Fetal neurosonography as accurate tool for diagnosis of brain involvement in tuberous sclerosis.

OBJECTIVE: To demonstrate the potential utility of dedicated neurosonography for the diagnosis of fetal brain involvement in tuberous sclerosis complex. METHODS: This was a multicenter retrospective study of fetuses at high risk for tuberous sclerosis complex. Dedicated neurosonographic, fetal magnetic resonance imaging (MRI) and postnatal reports were reviewed. Data collected included reason for referral, gestational age at which cardiac rhabdomyoma was first suspected and final number of cardiac rhabdomyomas detected on dedicated imaging. We searched for tuberous sclerosis complex-related brain involvement, defined as the presence of one or more of the following findings: white-matter lesions; subependymal nodules; cortical/subcortical tubers; and subependymal giant-cell astrocytoma. RESULTS: We included 20 patients at high risk of tuberous sclerosis complex, of whom 19 were referred for the presence of cardiac rhabdomyomas and one for a deletion in chromosome 16 involving the tuberous sclerosis complex gene locus. Cardiac rhabdomyomas were diagnosed at a mean gestational age of 27 + 2 weeks (range, 16 + 0 to 36 + 3 weeks) and the mean number of cardiac rhabdomyomas per patient was 4 (range, 1-10). Brain involvement was present in 15 fetuses, in 13 of which the disease was confirmed in one or more of the following ways: chromosomal microarray analysis (n = 1), exome sequencing (n = 7), autopsy (n = 4), clinical tuberous sclerosis complex in the newborn (n = 4) and a sibling diagnosed with clinical tuberous sclerosis complex (n = 1). In two cases, the disease could not be confirmed: one was lost to follow-up and autopsy, following termination of pregnancy, was not performed in the other. Among the five cases without brain findings, tuberous sclerosis complex was confirmed in three by exome sequencing (n = 2) and/or autopsy findings (n = 2). The two remaining cases had normal exome sequencing; one case had five cardiac rhabdomyomas, which was a highly suggestive finding, while in the final case, the autopsy was considered normal, representing the only false-positive case in our cohort. CONCLUSIONS: Contrary to current literature, dedicated neurosonography appears to be effective in the diagnosis of brain involvement in fetuses at risk of tuberous sclerosis complex and should be used as the first-line approach. Although the number of cases in which MRI was performed was small, it seems that, in the presence of ultrasound findings, the added value of MRI is low. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Malformation of cortical development with abnormal cortex: early ultrasound diagnosis between 14 and 24 weeks of gestation.

OBJECTIVE: To describe neurosonographic findings diagnostic or highly suggestive of the presence of malformations of cortical development involving the cortex that may be identified before 24 weeks of gestation. METHODS: This was a retrospective single-center study of fetuses referred for neurosonography, during 2012-2019, with an abnormal cortical or sulcation pattern diagnosed early in the mid trimester. Stored files were analyzed for demographic data, abnormal brain findings, non-central nervous system abnormalities, final diagnosis and postnatal outcome. RESULTS: The study cohort included 20 fetuses, with a mean gestational age at diagnosis of 18.7 (range, 14.4-23.6) weeks, in 11 of which the diagnosis was made before 20 weeks of gestation. Reasons for referral were: midline anomaly (n = 7), ventriculomegaly (n = 4), infratentorial findings (n = 3), suspected malformation of cortical development (n = 3), 'abnormal brain' (n = 2) and skeletal dysplasia (n = 1). On neurosonography, both the sulcation pattern and the cortical layer were abnormal in four cases, only the sulcation pattern was considered abnormal in seven and only the cortical layer was abnormal in nine. Nineteen fetuses presented with associated central nervous system anomalies and six also had non-central nervous system malformations. One case was recurrent. Eighteen parents opted for termination of pregnancy, including one selective termination in a twin pregnancy, and two fetuses were liveborn. CONCLUSIONS: Familiarity with fetal brain anatomy and its early sonographic landmarks allowed early diagnosis of malformations involving cortical development. These patients are likely to represent the most severe cases and all had associated malformations. The presence of an abnormal cortical layer and/or abnormal overdeveloped sulci appear to be early signs of malformation of cortical development. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Spectrum of brain malformations in fetuses with mild tubulinopathy.

OBJECTIVE: To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can facilitate prenatal diagnosis. METHODS: This was a retrospective multicenter study of fetuses diagnosed between January 2007 and February 2022 with a mild tubulinopathy (without lissencephaly or microlissencephaly). We collected and reviewed brain imaging and genetic data, and defined major criteria as findings observed in ≥ 70% of the patients and minor criteria as those observed in ≥ 50% but < 70% of the patients. RESULTS: Our cohort included 34 fetuses. The mean gestational age at ultrasound screening, when suspicion of a central nervous system anomaly was first raised, was 24.2 (range, 17-33) weeks. Callosal anomalies (n = 19 (56%)) and abnormal ventricles (n = 18 (53%)) were the main reasons for referral. The mean gestational age at neurosonography was 28.3 (range, 23-34) weeks and that at MRI was 30.2 (range, 24-35) weeks. Major ultrasound criteria were midline distortion, ventricular asymmetry, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation. Minor ultrasound criteria were distortion of the cavum septi pellucidi, abnormal corpus callosum, absent or asymmetric olfactory sulci, ventriculomegaly and basal ganglia dysmorphism. Major MRI criteria were midline distortion, distortion of the cavum septi pellucidi, ventricular asymmetry, dilatation (generally unilateral) and/or distortion, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation (mainly dysgyria). Minor MRI criteria were absent or asymmetric olfactory sulci, abnormal bulge of the pons, anteroposterior diameter of the pons ≤ 5th centile and brainstem asymmetry. A mutation was found in TUBB3 (44.1% of cases), TUBB (23.5%), TUBB2B (14.7%) or TUBA1A (17.6%). The mutation was inherited from a parent in 18/34 cases. The pregnancy was terminated in 23/34 cases. CONCLUSIONS: Prenatal diagnosis of mild forms of tubulinopathy is possible but challenging. We have defined, in this large series of fetuses, major and minor criteria that can help identify this entity in utero. Most findings can be visualized on ultrasound. This evaluation is also important for prenatal counseling. Once a prenatal diagnosis of mild tubulinopathy is suspected, the family members should be referred for exome sequencing and MRI. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Exome sequencing as first-tier test for fetuses with severe central nervous system structural anomalies.

OBJECTIVE: Prenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly. METHODS: This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed using ES to assess its ability to detect copy-number variants (CNVs). RESULTS: CMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty-six CMA-negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non-significantly higher compared with non-recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non-causative CNVs. CONCLUSIONS: In our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Early second-trimester three-dimensional transvaginal neurosonography of fetal midbrain and hindbrain: normative data and technical aspects.

OBJECTIVES: To provide a detailed description of the sonographic appearance and development of various fetal structures of the midbrain and hindbrain (MBHB) during the early second trimester, and to evaluate the impact of the frequency of the transvaginal sonography (TVS) transducer on the early recognition of these structures. METHODS: This was a retrospective analysis of three-dimensional volumetric datasets of the MBHB from apparently normal fetuses at 14-19 gestational weeks, acquired by TVS in the midsagittal view through the posterior fontanelle. Using a multiplanar approach, we measured the tectal thickness and length, aqueductal thickness, tegmental thickness and width and height of the Blake's pouch (BP) neck. In addition, we assessed the existence of early vermian fissures, the linear shape of the brainstem and the components of the fastigium. The correlation between gestational age according to last menstrual period and sonographic measurements of MBHB structures was evaluated using Pearson's correlation (r). A subanalysis was performed to assess the performance of a 5-9-MHz vs a 6-12-MHz TVS transducer in visualizing the MBHB structures in the early second trimester. RESULTS: Sixty brain volumes were included in the study, obtained at a mean gestational age of 16.2 weeks (range, 14.1-19.0 weeks), with a transverse cerebellar diameter range of 13.0-19.8 mm. We found a strong correlation between gestational age and all MBHB measurements, with the exception of the tectal, tegmental and aqueductal thicknesses, for which the correlation was moderate. There was good-to-excellent intraobserver and moderate-to-good interobserver correlation for most MBHB measurements. We observed that the BP neck was patent in all fetuses between 14 and 18 weeks with decreasing diameter, and that the aqueductal thickness was significantly smaller at ≥ 18 weeks compared with at < 16 weeks. The early vermian fissures and the linear shape of the brainstem were present in all fetuses from 14 weeks. We found that, in the early second trimester, the horizontal arm of the presumed 'fastigium' evolves from the fourth ventricular choroid plexus and not the posterior vermis, indicating that this is not the fastigium. Standard- and high-resolution TVS transducers performed similarly in the assessment of MBHB anatomy. CONCLUSION: Detailed early second-trimester assessment of the MBHB is feasible by transvaginal neurosonography and provides reference data which may help in the early detection of brain pathology involving the MBHB. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Functional ovarian reserve in transgender men receiving testosterone therapy: evidence for preserved anti-Müllerian hormone and antral follicle count under prolonged treatment.

STUDY QUESTION: Is the functional ovarian reserve in transgender men affected by testosterone therapy? SUMMARY ANSWER: Serum anti-Müllerian Hormone (AMH) levels slightly decrease during testosterone treatment but remain within the normal range, suggesting preserved follicular ovarian reserve. WHAT IS KNOWN ALREADY: Few small studies have investigated the impact of gender-affirming treatment on reproduction in transgender men. Conflicting results were reached concerning ovarian morphology and AMH levels in this context. STUDY DESIGN, SIZE, DURATION: The study consisted of two arms. The first arm was a prospective pilot study, which enrolled 56 transgender men (median age 22.5 [interquartile range (IQR)-19-27.7] years), 27 of whom had polycystic ovary syndrome (PCOS), prior to the initiation of gender-affirming testosterone therapy. A structured assessment was conducted prior to, and at 3 and 12 months after treatment initiation. The second arm was a cross-sectional study that comprised 47 transgender men (median age 24 [IQR-20-31] years) who received testosterone for a median duration of 35 [IQR 13-62] months. The main outcome measures were serum AMH and antral follicle count (AFC) as indices of ovarian follicular reserve. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at a tertiary center for transgender health. Gender-affirming therapy was administered according to standard practice. AFC was determined by pelvic (abdominal or transvaginal) ultrasound and blood collection for measurements of AMH, testosterone, estradiol, LH and FSH was performed at the designated time-points. MAIN RESULTS AND THE ROLE OF CHANCE: Prospective arm for the entire group we observed a decrease of 0.71 ng/ml in AMH levels between baseline and 12 months (P = 0.01). When expressed in age-specific percentiles, AMH went from the 47.37th to the 40.25th percentile at 12 months (P < 0.001). In a sub-group analysis, a decline of 9.52 points in age-specific percentile was seen in subjects with PCOS (P < 0.001), while no changes were detected in the non-PCOS group. Testosterone treatment did not affect AFC over time in the entire cohort. In the sub-group analysis, a mean decrease of 5.0 follicles was detected between baseline and the 12 months assessment (P = 0.047) only in subjects with PCOS. In the cross-sectional study, AMH inversely correlated with age but not with treatment duration. Notably AMH did not deviate from the 50th age-specific percentile. Finally, four men fathered biological children after being under testosterone treatment for up to 12 years. LIMITATIONS, REASONS FOR CAUTION: The limited sample size of the pilot study should be kept in mind. An additional limitation is the lack of a control group in the prospective study, as each participant served as his own control. Also, roughly 40% of the ultrasound examinations were performed transabdominally, potentially affecting the accuracy of the AFC measurements.As study participants were quite young, our reassuring data may not apply to older transgender men, either because of an age-related decline in ovarian reserve or to possible long-term effects of testosterone therapy. Furthermore, the chances for fertility preservation may be more limited in subjects with PCOS. WIDER IMPLICATIONS OF THE FINDINGS: This is an additional contribution to the emerging evidence that prolonged testosterone treatment may not be a major obstacle to later fertility potential in transgender men desirous of having children. Larger confirmatory studies, and particularly more with reproductive outcome data, are needed for evidence-based fertility counseling prior to treatment initiation in these subjects. STUDY FUNDING/COMPETING INTEREST(S): This study received no funding. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Prenatal diagnosis of rhombencephalosynapsis: neuroimaging features and severity of vermian anomaly.

OBJECTIVES: To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. METHODS: In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES. RESULTS: Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD) < 3rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption. CONCLUSIONS: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Normal cavum veli interpositi at 14-17 gestational weeks: three-dimensional and Doppler transvaginal neurosonographic study.

OBJECTIVES: To provide evidence to support the hypothesis that the midline cyst-like fluid collection that is frequently observed on fetal brain ultrasound (US) imaging during the early second trimester represents a normal transient cavum veli interpositi (CVI). METHODS: This was a retrospective analysis of 89 three-dimensional normal fetal brain volumes, acquired by transvaginal US imaging in 87 pregnant women between 14 and 17 gestational weeks. The midsagittal view was studied using multiplanar imaging, and the maximum length of the fluid collection located over (dorsal to) the tela choroidea of the third ventricle was measured. We calculated the correlation of the transverse cerebellar diameter (TCD) and of the maximum length of the fluid collection with gestational age according to last menstrual period. Color Doppler images were analyzed to determine the location of the internal cerebral veins with respect to the location of the fluid collection. Reports of the second-trimester anatomy scan at 22-24 weeks were also reviewed. RESULTS: Interhemispheric fluid collections of various sizes were found in 55% (49/89) of the volumes (mean length, 5 (range, 3.0-7.8) mm). There was a strong correlation between TCD and gestational age (Pearson's correlation, 0.862; P < 0.001). There was no correlation between maximum fluid length and gestational age (Pearson's correlation, -0.442; P = 0.773). Color Doppler images were retrieved in 32 of the 49 fetuses; in 100% of these, the internal cerebral veins coursed within the echogenic roof of the third ventricle. The midline structures were normal at the 22-24-week scan in all cases. CONCLUSIONS: In approximately half of normal fetuses, during the evolution of the midline structures of the brain, various degrees of fluid accumulate transiently in the velum interpositum, giving rise to a physiologic CVI. Patients should be reassured that this is a normal phenomenon in the early second trimester that, if an isolated finding, has no influence on fetal brain development. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fourth ventricle index: sonographic marker for severe fetal vermian dysgenesis/agenesis.

OBJECTIVE: Prenatal diagnosis of midbrain-hindbrain (MB-HB) malformations relies primarily on abnormal size and shape of the cerebellum and retrocerebellar space, particularly 'open fourth ventricle' (4V), the most common indicator of MB-HB malformations. The aim of this study was to present the fourth ventricle index (4VI), and to evaluate its role as a marker for severe vermian dysgenesis/agenesis in cases without open 4V. METHODS: This was a prospective cross-sectional study of patients with singleton low-risk pregnancy at 14 + 1 to 36 + 6 gestational weeks presenting between May 2016 and November 2017 for routine ultrasound examination. Axial images of the fetal 4V were obtained and the 4VI was calculated as the ratio between the laterolateral and the anteroposterior diameters. Reference ranges were constructed and retrospectively collected values from 44 fetuses with confirmed anomalies involving severe vermian dysgenesis/agenesis (Joubert syndrome and related disorders, rhombencephalosynapsis, cobblestone malformations and cerebellar hypoplasia) but without open 4V were compared with the normal values. RESULTS: In total, 384 healthy fetuses were enrolled into the study, from which reference ranges were produced, and 44 cases were collected retrospectively. The 4VI in the normal fetuses was always > 1. In affected fetuses, it was always below mean -2 SD and < 1. CONCLUSIONS: The 4VI is a sonographic marker for severe fetal vermian dysgenesis/agenesis in the absence of an open 4V. It may be incorporated easily into the routine brain scan; 4VI < 1 indicates a need for dedicated fetal neuroimaging for diagnosis and prenatal counseling. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.