Descriptive epidemiology of cerebellar hypoplasia in the National Birth Defects Prevention Study

Howley, Meredith M.; Keppler‐Noreuil, Kim M.; Cunniff, Christopher; Browne, Marilyn L.

doi:10.1002/bdr2.1388

Cited by 5 publications

(7 citation statements)

References 57 publications

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“…Cerebellar malformations, including Dandy-Walker malformation (DWM) and several cerebellar hypoplasia (CBLH) subtypes, are among the most common malformations recognized in utero, though their prevalence is unknown. 1 They have proven difficult to study due to incon-sistent classification, largely unknown pathogenesis, and diverse developmental outcomes that may include childhood epilepsy, intellectual disability (ID), cerebral palsy, autism, and other neuropsychiatric disorders. 2,3 Pathogenic variants in only a few genes have been implicated in CBLH or DWM.…”

Section: Introductionmentioning

confidence: 99%

Redefining the Etiologic Landscape of Cerebellar Malformations

Aldinger¹,

Timms

Thomson³

et al. 2019

The American Journal of Human Genetics

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Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

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Section: Introductionmentioning

confidence: 99%

Redefining the Etiologic Landscape of Cerebellar Malformations

Aldinger¹,

Timms

Thomson³

et al. 2019

The American Journal of Human Genetics

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“…In recent years, with the development of technology and the use of fetal MRI, the detection rate of cerebellar hypoplasia has increased (23). Also, In the study of Howley MM et al (24), it was shown that only 26.4% of cerebellar hypoplasia cases had isolated cerebellar hypoplasia and that other central nervous system malformations were accompanied in the majority of cases. In our study, it was observed that 19.0% of cerebellar hypoplasia/agenesia cases had accompanying multiple anomalies.…”

Section: Discussionmentioning

confidence: 99%

Prenatal characteristics and management of pregnants with fetal cerebellar malformation: 4-year single center experience

KORKMAZ

Alataş²,

AYDIN>

et al. 2022

Anatolian Current Medical Journal

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Introduction: Fetal cerebellar malformations (FCM) are known as very rare central nervous system malformations that occur as hypoplasia or agenesis of the cerebellum or vermis. In this study, the characteristics, diagnostic methods, risk factors and management of pregnant women diagnosed with FCM in the prenatal period were investigated. Material and Method: The patients who diagnosed with prenatal FCM in the perinatology center between March 2017-February 2021 were included, retrospectively. The frequency of fetal magnetic resonance imaging (MRI), amniocentesis and/or karyotype analysis rates, and termination frequency were evaluated. In addition, the factors affecting the amniocentesis and the termination/follow-up decision were investigated. Results: A total of 42 pregnant with FCM were included. The median gestational age was 24.0 years, and the mean gestational week was 25+2 (SD±5+1) weeks. Nearly half (40.5%) of patients were diagnosed before 24 weeks of gestation and 45.2% were primiparous. Cerebellar hypoplasia was observed in 47.6%, while vermis agenesis was observed in almost one third (31.0%); and also 19.0% had multiple FCM. The fetal USG was used in all pregnant women, fetal MRI was performed in only 4.8% for diagnosis of FCM. The rate of amniocentesis and karyotype analysis were 11.9% and 7.1%, retrospectively. No any complications were observed after the amniocentesis. The termination rate was 30.9%. The mean gestational week of those who had live birth was higher than those who were terminated (24+4 vs 20+5) (p=0.019). Conclusion: The frequency of FCM diagnosis has increased with the development of modern medicine and technology. There is no relationship between demographic characteristics of pregnant women and FCM. Socio-economic levels and religious belief differences affect the termination and birth rates.

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“…This long period of development(protracted development) makes the cerebellum vulnerable to common developmental disorders such as Dandy-Walker malformations and pontocerebellar hypoplasia (Ten Donkelaar and Lammens 2009).There are four important phases of cerebellar development namely, cerebellar territory characterization; the formation of ventricular zone and rhombic lip forming Purkinje cells, deep cerebellar nucleus and granule cells; the migration of granule layer from external to internal and lastly the cerebellar circuitry formation (ten Donkelaar et al 2003).Apart from the formation of cerebellar hemispheres, the cerebellar vermis, a small, hindbrain structure develop from the rostral segments of the rhombencephalon in early gestation (Martinez et al 2013, Millen andGleeson 2008).The cerebellum contribute to both motor and non-motor functions such as movement, proprioception, and cognition (Basson and Wingate 2013, Koziol et al 2014, Ben-Yehudah, Guediche, and Fiez 2007. Cerebellar malformations are common (Santoro et al 2019, Howley et al 2018 and have long term consequences in children (Pinchefsky et al 2019, Abel andTahir 2019),therefore frontiers in obstetric and radiological societies emphasize the important for routine screening of the cerebellum and vermis in utero (Haratz et al 2019, Quarello et al 2014. Early detection (prenatal diagnosis of the cerebellar abnormality is essential and have some prognostic impacts (Patek et al 2012, Gandolfi Colleoni et al 2012, Wuest et al 2017.Obstetric ultrasound has been a routine diagnostic tools in evaluation of fetal well-being in utero (Whitworth, Bricker, andMullan 2015, Henrichs et al 2019), however, the fetal cerebellar structures such as the vermis, being small in size and deep in skull base, the routine axial sonography may not suffice to depict the subtle changes during cerebellar development (Yang et al 2012, Pugash et al 2008.…”

Section: Introductionmentioning

confidence: 99%

“…The cerebellum contribute to both motor and non-motor functions such as movement, proprioception, and cognition(Basson and Wingate 2013, Koziol et al 2014, Ben-Yehudah, Guediche, and Fiez 2007). Cerebellar malformations are common (Santoro et al 2019, Howley et al 2018) and have long term consequences in children(Pinchefsky et al 2019, Abel and Tahir 2019),therefore frontiers in obstetric and radiological societies emphasize the important for routine screening of the cerebellum and vermis in utero(Haratz et al 2019, Quarello et al 2014). Early detection (prenatal diagnosis of the cerebellar abnormality is essential and have some prognostic impacts (Patek et al 2012, Gandolfi Colleoni et al 2012, Wuest et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Fetal cerebellar development: 3D morphometric analysis of fetal postmortem MRI among Chinese fetuses

Suluba

Liu

2021

Preprint

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The development of the cerebellum starts from early gestational period and extends postnatal. Because of its protracted development, the cerebellum is susceptible to developmental anomalies such as Dandy-Walker malformations, Blakes pouch cysts and vermin hypoplasia. Measurements of fetal cerebellar parameters of a normal growing fetus in each week of gestation is important for setting up morphometric standards and hence used as clinical reference data. Any deviation from the normal cerebellar parameters alerts the clinicians for the possibility of presence of cerebellar malformations. Study objective: The objective of this study was to assess the fetal cerebellar growth by quantifying the following parameters; fetal cerebellar volume, anterior-posterior diameter and superior-inferior diameter. Methods: We used 3T and 7T MRI to scan the postmortem fetal brains at different stages of development and subsequently analyze the images using ITK-SNAP software. Results: The mean superior-inferior cerebellar diameter was found to be 19.12+2. 70mm.The linear(y=bo+b1t) model was the best fit (r2=0.996, F=32022.961) to describe the relationship between the gestational age and the superior-inferior diameter(y=5.89+0.49t). There was significant correlation between the superior-inferior cerebellar diameter and the gestation age, Pearson correlation coefficient of 0.999, r=0.001. The median cerebellar volume was 8607.7mm, the mean rank high among males(78.12) as compared to female(68.25). There was no statistically significant difference of the cerebellar volume between males and females (u=2193.5,p=0.16). The quadratic(y=bo+b1t+b2t2) model was the best fit regression equation (r2=0.994,F=10791.157) describing the relationship between the cerebellar volume and the gestational age. The median anterior-posterior diameter was 12.45 mm. There was significant correlation between anterior-posterior diameter and the gestational age with Spearmans rho of (0.997, p=0.01). The linear model was the best fit the best fit model (y=bo+b1t) describing the relationship between anterior-posterior diameter and the gestational age(y=3.31+0.5t) r2=0.998, F=70646.838. Conclusion: Significant correlation between the superior-inferior cerebellar diameters, the anterior-posterior cerebellar diameter and the gestational age was found. These two linear parameters follow the first-degree polynomial in relation to the gestational age. The cerebellar volume follows the second-degree polynomial as it increases with the gestational age and correlate significantly with the gestational age. This study has provided new insight to the development of the cerebellum, and setup a benchmark data of which the deviation from it will alert the clinicians for the possibility of presence of cerebellar malformations. Key words: Cerebellar Development, Cranial Magnetic Resonance imaging, Cerebellar Malformations

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Descriptive epidemiology of cerebellar hypoplasia in the National Birth Defects Prevention Study

Abstract: Although unadjusted, our findings from a large, population-based study can contribute to new hypotheses regarding the etiology of cerebellar hypoplasia.

Cited by 5 publications

References 57 publications

Redefining the Etiologic Landscape of Cerebellar Malformations

Redefining the Etiologic Landscape of Cerebellar Malformations

Prenatal characteristics and management of pregnants with fetal cerebellar malformation: 4-year single center experience

Fetal cerebellar development: 3D morphometric analysis of fetal postmortem MRI among Chinese fetuses

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