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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 -
Journal of Pediatric Orthopedics Apr 2023Congenital synostosis of the knee is a rare condition with limited data on treatment options and outcomes. This study reports clinical findings, treatment approach, and...
BACKGROUND
Congenital synostosis of the knee is a rare condition with limited data on treatment options and outcomes. This study reports clinical findings, treatment approach, and surgical/clinical outcomes for congenital synostosis of the knee.
METHODS
An institutional review board-approved retrospective review of patients with congenital synostosis of the knee presenting to 2 institutions between 1997 and 2021 was performed.
RESULTS
Eight patients (13 knees) with a median follow-up of 11.3 years (3.3 to 17 y) were included. Seven patients had associated syndromes. Patients presented with an average knee flexion deformity of 100° (range 60 to 130°) and delayed walking ability. Seven patients had associated upper extremity hypoplasia/phocomelia. The average age at the index surgery was 4.3 years (range 1.2 to 9.2 y). Synostosis resection with gradual deformity correction was performed in most patients. An attempt was made at a mobile knee in some patients, but all went on to knee fusion. Mean flexion deformity at final follow-up was 11.6° (range: 0 to 40°) and 5 limbs were fused in full extension. Mean limb length discrepancy at final follow-up was 6.8 cm (range: 0 to 8 cm). All patients maintained their improved ambulation status at final follow-up. Twenty-two complications were identified.
CONCLUSIONS
Reliable correction of the deformity associated with congenital knee synostosis was achieved at a median follow-up of 11 years. Importantly, all patients maintained their improved ambulation at final follow-up. This is the largest study on patients with congenital knee synostosis and outlines a reconstructive approach to improve ambulatory status.
LEVEL OF EVIDENCE
Level IV.
Topics: Humans; Infant; Child, Preschool; Child; Osteotomy; Lower Extremity; Knee Joint; Synostosis; Arthrodesis; Retrospective Studies; Contracture; Treatment Outcome
PubMed: 36791408
DOI: 10.1097/BPO.0000000000002356 -
Prosthetics and Orthotics International Feb 2023The likelihood of patellar instability and consequently, risk of patellar dislocations is higher in those with anatomical abnormalities. Fibular hemimelia is a...
The likelihood of patellar instability and consequently, risk of patellar dislocations is higher in those with anatomical abnormalities. Fibular hemimelia is a congenital disorder resulting in partial or full absence of the fibula, often with absence of the lateral and cruciate ligaments, although this patient group rarely undergoes ligament reconstruction. There is potential for adverse outcomes, in the longer term, including, possible increased risk of patellar dislocation and pain in the knee and hip. We aim to investigate the potential risk of spontaneous, unprovoked patellar dislocation among patients with fibular hemimelia, through a review of medical records and radiological investigations. All patients with a diagnosis of fibular hemimelia were included (n = 25), regardless of ultimate approach to management. Tibiofemoral angle measurement and Caton-Deschamps indices were calculated where suitable radiology was available, to better establish extent of potential patellar instability. All the patients with normal Caton-Deschamps indices had only partial fibular absence, although this does not detract from absence or hypoplasia of the anterior cruciate ligament, as a risk factor for patellar dislocation by predisposing to anterior tibial translation. Notably, of the three patients with increased Caton-Deschamps indices, two had complete fibular absence and underwent definitive amputation surgery at age 18 months and 3 years, respectively. Ultimately, this was a young patient group and on-going follow-up might yield better understanding of knee stability. Maintaining a well-aligned lower limb throughout growth might be protective even in the presence of anatomical abnormalities. This article mainly aims to raise awareness among prosthetic and orthotic professionals regarding the increased risk of patella dislocations.
Topics: Humans; Infant; Anterior Cruciate Ligament; Ectromelia; Fibula; Joint Instability; Patella; Patellar Dislocation; Patellofemoral Joint; Tibia
PubMed: 36791384
DOI: 10.1097/PXR.0000000000000154 -
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 -
The Annals of Pharmacotherapy Oct 2023This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor... (Review)
Review
OBJECTIVE
This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the treatment of smallpox.
DATA SOURCES
A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms , and .
STUDY SELECTION AND DATA EXTRACTION
Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir.
DATA SYNTHESIS
Two surrogate animal models were included in the Food and Drug Administration's (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo.
CONCLUSIONS
Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.
Topics: Humans; Rabbits; Animals; Mice; Smallpox; Hematopoietic Stem Cell Transplantation; Antiviral Agents; Disease Models, Animal; Variola virus; Cytosine; Cytomegalovirus
PubMed: 36688308
DOI: 10.1177/10600280231151751 -
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