Fluorescent in situ hybridization and magnetic resonance imaging were used to define the chromosomal structure and structural brain abnormalities present in these three individuals. RESULTS: The regions of chromosome 21 found to be deleted in these individuals were as follows: case 1: KCNJ6 to the telomere; case 2: ITSN1 to the telomere; and case 3: ITSN1 to PCNT2. The abnormalities of brain structure shared by all included microcephaly, pachygyria, polymicrogyria, colpocephaly, hypoplastic corpus callosum and white matter, hypoplastic cerebellum, and enlarged ventricular system. The clinical features in common included mental retardation, microcephaly, facial dysmorphism, and epilepsy (severe in one patient). CONCLUSION: From analyses of the molecular, cytogenetic, and neuroimaging data from these three individuals, combined with those from previously reported cases, we infer that deletion of an 8.4-Mb region in chromosome band 21q22.2-22.3 (KCNJ6-COL6A2) is associated with cortical dysplasia. We propose that one or more dosage-sensitive genes in this region contributes to cortical development and that deletion of 21q22.2-22.3 should be considered in the diagnosis of mentally retarded patients with facial dysmorphism and cerebral dysplasia.

Adolescent↗

PubMed2005

Methadone maintenance program in pregnancy in a Swiss perinatal center (II): neonatal outcome and social resources.

BACKGROUND: The aim of the study was to analyze the neonatal impact of a methadone maintenance program in pregnancy, and the social resources of the families involved. METHODS: Descriptive analysis of neonatal data in live births after 24 weeks of gestation in pregnant women enrolled in a methadone maintenance program. The data of 86 babies were analyzed. RESULTS: Median gestational age was 38 (0)/(7) (31-41) weeks; 21 babies (24%) were premature. Median birthweight was 2662 (1340-4050) g; 27% of babies were growth retarded (<3rd centile), and 13% had microcephaly (<3rd centile). Sixty-two percent developed abstinence syndrome requiring pharmacological treatment for a median 47 days. Child Protective Services (CPS) were involved in 56% of cases, and 42% of newborns required placement outside the mother's home. CONCLUSIONS: Babies born to women on methadone had a fourfold higher incidence of prematurity, a ninefold higher incidence of intrauterine growth retardation (IUGR), and a fourfold higher incidence of microcephaly compared with the normal population. Sixty-two percent required pharmacological treatment for abstinence syndrome and 42% required placement.

Adult↗

PubMed1989

Evidence for a human mitotic mutant with pleiotropic effect.

Male and female sibs born to third-cousin parents presented with mental retardation, microcephaly, short stature, juvenile onset limb-girdle muscular dystrophy and multiple chromosome mosaicism in lymphocytes and fibroblasts. Different aneuploidies (mostly trisomies) were found in 15-20% of the cells and trisomies for chromosome 8 and chromosome 7 predominated in lymphocytes and fibroblasts respectively, while monosomies were rare. Increased cellular death due to aneuploidy could explain symptoms such as mental and growth retardation and microcephaly. This could be an instance of an autosomal recessive mitotic mutant, possibly affecting a protein simultaneously involved in spindle apparatus and muscle function.

Abnormalities, Multiple↗

PubMed1993

Pregnancy complicated by maternal phenylketonuria.

Pregnant women who have elevated levels of serum phenylalanine are more likely to have a spontaneous abortion or to give birth to an infant with congenital cardiac anomalies, symmetrical growth retardation, microcephaly and mental retardation than pregnant women with normal levels of this amino acid (1). Nine pregnancies in 7 women were managed in conjunction with the staff of the Children's Hospital, Sydney. In 6 patients, satisfactory serum levels of phenylalanine were attained and 6 offspring are all normal at follow-up, ranging from 15 years to 1 year. The 2 children of the poorly controlled mother were of low birth-weight and both had microcephaly at birth. The poor control of serum phenylalanine was due to poor compliance with the strict dietary regimen. It is concluded that dietary control of serum phenylalanine levels below 600 umol/l in pregnant women with PKU is possible and desirable and may improve perinatal and long-term outcome. This requires close co-operation between paediatrician, dietician, obstetrician and patient. Further data are required to confirm these findings in larger numbers and to provide long-term neurological follow-up.

Female↗

PubMed1981

Altered development of brain by neonatal ethanol exposure: zinc levels during and after exposure.

Neonatal rats, exposed to ethanol by use of an artificial rearing technique during the first postnatal week, have been shown to have a 20% reduction in brain weight compared to littermate controls. The mechanisms responsible for this deficit remain to be determined. One hypothesis, which has been suggested that could be responsible for the microcephaly observed in the Fetal Alcohol Syndrome is that human alcoholics have decreased serum zinc levels. It is well documented that zinc deficiency in rats results in microcephaly. Thus, ethanol administered in the diet could result in lowered zinc levels in serum and brain, and hence be the underlying factor for the brain growth deficiency reported. In these studies, serum and brain zinc levels were determined for animals exposed to ethanol using the artificial rearing procedure, and for their littermate controls, artificially reared on the same formula without ethanol. No differences at any time were found in either serum or brain zinc levels. This would suggest that zinc availability could not account for the effects found on brain growth.

Animals↗

PubMed2006

Diffusion tensor imaging in children with fetal alcohol spectrum disorders.

BACKGROUND: Prenatal alcohol exposure, which is associated with macrostructural brain abnormalities, neurocognitive deficits, and behavioral disturbances, is characterized as fetal alcohol syndrome (FAS) in severe cases. The only published study thus far using diffusion tensor imaging (DTI) showed microstructural abnormalities in patients with FAS. The current study investigated whether similar abnormalities are present in less severely affected, prenatally exposed patients who did not display all of the typical FAS physical stigmata. METHODS: Subjects included 14 children, ages 10 to 13, with fetal alcohol spectrum disorders (FASD) and 13 matched controls. Cases with full-criteria FAS, mental retardation, or microcephaly were excluded. Subjects underwent MRI scans including DTI. RESULTS: Although cases with microcephaly were excluded, there was a trend toward smaller total cerebral volume in the FASD group (p=0.057, Cohen's d effect size =0.73). Subjects with FASD had greater mean diffusivity (MD) in the isthmus of the corpus callosum than controls (p=0.013, effect size =1.05), suggesting microstructural abnormalities in this region. There were no group differences in 5 other regions of the corpus callosum. Correlations between MD in the isthmus and facial dysmorphology were nonsignificant. CONCLUSIONS: These results suggest that even relatively mild forms of fetal alcohol exposure may be associated with microstructural abnormalities in the posterior corpus callosum that are detectable with DTI.

Adolescent↗

PubMed2006

Wide clinical variability among 13 new Cockayne syndrome cases confirmed by biochemical assays.

Cockayne syndrome is a multi-systemic, autosomal recessive disease characterised by postnatal growth failure and progressive multi-organ dysfunction. The main clinical features are severe dwarfism (<-2 SD), microcephaly (<-3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness), and cutaneous photosensitivity. Here, 13 new cases of Cockayne syndrome are reported, which have been clinically diagnosed and confirmed using a biochemical transcription assay. The wide clinical variability, ranging from prenatal features to normal psychomotor development, is emphasised. When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered when presented with growth retardation, microcephaly, and one of the suggesting features such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging.

Abnormalities, Multiple↗

PubMed2002

Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly.

Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis. At the milder end of the HPE spectrum microcephaly, hypotelorism, and single central maxillary incisor may be recognised. Currently, four genes have been identified for this condition. These include Sonic Hedgehog (SHH) on chromosome 7q36, which is thought to be responsible for a significant proportion of autosomal dominant HPE. We report an index case with alobar holoprosencephaly caused by an SHH mutation and six members of his family over two generations with this mutation, with a broad range of clinical presentation, including attention deficit hyperactivity disorder (ADHD). The combination of microcephaly, hypotelorism, subtle midline facial anomalies, and ADHD within a sibship should alert the physician to the possible diagnosis of HPE.

Adult↗

PubMed2006

Clinical and molecular cytogenetic characterisation of a newly recognised microdeletion syndrome involving 2p15-16.1.

BACKGROUND: During whole genome microarray-based comparative genomic hybridisation (array CGH) screening of subjects with idiopathic intellectual disability, we identified two unrelated individuals with a similar de novo interstitial microdeletion at 2p15-2p16.1. Both individuals share a similar clinical phenotype including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. METHODS: Clinical assessments, and cytogenetic, array CGH and fluorescence in situ hybridisation (FISH) analyses were performed. RESULTS: The microdeletions discovered in each individual measured 4.5 Mb and 5.7 Mb, spanning the chromosome 2p region from 57.2 to 61.7 Mb and from 56 to 61.7 Mb, respectively. Each deleted clone in this range demonstrated a dosage reduction from two to one copy in each proband except for clone RP11-79K21, which was present in three copies in each proband and in four copies in their respective parents (two per each chromosome 2 homologue). DISCUSSION: The common constellation of features found in the two affected subjects indicates that they have a newly recognised microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 4.5-Mb segment of the 2p15-16.1 region.

Abnormalities, Multiple↗

PubMed2000

Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation.

We report on the association of absent patellae, genital and renal anomalies, dysmorphic features, and mental retardation in seven children (six boys and one girl) belonging to five unrelated families. Flexion deformities of the knees and hips with club feet and absent patellae were consistently observed and scrotal hypoplasia and cryptorchidism were present in all boys (6/6). Dysmorphic features included a coarse face, a large nose with a high nasal bridge, and microcephaly. Other features included renal anomalies (multicystic kidneys or hydronephrosis, 7/7), agenesis of the corpus callosum (4/7), swallowing difficulties, micrognathia (4/7), and pulmonary hypoplasia (3/7). Bilateral hypoplasia of the ischia and brachydactyly were also consistently observed (5/5). In two out of seven cases, prenatal ultrasound detection of microcephaly and renal anomalies led to termination of the pregnancy at 27 weeks. Three children died during the first years of life and the remaining two who survived exhibit severe developmental delay. High resolution cytogenetic studies performed on lymphocytes or fibroblasts or both were normal in all cases. Recurrence in two families suggests an autosomal recessive mode of inheritance. We propose that this unusual association, similar to that observed in a 4 year old boy by Goldblatt et al, represents a new syndrome distinct from previously reported hypoplastic patella syndromes.

Abnormalities, Multiple↗

PubMed1991

Lissencephaly-pachygyria associated with congenital cytomegalovirus infection.

We report the presence of major cerebral migrational defects in five severely, multiply handicapped children with congenital cytomegalovirus (CMV) infection. These patients had both computed tomographic (CT) scan and magnetic resonance imaging (MRI) evidence of marked migrational central nervous system defects consistent anatomically with the spectrum of lissencephaly-pachygyria, a disorder commonly idiopathic or associated with chromosomal abnormalities or with unknown early gestational insults. Neuroradiologic features included broad, flat gyri, shallow sulci, incomplete opercularization, ventriculomegaly, periventricular calcifications, and white-matter hypodensity on CT scans or increased signal intensity on long-TR MRI scans. Evidence for congenital CMV infection included prenatal onset of microcephaly, periventricular calcifications, neonatal jaundice, hepatomegaly, elevated CMV-specific immunoglobulin M, or viral isolation from urine. Previous reports of the neurologic sequelae of CMV have emphasized varying degrees of psychomotor retardation, cerebral palsy and epilepsy due to polymicrogyria, periventricular calcification, microcephaly, or rarely, hydrocephalus. Our patients appear to represent extremely severe examples of the effects of CMV on neurologic growth, maturation, and development. Recognition of these severe migrational abnormalities was improved by use of MRI, a technique that affords superior definition of the nature and extent of gyral and white-matter abnormalities. We suggest that these abnormalities may be more common than has previously been recognized.

Atrophy↗

PubMed1985

Growth enhancement by dopaminergic therapy in children with intrauterine growth retardation.

In a previous study we reported stimulation of growth velocity in hypopituitary children by dopaminergic therapy (DA), i.e. either L-dopa or bromocriptine. The purpose of the present study was to determine if DA stimulated endogenous GH release and growth in children with intrauterine growth retardation (IUGR), who also had microcephaly and psychomotor retardation. The effect of DA on serum LH, FSH, gonadal steroids, cortisol, T4, and TSH also was examined. Six prepubertal children [four girls and two boys; bone age (BA), 1.5-4 yr] with IUGR were divided into two study groups. Group I (n = 3) received L-dopa (15 mg/kg) orally every 6 h for 6 months. Group II (n = 3) received bromocriptine (1.25 mg) orally every 12 h for 6 months. At the end of the 6 months of DA therapy, both groups received human GH (hGH) (0.1 IU/kg) im thrice weekly for 6 months. The growth rate in group I was 6.5 +/- 0.1 (+/-SD) cm/yr after 6 months of DA compared with a pretreatment growth rate of 4.1 +/- 0.7 cm/yr. Individual increments ranged from 38-80%. All three children achieved normal growth rates for their BA. Similarly, the growth rate in group II increased to 7.7 +/- 0.9 cm/yr from a pretreatment growth velocity of 4.2 +/- 1.6 cm/yr. The growth increments of group II ranged from 43-133%. Two children of group II achieved normal growth rates for their BA, and all had a significant increase in height (P less than 0.05). Four of the six children achieved normal growth velocities after 6 months of hGH therapy. Five of the six children significantly increased their mean hGH responses to L-dopa or bromocriptine during chronic DA therapy compared with the pretreatment period. Maximum serum hGH values in group I increased from a pretreatment mean (and range) of 12 +/- 4 (+/-SE) ng/ml (5-18 ng/ml) to 46 +/- 12 ng/ml (21-64 ng/ml). The maximum hGH concentrations in group II increased from a pretreatment mean and range of 21 +/- 7 ng/ml (11-34 ng/ml) to 48 +/- 4 (42-56 ng/ml). Also, four of the six children had correspondingly increased somatomedin-C concentrations after DA therapy. The findings of this preliminary study indicate that dopaminergic therapy, i.e. L-dopa or bromocriptine, induced linear growth in patients with a form of IUGR associated with microcephaly and psychomotor retardation. DA therapy perhaps may be useful in treating other various forms of IUGR.

Age Determination by Skeleton↗

PubMed2000

Electrographic seizures in neonates correlate with poor neurodevelopmental outcome.

OBJECTIVE: To quantify the number, duration, and intensity of electrographic seizures (ESz) in neonates and to compare the outcome of neonates with ESz with those who were at risk but did not have ESz recorded. METHODS: The EEG and outcome data were reviewed from 68 infants who met at-risk criteria for neonatal seizures and underwent prolonged continuous EEG monitoring. Forty infants had ESz. The control group contained 28 infants monitored for at least 18 hours and found not to have ESz. Outcomes for both groups were evaluated using hospital and follow-up clinic records and a standardized telephone interview. RESULTS: The etiology of ESz included asphyxia (n = 23), stroke (n = 7), and other (n = 10, intraparenchymal, subdural, and subarachnoid bleeding; meningitis; sepsis; hyponatremia; and unknown). The cumulative recorded ESz duration was 8 minutes to 30 hours. Forty-three percent of infants with ESz spent 38 minutes to 32 hours in electrographic status. Despite doses of 40 mg/kg of phenobarbital and 20 mg/kg of phenytoin, 30% of infants continued to have ESz. Ten infants with ESz and one without died from causes related to neurologic instability. The occurrence of ESz was correlated with microcephaly (p = 0.04), severe cerebral palsy (CP) (p = 0.03), and failure to thrive (p = 0. 03). In the subgroup of infants with asphyxia, those with ESz were more likely to die of neurologic causes (p = 0.02) and have microcephaly (p = 0.05) or severe CP (p = 0.04). Additionally, those with the greatest number of ESz were more likely to have these severe outcomes. CONCLUSION: The authors' data indicate an association between the amount of electrographic seizure activity and subsequent mortality and morbidity in at-risk infants in general and in infants with perinatal asphyxia. Only with more effective treatment of neonatal electrographic seizures can their potential contribution to poor neurodevelopmental outcome, independent of degree of insult, be ascertained.

Anticonvulsants↗

PubMed2006

Lissencephaly, abnormal genitalia and refractory epilepsy: case report of XLAG syndrome.

INTRODUCTION: X-linked lissencephaly with ambiguous genitalia (XLAG) is a recently described genetic disorder caused by mutation in the aristaless-related homeobox (ARX) gene (Xp22.13). Patients present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia. CASE REPORT: Second child born to healthy nonconsanguineous parents, presented with seizures within the first hour of life that remained refractory to phenobarbital, phenytoin and midazolam. Examination identified microcephaly, axial hypotonia, pyramidal signs and ambiguous genitalia. EEG showed disorganized background activity and seizures starting at the right midtemporal, central and occipital regions. MRI showed diffuse pachygyria, moderate thickening of the cortex, enlarged ventricles, agenesis of the corpus callosum and septum pellucidum. Karyotype showed a 46,XY genotype. Additional findings were hypercalciuria, vesicoureteral reflux, patent ductus arteriosus and chronic diarrhea.

Electroencephalography↗

PubMed2000

Prenatal confirmation of periventricular leukomalacia in a surviving monochorionic-diamniotic twin after death of the other fetus: a case report.

A 30-year-old woman was found to be carrying monochorionic-diamniotic twins at 7 weeks of gestation. The growth-retarded fetus died at 21 weeks of gestation. At 28 weeks of gestation, periventricular leukomalacia was detected in the brain of the surviving fetus by transvaginal ultrasonography. A female baby presenting with microcephaly was born at 39 weeks of gestation, and CT of the brain showed microcephaly and marked hydrocephalus. At 12 months of age, the surviving infant presented with severe physical growth retardation, and frequent episodes of clonic convulsions.

Adult↗

PubMedDate not supplied

[Krabbe s disease - case report]

OBJECTIVE: Report a case of Krabbés disease with necropsy. METHODS: Review of medical and necropsy records. RESULTS: An 8 months-old male patient developed tremors, swallowing difficulty and excessive salivation for 4 months prior to admission, evolving with vomiting and fever. Physical examination showed microcephaly and diffuse pigmentation of the retinae. Neurological examination showed flexion of upper limbs with spastic hyperthony, symmetrical global hyperreflexia, nystagmus and spontaneous spasms. EEG showed multifocal irritative activity. There was increase in both CSF protein and gamaglobulin. The patient evolved with transitory hyperthermia, vomiting and pneumopathy, dying on the 23rd day after admission. Post mortem studies revealed microcephaly with widening of brain sulci. Histological examination revealed several globoid cells in the deep portion of the white matter, reactive gliosis and demyelination. CONCLUSIONS: These findings were similar to those in the world literature, indicating a poor prognosis due to substantial brain damage.

Journal Article↗

PubMed2004

[Clinical, cytogenetic and molecular characterization of a new case of Nijmegen breakage syndrome in Chile].

The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with microcephaly, immunodeficiency, chromosome instability and cancer proneness. The mutated gene that results in NBS codes for nibrin (Nbs1/p95), a DNA repair protein that is functionally linked to ATM, the kinase protein product of the gene responsible of ataxia-telangiectasia (A-T). We report the clinical, cytogenetic and molecular characterization of a second case of NBS in Chile detected by us. The patient is a 7 year old Chilean boy from a consanguineous marriage, with microcephaly, immunodeficiency and acute non lymphocytic leukemia (ANLL). As NBS shares chromosomal and cellular features with A-T, the cytogenetic studies of this patient also included 3 A-T patients. Our results showed that the frequency of spontaneous and X rays induced chromosomal aberrations in NBS are higher than in A-T cells. DNA analysis revealed that the patient is homozygous for the Slavic mutation 657del5 in the NBS1 gene. This finding and the absence of nibrin in patient's cells, confirmed the clinical diagnosis of NBS in our patient.

Child↗