MR insights into fetal brain development: what is normal and what is not.

Fetal brain development is a complex, rapid, and multi-dimensional process that can be documented with MRI. In the second and third trimesters, there are predictable developmental changes that must be recognized and differentiated from disease. This review delves into the key biological processes that drive fetal brain development, highlights normal developmental anatomy, and provides a framework to identify pathology. We will summarize the development of the cerebral hemispheres, sulci and gyri, extra-axial and ventricular cerebrospinal fluid, and corpus callosum and illustrate the most common abnormal findings in the clinical setting.

The "cortical invagination sign": a midtrimester sonographic marker of unilateral cortical focal dysgyria in fetuses with complete agenesis of the corpus callosum.

BACKGROUND: Agenesis of the corpus callosum is associated with several malformations of cortical development. Recently, features of focal cortical dysgyria have been described in fetuses with agenesis of the corpus callosum. OBJECTIVE: This study aimed to describe the "cortical invagination sign," a specific sonographic feature of focal cortical dysgyria, which is consistently seen at midtrimester axial brain ultrasound in fetuses with complete agenesis of the corpus callosum. STUDY DESIGN: This was a retrospective analysis of prospectively collected data from 2018 to 2021, including patients referred to 5 fetal medicine centers in the second trimester of pregnancy (19 0/7 to 22 0/7 weeks of gestation) with suspected complete agenesis of the corpus callosum. All cases with the diagnosis of complete agenesis of the corpus callosum were submitted to an axial sonographic assessment of the fetal brain on the transventricular plane. In this scanning section, the mesial profile of both cerebral hemispheres at the level of the frontal-parietal cortex was investigated. In this area, the operator looked for an abnormal invagination of the cortical surface along the widened interhemispheric fissure, which was referred to as the "cortical invagination sign." All fetuses were submitted to dedicated antenatal magnetic resonance imaging to reassess the ultrasound findings. Cases with additional brain anomalies, which did not involve the cortex, were excluded. The final diagnosis was confirmed at postnatal brain magnetic resonance imaging or postmortem examination, for cases undergoing termination of pregnancy. The primary outcome of this study was to evaluate the presence and laterality of the "cortical invagination sign" in fetuses with complete agenesis of the corpus callosum at antenatal ultrasound and magnetic resonance imaging. RESULTS: During the study period, 64 cases of complete agenesis of the corpus callosum were included; of those cases, 50 (78.1%) resulted in termination of pregnancy, and 14 (21.9%) resulted in a live birth. The "cortical invagination sign" was detected at ultrasound in 13 of 64 cases (20.3%) and at targeted brain magnetic resonance imaging in 2 additional cases (23.4%), all of which were electively terminated. Moreover, the "cortical invagination sign" was found to be exclusively unilateral and on the left cerebral hemisphere in all the cases. There was a predominant number, although nonsignificant, of male fetuses (80.0% of cases; P=.06) in the group of complete agenesis of the corpus callosum with the "cortical invagination sign." CONCLUSION: The "cortical invagination sign" is a specific marker of focal cortical dysgyria, which seems to characterize at midtrimester of pregnancy in a large group of fetuses with complete agenesis of the corpus callosum. The etiology, pathophysiology, and prognostic significance of this finding remain to be elucidated.

Aicardi syndrome in a Nigerian female child: A case report and literature review of a rare neuro-developmental disorder from North-Western Nigeria.

Aicardi syndrome is a very rare neurodevelopmental disorder, inherited as an X-linked dominant condition with a triad of infantile spasm, partial or complete agenesis of the corpus callosum, and chorio-retinal "lacunae." We report a case of a female infant with the classical triad of Aicardi syndrome. A female infant presented to the Paediatric Neurology Clinic of the Federal Medical Centre Birnin-Kebbi, North-western Nigeria, at the age of two months with complaints of recurrent afebrile convulsions typical for infantile spasms. The patient was delivered at term with normal Apgar scores and anthropometry. Examination revealed an infant with no dysmorphic features and normal systemic examination. Magnetic Resonance Imaging (MRI) of the brain however, showed complete agenesis of the corpus callosum and dilatation of the posterior horn of the lateral and third ventricles. Fundoscopy showed multiple yellowish spots along the vascular arcades in the right eye. The left eye had a one-disc diameter lacuna in the superior nasal quadrant adjacent to the optic disc with multiple yellowish spots. A diagnosis of Aicardi syndrome was made. The child was placed on oral phenobarbital and followed up. At the age of 18 months, the child can only sit without support, hold an object in each hand, smile socially, and babble. The frequency of the seizures had also reduced from >100 episodes per day to 2-3 episodes per day, but the child had developed right-sided spastic hemiparesis. The patient was commenced on physiotherapy and the anti-epileptic drugs were maintained. We recommend clinicians consider Aicardi syndrome in the differential diagnosis of any child presenting with infantile spasms.

Children with corpus callosum anomalies: clinical characteristics and developmental outcomes.

INTRODUCTION: Corpus callosum abnormalities are complex, aetiologically diverse, and clinically heterogeneous conditions. Counselling parents regarding their causes and associated syndromes, and predicting the neurodevelopmental and seizure risk prognosis, is challenging. MATERIAL AND METHODS: We describe the clinical characteristics, associated anomalies, and neurodevelopmental outcomes of children with agenesis of corpus callosum (ACC). Fifty-one neonates with ACC/hypoplasia of the corpus callosum were identified over a 17-year period, and their medical records were retrospectively reviewed. RESULTS: Patients were classified into two groups depending on the presence or absence of associated abnormalities. The first group (17 patients, 33.4%) presented with isolated callosal anomalies. The second group included 34 patients (66.6%) with associated cerebral and extracerebral anomalies. We achieved an identifiable genetic aetiology in 23.5% of our cohort. Magnetic resonance imaging was performed in 28 patients (55%), and of these 39.3% had additional brain anomalies. During the study period, five patients died early in the neonatal period and four were lost to follow up. Of the 42 followed patients, 13 (31%) showed normal neurodevelopment, 13 (31%) showed mild delay, and 16 (38%) had a severe delay. Fifteen (35.7%) had epilepsy. CONCLUSIONS AND CLINICAL IMPLICATIONS: We have confirmed that callosal defects are frequently accompanied by brain and somatic anomalies. Additional abnormalities were shown to be significantly associated with developmental delay and increased risk of epilepsy. We have highlighted essential clinical features that may provide diagnostic clues to physicians and we have given examples of underlying genetic disorders. We have provided recommendations about extended neuroimaging diagnostics and widespread genetic testing that may impact upon daily clinical practice. Paediatric neurologists may therefore use our findings to help base their decisions regarding this matter.

Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.

Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.

Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

Imaging Similarities Between Oral-Facial-Digital Syndrome Type 1 and Aicardi Syndrome: Prenatal and Postnatal Magnetic Resonance Imaging (MRI) Findings in 4 Patients.

Prenatal identification by magnetic resonance imaging (MRI) of callosal anomalies, particularly with accompanying intracranial abnormalities, poses a challenge for accurate prognostication and fetal counseling as outcome can vary widely depending on underlying etiology. In female patients, Aicardi syndrome is an important consideration, and prompt postnatal ophthalmologic assessment to identify ocular stigmata of Aicardi syndrome can aid with anticipatory guidance and greater vigilance for seizures. We present a case of a female with fetal and postnatal MRI findings of agenesis of corpus callosum and type 2b interhemispheric cysts, characteristically found in Aicardi syndrome, but was found to have oral-facial-digital syndrome type 1 (OFD1). We also present 3 other companion cases with pre- and postnatal imaging of patients with Aicardi syndrome. These cases highlight the importance of widening the differential diagnosis to also include OFD1 for female patients with callosal anomalies.

Neuropathological hallmarks of antenatal mitochondrial diseases with a corpus callosum defect.

Corpus callosum defects are frequent congenital cerebral disorders caused by mutations in more than 300 genes. These include genes implicated in corpus callosum development or function, as well as genes essential for mitochondrial physiology. However, in utero corpus callosum anomalies rarely raise a suspicion of mitochondrial disease and are characterized by a very large clinical heterogeneity. Here, we report a detailed pathological and neuro-histopathological investigation of nine foetuses from four unrelated families with prenatal onset of corpus callosum anomalies, sometimes associated with other cerebral or extra-cerebral defects. Next generation sequencing allowed the identification of novel pathogenic variants in three different nuclear genes previously reported in mitochondrial diseases: TIMMDC1, encoding a Complex I assembly factor never involved before in corpus callosum defect; MRPS22, a protein of the small mitoribosomal subunit; and EARS2, the mitochondrial tRNA-glutamyl synthetase. The present report describes the antenatal histopathological findings in mitochondrial diseases and expands the genetic spectrum of antenatal corpus callosum anomalies establishing OXPHOS function as an important factor for corpus callosum biogenesis. We propose that, when observed, antenatal corpus callosum anomalies should raise suspicion of mitochondrial disease and prenatal genetic counselling should be considered.

Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.

BACKGROUND: Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete. RESULTS: The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function variation c.747_750del in homozygosity in SLC16A1 (which codes for MCT1). Persistent ketotic and lactic acidosis was accompanied by an abnormal excretion of organic acids related to redox balance disturbances. Together with an altered bioenergetic profile detected in patient-derived fibroblasts, this suggests possible mitochondrial dysfunction. Brain MRI revealed extensive, diffuse bilateral, symmetric signal alterations for the subcortical white matter and basal ganglia, together with corpus callosum agenesia. CONCLUSIONS: These findings suggest that the clinical spectrum of MCT1 deficiency not only involves recurrent atacks of ketoacidosis, but may also cause lactic acidosis and neuromotor delay with a distinctive neuroimaging pattern including agenesis of corpus callosum and other brain signal alterations.

Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans.

PURPOSE: Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown. METHODS: We used exome sequencing to uncover ADD1 variants associated with intellectual disability (ID) and brain malformations. We studied ADD1 splice isoforms in mouse and human neocortex development with RNA sequencing, super resolution imaging, and immunoblotting. We investigated 4 variant ADD1 proteins and heterozygous ADD1 cells for protein expression and ADD1-ADD2 dimerization. We studied Add1 functions in vivo using Add1 knockout mice. RESULTS: We uncovered loss-of-function ADD1 variants in 4 unrelated individuals affected by ID and/or structural brain defects. Three additional de novo copy number variations covering the ADD1 locus were associated with ID and brain malformations. ADD1 is highly expressed in the neocortex and the corpus callosum, whereas ADD1 splice isoforms are dynamically expressed between cortical progenitors and postmitotic neurons. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. CONCLUSION: Our human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or ID.

Cubilin-, megalin-, and Dab2-dependent transcription revealed by CRISPR/Cas9 knockout in kidney proximal tubule cells.

The multiligand receptors megalin (Lrp2) and cubilin (Cubn) and their endocytic adaptor protein Dab2 (Dab2) play essential roles in maintaining the integrity of the apical endocytic pathway of proximal tubule (PT) cells and have complex and poorly understood roles in the development of chronic kidney disease. Here, we used RNA-sequencing and CRISPR/Cas9 knockout (KO) technology in a well-differentiated cell culture model to identify PT-specific transcriptional changes that are directly consequent to the loss of megalin, cubilin, or Dab2 expression. KO of Lrp2 had the greatest transcriptional effect, and nearly all genes whose expression was affected in Cubn KO and Dab2 KO cells were also changed in Lrp2 KO cells. Pathway analysis and more granular inspection of the altered gene profiles suggested changes in pathways with immunomodulatory functions that might trigger the pathological changes observed in KO mice and patients with Donnai-Barrow syndrome. In addition, differences in transcription patterns between Lrp2 and Dab2 KO cells suggested the possibility that altered spatial signaling by aberrantly localized receptors contributes to transcriptional changes upon the disruption of PT endocytic function. A reduction in transcripts encoding sodium-glucose cotransporter isoform 2 was confirmed in Lrp2 KO mouse kidney lysates by quantitative PCR analysis. Our results highlight the role of megalin as a master regulator and coordinator of ion transport, metabolism, and endocytosis in the PT. Compared with the studies in animal models, this approach provides a means to identify PT-specific transcriptional changes that are directly consequent to the loss of these target genes.NEW & NOTEWORTHY Megalin and cubilin receptors together with their adaptor protein Dab2 represent major components of the endocytic machinery responsible for efficient uptake of filtered proteins by the proximal tubule (PT). Dab2 and megalin expression have been implicated as both positive and negative modulators of kidney disease. We used RNA sequencing to knock out CRISPR/Cas9 cubilin, megalin, and Dab2 in highly differentiated PT cells to identify PT-specific changes that are directly consequent to knockout of each component.

Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome.

The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and is an essential factor controlling expansion of the dorsal telencephalon by promoting neuron and interneuron production. Heterozygous FOXG1 gene mutations cause FOXG1 syndrome characterized by severe intellectual disability, motor delay, dyskinetic movements and epilepsy. Neuroimaging studies in patients disclose constant features including microcephaly, corpus callosum dysgenesis and delayed myelination. Currently, investigative research on the underlying pathophysiology relies on mouse models only and indicates that de-repression of FOXG1 target genes may cause premature neuronal differentiation at the expense of the progenitor pool, patterning and migration defects with impaired formation of cortico-cortical projections. It remains an open question to which extent this recapitulates the neurodevelopmental pathophysiology in FOXG1-haploinsufficient patients. To close this gap, we performed neuropathological analyses in two foetal cases with FOXG1 premature stop codon mutations interrupted during the third trimester of the pregnancy for microcephaly and corpus callosum dysgenesis. In these foetuses, we observed cortical lamination defects and decreased neuronal density mainly affecting layers II, III and V that normally give rise to cortico-cortical and inter-hemispheric axonal projections. GABAergic interneurons were also reduced in number in the cortical plate and persisting germinative zones. Additionally, we observed more numerous PDGFRα-positive oligodendrocyte precursor cells and fewer Olig2-positive pre-oligodendrocytes compared to age-matched control brains, arguing for delayed production and differentiation of oligodendrocyte lineage leading to delayed myelination. These findings provide key insights into the human pathophysiology of FOXG1 syndrome.

DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation.

Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base-pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.

Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies.

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs.

DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation.

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

The Prenatal Morphomechanic Impact of Agenesis of the Corpus Callosum on Human Brain Structure and Asymmetry.

Genetic, molecular, and physical forces together impact brain morphogenesis. The early impact of deficient midline crossing in agenesis of the Corpus Callosum (ACC) on prenatal human brain development and architecture is widely unknown. Here we analyze the changes of brain structure in 46 fetuses with ACC in vivo to identify their deviations from normal development. Cases of complete ACC show an increase in the thickness of the cerebral wall in the frontomedial regions and a reduction in the temporal, insular, medial occipital and lateral parietal regions, already present at midgestation. ACC is associated with a more symmetric configuration of the temporal lobes and increased frequency of atypical asymmetry patterns, indicating an early morphomechanic effect of callosal growth on human brain development affecting the thickness of the pallium along a ventro-dorsal gradient. Altered prenatal brain architecture in ACC emphasizes the importance of conformational forces introduced by emerging interhemispheric connectivity on the establishment of polygenically determined brain asymmetries.

MED12-Related (Neuro)Developmental Disorders: A Question of Causality.

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

A novel MEIS2 mutation explains the complex phenotype in a boy with a typical NF1 microdeletion syndrome.

Concurrence of distinct genetic conditions in the same patient is not rare. Several cases involving neurofibromatosis type 1 (NF1) have recently been reported, indicating the need for more extensive molecular analysis when phenotypic features cannot be explained by a single gene mutation. Here, we describe the clinical presentation of a boy with a typical NF1 microdeletion syndrome complicated by cleft palate and other dysmorphic features, hypoplasia of corpus callosum, and partial bicoronal craniosynostosis caused by a novel 2bp deletion in exon 2 of Meis homeobox 2 gene (MEIS2) inherited from the mildly affected father. This is only the second case of an inherited MEIS2 intragenic mutation reported to date. MEIS2 is known to be associated with cleft palate, intellectual disability, heart defects, and dysmorphic features. Our clinical report suggests that this gene may also have a role in cranial morphogenesis in humans, as previously observed in animal models.

Apnea central del sueño como única manifestación de agenesia del cuerpo calloso / Central sleep apnea as the only manifestation of agenesis of the corpus callosum

La apnea central del sueño (ACS) es un trastorno que se caracteriza por la presencia durante el sueño de apneas que se acompañan de disminución o abolición del esfuerzo respiratorio. Su frecuencia no es bien conocida, pero se estima menor al 5%, presentándose en un grupo heterogéneo de entidades como serían la ACS primaria, con respiración periódica Cheyne-Stokes, condiciones médicas no Cheyne-Stokes, respiración periódica en las alturas, medicaciones o sustancias y emergente al tratamiento. Se describe el caso de un varón de 53 años con diagnóstico de ACS y hallazgo de agenesia del cuerpo calloso como único hallazgo patológico predisponente

Central sleep apnea (CSA) is a disorder characterized by the presence of apneas during sleep that are accompanied by a decrease or abolition of respiratory effort. Its frequency is not well known, but it is estimated to be less than 5%, occurring in a heterogeneous group of entities such as primary CSA, with periodic Cheyne-Stokes respiration, non-Cheyne-Stokes medical conditions, periodic respiration at heights, medications or substances and emergent to treatment. The case of a 53-year-old man with a diagnosis of CSA and finding agenesis of the corpus callosum as the only predisposing pathological finding is described