Toriello-Carey Syndrome Research Articles

A Novel Pathogenic Variant in the MN1 Gene in a Patient Presenting with Rhombencephalosynapsis and Craniofacial Anomalies, Expanding MN1 C-terminal Truncation Syndrome.

Meningioma-1 is a transcription activator that regulates mammalian palate development and is required for appropriate osteoblast proliferation, motility, differentiation, and function. Microdeletions involving the MN1 gene have been linked to syndromes including craniofacial anomalies, such as Toriello-Carey syndrome. Recently, truncating variants in the C-terminal portion of the MN1 transcriptional factor have been linked to a characteristic and distinct phenotype presenting with craniofacial anomalies and partial rhombencephalosynapsis, a rare brain malformation characterized by midline fusion of the cerebellar hemispheres with partial or complete loss of the cerebellar vermis. It has been called MN1 C-terminal truncation (MCTT) syndrome or CEBALID (Craniofacial defects, dysmorphic Ears, Brain Abnormalities, Language delay, and Intellectual Disability) and suggested to be caused by dominantly acting truncated protein MN1 instead of haploinsufficiency. As a proto-oncogene, MN1 is also involved in familial meningioma. In this study, we present a novel case of MCTT syndrome in a female patient presenting with craniofacial anomalies and rhombencephalosynapsis, harboring a de novo pathogenic variant in the MN1 gene: c.3686_3698del, p.(Met1229Argfs*87).

Uncommon and Rare Pediatric Syndromes Associated with Surgical Conditions in Iraqi Children.

Abstract Background: Many uncommon and rare pediatric clinical syndromes including genetic and dysmorphic disorders are known to be associated with surgical conditions and require various types of surgical interventions. Little is known about the pattern of surgical conditions associated with the uncommon and rare childhood syndromes in Iraq. The aim of this paper to describe our experience with uncommon and rare childhood syndromes associated with surgical conditions observed in two tertiary referral centers in Baghdad. Patients and methods: Twenty one unrelated patients (10 males and 11 females) with uncommon and rare syndromes associated with surgical conditions were observed. The patient’s age ranged from 3 days to 18 years. The patients were observed during the period from 1994 to December 2019 in two tertiary referral teaching hospitals (University Hospital in Al-Kadhimiyia which was called later “Al-Kadhimiyia Teaching Hospital” and the Children Teaching Hospital of Baghdad Medical City). Results: The twenty one patients had seventeen uncommon and rare syndromes associated with surgical conditions including ocular conditions (Cataracts and glaucoma), congenital heart disease, gastrointestinal surgical conditions (Imperforated anus, congenital primary cricopharyngeal achalasia, omphalocele and neonatal Hirschsprung disease), urologic surgical condition (Undescended testes) and orthopedic surgical conditions. (Hip dislocation and multiple fractures), gynecologic ocular conditions (Hematocolpos which is caused by hemivaginal obstruction) and surgical conditions needing plastic surgeries. Conclusion: This unique series of pediatric syndromes associated with surgical conditions included a new Iraqi variant of oculocerebrorenal syndrome, the cases number 35 and 36 of cutis laxa type II (Debre type) in the literature, the case number 52 of Ruprecht Majewski-Bosma syndrome in literature, the 58th case of Toriello-Carey syndrome in the literature, the case number 130 of Townes Brocks syndrome, the twenty eighth case of congenital Chevalier Jackson in the literature, the thirty fourth case of Goldberg Shprintzen syndrome and the fourth patient in the literature with the syndrome of microtia/anotia syndrome and congenital facial palsy without other abnormalities.

Clinical Genetics and Dysmorphology: Our Extraordinary Experiences.

Abstract Background: We have previously described our extensive experiences with clinical genetic and dysmorphology in a plethora of publications. In a previous study, we reported 43 children with uncommon, rare and very rare genetic and hereditary disorders whom were observed during three-year period (2016-2018). In that series, very rare genetic, the case number 104 of Sanjad-Sakati-Richardson-Kirk syndrome in the world, the case number 130 of Townes Brocks syndrome and the case number 170 of Coffin Siris syndrome in the world. The aim of this paper is to describe our 2019 extraordinary new experiences with genetic disorders and dysmorphic syndromes. Material and methods: During the year 2019, 37 patients (25 males and 12 female) with genetic disorders and dysmorphic syndromes and were studied at the Children Teaching Hospital of Baghdad Medical City. Their ages ranged from 2 days to sixteen years. Results: Eight patients had Down syndrome (6 boys and 2 girls), 5 patients had Cornelia De Lang syndrome (4 boys and one girl), 2 male patients had Fragile X-syndrome, 2 male patients with Prader Willi syndrome, two patients had Noonan syndrome (a boy and girl), 2 brothers had Goldberg Shprintzen syndrome. Ten patients each had Facioscapulohumeral muscular dystrophy, Virchow Seckel Syndrome, Mowat Wilson syndrome, Toriello-Carey Syndrome, Ruprecht Majewski-Bosma syndrome, congenital myotonic muscular dystrophy (Congenital dystrophia myotonica), extended Michelin tire baby, Congenital absent radii without thumb aplasia, Dandy walker syndrome and the syndrome of congenital facial palsy and unilateral anotia. In addition, six children patients had newly recognized syndromes (five boys and one girl). Many of the patients in this series were previously described or reported. Conclusion: This one-year Iraqi pioneering experience in the fields of clinical genetics and clinical dysmorphology should herald the end of the Dark Age in these fields in Iraq.

The 58th Case of Toriello-Carey Syndrome: The Association with Colpocephaly on Brain Magnetic Resonance Imaging and Computerized Tomography Scan

The 58th Case of Toriello-Carey Syndrome: The Association with Colpocephaly on Brain Magnetic Resonance Imaging and Computerized Tomography Scan

The 58th Case of Toriello-Carey Syndrome: The Association with Colpocephaly on Brain Magnetic Resonance Imaging and Computerized Tomography Scan

The 58th Case of Toriello-Carey Syndrome: The Association with Colpocephaly on Brain Magnetic Resonance Imaging and Computerized Tomography Scan

Expanding the phenome and variome of skeletal dysplasia

PurposeTo describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. MethodsDetailed phenotyping and next-generation sequencing (panel and exome). ResultsOur analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello–Carey syndrome–like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. ConclusionBy expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

A Chinese patient with Toriello–Carey syndrome and an interstitial deletion of 3q

Toriello-Carey syndrome (T-CS), which was first described by Toriello and Carey, is a rare multiple congenital anomaly syndrome characterized by agenesis of the corpus callosum, Pierre Robin sequence, unusual facial appearance, and other anomalies. Tracheal or laryngeal anomalies are reported as a common manifestation of T-CS. These anomalies can lead to respiratory distress and respiratory tract infection. The cause of T-CS is unknown, although there have been reports of patients with a clinical diagnosis of T-CS and a chromosome anomaly. We describe another such patient who was found to have an interstitial deletion of 3q (3q12.1-q21.3). © 2016 Wiley Periodicals, Inc.

Update on the Toriello-Carey syndrome.

Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. © 2016 Wiley Periodicals, Inc.

Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new" syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome".

A case of Toriello–Carey syndrome with severe congenital tracheal stenosis

Toriello-Carey syndrome is rare condition characterized by agenesis of the corpus callosum, the Pierre Robin sequence, and facial anomalies such as telecanthus, short palpebral fissures, and a small nose with anteverted nares [Toriello and Carey, 1988]. In addition, tracheal and laryngeal anomalies are common complications in patients with Toriello-Carey syndrome, and these anomalies can lead to death [Kataoka et al., 2003]. Congenital tracheal stenosis is a life-threatening condition with high mortality. Even if surgery is successful, several serious complications can result in a high risk of mortality. We describe a case of a Japanese boy with Toriello-Carey syndrome who had severe congenital tracheal stenosis, in whom surgical tracheal plasty was avoided because of adequate respiratory care, allowing the patient to be alive at 18 months of age.

Pancreatic insufficiency in Toriello–Carey syndrome: Report of a second patient

Toriello-Carey syndrome is characterized by multiple congenital anomalies. Pancreatic insufficiency is suspected when patients present with poor weight gain, diarrhea, or maldigestion. The diagnosis is confirmed by low stool elastase and pancreatic stimulation testing. To our knowledge, only one patient with Toriello-Carey syndrome has been reported to have pancreatic insufficiency. We report on a second patient with Toriello-Carey syndrome and pancreatic insufficiency, and describe the management of pancreatic insufficiency in patients with this syndrome.

Toriello‐Carey syndrome with a 6Mb interstitial deletion at 22q12 detected by array CGH

Toriello-Carey syndrome is a rare multiple congenital anomaly syndrome comprising agenesis of the corpus callosum, telecanthus, short palpebral fissures, abnormal ears, Pierre Robin sequence, and cardiac anomaly. Autosomal recessive inheritance has been hypothesized and chromosome abnormalities have been reported. The present case is a girl with agenesis of the corpus callosum, a large cleft palate, telecanthus, hypertelorism, atrial septal defect, ventricular septal defect, and patent ductus arteriosus. A routine karyotype and fluorescence in situ hybridization subtelomeric analysis were normal. Array comparative genomic hybridization (CGH) identified a de novo 6 Mb interstitial deletion at 22q12.1→22q12.2. These findings support recent findings of chromosomal abnormalities in patients with the Toriello-Carey phenotype. We suggest that the clinical features described in some cases with Toriello-Carey syndrome might be due to cryptic chromosomal rearrangements and that array CGH should be considered in any case presenting with clinical features of Toriello-Carey.

Siblings with phenotypic overlap with Toriello–Carey syndrome and complex cytogenetic imbalances including 3q29 microduplication and 6p25 microdeletion: Review of the literature and additional evidence for genetic heterogeneity

Toriello-Carey syndrome (TCS) is a multiple congenital anomaly syndrome of unknown etiopathogenesis with characteristic findings including corpus callosum defects, minor facial dysmorphisms, mental retardation, postnatal growth delays, cardiac defects, limb anomalies and genitourinary defects in affected males. This report describes two siblings with features of the TCS in whom array comparative genomic hybridization detected both a 3q29 microduplication as well as a 6p25 microdeletion due to an unbalanced translocation inherited from the father. Though neither microscopic copy number imbalance has been previously attributed to the TCS, this report supports the assertion that roughly 25% of patients with presumed TCS by phenotype may harbor underlying cytogenetic aberrations. Further, this report maintains that, until the specific causative gene is identified, a diagnosis of TCS be reserved for those patients who have not only the salient clinical features but also normal genetic studies that should include microarray.

Toriello–Carey syndrome in a patient with a de novo balanced translocation [46,XY,t(2;14)(q33;q22)] interrupting SATB2

Toriello-Carey syndrome (TCS; OMIM 217980) is a multiple congenital anomaly syndrome characterized by the common manifestations of corpus callosum agenesis, cardiac defects, cleft palate/Robin sequence, hypotonia, mental retardation, postnatal growth retardation and distinctive facial dysmorphology (including micrognathia, telecanthus, small nose and full cheeks). Both autosomal recessive and X-linked inheritance have been proposed, but chromosomal abnormalities involving disparate loci have also been detected in a small number of cases. We report a patient with classical features of TCS and an apparently balanced de novo translocation between chromosomes 2 and 14 [46,XY,t(2;14)(q33;q22)]. Molecular characterization revealed direct interruption of the special AT-rich sequence-binding protein-2 (SATB2) gene at the 2q33.1 translocation breakpoint, while the 14q22.3 breakpoint was not intragenic. SATB2 mutation or deletion has been associated with both isolated and syndromic facial clefting; however, an association with TCS has not been reported. SATB2 functions broadly as a transcription regulator, and its expression patterns suggest an important role in craniofacial and central nervous system development, making it a plausible candidate gene for TCS.

AGENESIS OF CORPUS CALLOSUM – CLINICS AND GENETICS

Objectives: The corpus callosum is the major connection between the two cerebral hemispheres. Hypoplasis or agenesis of corpus callosum (ACC) can be an isolated malformation of the central nervous system (CNS), may be associated with other CNS malformations or abnormalities of other organs. In present work the clinical signs and symptoms in an isolated ACC and in ACC with accompanying other cerebral malformations were analysed. Methods: Thirty children aged 4 months –15 years with ACC treated in clinics of the Medical University of Gdansk in Poland during the last three years were analysed. Agenesis of corpus callosum was diagnosed by USG and was confirmed by CT and/or MRI. Results: In 13 children (43%) ACC was an isolated CNS malformation; in 17 patients (57%) other CNS abnormalities have been established. In 77% of children ACC coexisted with the lesions of other organs including heart and sight malformations, the lesions of osteoarticular system, urogenital system and gastrointestinal system. The Apert syndrome, the Toriello-Carey syndrome and in one case the VATER sequence were diagnosed. In two females clinical signs were typical of Aicardi syndrome. In one case of newborn congenital cytomegalovirus infection has been established. In one infant the ring chromosome, in another the microdeletion of chromosome 22 were diagnosed. Conclusion: ACC with accompanying other cerebral malformations present more severe clinical manifestation. – Estimation of ACC is particulary important for wider diagnostics of the CNS and also for providing examinations of other organs.

Toriello-Carey syndrome: delineation and review.

Toriello and Carey [1988: Am J Med Genet 31:17-23] first described a syndrome with component manifestations of corpus callosum agenesis, unusual facial appearance, Robin sequence, and other anomalies. This was termed the Toriello-Carey syndrome by Lacombe et al. [1992: Am J Med Genet 42:374-376]. Since then, 11 reports describing 16 additional children have been published; in addition, we have had the opportunity to review over 30 unpublished cases. However, for various reasons, only 25 of the unpublished patients were included in this review. Based on this total, we can begin to better delineate this syndrome, as well as provide some information on natural history.

Toriello-Carey syndrome with endocardial fibroelastosis

Toriello-Carey syndrome with endocardial fibroelastosis

Toriello‐Carey syndrome: Evidence for X‐linked inheritance

Toriello-Carey syndrome is characterized by agenesis of the corpus callosum, telecanthus, short palpebral fissures, Robin sequence, abnormal ears, cardiac anomalies, and hypotonia. We describe two patients with Toriello-Carey syndrome and call attention to an unbalanced sex ratio. The first patient, a male, was born at term by Cesarean section and manifests micrognathia, cleft soft palate, hypoplastic right ear, anotia on the left side, cerebellar vermis hypoplasia, hydrocephalus, agenesis of the corpus callosum, and hypoplastic left heart. He died 2 days after birth. The second patient is the male sib of a patient reported previously [Am J Med Genet 42: 374–376; 1992]. He had large fontanelles, telecanthus, a short nose, small and malformed ears, micrognathia, a large ventricular septal defect, and pulmonary stenosis. At age 8 months he has growth retardation and developmental delay. A sister is unaffected. Review documented eight other patients with Toriello-Carey syndrome, six of whom were male. The two female patients are less severely affected and are still alive. Of the other male patients, all are deceased except one who is still alive at age 5 years; he has severe growth retardation (-3 SD), mental retardation (DQ44), severe speech delay, and characteristic anomalies. The predominance of affected males and the milder phenotype in the female patients suggests an X-linked gene or sex influenced gene. © 1996 Wiley-Liss, Inc.

Toriello-Carey syndrome

Toriello-Carey syndrome is a malformation syndrome characterized by cranio-facial defects, visceral defects, congenital heart defects, hypotonia, and postnatal growth retardation. To our knowledge, only five patients with this condition have been reported. We describe another case of the Toriello-Carey syndrome extending the phenotypic manifestations of the syndrome.