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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 -
International Journal of Infectious... Feb 2024Chikungunya virus (CHIKV), a reemerging global public health concern, which causes acute febrile illness, rash, and arthralgia and may affect both mothers and infants...
OBJECTIVES
Chikungunya virus (CHIKV), a reemerging global public health concern, which causes acute febrile illness, rash, and arthralgia and may affect both mothers and infants during pregnancy. Mother-to-child transmission (MTCT) of CHIKV in Africa remains understudied.
METHODS
Our cohort study screened 1006 pregnant women with a Zika/dengue/CHIKV rapid test at two clinics in Nigeria between 2019 and 2022. Women who tested positive for the rapid test were followed through their pregnancy and their infants were observed for 6 months, with a subset tested by reverse transcription-polymerase chain reaction (RT-PCR) and neutralization, to investigate seropositivity rates and MTCT of CHIKV.
RESULTS
Of the 1006, 119 tested positive for CHIKV immunoglobulin (Ig)M, of which 36 underwent detailed laboratory tests. While none of the IgM reactive samples were RT-PCR positive, 14 symptomatic pregnant women were confirmed by CHIKV neutralization test. Twelve babies were followed with eight normal and four abnormal outcomes, including stillbirth, cleft lip/palate with microcephaly, preterm delivery, polydactyly with sepsis, and jaundice. CHIKV IgM testing identified three possible antepartum transmissions.
CONCLUSION
In Nigeria, we found significant CHIKV infection in pregnancy and possible CHIKV antepartum transmission associated with birth abnormalities.
Topics: Infant; Infant, Newborn; Humans; Female; Pregnancy; Chikungunya virus; Pregnant Women; Cohort Studies; Nigeria; Cleft Lip; Infectious Disease Transmission, Vertical; Cleft Palate; Chikungunya Fever; Zika Virus Infection; Zika Virus; Stillbirth; Immunoglobulin M; Dengue
PubMed: 38056689
DOI: 10.1016/j.ijid.2023.11.036 -
Frontiers in Genetics 2023Meckel Syndrome (MKS, OMIM #249000) is a rare and fatal autosomal recessive ciliopathy with high clinical and genetic heterogeneity. MKS shows complex allelism with...
Meckel Syndrome (MKS, OMIM #249000) is a rare and fatal autosomal recessive ciliopathy with high clinical and genetic heterogeneity. MKS shows complex allelism with other related ciliopathies such as Joubert Syndrome (JBTS, OMIM #213300). In MKS, the formation and function of the primary cilium is defective, resulting in a multisystem disorder including occipital encephalocele, polycystic kidneys, postaxial polydactyly, liver fibrosis, central nervous system malformations and genital anomalies. This study aimed to analyze the genotype of MKS patients and investigate the correlation between genotype and phenotype. A nonconsanguineous couple who conceived four times with a fetus affected by multiorgan dysfunction and intrauterine fetal death was studied. Whole exome sequencing (WES) was performed in the proband to identify the potentially pathogenic variant. Sanger sequencing was performed in family members. In silico tools were used to analyse the pathogenicity of the identified variants. cDNA TA-cloning sequencing was performed to validate the effects of intronic variants on mRNA splicing. Quantitative real-time PCR was performed to investigate the effect of the variants on gene expression. Immunofluorescence was performed to observe pathological changes of the primary cilium in kidney tissue from the proband. Two splice site variants of (NM_001077418.2, c.583-1G>C and c.583-2_588delinsTCCTCCC) were identified in the proband, and the two variants have not been previously reported. The parents were confirmed as carriers. The two variants were predicted to be pathogenic by tools and were classified as pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics guideline. cDNA TA cloning analysis showed that both splice site variants caused a deletion of exon 5. RT-PCR revealed that the expression of was significantly decreased and immunofluorescence showed that the primary cilium was almost absent in the proband's kidney tissue. We reported the clinical, genetic, molecular and histochemical characterisation of a family affected by MKS. Our findings not only extended the mutation spectrum of the gene, but also revealed for the first time the pathological aetiology of primary cilia in humans and provide a basis for genetic counselling of the parents to their offspring.
PubMed: 37736303
DOI: 10.3389/fgene.2023.1252873 -
A diagnostic conundrum in Bardet-Biedl syndrome: when genetic diagnosis precedes clinical diagnosis.Endocrinology, Diabetes & Metabolism... Oct 2023Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive, multisystem non-motile ciliopathy of progressive onset. It is primarily characterised by rod-cone dystrophy,...
SUMMARY
Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive, multisystem non-motile ciliopathy of progressive onset. It is primarily characterised by rod-cone dystrophy, early-onset obesity and related complications, postaxial polydactyly, renal and genitourinary abnormalities, learning disabilities, and hypogonadism. The diagnosis is based on Beales' modified diagnostic criteria. We present a case of two monozygotic female twins, 17 years of age at presentation, referred for obesity since childhood. The initial hormonal work-up was negative and no dysmorphic features were noted. They were diagnosed with exogenous obesity. However, after ophthalmologic problems became apparent, rod-cone dystrophy was observed and genetic testing was performed. A mutation in the BBS2 gene led to the diagnosis of BBS, although the full diagnostic criteria were not met. This case not only highlights the need to raise awareness for BBS but also exposes two limitations of the current diagnostic standard. The first limitation is the low sensitivity of the clinical diagnostic model, due to the progressive onset and the high variability of the syndrome. The second limitation is the unclear role of genetic testing. As genetic testing becomes more widely available, genetic diagnosis preceding clinical diagnosis will become more common, leading to a diagnostic conundrum. We propose an update of the diagnostic model. A less strict application in the presence of confirmed genetic mutations should be applied, as this could facilitate earlier diagnosis and intervention. This is important because therapeutic agents are being developed that could have a significant impact on quality of life and prognosis.
LEARNING POINTS
Due to the low prevalence, the significant inter-and intrafamilial variation, and the slowly evolving phenotype, monogenic forms of obesity such as Bardet-Biedl syndrome are difficult to diagnose. Despite advances in the understanding of the presentation, pathophysiology and access to accurate genetic characterisation, a substantial number of diagnoses are still made by ophthalmology, as recognition of BBS in other departments of medicine, remains limited. Clinical diagnosis of BBS is based on Beales' modified diagnostic criteria which require the presence of four primary features or three primary features plus two secondary features. This model has its limitations. Due to the progressive onset of clinical symptoms, patients generally do not meet the diagnostic criteria early in life, leading to a delay in diagnosis. In addition, the role of genetic testing remains controversial. However, as it becomes more widely available, genetic diagnosis may precede a full clinical diagnosis. BBS has an impact on the quality of life and prognosis of both the patient and the family. Obesity management strategies are an important part of the multidisciplinary approach, as there is no cure available. Setmelanotide has shown promising results in a phase 3 trial, but its effect in clinical practice remains unproven.
PubMed: 37997784
DOI: 10.1530/EDM-23-0055 -
Molecular Genetics & Genomic Medicine Mar 2024Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by... (Review)
Review
BACKGROUND
Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by mutations of the RB1 gene or amplification of the MYCN gene. Rb may rarely present with polydactyly.
METHODS
We conducted karyotype analysis, copy number variation sequencing, and whole-genome sequencing on the infant proband and his family. The clinical course and laboratory results of the proband's infant were documented and collected. We also reviewed the relevant literature.
RESULTS
A 68-day-old boy presented with preaxial polydactyly and corneal edema. His intraocular pressure (IOP) was 40/19 mmHg, and color Doppler imaging revealed vitreous solid mass-occupying lesions with calcification in the right eye. Ocular CT showed flaky high-density and calcification in the right eye. This was classified as an International Retinoblastoma Staging System group E retinoblastoma with an indication for enucleation. Enucleation and orbital implantation were performed on the child's right eye. Karyotype analysis revealed an abnormal 46, XY, 15pstk+ karyotype, and the mother exhibited diploidy of the short arm of chromosome 15. The Alx-4 development factor, 13q deletion syndrome, and the PAPA2 gene have been reported as potential mechanisms for Rb combined with polydactyly.
CONCLUSION
We report the case of a baby boy with Rb and polydactyly exhibiting a 46, XY, 15pstk+ Karyotype. We discuss potential genetic factors related to both Rb and polydactyly. Furthermore, there is a need for further exploration into the impact of chromosomal polymorphisms in Rb with polydactyly.
Topics: Humans; Infant; Male; Calcinosis; DNA Copy Number Variations; Karyotype; Polydactyly; Retinal Neoplasms; Retinoblastoma
PubMed: 38465842
DOI: 10.1002/mgg3.2414 -
African Journal of Disability 2023Bardet-Biedl syndrome (BBS) is a rare, systemic, hereditary disorder characterised by obesity, polydactyly, visual and auditory impairment, and cognitive disability....
BACKGROUND
Bardet-Biedl syndrome (BBS) is a rare, systemic, hereditary disorder characterised by obesity, polydactyly, visual and auditory impairment, and cognitive disability. Providing quality education in appropriate schools for children who present with such complex chronic conditions is challenging.
OBJECTIVES
This study explored the dimensions of psycho-educational support needs for a child with BBS in South Africa to contribute to the improvement of early detection and holistic interventions.
METHOD
A descriptive in-depth qualitative case study of Gezani, an adolescent Tsonga boy diagnosed with BBS, was undertaken. Semi-structured interviews were conducted with his parents and teachers to ascertain the boy's psycho-educational support needs. Medical reports provided information on the complexities and prognosis of the syndrome. Observations in the classroom corroborated the learner's symptoms and behaviours.
RESULTS
Thematic content analysis revealed the key areas of support needs. Gezani's cognitive disability required a modified, slow-paced curriculum. His visual impairment required mobility orientation training and learning Braille. His emotional needs were supported with psychotherapy to maintain a sense of well-being. Medical monitoring was recommended with interventions for walking and managing his diet and weight. Speech therapy supported his communication skills.
CONCLUSION
Learners with multiple disabilities require carefully planned, individualised psycho-educational support programmes addressing their unique needs and delays with targeted remedial interventions in appropriate special needs schools.
CONTRIBUTION
This study informs educators about BBS and provides multi-faceted, holistic support. The Department of Basic Education could bring special schools and national policies in tighter alignment for learners presenting with complex disabilities.
PubMed: 38204908
DOI: 10.4102/ajod.v12i0.1181 -
Clinical Medicine Insights. Case Reports 2023Bardet-Biedl syndrome (BBS) also known as Laurence-Moon-Bardet-Biedl syndrome one of the rarely reported genetic disorder characterized by an intellectual disability,...
BACKGROUND
Bardet-Biedl syndrome (BBS) also known as Laurence-Moon-Bardet-Biedl syndrome one of the rarely reported genetic disorder characterized by an intellectual disability, limb, kidney abnormalities, obesity, and Rod-cone dystrophy. Other associated condition includes diabetes mellitus, hypertension, hypogonadism, facial dysmorphism, and congenital heart defects. This case highlights megaloblastic anemia associated with BBS.
CASE PRESENTATION
A 16-year-old female patient who had a moon face, truncal obesity, polydactyly, low IQ, and visual impairment presented with the complaint of shortness of breath and easy fatiguability. She had bilateral retinal pigmentosa in her eyes and her laboratory evaluation and bone marrow biopsy revealed megaloblastic anemia secondary to vitamin B12 deficiency. She received injectable vitamin B12, folate, and red cell contrate transfusion. Her symptoms improved and she was discharged with oral medication.
CONCLUSION
Megaloblastic anemia in BBS is rarely reported, further research is needed to find the exact cause that is necessary for proper management and better outcome.
PubMed: 37588947
DOI: 10.1177/11795476231193896 -
SAGE Open Medical Case Reports 2024Polydactyly is a common congenital malformation of the hand and foot characterized by an extra digit or duplication of digits. Polydactyly can present as preaxial,...
Polydactyly is a common congenital malformation of the hand and foot characterized by an extra digit or duplication of digits. Polydactyly can present as preaxial, complex, or postaxial types. It has various presentations, and it can be an isolated anomaly or part of other diseases or syndromic conditions. Incidences are more common in European and Asian descent. The first line of treatment commonly practiced is surgery to create an aesthetically normal functioning hand. In this report, we present a case of bilateral hand polydactyly in a 2-year 6-month-old boy of Asian descent. No other abnormalities or malformations were observed elsewhere in his body. He is otherwise a healthy boy with no family history of malformations. The pattern is not consistent with any syndromic disease. He subsequently underwent surgical resection of the extra digits and a follow-up review showed normal function of the hands without contracture and other complications of the surgical site.
PubMed: 38778910
DOI: 10.1177/2050313X241255244 -
Frontiers in Medicine 2023As the only hospital-based national surveillance spot of birth defects (BDs) in Changzhou city located in the economically developed eastern part of China, Changzhou...
OBJECTIVE
As the only hospital-based national surveillance spot of birth defects (BDs) in Changzhou city located in the economically developed eastern part of China, Changzhou Maternal and Child Health Care Hospital has encountered serious challenges in BD prevention. This study aimed to describe the epidemiology of total BDs born in the hospital from 2014 to 2018.
METHODS
The data were collected from the national hospital-based birth defect surveillance system. BD prevalence was calculated by Poisson distribution. Trends of prevalence and the associations regarding information with BDs were analyzed by Poisson regression.
RESULTS
The reported prevalence of total BDs was 313.92 (95% confidence interval [CI]: 299.59-328.76) per 10,000 perinatal infants (PIs), while the perinatal prevalence of BD was 160.19 (95% CI: 150.00-170.89) per 10,000 PIs. A remarkable uptrend in the prevalence of BDs was noticed with a prevalence rate ratio (PRR) of 1.09 (95% CI: 1.04-1.14) and 1.13 (95% CI: 1.09-1.16), respectively. Congenital heart disease (CHD), cleft lip with or without cleft palate (CL/P), congenital malformation of the kidney (CMK), polydactyly, Down syndrome (DS), cystic hygroma, neural tube defect (NTD), and congenital talipes equinovarus (CTE) were common types of total BDs. Mothers living in the urban area (PRR = 1.67, 95% CI:1.50-1.87), male fetuses (PRR = 1.16, 95% CI: 1.05-1.28), and maternal age younger than 20 (PRR = 2.28, 95% CI: 1.60-3.25) and 25 years (PRR = 1.41, 95% CI: 1.22-1.63) or older than 35 years (PRR = 1.18, 95% CI: 1.00-1.40) were risk factors for BD occurrence.
CONCLUSION
The reported prevalence of total BDs was nearly two times higher than the perinatal prevalence of BDs in PIs, and the ranks of total BDs and BDs in PIs were different. Mothers living in the urban area, male fetuses, and maternal ages younger than 25 or older than 35 years were risk factors for BD incidence. Thus, improving prenatal examination technology, expanding the surveillance time quantum of BDs, and keeping maternal health may be warranted.
PubMed: 37766918
DOI: 10.3389/fmed.2023.1138946 -
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