Prenatal diagnosis of a severe form of frontonasal dysplasia with severe limb anomalies, hydrocephaly, a hypoplastic corpus callosum, and a ventricular septal defect using 3D ultrasound: a case report and literature review.

BACKGROUND: Frontonasal dysplasia (FND) is a rare congenital anomaly resulting from the underdevelopment of the frontonasal process, and it can be syndromic or nonsyndromic. The typical features of FND include a deformed nose and ocular hypertelorism, which are sometimes associated with cleft lip and/or palate. Only approximately 10 cases of prenatally diagnosed nonsyndromic FND have been reported in the past 30 years. CASE PRESENTATION: A 33-year-old woman (G2P1) was referred to our center at 20 gestational weeks for bilateral hydrocephaly. We detected typical features of FND, including severe hypertelorism, median nasal bifidity, a minor cleft lip, and multiple limb anomalies using three-dimensional (3D) ultrasound. A hypoplastic corpus callosum, unilateral microtia, and a ventricular septal defect were also detected. Genetic testing, including karyotype analysis, copy number variation (CNV) analysis, trio-whole exome sequencing (trio-WES), and trio-whole-gene sequencing (trio-WGS), was performed; however, we did not find any de novo gene variants in the fetus as compared to the parents. Postmortem examination confirmed the prenatal diagnosis of FND. CONCLUSION: The present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.

Association of right aortic arch and agenesis of ductus arteriosus in prenatal tetralogy of Fallot spectrum and its clinical implications.

OBJECTIVE: In our center, we observed an increased frequency of right aortic arch (RAA) with an agenesis of the ductus arteriosus (ADA) in prenatally diagnosed tetralogy of Fallot (ToF) and its variations. This study aimed to determine whether there is an association of RAA and ADA in fetuses with ToF. Distribution of genetic anomalies and impact on postnatal outcome were further evaluated. METHOD: Single-center retrospective observational study including pregnancies with prenatal diagnosis of ToF from 2010 to 2023. All cases were subdivided into ToF with pulmonary stenosis (PS) and pulmonary atresia (PA). Clinical and echocardiographic databases were reviewed for pregnancy outcome, genetic anomalies, and postnatal course. RESULTS: The cohort included 169 cases, 124 (73.4%) with ToF/PS and 45(26.6%) with ToF/PA. Agenesis of the ductus arteriosus was significantly associated with RAA in both subtypes of ToF (p = 0.001) compared to left aortic arch and found in 82.5% (33/40) versus 10.7% (9/84) of fetuses with ToF/PS and in 57.1% (8/14) versus 12.9% (4/31) of fetuses with ToF/PA. In both ToF/PS and ToF/PA, RAA/ADA versus RAA/patent DA revealed a significantly higher risk for the presence of genetic abnormalities, especially microdeletion 22q11.2, major aorto-pulmonary collateral arteries and a shorter time to complete surgical repair. CONCLUSION: We demonstrated a significantly increased frequency of RAA/ADA in patients with prenatally diagnosed ToF. Although this association revealed no significant impact on overall survival, the prenatal detection of RAA/ADA has implications for counseling, genetic evaluation and postnatal management.

Fetus with multiple congenital anomaly syndrome caused by novel variant in ATP1A2.

We report a 32-year-old G3P1 at 35 weeks 3 days with a dichorionic, diamniotic twin gestation who presented for evaluation secondary to ventriculomegaly (VM) in one twin. Fetal ultrasound and MRI demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture, indicative of a prior insult in the affected twin. The co-twin was grossly normal. The family pursued a palliative care pathway for the affected twin and was delivered at 37 weeks and 6 days. The affected twin passed away within the first hour of life due to respiratory compromise. Postmortem trio exome sequencing identified a homozygous likely pathogenic variant in ATP1A2 (c.2439+1G>A). Although this variant is novel, it is predicted to affect the donor split site in intron 17, resulting in a frameshift and complete loss-of-function of the gene. Biallelic loss of function variants in this gene have been reported in seven individuals with multiple anomalies similar to those in the affected twin. However, only one other individual with a possible CDH has been previously reported. Our case suggests that CDH be included in the phenotypic spectrum of this disorder and reports the first frameshift mutation causing this autosomal recessive multiple congenital anomaly syndrome.

Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities.

Autosomal recessive ROR2-Robinow syndrome is caused by pathogenic variants in the ROR2 gene. Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed macrocephaly, brachycephaly, flat face, prominent forehead, mild frontal bossing, lower thoracic hemivertebrae, digital abnormalities and micropenis. Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene, c.1324 C > T; p.(Arg442*) maternally inherited and c.1366dup; p.(Leu456Profs*3) apparently de novo. c.1324 C > T; p.(Arg442*) is a nonsense variant resulting in protein truncation reported to be associated with RRS3. c.1366dup; p.(Leu456Profs*3) is a frameshift variant predicted to result in protein truncation reported to segregate with the disease in multiple affected individuals from a single large family with distal symphalangism of the fourth finger. Fetal autopsy following pregnancy termination showed a large head with low-set ears, facial abnormalities, mesomelic bone shortening, hemivertebra, fused S3 and S4 vertebral bodies, several fused rib heads and short penis with buried shaft.

Pancake kidney and jejunal atresia: An uncommon dual anomaly detected prenatally-A case report.

Pancake kidney is a renal fusion anomaly with only a few reported prenatal diagnoses. Other structural anomalies beyond the urogenital system may also be associated. This study describes a dual anomaly case detected prenatally, comprising of pancake kidney and jejunal atresia. A postnatal abdominal ultrasound confirmed both kidneys were fused in the midline at the aortic bifurcation level, along with a type 3b jejunal atresia. Based on the available limited evidence about pancake kidney, renal functions appear to remain largely preserved and unaffected as in our case according to 6 months of follow-up. However, further investigation is needed to explore any potential association with chromosomal and structural abnormalities in selected cases.

Cloacal Dysgenesis Sequence in a Preterm Neonate.

BACKGROUND Cloaca malformations result from a disproportion of apoptosis, cell growth, and maturation. The range of cloacal malformations is extensive and diverse, with a lack of a straightforward classification system. Cloacal dysgenesis sequence (CDS), also known as urorectal septum malformation sequence, is a rare cloaca variant described as the absence of a perineal orifice. Prenatal magnetic resonance imaging and antenatal ultrasounds may reveal a cloacal malformation; however, many patients are not diagnosed with cloacal malformation until birth. CASE REPORT We present a case of a female neonate delivered by a 23-year-old G2P1T1A0L0 mother who had received comprehensive prenatal care. During pregnancy, bilateral multicystic dysplastic kidneys were identified prenatally, leading to the in utero placement of a vesicoamniotic shunt. The physical exam revealed a distended abdomen with reduced abdominal musculature and laxity, ascites, a vesicoamniotic shunt in place, absent urethra, ambiguous genitalia with no vaginal opening, no perineal opening, and clubfoot. Abdominal radiograph showed findings consistent with significant abdominal ascites. An exploratory laparotomy was performed that included diverting colostomy, mucous fistula creation, tube vaginostomy, removal of the vesicoamniotic shunt, and suprapubic tube placement. The patient recovered well from this operation with no complications. CONCLUSIONS CDS is an uncommon condition in pediatric patients, and although sonographic findings can reveal urinary tract abnormalities, prenatal imaging might not always identify CDS. Our case underscores the uniqueness of the case and the significance of early detection and immediate medical and surgical intervention.

Sirenomelia: An anatomical assessment and genetic sex determination of two cases.

The etiology of sirenomelia is currently unknown. Data are limited in comparing external and internal abnormalities using modern imaging technologies and molecular genetic analysis. The purpose of the current study was designed to compare external and internal anatomical defects in two cases of sirenomelia and Potter's sequence. Considered rare, Potter's sequence is a fetal disorder with characteristic features of bilateral renal agenesis, obstructive uropathy, atypical facial appearance, and limb malformations. The internal and external malformations of two term fetuses with sirenomelia and Potter's sequence were compared using assessment of external features, radiography and MRI on internal structures, and molecular genetic studies on sex determination. Data reveal that both fetuses were male and manifested with an overlapping but distinct spectrum of abnormalities. Principal differences were noted in the development of the ears, brain, urogenital system, lower limbs, pelvis, and vertebral column. Defects of the axial mesoderm are likely to underlie the abnormalities seen in both fetuses. The first one, which had only caudal defects, was found to have a spectrum of abnormalities most similar to those associated with more severe forms of the small pelvic outlet syndrome, although the structure and orientation of the sacrum and iliae were different from previously reported cases. The other had both caudal and cranial defects, and was most similar to those described in the axial mesodermal dysplasia syndrome. Defects associated with sirenomelia can be evaluated with standard gross anatomy examination, radiology, MRI, and modified PCR techniques to determine anatomical abnormalities and the sex of preserved specimens, respectively. Evidence indicated that sirenomelia could be developed via various etiologies.

Hydrocephalus associated with a molar tooth sign: A distinct subtype of Joubert syndrome.

Hydrocephalus is rarely described in Joubert-Boltshauser syndrome (JBTS). The aim of this study was to investigate whether this association is a chance occurrence or potentially signifies a new phenotypic subtype. The databases of Wolfson Medical Center, Sourasky Medical Center, and EB's personal collection were reviewed. Records from an additional family were obtained from RG. The patients' medical records, prenatal ultrasounds, and magnetic resonance imaging were assessed. In addition, we reviewed the medical literature for the association of ventriculomegaly/hydrocephalus (VM/HC) in JBTS. Only seven cases (from five families) were found with prenatal onset of VM/HC, diagnosed during the second trimester; three pregnancies were terminated, one was stillborn and three were born, of which one died within a week, and another died at the age of 6 years. Additional central nervous system findings included dysgenesis of the corpus callosum, delayed sulcation, polymicrogyria, and pachygyria. We found 16 publications describing 54 patients with JBTS and VM/HC: only five were diagnosed at birth and three were diagnosed prenatally. Hydrocephalus is extremely rare in JBTS. The recurrence of this association, reported in several publications in multiple family members, suggests that it might represent a new phenotypic subtype of JBTS possibly associated with specific genes or variants. Further genetic studies are needed to confirm this hypothesis. WHAT THIS PAPER ADDS: The association of fetal hydrocephalus with Joubert-Boltshauser syndrome (JBTS) is very rare but not a chance association. This association represents a new phenotypic subtype of JBTS possibly linked to specific genes or variants.

Prenatal Diagnosis of Primrose Syndrome.

Primrose syndrome is a very rare congenital malformation. Symptoms of this disorder may appear during childhood, but the diagnosis is identified in adulthood in the majority of cases. The prenatal diagnosis of Primrose syndrome is not developed in the literature. We present herein a case series of 3 cases with characteristic sonographic features. A dysmorphic metopic suture, downslanting palpebral fissures, a wide forehead, and agenesis of corpus callosum are the main signs. A missense mutation in ZBTB20 identified in whole exome sequencing can confirm the prenatal diagnosis of Primrose syndrome.

Prenatal Detection and Postnatal Outcome of Persistent Left Superior Vena Cava and Agenesis of Ductus Venosus Associated with Postnatal Bovine Aortic Arch.

BACKGROUND: Isolated agenesis of ductus venosus (ADV) is usually a benign condition, but it may be associated with cardiovascular defects, hydrops, growth restriction, and chromosomal abnormalities. Additionally, persistent left superior vena cava (PLSVC) and bovine aortic arch are relatively common fetal anomalies. To the author's knowledge, this is the first report of prenatal detection of DV agenesis and PLSVC associated with the postnatal bovine aortic arch with a hypoplastic transverse aortic arch. CASE: A 25-year-old, G2P1 woman was referred to our department at 31 weeks due to fetal growth restriction and short femur. On fetal echocardiography, DV could not be viewed via two-dimensional (2D) and Doppler ultrasound (US) imaging; there was also evidence of the co-occurrence of PLSVC and an aortic arch anomaly. We revealed the intrahepatic continuation of the umbilical vein. A weekly follow-up program was scheduled for the patient and the rest of the pregnancy was uneventful. Postnatal, thorax computer tomography and transthoracic echocardiography (TTE) demonstrated PLSVC and bovine aortic arch associated with hypoplastic transverse aortic arch. Routine echocardiographic examinations revealed that the blood flow of the aortic arch had increased gradually, and the male infant's aortic arch had significantly widened and reached the normal range until the baby was discharged from the hospital. CONCLUSION: DV agenesis and PLSVC are usually benign conditions but underlying serious heart diseases may accompany them. Therefore, in situations like ours, a prenatal aortic arch evaluation is of capital importance. Postnatal hemodynamic changes should be taken into consideration in the management of these cases. This is the first example in the literature that these abnormalities co-existed in one case.

Characteristics of Neuroimaging and Behavioural Phenotype in Polish Patients with PIGV-CDG-An Observational Study and Literature Review.

Congenital disorders of glycosylation (CDGs) are a wide group of genetic diseases characterised by a severe clinical spectrum, consisting of developmental delays, dysmorphisms, and neurological deficits. Mutations in the PIGV gene lead to a disorder called hyperphosphatasia with impaired intellectual development syndrome 1 (HPMRS1), distinct from other CDGs in terms of hyperphosphatemia related to abnormal ALP activity and brachytelephalangy. This article discusses the phenotype of six Polish patients with HPMRS1 with a special focus on behavioural and imaging features, which were not addressed in 26 previously reported cases. The medical records of six patients aged 6 to 22 years were collected and analysed. In all cases, the same PIGV homozygotic mutation (c.1022C>A; p.Ala341Glu) was found, although the patients presented a diverse spectrum of neurological and developmental disorders, concerning in most cases the muscular tonus and general developmental delay. The most prevalent dysmorphic features included hypertelorism, high palate, and finger anomalies, whereas other characteristics present in all previously described cases, such as a short, broad nose and brachytelephalangy, were less frequently observed. Similarly to previous reports, the magnetic resonance (MR) and computed tomography (CT) head scans returned varied results, including physiological and pathological brain images in equal measure, the latter of which consisted of cortical atrophy, delayed myelination, hydrocephalus, and hypoplastic corpus callosum. Each patient exhibited symptoms characteristic of autism spectrum disorders, especially in terms of attention deficits, as well as controlling and expressing emotions. The most common type of sensory processing disorder was over-responsivity. Despite the low prevalence of HPMRS1, the patients reported in the literature presented a rather uniform phenotype, which does not correspond with the one found in each individual of the studied group. Behavioural disorders and sensory impairment require additional care and awareness considering the global developmental delay often observed in these patients.

Atypical caudal regression syndrome with lumbar agenesis, hypoplastic sacrum without sacroiliac joints in the eastern Democratic Republic of Congo: a case report.

The agenesis of any segment of the lower spinal column referred to as "caudal regression syndrome" (CRS) is a rare congenital defect of the spine. This malformation is characterized by the absence of some or the entire lumbosacral vertebral segment. Etiological factors remain unknown. We report an atypical caudal regression syndrome with lumbar agenesis, disconnected from the remaining hypoplastic sacrum, in the Eastern part of the Democratic Republic of Congo (DRC).An 11-month-old female infant with no particular fetal or maternal history presented limb weakness with flexed knees and flanges in the popliteal fossae, sphincter atony, and a sensation of emptiness on palpation in the lumbosacral region. A 3D CT scan of the spine showed the absence of the lumbar spine and disconnection of the upper segment of the thoracic spine from the hypoplastic sacrum. We noted also the absence of the sacroiliac joints bilaterally and an unusual trigonal shape of the iliac bones. MRI and sonographic examination are required in the investigation of the disease. The management is multidisciplinary and depends upon the degree of the defect. Spine reconstruction has proven to be a valuable management technique but has many complications. We wanted to draw the medical world's attention to the existence of this extremely rare malformation in the east of the Democratic Republic of Congo, a mining area.

X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus.

We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. A healthy Finnish couple was initially referred to the Fetomaternal Medical Center because of suspected fetal choroid plexus cyst at 11 + 2 weeks of pregnancy. At 20 + 0 weeks, multiple abnormalities were observed with ultrasound including narrow thorax, slightly enlarged heart, hypoplastic cerebellum, absent cerebellar vermis and ventriculomegaly. Autopsy and genetic analyses were performed after the termination of pregnancy. The findings of macroscopic examination included cleft palate, abnormally overlapping position of fingers and toes and dysmorphic facial features. Neuropathological examination confirmed the absence of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Nodular neuronal heterotopia was also observed. Trio exome sequencing revealed a novel hemizygous de novo variant c.1144C>T p.(Gln382*) in the PDHA1 gene, classified as likely pathogenic. We suggest that inherited metabolic disorders should be kept in mind as differential diagnoses in fetuses with structural brain abnormalities.

Prenatal Diagnosis of Fetal Obstructed Hemivagina and Ipsilateral Renal Agenesis (OHVIRA) Syndrome.

Background: Obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome, also known as Herlyn-Werner-Wunderlich syndrome, is a rare syndrome characterized by the triad of uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis. Most cases of OHVIRA have been reported in adolescents or adults. Gartner duct cysts, including those manifesting as vaginal wall cysts, are also rare. Fetal OHVIRA syndrome and Gartner duct cysts are difficult to diagnose. Case Presentation: Here, the authors report a case of combined OHVIRA and Gartner duct cyst diagnosed prenatally by ultrasonography, along with a brief review of the relevant published reports. A 30-year-old nulliparous female was referred to our institution at 32 weeks' gestation for fetal right kidney agenesis. Detailed ultrasonographic examinations using 2D, 3D, and Doppler ultrasounds revealed hydrocolpometra, and uterus didelphys, with a normal anus and right kidney agenesis. Conclusions: When encountering female fetuses with ipsilateral renal agenesis or vaginal cysts, clinicians should be aware of OHVIRA syndrome and Gartner duct cysts and perform systematic ultrasonographic examinations for other genitourinary anomalies.

A fetus of partial urorectal septum malformation sequence characterized by complete septate uterus: A case report.

RATIONALE: Urorectal septum malformation sequence (URSMS) is an extremely uncommon anomaly characterized by imperforate anus accompanied by multiple genitourinary malformations. Here, we report a case of URSMS identified by the autopsy and classified into partial URSMS. Prenatal diagnosis is challenging for clinicians due to the difficulty of early identification of URSMS and the relative lack of specific features in ultrasound. We intend to share our experiences. PATIENT CONCERNS: One fetus was indicated abdominal cystic structure, abdominal effusion and right renal pelvis separation (7 mm) by ultrasound at 28 + 1 week's gestation. After the pregnancy was terminated, the fetal tissues were performed to be tested by autopsy, copy number variation sequencing and whole exon sequencing. DIAGNOSES: Based on the clinical characteristics, ultrasound, autopsy, and genetic test findings, the fetus was diagnosed with URSMS. INTERVENTIONS: After genetic counseling, the couple opted to terminate her pregnancy. OUTCOMES: The copy number variation results of the fetus showed a 0.48-MB duplication fragment of uncertain significance on chromosome 8p23.3, while the whole-exome sequencing revealed a SAL-LIKE 1 gene mutation. The autopsy of the fetus showed imperforate anusa, the abdominal cyst was further confirmed with complete septate uterus and the lower urethra and vagina converge formed a lumen. LESSONS: Individuals with URSMS during the fetal period might be misdiagnosed due to atypical features of URSMS. Once structural abnormalities especially cystic mass of the futuses in the lower abdomen, URSMS should be considered.

Vaginoscopic Management of OHVIRA (Obstructive Hemivagina and Ipsilateral Renal Agenesis).

OBJECTIVE: To describe the vaginoscopic management of longitudinal vaginal septum in the case of obstructive hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome. DESIGN: Surgical video describing step-by-step management. SETTING: OHVIRA syndrome also known as Herlyn-Werner-Wunderlich syndrome is a triad of obstructed hemivagina, uterus didelphys, and ipsilateral renal anomaly [1] (Supplimentary Video 1). Patients usually present after menarche with progressive dysmenorrhea, lower abdominal pain, a paravaginal mass, foul mucopurulent discharge, and intermenstrual bleeding due to hemi hematocolpos [2]. Magnetic resonance imaging is the choice of investigation [3]. Surgical resection of the septum is the choice of treatment, which can be done vaginoscopically to reduce postoperative pain and promote enhanced recovery [4]. In this video, we will demonstrate a case of a 28-years old, nulliparous woman diagnosed with uterine didelphys having lower abdominal pain and persistent vaginal discharge. INTERVENTIONS: The video demonstrates the technique of vaginoscopic excision of the right hemi-vaginal septum that resulted in complete visualization of both cervices. Diagnostic laparoscopy confirmed uterine didelphys. The left cervix was visualized and the hysteroscope was negotiated into the cervical canal (Supplimentary Video 2). The left cavity was normal with left ostia. Intraoperative transrectal-ultrasound was done to localize the cystic collection in the right hemivagina. Needle aspiration of cystic collection was done over the bulging portion of the right hemivagina and mucoid material was aspirated. Longitudinal obstructive vaginal septum was incised using a collins knife and mucoid secretions were drained (Supplimentary Video 3). Hysteroscope inserted into opened right hemivagina, negotiated through the right cervix and right hemiuterus with right ostia was visualized. The residual septum was resected with a loop electrode and hemostasis was ensured. Cystoscopy done, left ureteric orifice with urine reflux visualized. Vaginal examination showed both cervices with near normal reconstructed vagina. CONCLUSION: The possibility of OHVIRA syndrome should be considered in all cases of uterine didelphys. Vaginoscopic management is a safe and effective method with a minimally invasive approach.