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Acta Medica Okayama Dec 2023A patient was born with a mass at the base of the thumb approximately 1.5 cm in diameter on the radial side of the fingers. The mass had globular swelling filled with...
A patient was born with a mass at the base of the thumb approximately 1.5 cm in diameter on the radial side of the fingers. The mass had globular swelling filled with hemorrhagic fluid and was dark red. X-rays and histology of the excised specimen suggested the diagnosis of gangrene and torsion of polydactyly. Prenatal torsion of polydactyly is not a common occurrence; moreover, prenatal torsion of polydactyly has only been found in ulnar polydactyly. Our case is a novel case of radial polydactyly that was gangrenous at birth owing to prenatal torsion. Diagnosing such a mass at the base of the thumb is important.
Topics: Infant, Newborn; Humans; Thumb; Gangrene; Polydactyly; Fingers
PubMed: 38145940
DOI: 10.18926/AMO/66158 -
American Journal of Human Genetics Jan 2024Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding...
Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAX (Max) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAX individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.
Topics: Humans; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Dimerization; Megalencephaly; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-myc
PubMed: 38141607
DOI: 10.1016/j.ajhg.2023.11.010 -
Genes Dec 2023Cornelia de Lange syndrome is a genetic and clinically heterogeneous entity, caused by at least five genes. It is characterized by short stature, gestalt facies,...
Cornelia de Lange syndrome is a genetic and clinically heterogeneous entity, caused by at least five genes. It is characterized by short stature, gestalt facies, microcephaly, neurodevelopmental disorders, and other anomalies. In this report, we present a 13-year-old female patient with microcephaly, cleft palate, polydactyly, short stature, triangular facies, frontal bossing, a bulbous nose, an overfolded helix, limited pronosupination, and an anomalous uterus. No neurodevelopmental disorders were reported. A chromosomal microarray analysis of 6.5 million markers was performed in the proband and her parents. The results showed a de novo heterozygous microdeletion of exons 9-14 within , which confirmed the diagnosis of Cornelia de Lange syndrome type 4. Our patient did not show any neurologic phenotype (until the time of diagnosis), although neurodevelopmental disorders are frequently present in patients with Cornelia de Lange syndrome type 4, and despite carrying a deletion that was larger than previously reported. Therefore, unknown genetic modifiers or intrinsic mechanisms of variants may exist and should be studied.
Topics: Humans; Female; Adolescent; De Lange Syndrome; Cell Cycle Proteins; Gene Deletion; Microarray Analysis
PubMed: 38137034
DOI: 10.3390/genes14122212 -
Cureus Dec 2023The pathophysiology of Patau's syndrome involves the triplication of chromosomes, leading to multiple comorbidities. An omphalocele is characterized by a protrusion of...
The pathophysiology of Patau's syndrome involves the triplication of chromosomes, leading to multiple comorbidities. An omphalocele is characterized by a protrusion of abdominal contents from the base of the umbilical cord through the peritoneum. An omphalomesenteric duct remnant occurs when there is a failure of duct closure that results in a diverticulum extending from the fetal midgut to the yolk sac. While congenital defects rarely occur simultaneously in patients with Patau's syndrome, this case report describes a newborn with Patau syndrome who presented with both an omphalocele and an omphalomesenteric duct remnant. The newborn exhibited various congenital abnormalities such as coloboma, microphthalmia, broad nasal bridge, cleft lip, cleft palate, low-set ears, systolic murmur, omphalocele, intestinal umbilical fistula (omphalomesenteric continuous vitelointestinal duct remnant), polydactyly, rocker-bottom feet, left-sided clubbed foot, and ruptured myelomeningocele. Imaging revealed additional complications such as a large patent ductus arteriosus, hypoplastic distal arch, markedly dilated right atrium and left ventricle, and cerebellar hypoplasia. Chromosomal analysis confirmed the diagnosis of Patau's syndrome. Given the untreatable medical condition, the patient was placed under "Do Not Resuscitate," and palliative care was initiated. The simultaneous appearance of an omphalocele and an omphalomesenteric continuous vitelointestinal duct is rare, and surgical intervention is the standard of care if the patient is deemed suitable for surgery. However, in cases where surgery is not feasible, palliative care is initiated. Regardless of the outcome, genetic counseling is essential and should include a discussion on paternal autonomy, understanding the disorder, suggesting alternative management methods, and making crucial decisions concerning future family care and planning.
PubMed: 38125687
DOI: 10.7759/cureus.50793 -
Gene Mar 2024Verheij syndrome (VRJS) is a craniofacial spliceosomopathy with a wide phenotypic spectrum. Haploinsufficiency of the poly-uridine binding splicing factor 60 gene...
Verheij syndrome (VRJS) is a craniofacial spliceosomopathy with a wide phenotypic spectrum. Haploinsufficiency of the poly-uridine binding splicing factor 60 gene (PUF60) and its loss-of-function (LOF) variants are involved in VRJS. We evaluated a human fetus with congenital heart defects and preaxial polydactyly. Clinical data were obtained from the medical record. Whole-exome sequencing (WES) was used to explore the potential genetic etiology, and the detected variant verified using Sanger sequencing. Functional studies were performed to validate the pathogenic effects of the variant. Using trio-WES, we identified a novel PUF60 variant (NM_078480.2; c.1678 T > A, p.*560Argext*204) in the pedigree. Bioinformatic analyses revealed that the variant is potentially pathogenic, and functional studies indicated that it leads to degradation of the elongated protein and subsequently PUF60 LOF, producing some VRJS phenotypes. These findings confirmed the pathogenicity of the variant. This study implicates PUF60 LOF in the etiopathogenesis of VRJS. It not only expands the PUF60 variant spectrum, and also provides a basis for genetic counseling and the diagnosis of VRJS. Although trio-WES is a well-established approach for identifying the genetic etiology of rare multisystemic conditions, functional studies could aid in verifying the pathogenicity of novel variants.
Topics: Humans; Fetus; Heart Defects, Congenital; Pedigree; Phenotype; RNA Splicing Factors
PubMed: 38110042
DOI: 10.1016/j.gene.2023.148092 -
A Rare Presentation of Postaxial Polydactyly in a 2-Year-Old Female with Ellis-van Creveld Syndrome.Journal of Hand Surgery Global Online Nov 2023Postaxial or ulnar polydactyly is the most common form of polydactyly that may present with the duplication of soft-tissue structures only or with additional bony...
Postaxial or ulnar polydactyly is the most common form of polydactyly that may present with the duplication of soft-tissue structures only or with additional bony involvement. Surgical excision is the only viable treatment option for postaxial polydactyly with bony involvement, and psychological or cosmetic reasons are the main rationale for treatment. Ellis-van Creveld syndrome (EVC) is a rare congenital disorder characterized by chondral and ectodermal dysplasia, particularly postaxial polydactyly. The exact prevalence of EVC is unknown, and fewer than 300 cases have been reported. We present a case of a 2-year-old Hispanic female with EVC who presented with bilateral postaxial polydactyly and complete duplication of the metacarpal and phalanges. We describe the presentation and treatment of this patient, who ultimately underwent staged resection of the duplicated digits with reconstruction of the abductor muscle.
PubMed: 38106942
DOI: 10.1016/j.jhsg.2023.08.007 -
BioRxiv : the Preprint Server For... Dec 2023Functional analysis of non-coding variants associated with human congenital disorders remains challenging due to the lack of efficient models. Here we introduce...
Functional analysis of non-coding variants associated with human congenital disorders remains challenging due to the lack of efficient models. Here we introduce dual-enSERT, a robust Cas9-based two-color fluorescent reporter system which enables rapid, quantitative comparison of enhancer allele activities in live mice of any genetic background. We use this new technology to examine and measure the gain- and loss-of-function effects of enhancer variants linked to limb polydactyly, autism, and craniofacial malformation. By combining dual-enSERT with single-cell transcriptomics, we characterize variant enhancer alleles at cellular resolution, thereby implicating candidate molecular pathways in pathogenic enhancer misregulation. We further show that independent, polydactyly-linked enhancer variants lead to ectopic expression in the same cell populations, indicating shared genetic mechanisms underlying non-coding variant pathogenesis. Finally, we streamline dual-enSERT for analysis in F0 animals by placing both reporters on the same transgene separated by a synthetic insulator. Dual-enSERT allows researchers to go from identifying candidate enhancer variants to analysis of comparative enhancer activity in live embryos in under two weeks.
PubMed: 38105996
DOI: 10.1101/2023.12.10.570890 -
PLoS Biology Dec 2023Ciliopathies are associated with wide spectrum of structural birth defects (SBDs), indicating important roles for cilia in development. Here, we provide novel insights...
Ciliopathies are associated with wide spectrum of structural birth defects (SBDs), indicating important roles for cilia in development. Here, we provide novel insights into the temporospatial requirement for cilia in SBDs arising from deficiency in Ift140, an intraflagellar transport (IFT) protein regulating ciliogenesis. Ift140-deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula (TEF), randomized heart looping, congenital heart defects (CHDs), lung hypoplasia, renal anomalies, and polydactyly. Tamoxifen inducible CAGGCre-ER deletion of a floxed Ift140 allele between E5.5 to 9.5 revealed early requirement for Ift140 in left-right heart looping regulation, mid to late requirement for cardiac outflow septation and alignment, and late requirement for craniofacial development and body wall closure. Surprisingly, CHD were not observed with 4 Cre drivers targeting different lineages essential for heart development, but craniofacial defects and omphalocele were observed with Wnt1-Cre targeting neural crest and Tbx18-Cre targeting epicardial lineage and rostral sclerotome through which trunk neural crest cells migrate. These findings revealed cell autonomous role of cilia in cranial/trunk neural crest-mediated craniofacial and body wall closure defects, while non-cell autonomous multi-lineage interactions underlie CHD pathogenesis, revealing unexpected developmental complexity for CHD associated with ciliopathies.
Topics: Animals; Mice; Cilia; Heart Defects, Congenital; Embryonic Development; Carrier Proteins; Skull; Ciliopathies
PubMed: 38079449
DOI: 10.1371/journal.pbio.3002425 -
Healthcare (Basel, Switzerland) Nov 2023Radial polydactyly or thumb duplication is a relatively common congenital malformation of the hand, whereby the surgical techniques can be broadly divided into simple...
Radial polydactyly or thumb duplication is a relatively common congenital malformation of the hand, whereby the surgical techniques can be broadly divided into simple excisions, reconstructions and a Bilhaut-Cloquet procedure. The aim of this study was to identify the appropriate surgical procedures and to present the clinical outcomes that can be achieved. We performed a multicenter analysis of cases of radial polydactyly surgically treated with reconstruction or a Bilhaut-Cloquet procedure between 2015 and 2022. The clinical outcome was assessed using a modification of the Tada score. A total of 28 cases of 27 patients with radial polydactyly were included in the study. The most common Wassel type was type IV (13 cases), and the most common surgical procedure was reconstruction (24 cases). Our study validates an algorithm from the literature as a helpful tool for decision making in selecting a surgical technique for radial polydactyly, although individual surgical experience should also be considered.
PubMed: 38063613
DOI: 10.3390/healthcare11233045 -
BMC Medical Genomics Dec 2023Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal...
BACKGROUND
Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.
METHODS
Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.
RESULTS
The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.
CONCLUSION
Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.
Topics: Pregnancy; Female; Humans; DNA Copy Number Variations; Ellis-Van Creveld Syndrome; Prenatal Diagnosis; Osteochondrodysplasias; Polydactyly; Ciliopathies; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing
PubMed: 38062428
DOI: 10.1186/s12920-023-01753-y