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.

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.

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.

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.

Two Siblings Showing a Mild Phenotype of Joubert Syndrome with a Specific CEP290 Variant.

Joubert syndrome (JS) is a genetic neurodevelopmental disorder characterized by lower brainstem dysplasia and cerebellar vermis agenesis termed molar tooth sign (MTS), psychomotor retardation, abnormal respiratory pattern in infancy, and oculomotor abnormalities. Arima syndrome (AS), which is a severe form of JS, is characterized by severe psychomotor retardation, congenital visual impairment, progressive renal dysfunction, and lower brainstem dysplasia from early infancy. Numerous patients with AS expire in early childhood. Recently, c.6012-12T> A in the CEP290 gene was reported as a specific variant of AS. Herein, we report the cases of two siblings showing a phenotype of JS with compound heterozygous mutations (c.6012-12T > A / c.5924delT) in the CEP290 gene. The older sister (aged 19 years) had hypotonia, hypertelorism, and anteverted nares since birth. As a neonate, she developed a transient abnormal respiratory pattern and nystagmus, and brain magnetic resonance imaging (MRI) showed MTS. The younger sister (aged 13 years) exhibited mild hypotonia and pendular nystagmus as a neonate; MRI revealed MTS. Both sisters had psychomotor retardation, oculomotor dysfunction, and bilateral renal cysts with normal renal function. They can walk and have simple conversation. They do not meet the diagnostic criteria for AS, and their symptoms were milder than those of previously reported cases with this specific mutation. This report indicates the expanding spectrum of the CEP290 variant.

Fatty filum terminale and low-lying conus medullaris in Gollop-Wolfgang complex: a case report and review of literature.

BACKGROUND/IMPORTANCE: Gollop-Wolfgang complex is a rare skeletal dysplasia with only 200 cases reported in the literature. This disorder is usually associated with several extraosseous anomalies. This report describes the first case of a fatty filum terminale and a low-lying conus medullaris in a patient with this complex. A review of the current literature of the Gollop-Wolfgang complex accompanies this case, highlighting the documented extraosseous anomalies seen in this complex. CLINICAL PRESENTATION: We report a case of an 18-month-old patient with Gollop-Wolfgang complex who underwent cord untethering with release of the filum terminale after extensive workup showed the presence of a dyssynergic bladder and radiological evaluation revealed a fatty filum terminale and low-lying conus medullaris. CONCLUSION: Gollop-Wolfgang complex is a skeletal dysplasia usually associated with several extra skeletal anomalies. Our report describes the first case of a fatty filum terminale and low-lying conus medullaris in this complex, as well as provides an overview of the documented anomalies seen in this disorder. A multidisciplinary approach is recommended when treating these infants in order to ensure that occult manifestations of the complex are not missed.

Síndrome del incisivo central maxilar medio único en neonato / Solitary median maxillary central incisor syndrome in neonates / Síndrome do incisivo central maxilar médio solitário em neonatos

Introducción: el síndrome del incisivo central maxilar medio único (SMMCI) es un trastorno de etiología desconocida, con base genética heterogénea, que se caracteriza por la erupción de un único incisivo central en el maxilar y que se puede relacionar con multitud de patologías y síndromes, entre los que destacan las alteraciones de la línea media, obstrucción nasal congénita, disfunción hipofisaria, talla baja y holoprosencefalia. Caso clínico: neonato mujer con síndrome dismórfico no filiado y obstrucción nasal congénita, que es diagnosticada de SMMCI tras consultar en repetidas ocasiones por cuadros de dificultad respiratoria y problemas para alimentarse. Conclusiones: el conocimiento de este raro síndrome es fundamental para la realización de un diagnóstico precoz por parte del equipo pediátrico y obstétrico, ya que un diagnóstico temprano es posible, mejorando la evaluación prenatal ecográfica, así como el adecuado manejo posnatal multidisciplinar posterior de nuestros pacientes.

Introduction: the Solitary Median Maxillary Central Incisor Syndrome (SMMCI) is a disorder of unknown etiology, with a heterogeneous genetic basis, characterized by the eruption of a single central incisor in the maxilla and that can be linked to various pathologies and syndromes, among which the alterations of the midline, congenital nasal obstruction, pituitary dysfunction, short stature and holoprosencephaly stand out. Clinical case: female newborns with unknown dysmorphic syndrome and congenital nasal obstruction, diagnosed with SMMCI after repeated consultations due to respiratory distress and feeding problems. Conclusions: understanding this rare syndrome is essential for an early diagnosis to be carried out by the pediatric and obstetric team, since it will improve the ultrasound prenatal assessment, as well as the adequate subsequent multidisciplinary postnatal patient management procedures.

Introdução: a síndrome do incisivo central maxilar médio solitário (SICMMS) é uma desordem de etiologia desconhecida, com base genética heterogênea, caracterizada pela erupção de um único incisivo central na maxila e que pode estar relacionada a uma infinidade de patologias e síndromes. onde se destacam alterações da linha média, obstrução nasal congênita, disfunção hipofisária, baixa estatura e holoprosencefalia. Caso clínico: recém-nascida com síndrome dismórfica de origem desconhecida e obstrução nasal congênita, diagnosticada com SICMSS após várias consultas por desconforto respiratório e problemas de alimentação. Conclusões: o conhecimento desta rara síndrome é essencial para que a equipe pediátrica e obstétrica possa fazer um diagnóstico precoce, pois ele pode melhorar a avaliação ultrassonográfica pré-natal, bem como o adequado manejo pós-natal multidisciplinar pós-natal dos pacientes.

A case report of serpentine-like syndrome and review of literature.

BACKGROUND: Serpentine-like syndrome (SLS) is a rare foetal abnormality, characterized by brachioesophagus, secondary intrathoracic stomach and vertebral deformity. Herein, we report a case of SLS diagnosed based on imaging, genetic examination and autopsy findings. CASE PRESENTATION: From the 19th to 23rd weeks of gestation, the foetus presented with brachioesophagus, secondary intrathoracic stomach, intrathoracic spleen with poly-spleen malformation, spinal deformity and diaphragm dysplasia, and some abdominal organs were partly located in the thoracic cavity. After extensive counselling, the couple opted to terminate the pregnancy. Whole genome sequencing and autopsy were performed. Then, the foetus was diagnosed with SLS. DISCUSSION AND CONCLUSIONS: SLS is characterized by multiorgan deformities and is associated with poor prognosis. Multiorgan deformities can be detected on prenatal sonography using three-dimensional ultrasound technology.

Multiple vas deferens with polyorchidism and many congenital malformations in a symptomatic 11-year-old male patient: a rare case report.

BACKGROUND: Ductus deferens may manifest in a variety of anomalies such as its absence, duplication, ectopy, or diverticulum. Ectopic seminal tract opening has two main types, ectopic ejaculatory duct opening, and ectopic vas deferens opening. Generally, ductus deferens anomalies affect approximately 0.05% of the population. Patients may be asymptomatic or complaining of urinary tract infections and/or epididymitis. Most of these cases are associated with renal dysplasia. To confirm the diagnosis Cystourethroscopy catheterization and retrograde urethrogram should be performed, but the definitive diagnosis is done by vasography. The definitive treatment is complete surgical resection of the pathological urogenital connection. This case is commonly discovered while exploring other findings such as testicular torsion and inguinal hernia. CASE PRESENTATION: We report a rare case of an 11-year-old male who presented with gross hematuria and numerous congenital malformations including a left polydactyly clubfoot, polyorchidism, with several surgical procedures, and left kidney dysgenesis. Surgery was performed for a left inguinal hernia, during which a third undescended testicle was discovered incidentally and was eradicated. A retrograde urethrogram was performed to establish the diagnosis. A fistula- that is connected with the left ureter- was resected. The histopathologic findings confirmed the diagnosis of true duplication of the Vas deferens, with communication between the ureter and the vas deferens. By follow-up, the kidney function tests were within normal limits. CONCLUSIONS: This case report aims to highlight the early diagnosis and management of the duplicated vas deferens and the associated congenital malformations to improve the prognosis and kidney function and to avoid long-term complications.

Prenatal ultrasound-assisted identification of multiple malformations caused by a deletion in the long-arm end of chromosome 7 and review of the literature.

Clinical cases of chromosome 7 long-arm end deletion are rare. Generally, 7q terminal deletion syndrome results in complex clinical phenotypes, such as microcephaly, growth and development retardation, holoprosencephaly, and sacral hypoplasia. Herein, we report the genetic and clinical features of a fetus with multiple malformations observed by prenatal ultrasound. The results showed that there was a large fragment deletion of approximately 27.7 Mb in 7q32.3-qter. The induced fetus showed facial abnormalities of cleft lip and palate, and some organ structural abnormalities (such as diaphragmatic hernia and polycystic renal dysplasia) were observed by autopsy and pathology. To provide more reliable information for disease diagnosis and genetic counseling, we reviewed and analyzed the reported cases of isolated 7q terminal syndrome.

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing.

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.

Multimodal ultrasound imaging of persistent urogenital sinus with uterus didelphys and double vagina malformation: A case report.

RATIONALE: Persistent urogenital sinus (PUG) with uterus didelphys and double vagina is a rare urogenital anomaly. The diagnosis is based on magnetic resonance examination and cystoscopy. To the best of our knowledge, there is no literature report of PUG diagnosed by ultrasound alone. PATIENT CONCERN: A 23-year-old woman presented with atypical menstruation and recurrent hematuria for 13 years and recurrent lower abdominal pain for 12 years. DIAGNOSIS: PUG was diagnosed through multiple ultrasound modalities, including transabdominal 2-dimensional ultrasound, transrectal bi-plane high-frequency ultrasound, and contrast-enhanced ultrasound. We diagnosed this malformation preoperatively by accurately measuring the length of urethra and common channel through multimodal ultrasound imaging. INTERVENTIONS: Urethra separation and reconstruction, vaginal pull-through and artificial vaginoplasty, and bilateral hysterosalpingectomy were performed. OUTCOMES: The postoperative course was uneventful. She was urinating normally after half a year and used continuous vaginal dilatation to avoid stenosis. LESSONS: PUG associated with uterus didelphys and double vagina is an extremely rare malformation of the reproductive system. Multimodal ultrasound imaging can be used to diagnose this malformation preoperatively clearly and to accurately measure the length of urethra and common channel, providing an imaging basis for preparing an operative plan.

Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants.

BACKGROUND: Joubert syndrome (JS) is a group of rare congenital disorders characterized by cerebellar vermis dysplasia, developmental delay, and retina dysfunctions. Herein, we reported a Chinese patient carrying a new variant in the AHI1 gene with mild JS, and the 3D structure of the affected Jouberin protein was also predicted. CASE PRESENTATION: The patient was a 31-year-old male, who presented difficulty at finding toys at the age of 2 years, night blindness from age of 5 years, intention tremor and walking imbalance from 29 years of age. Tubular visual field and retina pigmentation were observed on ophthalmology examinations, as well as molar tooth sign on brain magnetic resonance imaging (MRI). Whole exome sequence revealed two compound heterozygous variants at c.2105C>T (p.T702M) and c.1330A>T (p.I444F) in AHI1 gene. The latter one was a novel mutation. The 3D protein structure was predicted using I-TASSER and PyMOL, showing structural changes from functional ß-sheet and α-helix to non-functional D-loop, respectively. CONCLUSIONS: Mild JS due to novel variants at T702M and I444F in the AHI1 gene was reported. The 3D-structural changes in Jouberin protein might underlie the pathogenesis of JS.

Abnormal frontal gyrification pattern and uncinate development in patients with KBG syndrome caused by ANKRD11 aberrations.

KBG syndrome is characterized by dental, craniofacial and skeletal anomalies, short stature and global developmental delay or intellectual disability. It is caused by microdeletions or truncating mutations of ANKRD11. We report four unrelated probands with this syndrome due to de novo ANKRD11 aberrations that may contribute to a better understanding of the genetics and pathophysiology of this autosomal dominant syndrome. Clinical, cognitive and MRI assessments were performed. Three of the patients showed normal intellectual functioning, whereas the fourth had a borderline level of intellectual functioning. However, all of them showed deficits in various cognitive and socioemotional processes such as attention, executive functions, empathy or pragmatic language. Moreover, all probands displayed marked asymmetry of the uncinate fascicles and an abnormal gyrification pattern in the left frontal lobe. Thus, structural neuroimaging anomalies seem to have been overlooked in this syndrome. Disturbed frontal gyrification and/or lower structural integrity of the uncinate fascisulus might be unrecognized neuroimaging features of KBG syndrome caused by ANKRD11 aberrations. Present results also point out that this syndrome is not necessarily associated with global developmental delay and intellectual disability, but it can be related to other neurodevelopmental disorders or subclinical levels of attention-deficit hyperactivity disorder, autism, communication disorders or specific learning disabilities.

Neuroimaging in Kabuki syndrome and another KMT2D-related disorder.

Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder. We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.