[Congenital brain malformations]. / Angeborene Hirnfehlbildungen.

CLINICAL ISSUE: Malformations of the central nervous system belong to the most common developmental disorders in humans. The clinical presentation of brain malformations is nonspecific including developmental delay, hypotonia, and/or epilepsy. The great heterogeneity concerning etiology, mechanisms of development and morphology is challenging for diagnosis and classification of brain malformations. Thereby recognizing specific malformations is essential for optimal patient management and prognostic evaluation. The aim of this article is to give an overview of several clinically relevant brain malformations occurring from different disrupted developmental processes in brain formation. STANDARD RADIOLOGICAL METHODS: Several brain malformations are already diagnosed during routine ultrasound in pregnancy. However pre- and postnatal magnetic resonance imaging remains the gold standard in detecting the partially subtle changes and to classify the malformations. METHODICAL INNOVATIONS: Advances in pre- and postnatal neuroimaging techniques and increasing investigation of genetic mechanisms underlying brain formation and its abnormalities have led to a better understanding of embryologic development and pathogeneses of brain malformations. CONCLUSION: Besides patient's history and clinical phenotype, neuroimaging plays a key role in diagnosis. Not always a specific diagnosis can be made, but neuroimaging patterns often enable a focused genetic testing and therefore are revolutionary for etiologic and prognostic assignment. Basic knowledge of brain development facilitates understanding and classifying of structural brain abnormalities.

Cortical formation abnormalities on foetal MR imaging: a proposed classification system trialled on 356 cases from Italian and UK centres.

OBJECTIVE: To formulate a classification system for foetal cortical formation abnormalities (CFAs) based on in utero magnetic resonance (iuMR) appearances and trial it in 356 cases. METHODS: This retrospective study included all cases of foetal CFA diagnosed between 2000 and 2017 from seven centres in Italy and UK. All of the studies were reviewed by a panel of paediatric neuroradiologists experienced in iuMR with the aid of an algorithm designed to categorise the abnormalities. RESULTS: Consensus expert review confirmed 356 foetuses with CFA and the first level of classification distinguished bilateral CFA (229/356-64%) from unilateral CFA (127/356-36%) cases with sub-classification of the bilateral cases into asymmetric (65/356-18%) and symmetric (164/356-46%) involvement. There was a statistically significant excess of foetuses with small head size, e.g. 17% of the cohort had a bi-parietal diameter < 3rd centile. There was a small but statistically significant excess of males in the cohort. Further categorisation was made on fine anatomical structure. CONCLUSIONS: It is often not possible to classify foetal CFA using the principles and nomenclature used in paediatric neuroradiology. We have created a classification system for foetal CFA based on the analysis of 356 cases and believe that this will assist future research designed to correlate ante-natal and post-natal imaging features and understand the clinical sequelae of CFA described in utero. KEY POINTS: • We describe a morphological classification system of foetal brain cortical formation abnormalities that can be used in clinical practice. • This classification system can be used in future research studies to evaluate the long-term imaging and clinical outcomes of foetal brain cortical formation abnormalities in 17- to 38-week gestational age range. • The practical value of the work is in providing a framework and language to look for imaging clues that may differentiate between different CFA in further studies.

Analysis of 270 fetuses with non-visualization of cavum septi pellucidi and vergae on in-utero magnetic resonance imaging.

OBJECTIVE: To analyze a large retrospective cohort of fetuses in which the cavum septi pellucidi and vergae (CSPV) was not present or was not in its expected position on in-utero magnetic resonance imaging (iuMRI), in order to describe the possible causes of that finding and provide a diagnostic approach to assess such cases in clinical practice using iuMRI. METHODS: This was a retrospective study of fetuses that underwent iuMRI at a single institution, over an 18-year period (2000-2017 inclusive), in which the CSPV was not visualized or was abnormal. All iuMRI studies were reviewed and classified as CSPV being not present, disrupted (visualization of remnants of an otherwise normally placed CSPV) or malpositioned (CSPV was present, but not in its expected position). We describe the neuropathology present in each of the groups. RESULTS: Of the 270 fetuses that met the inclusion criteria, the CSPV was described as malpositioned in 150 (56%), disrupted in 71 (26%) and not present in 49 (18%). Malpositioned CSPV was present only in cases with agenesis of the corpus callosum and three specific patterns of malpositioning are described, depending on the location of the leaflets of the CSPV and fornix. Disrupted CSPV was present in fetuses with hydrocephalus or pathologies causing extensive brain parenchymal injury. Not present CSPV was found in cases with holoprosencephaly or when absence of the CSPV appeared to be an isolated finding. CONCLUSION: We have described a large cohort of fetuses with non-visualization of a normal CSPV on iuMRI and present a categorical classification system based on the CSPV being not present, disrupted or malpositioned. This approach should help in the diagnosis of the underlying cause of a CSPV abnormality. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Developmental Retrocerebellar Cysts: A New Classification for Neuroendoscopic Management and Systematic Review.

OBJECTIVE: Posterior fossa cystic malformations are diversely classified with considerable overlap without therapeutic relevance. These cysts posterior to the cerebellum, presenting in children younger than 5 years, are labeled developmental retrocerebellar cysts (DRCCs) under a new classification in relation to neuroendoscopy. METHODS: DRCC was categorized as type 0 for asymptomatic enlarged cistern magna and was not treated. Among symptomatic cases, cysts with a compressed fourth ventricle were labeled type 1, whereas cysts in continuity with the fourth ventricle were termed type 2. They were further categorized as subtype B if hydrocephalus was greater relative to the cyst, or otherwise as subtype A. The literature was reviewed according to PRISMA guidelines. RESULTS: There were 13 children aged 3-48 months. Type 1A DRCC was noted in 5 patients, with onset before 6 months, 4 of whom (80%) had intracranial hypertension. All underwent suboccipital endoscopic deroofing and cisternostomy (SEDC), a new technique. Type 1B DRCC was seen in 2 patients, with onset at 8-9 months, who underwent endoscopic third ventriculostomy (ETV) + endoscopic ventriculocystostomy (EVC). Type 2A DRCC was observed in 4 patients, with onset at 5-47 months, who underwent SEDC. Type 2B DRCC was noted in 2 patients, with onset 6-8 months, who underwent ETV. With a mean follow-up of 32 months, all showed clinicoradiologic improvement. The application of our classification to other studies showed ETV/EVC to be successful in only 67% of type 1A DRCC and 72% of type 2A DRCC, compared with 100% efficacy of SEDC in our series. CONCLUSIONS: This is probably the first ever endoscopic classification of pediatric posterior fossa cyts, elucidating pathophysiology, presentation, and treatment. Patients with type 1 DRCC present early because of extraneous compression. Among patients with type 2 DRCC, posterior fossa compliance determines the degree of hydrocephalus. The newly described SEDC seems more appropriate for types 1A and 2A DRCC. ETV is adequate in type 2B DRCC and effective with EVC in type 1B.

Electrophysiological Findings in Common Median-Ulnar Nerve Interconnections and Their Clinical Implications.

Median and ulnar nerve interconnections commonly occur in the brachial plexus, forearm, and hand. Each is classified based on location, fiber type (sensory fibers, motor fibers, or both), and directionality (ie, carrying fibers from median to ulnar or vice versa). There are 4 main interconnections found in the forearm and hand: Martin-Gruber and Marinacci anastomoses in the forearm and Riche-Cannieu and Berrettini anastomoses in the hand. The presence of an interconnection may skew electrodiagnostic findings, possibly resulting in misdiagnosis and iatrogenic injury. Clinicians should perform nerve studies of both nerves at proximal and distal stimulation sites to rule out interconnections and guide treatment. This review details anatomy, electrodiagnostic findings, and clinical approach.

Spectrum of prenatally detected central nervous system malformations: Neural tube defects continue to be the leading foetal malformation.

BACKGROUND & OBJECTIVES: Prenatal diagnosis of malformations is an important method of prevention and control of congenital anomalies with poor prognosis. Central nervous system (CNS) malformations amongst these are the most common. The information about the prevalence and spectrum of prenatally detected malformations is crucial for genetic counselling and policymaking for population-based preventive programmes. The objective of this study was to study the spectrum of prenatally detected CNS malformations and their association with chromosomal abnormalities and autopsy findings. METHODS: This retrospective study was conducted in a tertiary care hospital in north India from January 2007 to December 2013. The details of cases with prenatally detected CNS malformations were collected and were related with the foetal chromosomal analysis and autopsy findings. RESULTS: Amongst 6044 prenatal ultrasonographic examinations performed; 768 (12.7%) had structural malformations and 243 (31.6%) had CNS malformations. Neural tube defects (NTDs) accounted for 52.3 per cent of CNS malformations and 16.5 per cent of all malformations. The other major groups of prenatally detected CNS malformations were ventriculomegaly and midline anomalies. Chromosomal abnormalities were detected in 8.2 per cent of the 73 cases studied. Foetal autopsy findings were available for 48 foetuses. Foetal autopsy identified additional findings in eight foetuses and the aetiological diagnosis changed in two of them (4.2%). INTERPRETATION & CONCLUSIONS: Amongst prenatally detected malformations, CNS malformations were common. NTD, which largely is a preventable anomaly, continued to be the most common group. Moreover, 60 per cent of malformations were diagnosed after 20 weeks, posing legal issues. Chromosomal analysis and foetal autopsy are essential for genetic counselling based on aetiological diagnosis.

A morphometric study to establish criteria for fetal and neonatal cerebellar hypoplasia: A special emphasis on trisomy 18.

Cerebellar hypoplasia (CH) is one of the congenital abnormalities of the central nervous system and is seen in several diseases and syndromes. This study was conducted in order to examine methods for evaluating CH in fetus and neonate because CH has been diagnosed without any morphometric criteria at autopsy. We sampled 140 autopsied cases including nineteen trisomy 18 (T18), four non-T18 with presumed CH, and 117 control cases without any brain malformation. Statistical significance was present in the cerebellar weight and weight ratio of cerebellum per total brain between T18 and the control. The exponential regression models (ERM) showed that cerebral weight, cerebellar weight, and weight ratio of cerebellum per total brain increased gradually relative to gestational age in both T18 and the control. However, cerebellar weight and weight ratio of cerebellum per total brain of T18 showed growth delay with clear distinction between the two groups. The non-T18 with presumed CH showed similar results. Body weight, total brain, and gestational age should be considered totally when evaluating fetal and neonatal cerebellar development. Furthermore, the ERM results may be useful to evaluate the cerebellar development of fetus and neonate at autopsy.

Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states.

Mendelian disorders of the epigenetic machinery are a newly delineated group of multiple congenital anomaly and intellectual disability syndromes resulting from mutations in genes encoding components of the epigenetic machinery. The gene products affected in these inherited conditions act in trans and are expected to have widespread epigenetic consequences. Many of these syndromes demonstrate phenotypic overlap with classical imprinting disorders and with one another. The various writer and eraser systems involve opposing players, which we propose must maintain a balance between open and closed chromatin states in any given cell. An imbalance might lead to disrupted expression of disease-relevant target genes. We suggest that classifying disorders based on predicted effects on this balance would be informative regarding pathogenesis. Furthermore, strategies targeted at restoring this balance might offer novel therapeutic avenues, taking advantage of available agents such as histone deacetylase inhibitors and histone acetylation antagonists.

Cerebellar hypoplasia: differential diagnosis and diagnostic approach.

Cerebellar hypoplasia (CH) refers to a cerebellum with a reduced volume, and is a common, but non-specific neuroimaging finding. The etiological spectrum of CH is wide and includes both primary (malformative) and secondary (disruptive) conditions. Primary conditions include chromosomal aberrations (e.g., trisomy 13 and 18), metabolic disorders (e.g., molybdenum cofactor deficiency, Smith-Lemli-Opitz syndrome, and adenylosuccinase deficiency), genetic syndromes (e.g., Ritscher-Schinzel, Joubert, and CHARGE syndromes), and brain malformations (primary posterior fossa malformations e.g., Dandy-Walker malformation, pontine tegmental cap dysplasia and rhombencephalosynapsis, or global brain malformations such as tubulinopathies and α-dystroglycanopathies). Secondary (disruptive) conditions include prenatal infections (e.g., cytomegalovirus), exposure to teratogens, and extreme prematurity. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Neuroimaging provides key information to categorize CH based on the pattern of involvement: unilateral CH, CH with mainly vermis involvement, global CH with involvement of both vermis and hemispheres, and pontocerebellar hypoplasia. The category of CH, associated neuroimaging findings and clinical features may suggest a specific disorder or help plan further investigations and interpret their results. Over the past decade, advances in neuroimaging and genetic testing have greatly improved clinical diagnosis, diagnostic testing, recurrence risk counseling, and information about prognosis for patients and their families. In the next decade, these advances will be translated into deeper understanding of these disorders and more specific treatments.

Malformaciones del sistema nervioso central: correlación neuroquirúrgica / Central nervous system malformations: neurosurgery correlates

Las malformaciones congénitas del sistema nervioso central se relacionan con alteraciones en la formación del tubo neural, en las que se incluyen la mayoría de las entidades de tratamiento neuroquirúrgico, disrafismos y craneosinostosis, alteraciones de la proliferación neuronal, microcefalias y megalencefalias, anomalías de la migración neuronal, lisencefalia, paquigiria, esquisencefalia, agenesia del cuerpo calloso, heterotopías y displasias corticales, malformaciones raquimedulares y disrafias medulares. En el presente trabajo se clasifican las diferentes malformaciones del sistema nervioso central susceptibles de corregirse mediante cirugía en el menor tiempo posible y se exponen los mecanismos de génesis de estas lesiones cada vez mejor estudiadas desde las áreas neurogenética y neuroembriológica. Esto involucra la posible conexión de áreas de conocimiento novedosas, como los mecanismos de alteración de la inducción dorsal (cierre del tubo neural) y ventral (telencefalización) con los mecanismos actuales de corrección, y también las anomalías de la proliferación y diferenciación celular de la migración neuronal y, finalmente, el complejo de malformaciones que afectan la fosa posterior y las posibilidades actuales de corrección de éstas (AU)

Congenital malformations of the central nervous system are related to alterations in neural tube formation, including most of the neurosurgical management entities, dysraphism and craniosynostosis; alterations of neuronal proliferation; megalencefaly and microcephaly; abnormal neuronal migration, lissencephaly, pachygyria, schizencephaly, agenesis of the corpus callosum, heterotopia and cortical dysplasia, spinal malformations and spinal dysraphism. We expose the classification of different central nervous system malformations that can be corrected by surgery in the shortest possible time and involving genesis mechanisms of these injuries getting better studied from neurogenic and neuroembryological fields, this involves connecting innovative knowledge areas where alteration mechanisms in dorsal induction (neural tube) and ventral induction (telencephalization) with the current way of correction, as well as the anomalies of cell proliferation and differentiation of neuronal migration and finally the complex malformations affecting the posterior fossa and current possibilities of correcting them (AU)

[Central nervous system malformations: neurosurgery correlates]. / Malformaciones del sistema nervioso central: correlación neuroquirúrgica.

Congenital malformations of the central nervous system are related to alterations in neural tube formation, including most of the neurosurgical management entities, dysraphism and craniosynostosis; alterations of neuronal proliferation; megalencefaly and microcephaly; abnormal neuronal migration, lissencephaly, pachygyria, schizencephaly, agenesis of the corpus callosum, heterotopia and cortical dysplasia, spinal malformations and spinal dysraphism. We expose the classification of different central nervous system malformations that can be corrected by surgery in the shortest possible time and involving genesis mechanisms of these injuries getting better studied from neurogenic and neuroembryological fields, this involves connecting innovative knowledge areas where alteration mechanisms in dorsal induction (neural tube) and ventral induction (telencephalization) with the current way of correction, as well as the anomalies of cell proliferation and differentiation of neuronal migration and finally the complex malformations affecting the posterior fossa and current possibilities of correcting them.

TITLE: Malformaciones del sistema nervioso central: correlacion neuroquirurgica.Las malformaciones congenitas del sistema nervioso central se relacionan con alteraciones en la formacion del tubo neural, en las que se incluyen la mayoria de las entidades de tratamiento neuroquirurgico, disrafismos y craneosinostosis, alteraciones de la proliferacion neuronal, microcefalias y megalencefalias, anomalias de la migracion neuronal, lisencefalia, paquigiria, esquisencefalia, agenesia del cuerpo calloso, heterotopias y displasias corticales, malformaciones raquimedulares y disrafias medulares. En el presente trabajo se clasifican las diferentes malformaciones del sistema nervioso central susceptibles de corregirse mediante cirugia en el menor tiempo posible y se exponen los mecanismos de genesis de estas lesiones cada vez mejor estudiadas desde las areas neurogenetica y neuroembriologica. Esto involucra la posible conexion de areas de conocimiento novedosas, como los mecanismos de alteracion de la induccion dorsal (cierre del tubo neural) y ventral (telencefalizacion) con los mecanismos actuales de correccion, y tambien las anomalias de la proliferacion y diferenciacion celular de la migracion neuronal y, finalmente, el complejo de malformaciones que afectan la fosa posterior y las posibilidades actuales de correccion de estas.

Distinguishing 3 classes of corpus callosal abnormalities in consanguineous families.

OBJECTIVE: We sought to create a classification system for pediatric corpus callosal abnormalities (CCA) based upon midline sagittal brain MRI. We used the term CCA for patients with structural variants of the corpus callosum, excluding patients with interhemispheric cyst variant or pure dysplasia without hypoplasia. Currently, no system exists for nonsyndromic forms of CCA, and attempts to create such a system have been hampered by highly variable morphology in patients with sporadic CCA. We reasoned that any useful strategy should classify affected family members within the same type, and that phenotypic variability should be minimized in patients with recessive disease. METHODS: We focused recruitment toward multiplex consanguineous families, ascertained 30 patients from 19 consanguineous families, and analyzed clinical features together with brain imaging. RESULTS: We identified 3 major CCA classes, including hypoplasia, hypoplasia with dysplasia, and complete agenesis. Affected individuals within a given multiplex family usually displayed the same variant of the class of abnormality and they always displayed the same class of abnormality within each family, or they displayed complete agenesis. The system was validated among a second cohort of 10 sporadic patients with CCA. CONCLUSIONS: The data suggest that complete agenesis may be a common end-phenotype, and implicate multiple overlapping pathways in the etiology of CCA.

Abnormal development of the human cerebral cortex.

This review presents an overview of human cortical malformation based on the insights gained from examination of human fetal brains. Examination at early stages of fetal brain development allows the identification of the specific pathways which are disrupted in human cortical malformation. Detailed examination of human fetal brains in parallel with studies of genetics and animal models is leading to new concepts of cortical malformations. Here we review a range of human cortical malformations based on a simple classification according to the developmental process thought to be disrupted: neuroblast proliferation, undermigration, overmigration, cortical maturation and destructive lesions. A single case example of a dated intrauterine injury illustrates the spectrum of malformations which may result at a single period in development. The recommended methods of examination of human fetal brain are described together with some of their pitfalls. Detailed neuropathological observations indicate the need for caution in the classification of malformations; radiological findings and pathology of the mature brain do not reflect the specific disruptive pathways of cortical malformations. While many insults may lead to the same pattern of malformation, a single insult can lead to multiple patterns of malformation. Our detailed studies of the human fetal brain suggest that the interface between the meninges and the radial glial end feet may be an intriguing new focus of interest in understanding cortical development.

Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation.

Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally completed by the fifth week of gestation. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE in living humans. This has led to better classification of types of HPE, identification of newer subtypes, and understanding of the pathogenesis. Currently, there are four generally accepted subtypes of HPE: alobar, semilobar, lobar, and middle interhemispheric variant. These subtypes are defined primarily by the degree and region of neocortical nonseparation. Rather than there being four discrete subtypes of HPE, we believe that there is a continuum of midline neocortical nonseparation resulting in a spectrum disorder. Many patients with HPE fall within the border zone between the neighboring subtypes. In addition, there are patients with very mild HPE, where the nonseparation is restricted to the preoptic (suprachiasmic) area. In addition to the neocortex, other midline structures such as the thalami, hypothalamic nuclei, and basal ganglia are often nonseparated in HPE. The cortical and subcortical involvements in HPE are thought to occur due to a disruption in the ventral patterning process during development. The severity of the abnormalities in these structures determines the severity of the neurodevelopmental outcome and associated sequelae.

A developmental and genetic classification for midbrain-hindbrain malformations.

Advances in neuroimaging, developmental biology and molecular genetics have increased the understanding of developmental disorders affecting the midbrain and hindbrain, both as isolated anomalies and as part of larger malformation syndromes. However, the understanding of these malformations and their relationships with other malformations, within the central nervous system and in the rest of the body, remains limited. A new classification system is proposed, based wherever possible, upon embryology and genetics. Proposed categories include: (i) malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones; (ii) malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have a pathogenesis that is at least partly understood); (iii) localized brain malformations that significantly affect the brain stem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, migration and axonal guidance); and (iv) combined hypoplasia and atrophy of putative prenatal onset degenerative disorders. Pertinent embryology is discussed and the classification is justified. This classification will prove useful for both physicians who diagnose and treat patients with these disorders and for clinical scientists who wish to understand better the perturbations of developmental processes that produce them. Importantly, both the classification and its framework remain flexible enough to be easily modified when new embryologic processes are described or new malformations discovered.

Fetal central nervous system malformations on MR images.

Sonography is the method of choice for prenatal malformation screening but it does not always provide sufficient information for correct diagnosis or adequate abnormality evaluation. Fetal magnetic resonance imaging (MRI) is considered as a valuable second line imaging tool for confirmation, completion and correction of sonographic findings. Fetal MRI has proven its value in the evaluation of central nervous system pathologies, especially of midline and posterior fossa malformations. The role of MRI is not only to confirm or exclude possible lesions but also to define their full extent, aiding in their characterization, and to demonstrate associated abnormalities. The authors describe the most common anomalies of CNS revealed by fetal MRI in a chronological way related to the age of pregnancy, with a review of own MR images and with reference to the literature and own experience.

Congenital bilateral perisylvian syndrome: familial occurrence, clinical and psycholinguistic aspects correlated with MRI.

OBJECTIVE: Congenital bilateral perisylvian syndrome (CBPS) is frequently caused by polymicrogyria (PMG). The aim of this study was to correlate the clinical and psycholinguistic aspects with neuroradiological data of patients with CBPS. METHODS: Thirty-one patients were studied. We performed a clinical investigation of the patients and their families, including MRI scanning, neuropsychological tests and language evaluation. RESULTS: The statistical analysis showed that: a) prenatal events are associated with the non-familial type of PMG; b) diffuse PMG is associated with pseudobulbar signs, as opposed to BPPP; c) motor deficit is associated with diffuse PMG; d) epilepsy is equally present in patients with both familial or non-familial PMG, but is more frequently seen in patients with diffuse PMG; e) dyslexia and SLI can be a feature of both the diffuse or BPPP, and either familial or sporadic cases of PMG. CONCLUSIONS: The severity of clinical manifestations in CBPS is correlated with the extent of cortical involvement. Most patients with CBPS have a history of speech delay or language difficulties and no epilepsy. Dyslexia can be found in patients with PMG.

Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification.

BACKGROUND: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear. OBJECTIVE: To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification. DESIGN: A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006. SETTING: The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center. PATIENTS: Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype. RESULTS: We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients). CONCLUSIONS: In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.