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Molecular Genetics & Genomic Medicine Jun 2023Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene....
OBJECTIVE
Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene. Cardinal clinical manifestations are pre- and postnatal growth retardation and craniofacial and limb malformations. Here, we report RBS in a Chinese adolescent with novel biallelic ESCO2 variations and complex cerebrovascular diseases.
METHODS
Medical history, neurological examinations, neuroimaging, and pathology were collected in the proband and the family. Whole exome sequencing (WES) with copy number variation analysis was performed to screen for genetic variations.
RESULTS
The clinical features of the proband were craniofacial and limb malformations together with complex cerebrovascular diseases. She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old. Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts. Brain histopathology revealed angiomatous changes and perivascular cysts suggesting chronic small cerebral vasculopathy. Whole exome sequencing (WES) identified novel biallelic variations in the ESCO2 gene (c.1220A>T, p.H407L and c.1562delC, p.A521fs).
CONCLUSIONS
We describe complex cerebrovascular diseases in Roberts syndrome caused by novel ESCO2 biallelic variations. This case expands not only the cerebral involvement in Roberts syndrome but also the disease spectrum of the neuroimaging triad with leukoencephalopathy, calcifications, and cysts.
Topics: Craniofacial Abnormalities; Humans; Female; Adolescent; Acetyltransferases; Chromosomal Proteins, Non-Histone; East Asian People; Cerebrovascular Disorders
PubMed: 37002187
DOI: 10.1002/mgg3.2177 -
International Medical Case Reports... 2023Phocomelia is an uncommon congenital condition in which the hand or foot are normal or almost normal but the proximal section of the limb - the humerus or femur, radius...
INTRODUCTION
Phocomelia is an uncommon congenital condition in which the hand or foot are normal or almost normal but the proximal section of the limb - the humerus or femur, radius or tibia, ulna or fibula -_is missing or noticeably hypoplastic. It refers to how the patient's limbs resemble marine creatures' flippers and its prevalence is 0.62 in 100,000 births.
CASE
We present a 15-min-old male neonate born to a para-four mother who did not remember her LNMP but claimed to be amenorrheic for the past nine months. The mode of delivery was by cesarean section to extract alive neonate weighing 2.01 kg with APGAR scores of 5 and 6 at first and fifth minutes, respectively. The neonate did not cry and was resuscitated for five minutes. He was then transferred to neonatal intensive care unit for further management and investigations. His vital signs were pulse rate 160 beats per minute, respiratory rate 70 breaths per minute, temperature 33.4 degrees centigrade and saturation was 60% off oxygen. On HEENT anterior fontanelle measures 2 cm by 2 cm and has micrognathia and short neck. On the respiratory system, there were intercostal and subcostal retractions, labored breathing and grunting. On the musculoskeletal system there is bilateral upper extremity shortening, the right lower limb was normal in position and structure, the left leg rotated inward (bent in medially) at the knee joint and foot was normal in structure.
CONCLUSION
Phocomelia is a rare congenital anomaly in which the hand or foot are directly attached to the trunk. Ultrasonography should be done as early as possible to identify fetal anomalies in order to plan subsequent management.
PubMed: 36942046
DOI: 10.2147/IMCRJ.S401298 -
The Journal of Hand Surgery, European... Dec 2023In this study, we studied historical case notes to examine nomenclature of congenital upper limb anomalies and explore the changes in terminologies over time. Original...
In this study, we studied historical case notes to examine nomenclature of congenital upper limb anomalies and explore the changes in terminologies over time. Original diagnoses were reclassified according to previously published classifications and the most recent Oberg, Manske and Tonkin system. Two hundred and thirty-eight case notes were obtained from the period 1961-1991. Hand plate malformations where the diagnosis was obvious or traumatic defects, were excluded. Eighty-six cases (106 extremities) were finally included where an ambiguous diagnosis, such as 'congenital absence' was initially given. None of the re-classifications matched the original diagnoses except for cleft hand and radial dysplasia ( = 31). Eighteen phocomelia-type limbs were re-classifiable when seen as a continuum of longitudinal deficiency, but not as an intercalary deficit. This study provided further insights into the evolving nature of nomenclature in congenital upper limb anomalies, especially for the condition of phocomelia. IV.
Topics: Humans; Upper Extremity Deformities, Congenital; Ectromelia; Hand Deformities, Congenital; Syndrome; Upper Extremity
PubMed: 36927201
DOI: 10.1177/17531934231160400 -
SAGE Open Medical Case Reports 2023The treatment of osteoarthritis in patients with phocomelia with total knee arthroplasty is challenging due to the unusual anatomy and severe deformities. The authors...
The treatment of osteoarthritis in patients with phocomelia with total knee arthroplasty is challenging due to the unusual anatomy and severe deformities. The authors present a case of phocomelia caused by thalidomide with end-stage osteoarthritis and grossly medialized patella. The patient was treated with a cemented constrained non-hinged prosthesis and patelloplasty. Six months later, the patient had complete relief of pain and was able to walk without walking assistance. To our knowledge, total knee replacement in a patient with phocomelia caused by thalidomide has not been described in literature.
PubMed: 36798679
DOI: 10.1177/2050313X231154635 -
Polish Journal of Pathology : Official... 2022The mermaid syndrome, also known as sirenomelia, is considered an extremely rare congenital developmental disorder characterized by anomalies of the lower spine and...
The mermaid syndrome, also known as sirenomelia, is considered an extremely rare congenital developmental disorder characterized by anomalies of the lower spine and lower limbs. Affected babies are born with partial or total leg fusion. Sirenomelia is thought to affect one in every 60,000 to 100,000 infants. We report a case of sirenomelia occurring in a 28-year-old multiparous woman, a heavy smoker with gestational diabetes. In the other 5 pregnancies, however, she gave birth to normal babies. The post mortem examination completed the diagnosis, revealing also multiple malformations of several systems: respiratory, gastro-intestinal, genito-urinary and cardiovascular. In our full term neonate case with grade VI sirenomelia, the presence of a single umbilical artery plus the abdominal aorta with an aberrant trajectory that ends in the umbilical cord differentiates this condition from caudal regression syndrome and also explains the under-development of pelvic organs (secondary to vascular steal phenomena).
Topics: Pregnancy; Female; Infant, Newborn; Humans; Adult; Ectromelia; Autopsy; Abnormalities, Multiple
PubMed: 36734442
DOI: 10.5114/pjp.2022.124494 -
Acta Naturae 2022The spread of the monkeypox virus infection among humans in many countries outside of Africa, which started in 2022, is now drawing the attention of the medical and...
The spread of the monkeypox virus infection among humans in many countries outside of Africa, which started in 2022, is now drawing the attention of the medical and scientific communities to the fact that immunization against this infection is sorely needed. According to current guidelines, immunization of people with the first-generation smallpox vaccine based on the vaccinia virus (VACV) LIVP strain, which is licensed in Russia, should be performed via transepidermal inoculation (skin scarification, s.s.). However, the long past experience of using this vaccination technique suggests that it does not ensure virus inoculation into patients' skin with enough reliability. The procedure of intradermal (i.d.) injection of a vaccine can be an alternative to s.s. inoculation. The effectiveness of i.d. vaccination can depend on the virus injection site on the body. Therefore, the aim of this study was to compare the development of the humoral and cellular immune responses in BALB/c mice immunized with the LIVP VACV strain, which was administered either by s.s. inoculation or i.d. injection into the same tail region of the animal. A virus dose of 105 pfu was used in both cases. ELISA of serum samples revealed no significant difference in the dynamics and level of production of VACV-specific IgM and IgG after i.d. or s.s. vaccination. A ELISpot analysis of splenocytes from the vaccinated mice showed that i.d. administration of VACV LIVP to mice induces a significantly greater T-cell immune response compared to s.s. inoculation. In order to assess the protective potency, on day 45 post immunization, mice were intranasally infected with lethal doses of either the cowpox virus (CPXV) or the ectromelia virus (ECTV), which is evolutionarily distant from the VACV and CPXV. Both vaccination techniques ensured complete protection of mice against infection with the CPXV. However, when mice were infected with a highly virulent strain of ECTV, 50% survived in the i.d. immunized group, whereas only 17% survived in the s.s. immunized group. It appears, therefore, that i.d. injection of the VACV can elicit a more potent protective immunity against orthopoxviruses compared to the conventional s.s. technique.
PubMed: 36694907
DOI: 10.32607/actanaturae.11857 -
Journal of Virology Feb 2023Receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL) are proteins that are critical for necroptosis, a mechanism of...
Receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL) are proteins that are critical for necroptosis, a mechanism of programmed cell death that is both activated when apoptosis is inhibited and thought to be antiviral. Here, we investigated the role of RIPK3 and MLKL in controlling the Orthopoxvirus ectromelia virus (ECTV), a natural pathogen of the mouse. We found that C57BL/6 (B6) mice deficient in RIPK3 () or MLKL () were as susceptible as wild-type (WT) B6 mice to ECTV lethality after low-dose intraperitoneal infection and were as resistant as WT B6 mice after ECTV infection through the natural footpad route. Additionally, after footpad infection, mice, but not mice, endured lower viral titers than WT mice in the draining lymph node (dLN) at three days postinfection and in the spleen or in the liver at seven days postinfection. Despite the improved viral control, mice did not differ from WT mice in the expression of interferons or interferon-stimulated genes or in the recruitment of natural killer (NK) cells and inflammatory monocytes (iMOs) to the dLN. Additionally, the CD8 T-cell responses in and WT mice were similar, even though in the dLNs of mice, professional antigen-presenting cells were more heavily infected. Finally, the histopathology in the livers of and WT mice at 7 dpi did not differ. Thus, the mechanism of the increased virus control by mice remains to be defined. The molecules RIPK3 and MLKL are required for necroptotic cell death, which is widely thought of as an antiviral mechanism. Here we show that C57BL/6 (B6) mice deficient in RIPK3 or MLKL are as susceptible as WT B6 mice to ECTV lethality after a low-dose intraperitoneal infection and are as resistant as WT B6 mice after ECTV infection through the natural footpad route. Mice deficient in MLKL are more efficient than WT mice at controlling virus loads in various organs. This improved viral control is not due to enhanced interferon, natural killer cell, or CD8 T-cell responses. Overall, the data indicate that deficiencies in the molecules that are critical to necroptosis do not necessarily result in worse outcomes following viral infection and may improve virus control.
Topics: Animals; Mice; Ectromelia virus; Ectromelia, Infectious; Interferons; Mice, Inbred C57BL; Necroptosis; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 36651749
DOI: 10.1128/jvi.01945-22 -
Viruses Dec 2022In west and central Africa, monkeypox occurs mainly in older children, adolescents and young adults. In two large epidemiology studies of monkeypox outbreaks, the... (Review)
Review
In west and central Africa, monkeypox occurs mainly in older children, adolescents and young adults. In two large epidemiology studies of monkeypox outbreaks, the investigators observed a sizable number of coinfections of chickenpox (varicella) and monkeypox. Based on a review of the literature, we propose that chickenpox (human herpesvirus-3 infection) is a risk factor for acquisition of monkeypox infection. Our hypothesis states that the chickenpox skin lesion provides an entry site for the monkeypox virus, which is harbored on a fomite in the environment of the patient. The fact that monkeypox can enter via a scratch or abrasion is a known mechanism of spread for three other poxviruses, including mousepox (ectromelia), orf and molluscum contagiosum. There are many similarities in pathogenesis between certain poxviruses and chickenpox, including a viremia with a cellular stress response leading to high levels of the IL-6 cytokine. One very revealing observation in the two epidemiology studies was that the number of pox as well as the severity of disease in children with chickenpox and monkeypox coinfection was not greater than found in children with monkeypox alone. Based on the above observations, we conclude that, when chickenpox precedes monkeypox, priming of the immune system by the earlier chickenpox infection moderates the severity of the secondary infection with monkeypox. This conclusion also has important public health implications about chickenpox surveillance.
Topics: Adolescent; Young Adult; Humans; Child; Chickenpox; Mpox (monkeypox); Coinfection; Herpesvirus 3, Human; African People
PubMed: 36560805
DOI: 10.3390/v14122800 -
Microorganisms Dec 2022Amidst the ongoing monkeypox outbreak, global awareness has been directed towards the prevention of viral transmission and case management, with the World Health... (Review)
Review
Amidst the ongoing monkeypox outbreak, global awareness has been directed towards the prevention of viral transmission and case management, with the World Health Organization declaring the outbreak a public health emergency of international concern. Monkeypox virus is one of several species in the Orthopoxvirus genus, with other species of the genus including the variola, cowpox, mousepox, camelpox, raccoonpox, skunkpox, and volepox viruses. Although the nomenclature of these species is based on the animal host from which they were originally isolated, transmission from animals to humans has been reported with several species. The progression of disease, following an incubation period, typically consists of a prodromal phase with systemic flu-like symptoms. Various organ systems may be affected in addition to the formation of pathognomonic skin lesions. As monkeypox poses a continued public health concern, the ophthalmic sequelae of monkeypox virus, especially those leading to vision loss, warrant consideration as well. This review provides a comprehensive summary of the ophthalmic implications of poxviruses in clinical and laboratory settings reported in the literature, as well as areas of unmet need and future research.
PubMed: 36557740
DOI: 10.3390/microorganisms10122487 -
ELife Dec 2022Axin1 is a key regulator of canonical Wnt signaling pathway. Roles of Axin1 in skeletal development and in disease occurrence have not been fully defined. Here, we...
Axin1 is a key regulator of canonical Wnt signaling pathway. Roles of Axin1 in skeletal development and in disease occurrence have not been fully defined. Here, we report that Axin1 is essential for lower limb development. Specific deletion of in limb mesenchymal cells leads to fibular hemimelia (FH)-like phenotype, associated with tarsal coalition. Further studies demonstrate that FH disease is associated with additional defects in knockout (KO) mice, including decreased osteoclast formation and defects in angiogenesis. We then provide in vivo evidence showing that Axin1 controls limb development through both canonical β-catenin and BMP signaling pathways. We demonstrate that inhibition of β-catenin or BMP signaling could significantly reverse the FH phenotype in mice. Together, our findings reveal that integration of β-catenin and BMP signaling by Axin1 is required for lower limb development. Defect in Axin1 signaling could lead to the development of FH disease.
Topics: Mice; Animals; Ectromelia; beta Catenin; Wnt Signaling Pathway; Phenotype; Mice, Knockout; Axin Protein
PubMed: 36541713
DOI: 10.7554/eLife.80013