-
Psychiatric Genetics Jun 2024Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with...
BACKGROUND
Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with neurodevelopmental disorders with microcephaly, arthrogryposis, and structural brain anomalies. SMPD4 encodes a sphingomyelinase that hydrolyzes sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes.
MATERIALS AND METHODS
For the efficient prenatal diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using whole-exome analysis is required. A physical examination of the parents was performed. Karyotype and whole-exome analysis were performed for the fetus and the parents.
RESULTS
A fetus with microcephaly and arthrogryposis; biallelic null variants (c.387-1G>A; Chr2[GRCh38]: g.130142742_130202459del) were detected by whole-exome sequencing (WES). We have reported for the first time the biallelic loss-of-function mutations in SMPD4 in patients born to unrelated parents in China.
CONCLUSION
WES could replace chromosomal microarray analysis and copy number variation sequencing as a more cost-effective genetic test for detecting CNVs and diagnosing highly heterogeneous conditions.
Topics: Humans; DNA Copy Number Variations; Exome Sequencing; Female; Prenatal Diagnosis; Sphingomyelin Phosphodiesterase; Polymorphism, Single Nucleotide; Pregnancy; Microcephaly; Heterozygote; Arthrogryposis; Male; Exome; Mutation; Neurodevelopmental Disorders
PubMed: 38690959
DOI: 10.1097/YPG.0000000000000369 -
Journal of Pediatric Orthopedics Apr 2024The Ponseti serial casting method is the method of choice in treating children with congenital clubfeet. The arthrogrypotic clubfoot has traditionally been considered...
INTRODUCTION
The Ponseti serial casting method is the method of choice in treating children with congenital clubfeet. The arthrogrypotic clubfoot has traditionally been considered challenging to treat, with higher rates of recurrence and the need for more corrective surgeries. However, initial reports have found promising results in using the Ponseti method to treat arthrogrypotic feet. This study aims to compare the outcomes of idiopathic versus arthrogrypotic clubfeet following initial treatment with the Ponseti serial casting method.
METHODS
A retrospective review of medical records from a single institution was conducted. Data was collected from children ages 0 to 18 with idiopathic or arthrogrypotic clubfoot treated from 2002 to 2022 with Ponseti-style serial casting with a minimum 2-year follow-up. Recurrence was defined as the need for additional casting or subsequent surgeries following initial correction. Data was collected on relevant patient demographics, previous treatment, casting records, Achilles tenotomies, and surgical treatments.
RESULTS
A total of 352 patients (546 feet) met inclusion criteria. In all, 334 idiopathic and 18 arthrogrypotic patients were analyzed with an average follow-up duration of 3.4 and 4.2 years, respectively. Twelve patients had distal arthrogryposis, and 6 had amyoplasia. In all, 93.4% of idiopathic and 72.2% of arthrogrypotic patients successfully achieved correction with Ponseti casting and Achilles tenotomy. Recurrence rates were significantly higher in the arthrogrypotic group at 83.3% compared with 44.6% in the idiopathic group (P=0.001). A posterior or posterior medial release was performed in 35.0% of idiopathic and 66.7% arthrogrypotic feet.
CONCLUSIONS
We report the largest series of arthrogrypotic clubfeet treated by Ponseti casting to the best of our knowledge. In contrast to earlier reports, our investigation underscores that while the Ponseti method may be able to secure initial correction in arthrogrypotic clubfeet, on average, at a 3-year follow-up, the prognosis is less favorable. These patients exhibit higher recurrence and often require operative treatment. Notably, a posterior medial release may eventually be needed in up to 6 of 10 patients.
LEVEL OF EVIDENCE
Level III-therapeutic studies-investigating the results of treatment.
PubMed: 38689454
DOI: 10.1097/BPO.0000000000002715 -
Neurology. Genetics Jun 2024To report novel biallelic variants in a family presenting with pure hereditary spastic paraparesis.
OBJECTIVES
To report novel biallelic variants in a family presenting with pure hereditary spastic paraparesis.
METHODS
Two affected sisters presented with unsolved hereditary spastic paraparesis and underwent clinical and imaging assessments. This was followed by short-read next-generation sequencing.
RESULTS
Analysis of next-generation sequencing data uncovered compound heterozygous variants in (NM_058004.4: c.[3883C>A];[5785A>C]; p.[(His1295Asn);(Thr1929Pro)]. Using ACMG guidelines, both variants were classified as likely pathogenic.
DISCUSSION
Here, next-generation sequencing revealed 2 novel compound heterozygous variants in the phosphatidylinositol 4-kinase alpha gene () in 2 sisters presenting with progressive pure hereditary spastic paraparesis. Pathogenic variants in have previously been associated with a spectrum of disorders including autosomal recessive perisylvian polymicrogyria, with cerebellar hypoplasia, arthrogryposis, and pure spastic paraplegia. The cases presented in this study expand the phenotypic spectrum associated with variants and contribute new likely pathogenic variants for testing in patients with otherwise unsolved hereditary spastic paraparesis.
PubMed: 38685974
DOI: 10.1212/NXG.0000000000200152 -
Journal of Pediatric Orthopedics Apr 2024Congenital dislocation of the knee (CDK) may be idiopathic or associated with another condition, such as Larsen syndrome or arthrogryposis. Surgical reduction of type-3...
BACKGROUND
Congenital dislocation of the knee (CDK) may be idiopathic or associated with another condition, such as Larsen syndrome or arthrogryposis. Surgical reduction of type-3 dislocation may require quadricepsplasty (QP) or femoral diaphyseal shortening (FS). Because it is unknown which treatment is more effective, we evaluated long-term outcomes using patient-reported questionnaires and gait analysis, comparing results by surgery type and underlying diagnosis.
METHODS
Twelve patients (mean age, 19 mo) were treated surgically for CDK from 1985 to 2015 and studied 9 to 30 years postoperatively. Three participants had idiopathic CDK, 5 had Larsen syndrome, and 4 had arthrogryposis. Eleven knees underwent QP and 7 underwent FS. Participants were evaluated in our movement science laboratory and completed patient-reported outcome questionnaires. Data were compared with healthy, age-matched control values at the same visit.
RESULTS
Surgically treated knees had less flexion during swing (P<0.01), less overall motion (P<0.01), greater coronal instability (P<0.04), and slower gait (P<0.01) compared with controls. QP knees had more instability in midstance (P=0.03) and less flexion during gait compared with FS knees, less sagittal power generation than controls (P<0.01), and trended toward lower scores on Knee Injury and Osteoarthritis Outcome and Lysholm Knee Questionnaires than FS patients did. The idiopathic group had the gait most similar to that of controls, followed by the Larsen syndrome group and then the arthrogryposis group. The idiopathic group also had a better UCLA Activity Score (P=0.03) than the arthrogryposis group did.
CONCLUSIONS
Surgical treatment of type-3 CDK will not likely restore normal knee function, suggesting teratologic joint abnormality. In this small series, FS produced better gait mechanics and patient-reported outcomes compared with QP. Not surprisingly, patients with idiopathic CDK had better outcomes than those with a syndromic diagnosis, likely related to having only a single joint affected.
LEVEL OF EVIDENCE
Level III.
PubMed: 38666580
DOI: 10.1097/BPO.0000000000002711 -
Journal of Pediatric Orthopedics Apr 2024The Oberg-Manske-Tonkin (OMT) classification established excellent reliability scores in several validation studies. However, one study published in 2022 found much...
BACKGROUND
The Oberg-Manske-Tonkin (OMT) classification established excellent reliability scores in several validation studies. However, one study published in 2022 found much lower scores in a subanalysis of their sample when very simple anomalies were excluded. Our study assessed the reliability of the OMT among physicians with a different background, all involved in congenital hand anomaly care, and analyzed codes with less agreement. Time required for classification was recorded to give an indication on its usability.
METHODS
One hundred digital cases were classified twice with a minimal 1-month time interval, with the use of the 2020 version of the OMT. Two pediatric hand surgeons, 2 rehabilitation specialists, and 2 plastic surgery residents participated in this reliability analysis. The use of multiple codes was allowed. The intra- and interrater reliability was assessed for all 15 possible rater couples by calculating percentage of agreement. Cohen's kappa was calculated along with a 95% confidence interval. For the analysis of individual codes with less agreement, we calculated positive agreement with the use of a summed agreement table. Time necessary for classification was documented in seconds.
RESULTS
The inter- and intrarater agreement was moderate with a mean Cohen's kappa of 0.45 and 0.60 retrospectively. On average, 39 seconds per case were necessary for the first and 24 seconds for the second rating. Background did not influence the level of agreement. Lowest agreement levels (ie, lowest positive agreement) were observed with all the arthrogryposis multiplex congenita subgroups, the "other" subgroups of isolated congenital contractures, syndromic syndactyly, and synpolydactyly. Codes commonly used interchangeably were symbrachydactyly and transverse deficiency and the distinction between these anomalies of only the hand or the entire upper limb; symbrachydactyly and brachydactyly; and camptodactyly and distal arthrogryposis.
CONCLUSIONS
Our study showed a moderate reliability, emphasizing the complexity of this heterogeneous patient population. Despite its imperfections, the OMT remains the best and most versatile classification tool at hand. Its main purpose may lie in contributing to a universal language for research.
LEVEL OF EVIDENCE
I.
PubMed: 38666494
DOI: 10.1097/BPO.0000000000002705 -
Respirology Case Reports Apr 2024This case highlights arthrogryposis multiplex congenita (AMC) as a rare cause of hypercapnoeic respiratory failure and airway obstruction in adults and emphasizes the...
This case highlights arthrogryposis multiplex congenita (AMC) as a rare cause of hypercapnoeic respiratory failure and airway obstruction in adults and emphasizes the usage of leak-port in tracheostomy-NIV (non-invasive-ventilation) specially in resource poor setting when the tracheostomy-NIV mask is unavailable.
PubMed: 38660342
DOI: 10.1002/rcr2.1361 -
Veterinary Research Communications Apr 2024Neosporosis and toxoplasmosis are important parasitic causes of abortions in small ruminants. This study verified the occurrence of these diseases in sheep fetuses from...
Neosporosis and toxoplasmosis are important parasitic causes of abortions in small ruminants. This study verified the occurrence of these diseases in sheep fetuses from Santa Catarina State, Southern Brazil from 2015 to 2022. Sheep fetuses were necropsied with organ sampling for histopathology, and polymerase chain reaction (PCR) for Neospora caninum and Toxoplasma gondii using the Nc5 and SAG2 targets, respectively, in frozen brain tissue. Microbiological culture and RT-PCR for Pestivirus were conducted to discard other abortion causes. One positive fetus for toxoplasmosis was genotyped using multiplex multilocus nested PCR-RFLP (Mn-PCR-RFLP) with ten genetic markers. Fifty-five sheep fetuses were evaluated, with 10 (18.2%) cases of neosporosis and 7 (12.7%) cases of toxoplasmosis, comprising six and four flocks, respectively. Macroscopically, neosporosis abortions exhibited fetal mummification, maceration, and arthrogryposis. Toxoplasmosis abortions showed fetal mummification and maceration. The neosporosis abortions included lymphoplasmacytic myositis (70%; 7/10) and myocarditis (60%; 6/10), in addition to necrotizing encephalitis and gliosis (50%; 5/10). Toxoplasmosis abortions included lymphoplasmacytic necrotizing encephalitis (71.4%; 5/7), lymphoplasmacytic myositis (42.8%, 3/7), and myocarditis (14.3%; 1/7). Through PCR, N. caninum and T. gondii were detected in 6 (60%) and 5 (71.4%) fetuses, respectively. In one fetus, T. gondii genotyping was conducted, which was characterized as atypical genotype ToxoDB #98. All of the cases were negative for Pestivirus and bacterial agents. This study establishes the occurrence of these diseases as causes of abortions, malformations, mummification, and fetal maceration in sheep, with the characterization of an atypical T. gondii genotype in one of the fetuses.
PubMed: 38653939
DOI: 10.1007/s11259-024-10390-4 -
Ultrasound in Obstetrics & Gynecology :... Apr 2024The finding of an abdominal cyst during pregnancy has an estimated prevalence of 1 in 1000 pregnancies, mostly in second and third trimester. The detection of a fetal... (Review)
Review
OBJECTIVES
The finding of an abdominal cyst during pregnancy has an estimated prevalence of 1 in 1000 pregnancies, mostly in second and third trimester. The detection of a fetal abdominal cyst during the first trimester scan is a rare event, whose natural history and prognosis are often unknown and unpredictable as these anomalies can be related to various underlying conditions and originate from different structures. The aim of this study is to evaluate the outcome of fetal abdominal cysts detected in the first trimester in order to understand their possible clinical significance and to offer the proper management according to the available data.
METHODS
We present a case report of a first trimester fetal abdominal cyst detected with subsequent diagnosis of congenital multiple arthrogryposis and we performed a systematic review of the literature to identify the incidence and the outcomes of similar cases. The systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and registered with PROSPERO (CRD42023491729).
RESULTS
A total of 60 cases of first trimester abdominal cysts were included. Of these, 35% were associated with concurrent or late onset structural anomalies, as in our case report, and 65% were isolated. In pregnancies with isolated fetal abdominal cysts, 56% had a completely normal outcome.
CONCLUSIONS
The finding of an abdominal cyst during the first trimester of pregnancy is in most cases an isolated event with a moderate to good prognosis but it could also be an early sign of other associated abnormalities, including arthrogryposis. Increased ultrasound surveillance and additional genetic testing to rule out possible associated anomalies are pivotal to assess the risk of adverse pregnancy outcomes and to provide appropriate counselling to the patient. This article is protected by copyright. All rights reserved.
PubMed: 38642342
DOI: 10.1002/uog.27663 -
American Journal of Obstetrics and... Apr 2024This study aimed to synthesize the existing evidence on perinatal outcomes after autologous cryopreserved ovarian tissue transplantation, concurrently identifying key... (Review)
Review
OBJECTIVE
This study aimed to synthesize the existing evidence on perinatal outcomes after autologous cryopreserved ovarian tissue transplantation, concurrently identifying key factors influencing these outcomes.
DATA SOURCES
A comprehensive search was performed on MEDLINE, Embase, and Cochrane Library databases to identify relevant studies on the effect of autologous cryopreserved ovarian tissue transplantation on perinatal outcomes from inception to October 22, 2023. Where there was missing information, the authors were contacted for updated data.
STUDY ELIGIBILITY CRITERIA
Observational studies, such as cohort studies, case series, and case reports that reported a live birth after autologous cryopreserved ovarian tissue transplantation, were considered eligible. Studies lacking data on women's demographic characteristics, autologous cryopreserved ovarian tissue transplantation procedure details, or perinatal outcomes were excluded. In addition, cases involving fresh or nonautologous transplantations and those addressing primary ovarian insufficiency were excluded.
METHODS
Two reviewers (M.E. and E.U.) independently performed the study selection, data extraction, and risk of bias assessment, and the results were then reviewed together. The PRISMA guidelines were followed, and the protocol was registered on PROSPERO (CRD42023469296).
RESULTS
This review included 58 studies composed of 122 women with 162 deliveries (154 singletons and 8 twins) after autologous cryopreserved ovarian tissue transplantation, resulting in 170 newborns. Of note, 83.6% of the women had a malignant disease. Moreover, most of these women (51.0%) were exposed to some form of chemotherapy before ovarian tissue cryopreservation. Of the 162 childbirths, 108 (66.7%) were conceived naturally, and 54 (33.3%) were conceived through assisted reproductive techniques. The birthweight of 88.5% of newborns was appropriate for gestational age, whereas 8.3% and 3.1% were small for gestational age and large for gestational age, respectively. The preterm birth rate was 9.4%, with the remaining being term deliveries. Hypertensive disorders of pregnancy were noted in 18.9% of women, including pregnancy-induced hypertension in 7.6%, preeclampsia in 9.4%, and hemolysis, elevated liver enzymes, and low platelet count in 1.9%. The incidences of gestational diabetes mellitus and preterm premature rupture of membranes were 3.8% for each condition. Neonatal anomalies were reported in 3 transplant recipients with 4 newborns: arthrogryposis, congenital cataract, and diaphragmatic hernia in a twin. Finally, among the recipients' characteristics, not receiving chemotherapy before ovarian tissue cryopreservation (odds ratio, 0.23; 95% confidence interval, 0.07-0.72; P=.012) and natural conception (odds ratio, 0.29; 95% confidence interval, 0.09-0.92; P=.035) were associated with a lower perinatal complication rate.
CONCLUSION
On the basis of low certainty evidence from observational studies, perinatal complication rates did not increase after autologous cryopreserved ovarian tissue transplantation compared with the general pregnant population, except for preeclampsia. This could be due to chemotherapy exposure, underlying medical conditions, and the common use of assisted reproductive techniques. Further larger studies are needed to explore the causes of increased preeclampsia incidence in autologous cryopreserved ovarian tissue transplantation pregnancies.
PubMed: 38621483
DOI: 10.1016/j.ajog.2024.04.012 -
Scientific Reports Apr 2024The primary objective of this study was to evaluate the prevalence of low femoral and lumbar spine bone mineral density (BMD) in adults with arthrogryposis multiplex...
The primary objective of this study was to evaluate the prevalence of low femoral and lumbar spine bone mineral density (BMD) in adults with arthrogryposis multiplex congenita (AMC). We performed a retrospective cohort analysis of adults with AMC who were enrolled in the French Reference Center for AMC and in the Pediatric and Adult Registry for Arthrogryposis (PARART, NCT05673265). Patients who had undergone dual-energy X-ray absorptiometry (DXA) and/or vitamin D testing were included in the analysis. Fifty-one patients (mean age, 32.9 ± 12.6 years) were included; 46 had undergone DXA. Thirty-two (32/51, 62.7%) patients had Amyoplasia, and 19 (19/51, 37.3%) had other types of AMC (18 distal arthrogryposis, 1 Larsen). Six patients (6/42, 14.3%) had a lumbar BMD Z score less than - 2. The mean lumbar spine Z score (- 0.03 ± 1.6) was not significantly lower than the expected BMD Z score in the general population. Nine (9/40, 22.5%) and 10 (10/40, 25.0%) patients had femoral neck and total hip BMD Z scores less than - 2, respectively. The mean femoral neck (- 1.1 ± 1.1) and total hip (- 1.2 ± 1.2) BMD Z scores in patients with AMC were significantly lower than expected in the general population (p < 0.001). Femoral neck BMD correlated with height (rs = 0.39, p = 0.01), age (rs = - 0.315, p = 0.48); total hip BMD correlated with height (rs = 0.331, p = 0.04) and calcium levels (rs = 0.41, p = 0.04). Twenty-five patients (25/51, 49.0%) reported 39 fractures. Thirty-one (31/36, 86.1%) patients had 25-hydroxyvitamin D levels less than 75 nmol/l, and 6 (6/36, 16.7%) had 25-hydroxyvitamin D levels less than 75 nmol/l. Adults with AMC had lower hip BMD than expected for their age, and they more frequently showed vitamin D insufficiency. Screening for low BMD by DXA and adding vitamin D supplementation when vitamin D status is insufficient should be considered in adults with AMC, especially if there is a history of falls or fractures.
Topics: Adult; Humans; Middle Aged; Young Adult; Abnormalities, Multiple; Absorptiometry, Photon; Arthrogryposis; Bone Density; Retrospective Studies; Vitamin D
PubMed: 38589451
DOI: 10.1038/s41598-024-58083-x