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HGG Advances Oct 2023MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline...
MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis.
Topics: Mice; Animals; Humans; Female; Microcephaly; Gain of Function Mutation; N-Myc Proto-Oncogene Protein; Polydactyly; Phenotype; Megalencephaly; Eyelids; Intellectual Disability; Tracheoesophageal Fistula; Limb Deformities, Congenital
PubMed: 37710961
DOI: 10.1016/j.xhgg.2023.100238 -
Expert Reviews in Molecular Medicine Oct 2015Polydactyly is one of the most common inherited limb abnormalities, characterised by supernumerary fingers or toes. It results from disturbances in the normal programme... (Review)
Review
Polydactyly is one of the most common inherited limb abnormalities, characterised by supernumerary fingers or toes. It results from disturbances in the normal programme of the anterior-posterior axis of the developing limb, with diverse aetiology and variable inter- and intra-familial clinical features. Polydactyly can occur as an isolated disorder (non-syndromic polydactyly) or as a part of an anomaly syndrome (syndromic polydactyly). On the basis of the anatomic location of the duplicated digits, non-syndromic polydactyly is divided into three kinds, including preaxial polydactyly, axial polydactyly and postaxial polydactyly. Non-syndromic polydactyly frequently exhibits an autosomal dominant inheritance with variable penetrance. To date, in human, at least ten loci and four disease-causing genes, including the GLI3 gene, the ZNF141 gene, the MIPOL1 gene and the PITX1 gene, have been identified. In this paper, we review clinical features of non-syndromic polydactyly and summarise the recent progress in the molecular genetics, including loci and genes that are responsible for the disorder, the signalling pathways that these genetic factors are involved in, as well as animal models of the disorder. These progresses will improve our understanding of the complex disorder and have implications on genetic counselling such as prenatal diagnosis.
Topics: Animals; DNA-Binding Proteins; Female; Gene Expression; Genetic Loci; Genotype; Humans; Kruppel-Like Transcription Factors; Male; Mutation; Nerve Tissue Proteins; Paired Box Transcription Factors; Phenotype; Polydactyly; Signal Transduction; Tumor Suppressor Proteins; Zinc Finger Protein Gli3
PubMed: 26515020
DOI: 10.1017/erm.2015.18 -
Neurology India 2023
Topics: Child; Humans; Polydactyly; Seizures
PubMed: 37929493
DOI: 10.4103/0028-3886.388066 -
Plastic and Reconstructive Surgery Aug 2015After reading this article, the participant should be able to: 1. Accurately diagnose congenital differences that affect the hand. 2. Develop a surgical plan for... (Review)
Review
LEARNING OBJECTIVES
After reading this article, the participant should be able to: 1. Accurately diagnose congenital differences that affect the hand. 2. Develop a surgical plan for syndactyly with regard to timing of intervention to prevent progressive deformity and principles to restore the commissure. 3. List the potential complications following polydactyly reconstruction. 4. State the indications for pollicization for thumb hypoplasia.
SUMMARY
Congenital conditions of the hand are commonly encountered in a pediatric hand surgery practice. The physician must be comfortable and have a sound understanding of the diagnosis and treatment algorithm. Certain diagnoses are inheritable and require genetic testing and/or genetic counseling. Appropriate referral is necessary to facilitate education about the congenital difference and its effect on subsequent generations. Syndactyly, polydactyly, thumb hypoplasia, and cleft hand are particularly commonplace and are discussed in this article. The treatment principles and surgical techniques are emphasized to maximize hand function and aesthetic outcome.
Topics: Education, Medical, Continuing; Female; Follow-Up Studies; Hand Deformities; Hand Deformities, Congenital; Humans; Incidence; Male; Orthopedic Procedures; Polydactyly; Plastic Surgery Procedures; Recovery of Function; Thumb; Treatment Outcome
PubMed: 26218399
DOI: 10.1097/PRS.0000000000001499 -
Clinical Genetics Jul 2016Bardet-Biedl syndrome (BBS) is an autosomal recessive multisystemic human genetic disorder characterized by six major defects including obesity, mental retardation,... (Review)
Review
Bardet-Biedl syndrome (BBS) is an autosomal recessive multisystemic human genetic disorder characterized by six major defects including obesity, mental retardation, renal anomalies, polydactyly, retinal degeneration and hypogenitalism. In several cases of BBS, few other features such as metabolic defects, cardiovascular anomalies, speech deficits, hearing loss, hypertension, hepatic defects and high incidence of diabetes mellitus have been reported as well. The BBS displays extensive genetic heterogeneity. To date, 19 genes have been mapped on different chromosomes causing BBS phenotypes having varied mutational load of each BBS gene. In this review, we have discussed clinical spectrum and genetics of BBS. This report presents a concise overview of the current knowledge on clinical data and its molecular genetics progress upto date.
Topics: Bardet-Biedl Syndrome; Diabetes Mellitus; Female; Gene Expression; Genetic Heterogeneity; Humans; Intellectual Disability; Male; Microtubule-Associated Proteins; Multigene Family; Mutation; Obesity; Pedigree; Phenotype; Polydactyly; Protein Isoforms; Retinal Degeneration
PubMed: 26762677
DOI: 10.1111/cge.12737 -
Neuro Endocrinology Letters Oct 2017Pallister Hall syndrome is autosomal dominant disorder usually diagnosed in infants and children. Current diagnostic criteria include presence of hypothalamic hamartoma,...
Pallister Hall syndrome is autosomal dominant disorder usually diagnosed in infants and children. Current diagnostic criteria include presence of hypothalamic hamartoma, post axial polydactyly and positive family history, but the disease has variable manifestations. Herein we report Pallister Hall syndrome diagnosed in a family where both patients were adults. A 59 year old man developed seizures 4 years prior to our evaluation of him, at which time imaging showed a hypothalamic hamartoma. The seizures were controlled medically. He did well until he had visual changes after a traumatic head injury. Repeat MRI showed slight expansion of the mass with formal visual field testing demonstrating bitemporal hemianopsia. There was no evidence of pituitary dysfunction except for large urine volume. He underwent surgery to debulk the hamartoma and the visual field defects improved. There was no hypopituitarism post-operatively, and the polydyspia resolved. His 29 year old daughter also had seizures and hypothalamic hamartoma. Both patients had had polydactyly with prior surgical correction in childhood. The daughter underwent genetic testing, which revealed a previously undescribed heterozygous single base pair deletion in exon 13 of the GLI3 gene causing a frameshift mutation. Further investigation into family history revealed multiple members in previous generations with polydactyly and/or seizures. Pallister-Hall syndrome is caused by an inherited autosomal dominant or de novo mutation in GLI3 gene. This rare syndrome has not had prevalence defined, however. Generally, diagnoses are made in the pediatric population. Our report adds to the few cases detected in adulthood.
Topics: Adult; DNA Mutational Analysis; Delayed Diagnosis; Family; Female; Frameshift Mutation; Humans; Male; Middle Aged; Nerve Tissue Proteins; Pallister-Hall Syndrome; Zinc Finger Protein Gli3
PubMed: 29106787
DOI: No ID Found -
JBJS Reviews Mar 2022Surgical timing for pediatric trigger thumb treatment is controversial for numerous reasons including the potential for spontaneous resolution, the possibility of...
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Surgical timing for pediatric trigger thumb treatment is controversial for numerous reasons including the potential for spontaneous resolution, the possibility of bilateral involvement, and anesthesia concerns regarding the developing brain. Hence, a reasonable approach is to delay the surgical procedure until the patient is ≥3 years of age.
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Preaxial polydactyly is usually unilateral and sporadic, with the most common reconstruction method consisting of excision of the diminutive thumb with preservation and soft-tissue reconstruction of the dominant thumb. The surgical procedure is typically performed around the patient age of 1 year to decrease the risks of anesthesia but allow reconstruction prior to the development of a tip-to-tip pinch.
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Triphalangeal thumb and thumb hypoplasia are often found in the setting of systemic anomalies such as Holt-Oram syndrome, thrombocytopenia absent radius syndrome, Fanconi anemia, VACTERL (vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophageal fistula, renal defects, and limb anomalies), and/or Blackfan-Diamond anemia. As such, patients should receive adequate workup for these entities. A surgical procedure should be performed only once patients have been medically cleared.
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The status of the carpometacarpal joint in thumb hypoplasia determines whether reconstruction with first web space deepening, collateral ligament stabilization, and opponensplasty compared with index pollicization is performed.
Topics: Child; Hand Deformities; Hand Deformities, Congenital; Humans; Polydactyly; Thumb; Upper Extremity Deformities, Congenital
PubMed: 35230999
DOI: 10.2106/JBJS.RVW.21.00147 -
Archives of Gynecology and Obstetrics Jul 2022Report on the diagnosis of prenatally suspected multisystem ciliopathies in a single center between 2002 and 2020. (Observational Study)
Observational Study
PURPOSE
Report on the diagnosis of prenatally suspected multisystem ciliopathies in a single center between 2002 and 2020.
METHODS
Retrospective observational single-center study including pregnancies with prenatal ultrasound features of multisystem ciliopathies, such as hyperechogenic kidneys together with polydactyly and/or other skeletal and extraskeletal findings. Cases were compared according to their prenatal findings and outcomes.
RESULTS
36 cases of multisystem ciliopathies were diagnosed. Meckel-Gruber syndrome (MKS) was the most common ciliopathy (n = 19/36, 52.8%), followed by disorders that belong to the group of short-rib thoracic dysplasia (SRTD, n = 10/36, 27.8%) McKusick-Kaufmann syndrome (MKKS, n = 4/36, 11.1%), Bardet-Biedl syndrome (BBS, n = 2/36, 5.5%) and Joubert syndrome (n = 1/36, 2.8%). All cases showed abnormalities of the kidneys, most often hyperechogenic parenchyma (n = 26/36, 72.2%), cystic dysplasia (n = 24/36, 66.7%), and/or bilateral kidney enlargement (n = 22/36, 61.1%). Oligohydramnios was mainly present in fetuses with MKS. Polydactyly (n = 18/36), abnormalities of the CNS (n = 25/36), and heart defects (n = 10/36) were associated in 50%, 69.4%, and 27.8%, respectively.
CONCLUSION
Prenatal detection of renal abnormalities associated with skeletal or brain abnormalities should raise the suspicion for multisystem ciliopathies. Prenatal ultrasound can help to differentiate between different diseases and pave the way for subsequent targeted genetic testing.
Topics: Ciliary Motility Disorders; Ciliopathies; Encephalocele; Female; Fetus; Humans; Polycystic Kidney Diseases; Polydactyly; Pregnancy; Retinitis Pigmentosa; Retrospective Studies
PubMed: 34596737
DOI: 10.1007/s00404-021-06265-7 -
Handchirurgie, Mikrochirurgie,... Feb 2016Radial polydactyly or 'thumb duplication' is the most common congenital upper limb anomaly ('CULA') affecting the thumb. The clinical presentation is highly diverse,... (Review)
Review
Radial polydactyly or 'thumb duplication' is the most common congenital upper limb anomaly ('CULA') affecting the thumb. The clinical presentation is highly diverse, ranging from an extra thumb floating on a skin bridge to complicated thumb triplications with triphalangeal, deviating, and hypoplastic components. Radial polydactyly can be classified into one of 7 osseous presentations using the Wassel classification, with type IV (45%), type II (20%), and type VII (15%) occurring most frequently. When faced with a radial polydactyly case, hand surgeons specialised in congenital anomalies must weigh the preoperative functional potential and degree of hypoplasia of both thumbs in order to decide whether to resect one thumb and reconstruct the other ('resection and reconstruction'), excise a central part of both thumbs and unite the lateral tissues into one thumb ('the Bilhaut procedure'), transfer the better-developed distal tissues of one thumb onto the better-developed proximal tissues of the other ('on-top plasty'), or discard both severely hypoplastic thumbs and pollicise the index finger. Mere excision of the hypoplastic thumb is rarely indicated since it often requires subsequent revision surgery. Even after being treated by experienced surgeons, about 15% of patients with polydactyly will need additional procedures to correct residual and/or new problems such as deviation from the longitudinal axis and joint instability. Nevertheless, radial polydactyly patients usually achieve unimpaired everyday hand function postoperatively.
Topics: Adolescent; Child; Child, Preschool; Female; Hand Strength; Humans; Infant; Infant, Newborn; Male; Motor Skills; Orthopedic Procedures; Polydactyly; Postoperative Complications; Pregnancy; Prognosis; Plastic Surgery Procedures; Thumb; Treatment Outcome
PubMed: 26895514
DOI: 10.1055/s-0042-100460 -
Indian Journal of Pediatrics Jan 2023Desbuquois dysplasia (DBQD) is an uncommon, autosomal recessive disorder with multiple joint dislocations. It is caused by pathogenic variants in CANT1...
Desbuquois dysplasia (DBQD) is an uncommon, autosomal recessive disorder with multiple joint dislocations. It is caused by pathogenic variants in CANT1 (calcium-activated nucleotidase 1) [NM_001159773.2]. This study adds to the scant data of nine reported antenatal phenotypes of DBQD. The present paper describes two unrelated consanguineous families with antenatal features of lethal skeletal dysplasia. The defining radiological changes were identified in only one patient who presented in the late second and third trimesters. Solo exome sequencing was performed and two previously reported homozygous variants c.896C>T (p.Pro299Leu) in patient 1 and c.902_906dup (p.Ser303fs*20) in patient 2 were identified. This study highlights the fetal presentations in DBQD and adds to its phenotypic spectrum. A complete clinical workup, including fetal autopsy and radiographs is essential to confirm the diagnosis of lethal skeletal dysplasia. Molecular diagnosis remains the diagnostic modality to define the causative variant. A definitive diagnosis is essential to inform management and offer reproductive care.
Topics: Female; Pregnancy; Humans; Mutation; Dwarfism; Polydactyly; Phenotype; Osteochondrodysplasias
PubMed: 36331722
DOI: 10.1007/s12098-022-04386-8