Successful therapeutic intervention in new mouse models of frizzled 2-associated congenital malformations.

Frizzled 2 (FZD2) is a transmembrane Wnt receptor. We previously identified a pathogenic human FZD2 variant in individuals with FZD2-associated autosomal dominant Robinow syndrome. The variant encoded a protein with a premature stop and loss of 17 amino acids, including a region of the consensus dishevelled-binding sequence. To model this variant, we used zygote microinjection and i-GONAD-based CRISPR/Cas9-mediated genome editing to generate a mouse allelic series. Embryos mosaic for humanized Fzd2W553* knock-in exhibited cleft palate and shortened limbs, consistent with patient phenotypes. We also generated two germline mouse alleles with small deletions: Fzd2D3 and Fzd2D4. Homozygotes for each allele exhibit a highly penetrant cleft palate phenotype, shortened limbs compared with wild type and perinatal lethality. Fzd2D4 craniofacial tissues indicated decreased canonical Wnt signaling. In utero treatment with IIIC3a (a DKK inhibitor) normalized the limb lengths in Fzd2D4 homozygotes. The in vivo replication represents an approach for further investigating the mechanism of FZD2 phenotypes and demonstrates the utility of CRISPR knock-in mice as a tool for investigating the pathogenicity of human genetic variants. We also present evidence for a potential therapeutic intervention.

Vaginal bleeding in a newborn as initial presentation of uterus didelphys.

Vaginal bleeding of the newborn is described as a normal phenomenon, occurring physiologically in a subset of baby girls as a response to decreased oestrogen levels in the postnatal period compared with in utero exposure. Here, we present the case of heavy vaginal bleeding prompting an evaluation via transabdominal ultrasound, which was ultimately diagnostic for uterus didelphys. We suggest that neonates with uterus didelphys are predisposed to heavy bleeding due to relatively larger amount of the endometrial tissue in two cavities. While diagnosis of Müllerian anomalies is typically made in adulthood, an earlier diagnosis facilitates timely medical and surgical intervention and prompts screening for concurrent and associated conditions. In summary, we recommend routine consideration of transabdominal ultrasound to investigate abnormal vaginal bleeding in the newborn.

Genetic and phenotypic continuum of HOXA genes: A case with double HOXA9/HOXA13 mutations.

The HOXA genes cluster plays a key role in embryologic development. Mutations in HOXA genes have been linked to different human phenotypes, including developmental delay, limb anomalies, and urogenital malformations. The present study reported a clinical and genetic investigation of a female patient with polymalformative syndrome including left arm agenesis, bicornuate uterus and bicuspid aortic valve. Using whole exome sequencing, two heterozygous missense variants were identified. Of these, one was a novel variant in the HOXA13 gene [p.(Tyr290Ser)] and the second a heterozygous variant in the HOXA9 gene [p.(Ala102Pro)]. To the best of our knowledge, this is the first association of HOXA9/HOXA13 point mutations linked to a syndromic case. In conclusion, the present study suggested that the phenotypic spectrum of vertebral anomalies, anal atresia, cardiac defects, tracheo­esophageal fistula, renal anomalies and limb abnormalities/hand­foot­genital syndrome may be attributable to the combination of different HOXA variants, particularly in patients with a severe clinical presentation. The current report contributed as well to the molecular understanding of HOXA genes­related phenotypes via the identification of novel variant and genes associations.

Spatio-Temporal Expression Pattern of CAKUT Candidate Genes DLG1 and KIF12 during Human Kidney Development.

We aimed to investigate expression of the novel susceptibility genes for CAKUT, DLG1 and KIF12, proposed by a systematic in silico approach, in developing and postnatal healthy human kidneys to provide information about their spatiotemporal expression pattern. We analyzed expression of their protein products by immunohistochemistry and immunofluorescence and quantified relative mRNA levels by RT-qPCR. Statistically significant differences in expression patterns were observed between certain developmental stages. Strong expression of DLG1 was observed in the developing kidney, with a gradual decrease from the first phase of kidney development (Ph1) until the third phase (Ph3), when most nephrons are formed; at later stages, the highest expression was observed in the tubules. KIF12 was highly expressed in the developing structures, especially in Ph1, with a gradual decrease until the postnatal phase, which would indicate a significant role in nephrogenesis. Co-localization of DLG1 and KIF12 was pronounced in Ph1, especially on the apical side of the tubular epithelial cells. Thereafter, their expression gradually became weaker and was only visible as punctate staining in Ph4. The direct association of DLG1 with KIF12 as control genes of normal kidney development may reveal their new functional aspect in renal tubular epithelial cells.

Selection of operative approach in children with Currarino syndrome.

PURPOSE: To summarize the experience of surgical treatment of children diagnosed with Currarino syndrome, with an emphasis on the selection of an optimal operative approach. METHODS: The clinical materials of patients diagnosed with Currarino syndrome were recorded. Special attention was given to the operative management, particularly the different routes for operation. The type of ARM was the critical point. The Rintala score was used for the evaluation of bowel function. RESULTS: The medical records of 26 patients were reviewed. Seven were male, and 19 were female, with a mean age of 19.38 ± 13.80 months. The standard posterior sagittal approach (SPS) group included three perineal fistulae, one anal stenosis, one retraction of the rectum after anoplasty for vestibular fistula, one ARM with no fistula, one rectourethral fistula, and one cloaca. In the limited posterior sagittal approach (LPS) group, there were 13 perineal fistulae, one displacement of the rectum, and one retraction of the rectum after anoplasty for the vestibular fistula. In addition, the transanal approach (TA) and anterior sagittal approach (AS) were also used. The mean follow-up time was 39.48 ± 26.84 m. The Rintala score was 16.74 ± 2.93. CONCLUSION: For a perineal fistula, SPS or LPS should be used to reach anoplasty and remove the presacral mass. For a vestibular fistula, the AS or LPS should be chosen. For anal stenosis, SPS or LPS should be used.

Ovarian absence: a systematic literature review and case series report.

Ovarian absence is an uncommon condition that most frequently presents unilaterally. Several etiologies for the condition have been proposed, including torsion, vascular accident, and embryological defect. A systematic review was conducted to describe the clinical presentation of ovarian absence, as well as its associations with other congenital anomalies, through a systematic search of Cochrane Library, ClinicalTrials.gov, Google Scholar, Ovid Embase, Ovid Medline, PubMed, Scopus, and Web of Science. Exclusion criteria included cases with suspicion for Differences of Sex Development, lack of surgically-confirmed ovarian absence, and karyotypes other than 46XX. Our search yielded 12,120 citations, of which 79 studies were included. 10 additional studies were found by citation chasing resulting in a total 113 cases including two unpublished cases presented in this review. Abdominal/pelvic pain (30%) and infertility/subfertility (19%) were the most frequent presentations. Ovarian abnormalities were not noted in 28% of cases with pre-operative ovarian imaging results. Approximately 17% of cases had concomitant uterine abnormalities, while 22% had renal abnormalities. Renal abnormalities were more likely in patients with uterine abnormalities (p < 0.005). Torsion or vascular etiology was the most frequently suspected etiology of ovarian absence (52%), followed by indeterminate (27%) and embryologic etiology (21%). Most cases of ovarian absence are likely attributable to torsion or vascular accidents, despite many references to the condition as "agenesis" in the literature. Imaging may fail to correctly diagnose ovarian absence, and diagnostic laparoscopy may be preferable in many cases as genitourinary anatomy and fertility considerations can be assessed during the procedure. Fertility is likely minimally or not affected in women with unilateral ovarian absence.

A Common Path: Magnetic Resonance Imaging of Müllerian and Wolffian Duct Anomalies.

PURPOSE OF REVIEW: This review summarizes the pathway of Mullerian and Wolffian duct development, anomalies that result from disruptions to this pathway, and the characteristics on advanced imaging that identify them. RECENT FINDINGS: In-office evaluation for reproductive anomalies is usually inadequate for the diagnosis of congenital reproductive anomalies. Magnetic resonance imaging (MRI) has usurped invasive diagnostic methods including laparoscopy, hysteroscopy, and vasography as the new gold standard. Because of its superior soft-tissue delineation and the availability of advanced functional sequences, MRI offers a sophisticated method of distinguishing reproductive anomalies from one another, characterizing the degree of defect severity, and evaluating for concomitant urogenital anomalies non-invasively and without radiation exposure to the patient. Congenital anomalies of the Mullerian and Wolffian duct can be incredibly nuanced, requiring prompt and accurate diagnosis for management of infertility. Definitive diagnosis should be made early with MRI.

The Reasons behind COVID-19 Vaccination Hesitancy among the Parents of Children Aged between 5 to 11 Years Old in Saudi Arabia.

Simultaneously with the development of the COVID-19 vaccination plan for minors, it is critical to understand the reasons related to parental COVID-19 vaccination hesitancy. This study aims to determine the reasons associated with vaccination hesitancy among parents, and the prevalence and the characteristics of the parents who are hesitant to allow their children aged between 5 to 11 years old to be administered the COVID-19 vaccines. A web-based questionnaire was used to perform this study between May 2022 to September 2022 in Saudi Arabia (SA). Several factors, personal and social, affected the participants' willingness to vaccinate their children with the COVID-19 vaccines. The age of the parents was found to have a significant impact on their decision to vaccinate their children. Those between the age of 40-49 years of age were the most willing to vaccinate (almost 41%) compared to those 50 years or older who were most resistant to vaccination. Female participants were more resistant to vaccinating their children compared to their male counterparts. Saudis were more resistant to vaccinating their children compared to the non-Saudi participants. Those private sector-employed parents were the most willing to vaccinate (16.6%), followed by those working in the governmental sector (13.8%). About 40.7% of non-healthcare workers were resistant to vaccinating their minor compared to healthcare workers (8.7%). In conclusion, the study presents several factors that affect the parental willingness to vaccinate their children in SA. These factors should be properly addressed when developing public health strategies to promote the COVID-19 vaccination of children in SA.

Hand-foot-genital syndrome due to a duplication variant in the GC-rich region of HOXA13.

BACKGROUND: Hand-Foot-Genital Syndrome (HFGS) is an autosomal dominant disorder characterized by a broad phenotypic spectrum. Variants in HOXA13 gene were associated with HFGS. To date, only twenty families with HFGS have been reported. However, the challenge in HFGS is the limited sample sizes and phenotypic heterogeneity. The advent of next-generation sequencing has permitted the identification of patients with HOXA13 variants who do not manifest with the full HFGS syndromic features. METHODS: Trio (parents-proband) Whole-exome sequence(WES) and whole-genome sequencing(WGS) was carried out in this study to investigate the underlying pathogenic genetic factor of the neonate with a wide variety of clinical abnormalities. RESULTS: No possible pathogenetic variation was detected by trio-WES, and a duplication variant in HOXA13 (c.360_377dup, p.Ala128_Ala133dup), inherited from her mother, was identified by the subsequent WGS in the proband with malnutrition, feeding difficulties, electrolyte disorders, metabolic acidosis, recurrent urinary tract infections, hydronephrosis, nephrolithiasis, abnormal ureter morphology, cholelithiasis, uterus didelphys. Sequence analysis of the variant region (exon1) indicated a high GC content of 73.92%. In addition, further enquiry of the family history revealed that 5 members of the family in 4 generations had hand and foot anomalies. CONCLUSION: The neonate was diagnosed with HFGS by genetic analysis. GC content had less influence on sequence coverage in WGS than WES analysis. This was the first report of trio-WGS study for HFGS genetic diagnosis, revealed that subsequent WGS was necessary for identification of potentially pathogenic variants in unexplained genetic disorders.

Clinically diverse and perinatally lethal syndromes with urorectal septum malformation sequence.

Urorectal septum malformation sequence (URSMS) is characterized by a spectrum of anomalies of the urogenital system, hindgut and perineum. It is presumed to be a constellation of an embryonic defect. Herein, we analyzed the clinically diverse syndromes associated with URSMS in our perinatal evaluation unit. We reviewed fetuses with URSMS in referrals for perinatal autopsy over a period of 3 years. Chromosomal microarray and genome sequencing were performed whenever feasible. Literature was reviewed for syndromes or malformations with URSMS. We ascertained URSMS in 12 of the 215 (5%) fetuses. Nine fetuses (75%) had complete URSMS and remainder had partial/intermediate URSMS. Eleven fetuses had malformations of other systems that included: cerebral ventriculomegaly; right aortic arch with double outlet right ventricle; microcephaly with fetal akinesia deformation sequence; ventricular septal defect and radial ray anomaly; thoraco-abdominoschisis and limb defects; myelomeningocele; spina bifida and fused iliac bones; omphalocele; occipital encephalocele; lower limb amelia and cleft foot. We report on six fetuses with recurrent and five fetuses with unique malformations/patterns where URSMS is a component. Exome sequencing (one family) and genome sequencing (eight families) were performed and were nondiagnostic. Additionally, we review the literature for genetic basis of this condition. URMS is a clinically heterogeneous condition and is a component of several multiple malformation syndromes. We describe several unique and recurrent malformations associated with URSMS.

Surgical management of a congenital genital tract abnormality in a patient with Lynch syndrome.

Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer, is an inherited cancer syndrome which increases the risk of developing colorectal cancer and endometrial cancer. Individuals with LS have an increased risk of cancers of the ovary, urinary tract, stomach, small intestine, pancreas, biliary tract, brain and skin. Cancer risk reduction is recommended through chemoprevention (aspirin), surveillance (colonoscopy, assessment of the endometrium and ovaries via USS, aspiration biopsy and tumour marker monitoring; CA125) or risk reduction surgery, that is, total hysterectomy and bilateral salpingo-oophorectomy.This is a case of a nulliparous woman in her early 30s with LS and a congenital genital tract malformation. She had a unicornuate (left) uterus and a vestigial (right) uterine horn. There was an inability to obtain a conclusive set of endometrial biopsies in this patient due to the nature of the patient's congenital uterine abnormality. In this case, surgery was recommended to excise the vestigial horn and fallopian tube in order to optimise surveillance and fertility.

Aberrations in FGFR1, FGFR2, and RIP5 Expression in Human Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).

This study aimed to explore the spatio-temporal expression patterns of congenital anomalies of kidney and urinary tract (CAKUT) candidate genes, Fibroblast Growth Factor Receptor 1 (FGFR1), Fibroblast Growth Factor Receptor 2 (FGFR2) and Receptor-Interacting Protein Kinase 5 (RIP5), in human fetal kidney development (CTRL) and kidneys affected with CAKUT. Human fetal kidneys from the 22nd to 41st developmental week (duplex, hypoplastic, dysplastic, and controls) were stained with antibodies and analyzed by epifluorescence microscopy and RT-qPCR. The effect of CAKUT candidate genes on kidney nephrogenesis and function is confirmed by statistically significant variations in the spatio-temporal expression patterns of the investigated markers. The nuclear localization of FGFR1, elevated expression score of FGFR1 mRNA, the increased area percentage of FGFR1-positive cells in the kidney cortex, and the overall decrease in the expression after the peak at the 27th developmental week in dysplastic kidneys (DYS), suggest an altered expression pattern and protein function in response to CAKUT pathophysiology. The RT-qPCR analysis revealed a significantly higher FGFR2 mRNA expression score in the CAKUT kidneys compared to the CTRL. This increase could be due to the repair mechanism involving the downstream mediator, Extracellular Signal-Regulated Kinase 1/2 (ERK1/2). The expression of RIP5 during normal human kidney development was reduced temporarily, due to urine production and increased later since it undertakes additional functions in the maturation of the postnatal kidney and homeostasis, while the expression dynamics in CAKUT-affected kidneys exhibited a decrease in the percentage of RIP5-positive cells during the investigated developmental period. Our findings highlight the importance of FGFR1, FGFR2, and RIP5 as markers in normal and pathological kidney development.

Update on Mayer-Rokitansky-Küster-Hauser syndrome.

This review presents an update of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome on its etiologic, clinical, diagnostic, psychological, therapeutic, and reproductive aspects. The etiology of MRKH syndrome remains unclear due to its intrinsic heterogeneity. Nongenetic and genetic causes that may interact during the embryonic development have been proposed with no definitive etiopathogenesis identified. The proportion of concomitant extragenital malformations varies in different studies, and the discrepancies may be explained by ethnic differences. In addition to physical examination and pelvic ultrasound, the performance of pelvic magnetic resonance imaging is crucial in detecting the presence of rudimentary uterine endometrium. MRKH syndrome has long-lasting psychological effects on patients, resulting in low esteem, poor coping strategies, depression, and anxiety symptoms. Providing psychological counseling and peer support to diagnosed patients is recommended. Proper and timely psychological intervention could significantly improve a patient's outcome. Various nonsurgical and surgical methods have been suggested for treatment of MRKH syndrome. Due to the high success rate and minimal risk of complications, vaginal dilation has been proven to be the first-line therapy. Vaginoplasty is the second-line option for patients experiencing dilation failure. Uterine transplantation and gestational surrogacy are options for women with MRKH syndrome to achieve biological motherhood.

Síndrome De Herlyn ­ Werner ­ Wünderlich. A proposito de un caso / Herlyn ­ Werner ­ Wünderlich Syndrome. About a case

Presentamos el caso de una paciente de 11 años que presento un cuadro clínico de oligomenorrea, leucorrea y dolor pélvico tipo cólico. Se ha pensado por el dolor abdominal en la posibilidad de apendicitis modificada por lo que se realizó ecografía pélvica con los hallazgos de útero didelfo, quiste anexial derecho y agenesia renal izquierda, datos compatibles con síndrome de Herlyn ­ Werner ­ Wünderlich

We present the case of an 11-year-old patient who presented a clinical picture of oligomenorrhea, leucorrhoea and pelvic pain type colic. It has been thought for abdominal pain in the possibility of modified appendicitis so pelvic ultrasound was performed with the findings of didelphic uterus, right adnexal cyst and left renal agenesis, data compatible with Herlyn ­ Werner ­ Wünderlich syndrome.

Rare case of an isolated scaphoid congenital megalourethra: before and after reconstruction.

Congenital megalourethra, first described in 1955, is a rare urethral anomaly resulting from dysgenesis of the penile corpus spongiosum, with or without corpus cavernosum involvement, leading to dilatation of the penile urethra. Presentations come in two forms, scaphoid and fusiform, with the former being more common and resulting from deficient or absent corpus spongiosum. Fusiform types are much rarer, and consist of absence of both the corpus spongiosum and cavernosum.3 Here, we present a case involving the surgical correction of an isolated scaphoid-type congenital megalourethra with significantly improved postoperative cosmetic and functional outcomes.

Laparoscopic ovariectomy in 2 queens with uterine unicornis.

Two unrelated queens were presented for persistent signs of estrus despite a history of ovariohysterectomy. Uterine unicornis was suspected based on historical surgical findings. Anti-Müllerian hormone testing was consistent with the presence of ovarian tissue in both queens. Based on the ultrasonographic confirmation of unilateral abnormal structures in the ovarian region and ipsilateral absence of the kidney, a laparoscopic surgical approach was performed on each queen to remove remnant ovarian tissue. Laparoscopy confirmed the absence of a kidney ipsilateral to the remnant ovarian tissue. Both cats recovered from surgery and displayed no further signs of estrus. Key clinical message: To our knowledge, these are the first reported cases of feline uterine unicornis treated with a laparoscopic surgical approach. This minimally invasive approach, preceded by a thorough diagnostic work-up, may be of benefit to future queens with uterine unicornis. In addition, anti-Müllerian hormone testing has not been well-described in the literature when used in cats with remnant ovarian tissue. These cases may be of value to clinicians discovering the absence of a uterine horn when performing an ovariohysterectomy on queens.

Résumé ­ Ovariectomie laparoscopique chez deux chattes avec un utérus unicorne. Deux chattes non apparentées ont été présentées pour des signes persistants d'oestrus malgré des antécédents d'ovariohystérectomie. Un utérus unicorne a été suspecté sur la base des résultats chirurgicaux antérieurs. Un test d'hormone anti-müllérienne était compatible avec la présence de tissu ovarien chez les deux chattes. Sur la base de la confirmation échographique des structures anormales unilatérales dans la région ovarienne et de l'absence ipsilatérale du rein, une approche chirurgicale laparoscopique a été réalisée sur chaque chatte pour retirer le tissu ovarien restant. La laparoscopie a confirmé l'absence d'un rein ipsilatéral au tissu ovarien résiduel. Les deux chattes se sont remises de la chirurgie et n'ont montré aucun autre signe d'oestrus.Message clinique clé:À notre connaissance, ce sont les premiers cas rapportés d'utérus unicorne félin traités par une approche chirurgicale laparoscopique. Cette approche peu invasive, précédée d'un bilan diagnostique approfondi, peut être bénéfique pour les futures chattes atteintes d'utérus unicorne. De plus, le test d'hormone anti-müllérienne n'a pas été bien décrit dans la littérature lorsqu'il est utilisé chez des chats avec du tissu ovarien résiduel. Ces cas peuvent être utiles aux cliniciens qui découvrent l'absence de corne utérine lors de la réalisation d'une ovariohystérectomie sur des chattes.(Traduit par Dr Serge Messier).

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract American Journal of Medical Genetics Part C.

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito-urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%-20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.

Laparoscopic removal of bilateral uterine remnants for symptomatic unilateral leiomyomas in a patient with Müllerian agenesis.

OBJECTIVE: To our knowledge, we present the first video demonstration of the laparoscopic removal of bilateral uterine remnants for symptomatic unilateral leiomyomas in a patient with Müllerian agenesis. DESIGN: A video case report. SETTING: An academic medical center. PATIENT: A 44-year-old woman, gravida 0, with a history of Müllerian agenesis with presumed single uterine remnant who presented with worsening lower abdominal fullness and discomfort in the setting of known leiomyomas. Magnetic resonance imaging of the pelvis revealed a single rudimentary uterine remnant with 3 dominant leiomyomas, with the largest measuring 5.8 × 5.3 × 5.2 cm. After extensive counseling, she opted for definitive surgical management. She provided written consent for video recording and publication of this surgical case. INTERVENTION(S): Laparoscopic removal of bilateral uterine remnants, bilateral salpingectomy, and cystoscopy. MAIN OUTCOME MEASURE(S): Laparoscopic removal of bilateral uterine remnants with multiple unilateral leiomyomas, leading to resolution of lower abdominal bulk symptoms. RESULT(S): Diagnostic laparoscopy revealed a right 12-cm pelvic mass consisting of a uterine remnant with 3 dominant leiomyomas, left 2-cm rudimentary uterine remnant, bilateral atrophic fallopian tubes, bilateral normal ovaries, and absent cervix and upper vagina. Procedure was uncomplicated with an estimated blood loss of 25 mL. Patient was discharged on the same day of surgery after meeting required milestones. Pathologic examination of the specimens was consistent with intraoperative findings. CONCLUSION(S): Müllerian agenesis is a rare congenital anomaly of the female reproductive tract in which uterine remnants may be found. Leiomyoma formation in uterine remnants is rare but possible. Magnetic resonance imaging is the most sensitive imaging modality for uterine remnants but not always accurate. When leiomyomas become symptomatic, surgery is the only definitive management option with laparoscopy as the standard of care when possible. Minor changes to the minimally invasive approach may be necessary to accommodate for anatomical differences.