Congenital hypotonia: systematic approach for prenatal detection.

OBJECTIVES: Congenital hypotonic conditions are rare and heterogeneous, and some are severely debilitating or lethal. Contrary to its prominent postnatal manifestation, the prenatal presentation of hypotonia is frequently subtle, inhibiting prenatal detection. We aimed to characterize the prenatal sonographic manifestation of congenital hypotonia throughout pregnancy, evaluate the yield of diagnostic tests and propose diagnostic models to increase its prenatal detection. METHODS: This was a retrospective observational study of singleton pregnancies with congenital hypotonia, diagnosed either prenatally or immediately after birth, at a single tertiary center between the years 2012 and 2020. Prenatally, hypotonia was diagnosed if a fetus showed sonographic or clinical signs suggestive of hypotonia and had a confirmed underlying genetic condition, or in the absence of a known genetic abnormality if the fetus exhibited multiple prominent signs suggestive of hypotonia. Postnatally, it was diagnosed in neonates displaying reduced muscle tone leading to reduced spontaneous movement, reduced swallowing or feeding difficulty. We reviewed the medical records of pregnant patients carrying fetuses subsequently diagnosed with congenital hypotonia and assessed the yield of ultrasound scans, fetal magnetic resonance imaging, computed tomography and genetic tests. The detection rate of sonographic signs suggesting fetal hypotonia was calculated. The prevalence of non-specific signs, including polyhydramnios, persistent breech presentation, intrauterine growth restriction and maternal perception of reduced fetal movement, were compared between the study group and the local liveborn singleton population. Potential detection rates of different theoretical semiotic diagnostic models, differing in the threshold for referral for a targeted scan, were assessed based on the cohort's data. RESULTS: The study group comprised 26 cases of congenital hypotonia, of which 10 (38.5%) were diagnosed prenatally, and the controls included 95 105 singleton live births, giving a prevalence of congenital hypotonia of 1:3658. Nuchal translucency thickness and the early anomaly scan at 13-17 weeks were normal in all 22 and 23 cases, respectively, in which this was performed. The mid-trimester scan performed at 19-25 weeks was abnormal in four of 24 (16.7%) cases. The overall prenatal detection rate of congenital hypotonic conditions in our cohort was 38.5%. Only cases which underwent a targeted scan were detected and, among the 16 cases which underwent this scan, the prenatal detection rate was 62.5% compared with 0% in pregnancies that did not undergo this scan (P = 0.003). An abnormal genetic diagnosis was obtained in 21 (80.8%) cases using the following modalities: chromosomal microarray analysis (CMA) in two (9.5%), whole-exome sequencing (WES) in 14 (66.7%) and methylation analysis in five (23.8%). CMA was abnormal in 8% (2/25) of the cases and WES detected a causative genetic mutation in 87.5% (14/16) of the cases in which these were performed. Comparison of non-specific signs in the study group with those in the local singleton population showed that hypotonic fetuses had significantly more polyhydramnios (64.0% vs 3.0%, P < 0.0001), persistent breech presentation (58.3% vs 4.2%, P < 0.0001), intrauterine growth restriction (30.8% vs 3.0%, P < 0.0001) and maternal perception of reduced fetal movement (32.0% vs 4.7%, P < 0.0001). Prenatally, the most commonly detected signs supporting a diagnosis of hypotonia were structural anomaly (62.5%, 10/16), reduced fetal movement (46.7%, 7/15), joint contractures (46.7%, 7/15) and undescended testes ≥ 30 weeks (42.9%, 3/7 males). Proposed diagnostic strategies that involved performing a targeted scan for a single non-specific ultrasound sign or two such signs, and then carrying out a comprehensive genetic evaluation for any additional sign, offered theoretical detection rates in our cohort of 88.5% and 57.7%, respectively. CONCLUSIONS: Congenital hypotonic conditions are rare and infrequently detected prenatally. Sonographic signs are visible from the late second trimester. A targeted scan increases prenatal detection significantly. Comprehensive genetic testing, especially WES, is the cornerstone of diagnosis in congenital hypotonia. Theoretical diagnostic models which may increase prenatal detection are provided. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Apparent Diffusion Coefficient Levels and Neurodevelopmental Outcome in Fetuses with Brain MR Imaging White Matter Hyperintense Signal.

BACKGROUND AND PURPOSE: One of the perplexing findings of fetal brain MR imaging is white matter T2 hyperintense signal. The aims of our study were initially to determine the main etiologies associated with white matter T2 hyperintense signal, then to examine whether the different etiologies have different ADC values, and, last, to assess the association of white matter T2 hyperintense signal with developmental outcome. MATERIALS AND METHODS: This was a prospective cohort study of 44 MR imaging scans of fetal brains obtained for suspected brain pathologies at a tertiary medical center during 2011-2015. Clinical data were collected from electronic medical charts. ADC values were measured and averaged in the frontal, parietal, occipital, and temporal lobes. Neurodevelopmental assessments were performed with the Vineland Adaptive Behavior Scales II. RESULTS: Half of the cases of MRI hyperintense T2 signal of the fetal brain were associated with congenital cytomegalovirus infection. The other half were mainly idiopathic. Thus, the study group was divided to subgroups positive and negative for cytomegalovirus. Both groups had hyperintense signal in the temporal lobe. The group positive for cytomegalovirus had involvement of the parietal lobe. Only this group had increased ADC values in the temporal and parietal lobes. There was no association between the neurodevelopment outcome and the etiologies or ADC values. CONCLUSIONS: T2 hyperintense signal in fetal brain MRI associated with positive cytomegalovirus infection has increased ADC values in the temporal and parietal lobes, suggestive of brain edema in these areas. However, the association between this finding and neurodevelopment outcome requires further evaluation.

Prenatal Evaluation, Imaging Features, and Neurodevelopmental Outcome of Prenatally Diagnosed Periventricular Pseudocysts.

BACKGROUND AND PURPOSE: Periventricular pseudocysts are cystic cavities that lack the ependymal cell lining found in true cysts. The aim of this study was to characterize periventricular pseudocysts and related findings and their neurodevelopmental outcome. MATERIALS AND METHODS: This was a retrospective study of periventricular pseudocysts detected prenatally on fetal MR imaging in 26 fetuses. The fetuses were divided into group A (n = 8), which included cases with isolated periventricular pseudocysts, and group B (n = 18), which included cases of periventricular pseudocysts with additional findings. Cases were further subdivided into connatal cysts and subependymal pseudocysts. Data collected included prenatal history, MR imaging features, sonographic follow-up, and neurodevelopmental outcome. RESULTS: All cases in group A (n = 8) had a normal outcome. In group B (n = 18), 6 pregnancies were terminated and 2 had an abnormal outcome. Both cases with an abnormal outcome involved patients with subependymal pseudocysts. No significant association was found between the morphologic features on MR imaging and the neurodevelopmental outcome. CONCLUSIONS: Neurodevelopmental outcome in cases of isolated periventricular pseudocysts detected prenatally appears to be normal. A detailed evaluation should be performed to rule out additional brain findings, chromosomal aberration, and fetal malformation. This evaluation should include the following: maternal TORCH status, detailed fetal sonographic anatomic evaluation, fetal echocardiogram, fetal brain MR imaging, amniocentesis and karyotyping/comparative genomic hybridization, and genetic counseling. Additional findings on MR imaging, including mild-to-moderate dilated ventricles, asymmetric ventricles, or T2 hyperintense signal in the white matter without other findings or major fetal abnormality, appear to be benign. Connatal cysts appear to be benign.

Umbilical vein anomaly in fetuses with Down syndrome.

OBJECTIVE: To describe the prevalence of abnormal umbilical vein (UV) anatomy in fetuses with Down syndrome. METHODS: This was a retrospective survey covering a 24-month period of fetuses with a genetic diagnosis of Down syndrome following a routine early second-trimester (12-16-week) detailed fetal anomaly scan at a single academic tertiary referral center. In our unit this exam includes fetal umbilicoportal venous system evaluation. RESULTS: During the study period, 37 fetuses were diagnosed with Down syndrome and had a detailed early anatomy scan. In four (11%) the detailed early anomaly scan revealed that the UV was connected to the hepatic portion of the inferior vena cava (IVC) at a position lower than its usual site. Their average gestational age at diagnosis was 13 + 6 (range, 11 + 6 to 15 + 2) weeks. Three of the four fetuses had a nuchal translucency thickness of 3-4 mm. In one fetus there was an additional finding of significant tricuspid regurgitation and the one with normal nuchal translucency thickness had an atrioventricular septal defect (atrioventricular canal) and umbilical cord hernia. During the same period three of 2500 (0.12%) fetuses with normal karyotype demonstrated similar anomalous insertion of the UV into the IVC, creating a portocaval shunt which had normal ductus venosus-like Doppler flow in all three cases. The odds ratio for abnormal umbilicoportal venous system in fetuses with Down syndrome compared with the normal population was 107.4 (95% CI, 19.2-637.1). CONCLUSIONS: Fetuses with Down syndrome demonstrate an increased prevalence of abnormal connection of the UV to the IVC.

Screening for fragile X syndrome in women of reproductive age.

We conducted a prospective intervention study of screening for fragile X syndrome in the general population. Antenatal and preconceptional screening were carried out in 9459 women aged between 19 and 44 with no known family history of fragile X syndrome. 80% were tested antenatally. 134 carriers were detected (a frequency of 1 in 70); 130 had a premutation (PM) and 4 had a full mutation (FM). Prenatal diagnosis was carried out in 108 concurrent or subsequent pregnancies among carriers involving 111 fetuses. Nine had an FM, a rate of 1 in 12; two of the affected embryos received the FM directly from the mother and in seven it was the result of expansion from a PM. In all cases with an FM the pregnancy was terminated. In PM carriers there was evidence of a selection against the mutated chromosome with a segregation ratio of 0.40. Owing to the high rate of premutated chromosomes in our population we conclude that screening for fragile X syndrome among women of reproductive age should be more widely available.

Pulmonary agenesis, microphthalmia, and diaphragmatic defect (PMD): new syndrome or association?

We present the prenatal diagnosis of a 22-week-gestation fetus with unilateral pulmonary agenesis, diaphragmatic hernia, microphthalmia, pulmonary vessel agenesis, and intrauterine growth retardation. The "association" of pulmonary agenesis, diaphragmatic defect, and microphthalmia was described previously in two patients but the resemblance was not noted by the authors. While each case differs slightly in some of the associated anomalies, it is evident that the mainstay of diagnosis is similar to the case presented here and that this represents a new syndrome or association.

Perceived personal control (PPC): a new concept in measuring outcome of genetic counseling.

Many researchers have tried to establish criteria for the evaluation of genetic counseling and the assessment of its success. Most studies focused on counseling outcomes mainly educational and reproductive variables. In the present study we introduced the concept of "perceived personal control" (PPC), which captures a wider and more meaningful range of effects of genetic counseling. It was found to be central to coping with health threats and to adapting to a broad spectrum of health problems. This study investigated 154 counseling cases. Counselees were requested to complete pre- and post-counseling questionnaires consisting of a knowledge test, measures of PPC, expectations/evaluations of counseling, and satisfaction with the procedure. Comparisons of mean PPC scores before and after counseling showed significant increases. Higher post-counseling PPC was found among counselees who had been given a definite diagnosis, a specific recurrence risk, and been offered prenatal diagnosis. Post-counseling PPC also correlated with knowledge, satisfaction, counseling evaluations, and expectation fulfillment. The findings suggest that PPC is a valid measure for the evaluation of genetic counseling outcomes. The psychometrically reliable scales developed in this study can become helpful tools for assessing genetic counseling both in research and in clinical practice, helping the counselor evaluate the counseling session and focus on the counselees' needs.

Second-trimester ultrasonographic diagnosis of segmental vertebral abnormalities associated with neurological deficit: a possible new variant of occult spinal dysraphism.

Sonographic evaluation of the fetal spine in a second-trimester, low-risk patient revealed segmentary, low thoracic vertebral abnormalities, including hemi- and butterfly vertebrae, resulting in severe fetal scoliosis with fetal paraplegia and bilateral club-feet. X-ray and magnetic resonance imaging studies of the abortus confirmed the prenatal vertebral findings in addition to rib defects and transection of the spinal cord. We believe that these findings which, to the best of our knowledge, have not been previously reported, represent a new variant of occult spinal dysraphism.

Concordance of auriculo-cardiovascular-skeletal malformations: a new malformation complex in an infant of a diabetic mother?

The incidence of malformations among infants of diabetic mothers (IDM) is known to be higher than in the general population. These malformations usually involve several organ systems and in the past few years there has been an attempt to group them into distinct "syndromes." The present report concerns a child with a specific constellation of findings not yet reported in the infant of a diabetic mother, and we urge our colleagues to look for other associations existing in these infants, rather than just listing series of individual malformations.

Megalocornea, macrocephaly, mental and motor retardation (MMMM).

Two patients with macrocephaly, mild mental retardation and megalocornea are reported. Hypotonia, poor coordination and swallowing difficulties were present. One patient was obese and the other had scoliosis. Both had large fleshy ears and long fingers. The spectrum of the mental retardation megalocornea syndrome is not fully defined. These two patients resemble a previously reported case, and although there are distinct differences from patients with familial or sporadic Neuhauser syndrome, these cases may represent clinical variability of that syndrome.

Brachydactyly type A-7 (Smorgasbord): a new entity.

We report a family with a form of brachydactyly that involves characteristic features of types A2 and D brachydactyly plus features found in other types of brachydactyly and also features not previously noted. This set of findings represents a new syndrome, which we have termed brachydactyly type A7 (Smorgasbord).

Congenital heart disease and external ear anomalies with hearing loss: a report of two new cases and a review of the literature.

Two cases of infants presenting primarily with congenital heart disease and external ear anomalies with hearing loss are reported. There is a clear, clinically important, association between these two birth defects; this association discussed along with a review of other syndromes with such features.

Absence of a vagina and right sided adnexa uteri in the Waardenburg syndrome: a possible clue to the embryological defect.

An 18 year old single Jewish woman with the Waardenburg syndrome and absence of a vagina and right sided adnexa uteri is reported. Other congenital malformations associated with the Waardenburg syndrome are mentioned and it is postulated that they may be the result of an altered invasion of neurones or altered neurones in certain organ systems early in embryogenesis.

Partial duplication of the eyebrows with other congenital malformations: a new syndrome.

Congenital malformations involving the eyebrows are a rare phenomenon. Recently we have seen a case with partial duplication of the eyebrows and multiple other malformations. Because of the presence of close parental consanguinity, we believe this constellation of findings represents a new syndrome, possibly transmitted as an autosomal recessive disorder.