Seizures and electroencephalography findings in 61 patients with fetal alcohol spectrum disorders

Fetal alcohol spectrum disorders (FASD) cause neurodevelopmental abnormalities. However, publications about epilepsy and electroencephalographic features are scarce. In this study, we prospectively performed electroencephalography (EEG) and brain magnetic resonance (MR) imaging in 61 patients with diagnosis of FASD. One patient had multiple febrile seizures with normal EEGs. Fourteen children showed EEG anomalies, including slow background activity and interictal epileptiform discharges, focal and/or generalized, and 3 of them had epilepsy. In one patient, seizures were first detected during the EEG recording and one case had an encephalopathy with electrical status epilepticus during slow sleep (ESES). Focal interictal discharges in our patients did not imply the presence of underlying visible focal brain lesions in the neuroimaging studies, such as cortical dysplasia or polymicrogyria. However, they had nonspecific brain MR abnormalities, including corpus callosum hypoplasia, vermis hypoplasia or cavum septum pellucidum. The latter was significantly more frequent in the group with EEG abnormal findings (p < 0.01).     

Fetal alcohol spectrum disorders in Finland: clinical delineation of 77 older children and adolescents

The adverse effects of alcohol on the developing human comprise a spectrum of structural anomalies and behavioral and neurocognitive disabilities, most accurately termed fetal alcohol spectrum disorders (FASD). We previously have proposed revisions to the 1996 Institute of Medicine Diagnostic Criteria for diagnoses in the FASD continuum [fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (PFAS), alcohol related birth defects (ARBD), and alcohol related neurodevelopmental disorder (ARND)], allowing for more reproducible and accurate FASD diagnosis in a clinical setting [Hoyme et al., 2005]. The NIAAA recently has coordinated and funded an international consortium of projects aimed at more complete characterization of the teratogenic spectrum of alcohol. One of the projects sites is in Finland. The aims of this project are: (1) to completely clinically characterize the structural and learning/behavioral phenotypes of a large cohort of older children and adolescents with moderate to severe disability within the FASD continuum; (2) to correlate FASD dysmorphology and behavioral phenotypes with CNS structure and function (i.e., MRS, MRI correlations); (3) to compare the phenotype of a genetically homogeneous population of Finnish children with FASD to that observed in other populations. We have recently completed dysmorphology examination and parent/guardian interviews of the 77 children in the Finnish cohort. The purpose of this report is to present historical and morphometric data on these patients, thereby more completely delineating the clinical spectrum of FASD in older children and adolescents, contrasting the phenotype with that described in other populations and examining whether a weighted dysmorphology score could be used as a clinical and research adjunct when fetal alcohol exposure is being suspected. All children were previously diagnosed with FASD by an experienced pediatric specialist in Finland, and all were exposed to significant maternal alcohol abuse prenatally. The sex ratio of the cohort was 0.38 (male: female) and ages ranged from 8 to 20 years, with a mean of 13 years. After application of the Revised IOM Diagnostic Criteria, 53% of the subjects were diagnosed as having FAS, 30% PFAS, 12% ARND, and 5% other diagnoses. Of note, although a family history of mental retardation or birth defects was rare, 43% of the children had one or more sibling who also carried a diagnosis of FAS. Eighty-nine percent of the mothers smoked cigarettes during gestation; other teratogenic exposures were rare. Almost none had undergone genetics evaluation in the past. Almost all of the subjects had resided in multiple foster placements since early childhood and had been followed regularly by pediatric specialists. Although 11% were born prematurely, 70% demonstrated prenatal growth deficiency, and 45% were microcephalic. Other than growth deficits and the cardinal facial features, the most common major and minor anomalies noted were: camptodactyly (55%), "hockey stick" or other altered palmar creases (51%), refractive errors (40%), strabismus (38%), dental crowding (43%), nail hypoplasia (38%), GU anomalies (22%), and congenital heart defects (18%), "Railroad track" ears were not observed in this population.     

Fetal alcohol syndrome: Craniofacial and central nervous system manifestations

Magnetic resonance imaging (MRI) is undertaken on fetal alcohol syndrome (FAS) subjects to document central nervous system (CNS) anomalies. The abnormalities found include agenesis and hypoplasia of the corpus callosum, cavum septi pellucidi, cavum vergae, ventriculomegaly, hypoplasia of inferior olivary eminences, small brain stem, and micrencephaly. Craniofacial anomalies range from the well-recognized FAS physiognomy to the more severe frontonasal “dysplasia” (median cleft face). CNS and craniofacial abnormalities are predominantly symmetric and central or midline. The association of these anomalies becomes self-evident with recognition of the concept of the midline as a special developmental field, vulnerable to adverse factors during embryogenesis and fetal growth and development. © 1996 Wiley-Liss, Inc.     

Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood?

Two brothers with severe mental retardation of unknown origin were found to share several physical anomalies, including large round head, small concave nose, downslanted palpebral fissures, and gingival hyperplasia. In addition to relative macrocephaly, magnetic resonance imaging (MRI) showed severe cerebral atrophy, especially fronto-temporally. The brothers also had a thin corpus callosum and atrophic caudate nuclei. The reduced white matter showed patchy periventricular signal intensity changes. The lateral and third ventricles were large, but the fourth ventricle was of normal size. The boys had large cisterna magna, communicating widely with the fourth ventricle, but no vermian hypoplasia. Both boys had Lennox-Gastaut spectrum type epilepsy. No chromosomal anomalies were found, despite the suggestive clinical picture. Some of the clinical findings resembled fetal alcohol effects/fetal alcohol syndrome (FAE/FAS), which was also suggested by history. Current diagnostic criteria for FAE/FAS, however, excluded full-blown FAS in these cases and failed to explain the entire clinical picture in the boys. We argue that these boys had an unidentified inherited syndrome, possibly modified by fetal alcohol exposure.     

De novo heterozygous missense and loss‐of‐function variants in CDC42BPB are associated with a neurodevelopmental phenotype

CDC42BPB encodes MRCKβ (myotonic dystrophy‐related Cdc42‐binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi‐Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene‐disrupting and lead to haploinsufficiency via nonsense‐mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20‐amino acid sequence between 2 coiled‐coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.     

Two siblings with midline field defects and Hirschsprung disease: Variable expression of Toriello-Carey or new syndrome?

We describe 2 sibs with multiple congenital anomalies. The main manifestations include hypoplasia of the corpus callosum and/or cerebellar hypoplasia, Robin sequence, pharyngeal and laryngeal hypoplasia, abnormal ears, excessive neck skin, cardiac defect, and Hirschsprung disease. The presence in 2 sibs born to healthy, consanguineous parents suggests autosomal recessive inheritance. These anomalies must have arisen during blastogenesis; the syndrome resembles most the condition described in 1988 by Toriello and Carey (Am J Med Genet 31:17–23). © 1993 Wiley-Liss, Inc.     

Prenatal diagnosis of ring chromosome 6 in a fetus with cerebellar hypoplasia and partial agenesis of corpus callosum: case report and review of the literature

Ring chromosome 6 (RC6) is a rare constitutional abnormality, with variable material loss, leading to a variable clinical phenotype: minimal physical anomalies and mild psychomotor retardation to severe physical and mental defects. Among the 22 published cases, only five have been prenatally detected. We describe here a RC6 prenatally diagnosed. Ultrasound follow-up showed growth retardation and cerebellar hypoplasia. Magnetic resonance imaging (MRI) confirmed this, but showed a partial corpus callosum agenesis, leading to amniocentesis and revealing the chromosomal abnormality. Imaging features were correlated with autopsy findings.     

Inherited 18q23 duplication in a fetus with multiple congenital anomalies

We report on a fetus with multiple congenital anomalies including atypical lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, cleft palate, ventricular septal defect, and hypoplastic aortic arch. The initial routine chromosome study failed to detect any abnormality. Subtelomeres analysis by MLPA identified an 18q23 duplication inherited from its healthy father. We describe the anomalies identified and discuss diagnosis and the causability of this telomeric duplication.     

Dandy-Walker variant malformation, spastic paraplegia, and mental retardation in two sibs

Two sibs, a boy and a girl, had both hypoplasia of the cerebellar hemispheres and partial agenesis of the cerebellar vermis with normal communication between the fourth ventricle and arachnoid spaces, i.e., the manifestations of the Dandy-Walker variant malformation associated with agenesis of the corpus callosum. Both sibs were mentally retarded and had spastic paraplegia. The occurrence of a distinct and similar pattern of congenital anomalies in sibs born to healthy parents points toward a "new" syndrome caused by the homozygous state of an autosomal recessive gene. Prenatal ultrasonographic diagnosis is possible at least for the more severe form of the brain anomalies.     

Agenesis of the corpus callosum and macrocephaly in siblings

A brother and sister with developmental delay, relative macrocephaly and agenesis of the corpus callosum are described. The brother also had unilateral cerebellar hypoplasia and malrotation of the large bowel. Published cases of familial agenesis of the corpus callosum are reviewed and the value of ultrasonography in demonstrating agenesis of the corpus callosum in the neonate is emphasised.     

Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation

Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11.     

A review of the physical features of the fetal alcohol spectrum disorders

The fetal alcohol spectrum of disorders (FASD) includes four diagnostic categories for the clinical consequences of prenatal alcohol exposure (PAE) in the unborn child. Physical features are necessary for the diagnosis of the fetal alcohol syndrome (FAS) and partial pFAS. Moreover, these features are specific and a diagnosis of FAS can be made even in the absence of knowledge of PAE. Not only growth deficits, microcephaly and the 3 facial features (short palpebral fissures, smooth philtrum and narrow vermillion of the upper lip) are characteristic, since other dysmorphic features particularly in the hands are key to the recognition of FAS. Most features can be explained by the damage to the brain during pregnancy and can be replicated in animal models. Many different diagnostic guidelines are used for the diagnosis of FASD and the physical features are considered differently in each of them. There is a need for universal clinical criteria for the diagnosis of FASD if our goal is to favor universal recognition.     

Fetal alcohol spectrum disorders: Extending the range of structural defects

Although the structural phenotype of fetal alcohol syndrome (FAS) is established, prenatal exposure to alcohol may produce a broader spectrum of defects, fetal alcohol spectrum disorder (FASD). Documenting the full spectrum of defects associated with FASD is critical to determining the true incidence of this disorder. We examined 831 children from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders using a structured protocol for diagnosis of FAS using the cardinal facial and growth features, and assessment of additional structural defects thought to occur more often in children with prenatal alcohol exposure. Subjects were classified as FAS, Deferred (some characteristic features of FAS), or No FAS, Groups were compared on prevalence of additional features and number of additional features observed, stratified by diagnostic category, sex, race, and age. Prevalence of most additional features was greatest among subjects with FAS and least among No FAS. A higher frequency of additional features was observed among FAS and Deferred subjects ≥12 years of age than among those under 12. FAS and Deferred Whites had greater frequency of additional features than Cape Colored. Prenatal alcohol exposure may produce a broad spectrum of structural defects that goes beyond FAS with implications regarding the impact of alcohol on the developing fetus, a prerequisite for ultimate prevention of FASD.     

MAST1 variant causes mega‐corpus‐callosum syndrome with cortical malformations but without cerebellar hypoplasia

We report the case of a Caucasian Spanish origin female who showed severe psychomotor developmental delay, hypotonia, strabismus, epilepsy, short stature, and poor verbal language development. Brain magnetic resonance imaging scans showed thickened corpus callosum, cortical malformations, and dilated and abnormal configuration of the lateral ventricles without hydrocephalus. Whole‐exome sequence uncovered a de novo variant in the microtubule associated serine/threonine kinase 1 gene (MAST1; NM_014975.3:c.1565G>A:p.(Gly522Glu)) that encodes for the MAST1. Only 12 patients have been identified worldwide with 10 different variants in this gene: six patients with mega‐corpus‐callosum syndrome with cerebellar hypoplasia and cortical malformations; two patients with microcephaly and cerebellar hypoplasia; two patients with autism, one patient with diplegia, and one patient with microcephaly and dysmorphism. Our patient shows a new phenotypic subtype defined by mega‐corpus‐callosum syndrome with cortical malformations without cerebellar hypoplasia. In conclusion, our data expand the phenotypic spectrum associated to MAST1 gene variants.     

Fryns syndrome: a review of the phenotype and diagnostic guidelines

Fryns syndrome (FS) is the commonest autosomal recessive syndrome associated with congenital diaphragmatic hernia (CDH) and comprises CDH, pulmonary hypoplasia, craniofacial anomalies, distal limb hypoplasia, and internal malformations. Although there have been more than 50 case reports on probands with FS, the diagnostic guidelines were formulated from a review of eight patients and modifications to the guidelines have only once been suggested. Recently, several case reports have described new anomalies in FS and other papers have highlighted the variation in expressivity found in FS. This paper examines the medical literature on FS to define the phenotype and to review the diagnostic guidelines. We conclude that CDH with brachytelephalangy and/or nail hypoplasia is strongly suggestive of the diagnosis and that pulmonary hypoplasia, craniofacial dysmorphism, orofacial clefting, and polyhydramnios are sufficiently frequent to be diagnostically useful. Other distinctive malformations that are consistent with FS include ventricular dilatation or hydrocephalus, agenesis of the corpus callosum, neuronal or cerebellar heterotopias, abnormalities of the aorta, renal cysts, dilatation of the ureters, bicornuate uterus, renal dysplasia, proximal thumbs, and broad clavicles.     

Brain magnetic resonance imaging findings in the Opitz G/BBB syndrome: Extension of the spectrum of midline brain anomalies

We report the brain magnetic resonance imaging findings in 4 patients with the Opitz BBB/G syndrome. The scans were assessed by subjective interpretation and computerized image analysis. Findings noted in 3 of the 4 patients include hypoplasia or agenesis of the corpus callosum (3 patients), cortical atrophy and ventriculomegaly (3 patients), macro cisterna magna (3 patients), and a wide cavum septum pellucidum (1 patient). One patient had a normal scan. The demonstration of a wide cavum septum pellucidum extends the spectrum of midline brain anomalies (ventral induction defects) reported in this condition. This study along with other recent reports suggests that midline brain anomalies may be frequent findings in Opitz syndrome. © 1993 Wiley-Liss, Inc.     

Antenatal presentation of the oculo-auriculo-vertebral spectrum (OAVS)

We describe a fetus with abnormal ultrasound (US) imaging at 20 weeks showing hydrocephalus and radial aplasia. Post-mortem examination followed pregnancy termination and confirmed the diagnosis of oculo-auriculo-vertebral spectrum (OAVS). To delineate the pattern of prenatal features in OAVS, we reviewed 20 published fetuses showing abnormal US and/or magnetic resonance imaging. Gestational age at diagnosis ranged from 14 to 34-35 weeks. Cephalic abnormalities were found in only 52.4% (i.e., micro/anophthalmia, ear anomalies, hemifacial microsomia, and facial cleft). CNS defects occurred in 47.6% (i.e., hydrocephalus, occipital encephalocele, cerebellar hemisphere/vermis hypoplasia, and lipoma of the corpus callosum), together with abnormal amniotic fluid volume (AFV), either poly- or oligohydramnios. Nineteen percent had congenital heart disease, mainly atrioventricular septal defect. Hydroureteronephrosis, radial aplasia, lung, and kidney agenesis were additional findings. Recurrent patterns of anomalies included multiple asymmetric facial lesions (i.e., hemifacial microsomia, ipsilateral micro/anophthalmia, malformed ear) and CNS (particularly hydrocephalus) plus AFV abnormalities. In addition, prognosis of prenatally detected OAVS patients resulted more severe than generally observed in this condition.     

Brain white matter abnormalities associated with copy number variants

White matter (WM) signal abnormalities are demonstrated in various neurodevelopmental disorders on brain magnetic resonance imaging (MRI). The pattern of WM abnormalities can aid in the diagnostic process. This study aims to characterize the WM changes found in microdeletion/microduplication syndromes. Thirteen patients with neurodevelopmental disorders due to copy number variations were collected from a cohort of children with evidence of WM abnormalities on brain MRI, in two medical centers. A pediatric neuroradiologist blindly interpreted the MRI scans. Clinical and genetic findings were retrospectively extracted from the medical records. WM changes included: multifocal (10/13) periventricular (12/13) and subcortical (5/13) signal abnormalities and WM volume loss (6/13). Dysgenesis of the corpus callosum was depicted in 12/13. The main clinical features were: global developmental delay (13/13), hypotonia (11/13), epilepsy (10/13), dysmorphic features (9/13), microcephaly (6/13), short stature (6/13), and systemic involvement (6/13). We showed that different chromosomal micro‐rearrangement syndromes share similar MRI patterns of nonspecific multifocal predominantly periventricular WM changes associated with corpus callosum dysgenesis with or without WM and gray matter loss. Hence, the association of these features in a patient evaluated for global developmental delay/intellectual disability suggests a chromosomal micro‐rearrangement syndrome, and a chromosomal microarray analysis should be performed.     

Dandy-Walker variant in Coffin-Siris syndrome

We describe a five-month-old male infant with Coffin-Siris syndrome, the so-called Dandy-Walker variant (hypoplasia of the cerebellar vermis with cystic dilatation of the fourth ventricle, but without enlargement of the posterior fossa), and partial agenesis of the corpus callosum. Dandy-Walker malformation and mega cisterna magna, but not Dandy-Walker variant, have been reported in Coffin-Siris syndrome. The presence of Dandy-Walker variant in the infant we described confirms that the full continuum of the Dandy-Walker complex can occur in Coffin-Siris syndrome. The yet unidentified gene(s) for the syndrome may be related to the development of the hindbrain.     

Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance.

We report on two sibs and two other unrelated patients with agenesis of corpus callosum, oculocutaneous albinism, repeated infections, and cardiomyopathy. All manifested postnatal growth retardation, microcephaly, and profound developmental delay. Additional central nervous system anomalies present in at least one patient included hypoplasia of the cerebellar vermis, white matter neuronal heterotopia, or bilateral schizencephaly. Repeated viral, bacterial, and fungal infections were consistent with a primary immunodeficiency. However, immunological studies showed variable, nonspecific findings. Cardiomyopathy with progressive heart failure or infection led to death before age 2 years in three of the patients. This syndrome was first described by Vici et al. [1988: Am. J. Med. Genet. 29:1-8]. The four patients reported herein confirm this unique disorder. Affected sibs of both sexes born to unaffected parents provide evidence for autosomal recessive inheritance.