The First Patient with Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb Syndrome Caused by De Novo c.423+4916 T>C ZRS Variant: A Case Report.

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from "uncertain significance" to "likely pathogenic" according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype-genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS.

Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.

Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.

Outcomes of Simultaneous Lengthening and ACL Reconstruction in Fibular Hemimelia: A Retrospective Case Series.

Background: Fibular hemimelia is the most common congenital long bone deficiency. It is often associated with femoral and tibial deficiencies which result in a clinically evident leg length discrepancy. The primary soft tissue concern is ACL/PCL deficiency. If treatment includes bony lengthening, joint stability is imperative to avoid complications. In this study, we detail a novel technique for long bone lengthening and ACL reconstruction in a single, cohesive surgery. This consolidates the need for multiple procedures and offers improved limb length symmetry and knee stability for this patient population. Clinical outcomes of pediatric patients with hemimelia who underwent either femoral or tibial lengthening with PRECICE® nail and concomitant ACL reconstruction are presented. Methods: After IRB approval, we identified five patients with complex fibular hemimelia who underwent ACL reconstruction and concomitant lengthening with at least two years of follow-up. Two patients (40%) presented with congenital short femur, and three (60%) with congenital short tibia. In each case, ACL reconstruction and either femoral or tibial guided growth via PRECICE® nail were performed. Operative techniques involving both soft tissue and bony methodology are described in detail. Results: All patients had objective improvement in knee stability as assessed both intra and post operatively, as well as successful intermedullary lengthening without complications related to joint stability. Three patients had minor complications unrelated to joint stability that did not interfere with overall result. Conclusion: Fibular hemimelia associated with hypoplasia of bony and soft tissue structures can be successfully addressed with concomitant ligamentous reconstruction at the time of implantation of lengthening devices. This addresses knee instability and reduces both number of operative procedures and potential complications related to joint instability while pursuing bony lengthening. Level of Evidence: V.

Sirenomelia or mermaid syndrome with a cleft lip in a Tanzanian newborn: a case report.

BACKGROUND: Sirenomelia or sirenomelia sequence, also known as mermaid syndrome, is a rare congenital anomaly involving the caudal region of the body. The syndrome is characterized by partial or complete fusion of lower extremities, renal agenesis, absent urinary tract, ambiguous external genitalia, imperforate anus, and single umbilical artery. Sirenomelia is often associated with several visceral congenital malformations, rendering it invariably incompatible with extrauterine life. CASE PRESENTATION: We present the case of 22-year-old Black African woman who delivered a term newborn by caesarean section at a gestation age of 37 weeks due to obstructed labor with fetal distress. The newborn was a fresh stillbirth weighing 2100 g and had fusion of the lower extremities, a single upper limb, ambiguous genitalia, imperforate anus, and a cleft lip. The mother had made only two prenatal visits, at which she was found to be normotensive and normoglycemic. She was not screened for routine fetomaternal infections and missed supplementation for folic acid during the critical first trimester. She did not undergo any obstetric ultrasonography. The parents of the newborn were not close relatives and there was no family history of consanguinity. Further genetic testing was not performed due to lack of laboratory capacity, and post mortem examination was not permitted due to cultural taboo and restrictions relating to handling of deceased newborns. CONCLUSION: Sirenomelia is a rare congenital malformation with very poor prognosis. Specific interventions during pre-conception and early prenatal care are critical in the prevention of specific congenital anomalies. Early obstetric ultrasonography is invaluable for diagnosis of sirenomelia as well as counseling for possible termination of pregnancy.

Fibular hemimelia: reconstruction of difficult cases with tibial lengthening and ankle arthrodesis.

PURPOSE: Management of fibular hemimelia includes either prosthetic care with or without a suitable amputation or tibial lengthening. Many studies have documented the success of both procedures. Most parents of these children refuse an amputation or have no access to good prosthetic care. The author presents a limb-salvage procedure with tibial lengthening and ankle stabilization. METHODS: Twelve children of fibular hemimelia with 14 extremities had been subjected to limb lengthening after lateral leg release. To correct the valgus procurvatum, double oblique diaphyseal osteotomy (DODO) of the tibia was performed in 11 extremities. The age of the patients ranged from two to 15 years with the median of five years. All were male. The proposed procedure included three stages of loosening, lengthening, and stabilization with ankle arthrodesis at a later stage. RESULTS: All patients returned for follow-up for the first four years and had been walking on their sensate feet. With DODO followed by fixator/traction could straighten and lengthen the tibia simultaneously and correct the valgus procurvatum. Ankle stabilization provided stability and a plantigrade foot. A follow-up of six to 30 years with a median of ten years has been reported. CONCLUSION: A new procedure of loosening, lengthening, and stabilization of the leg with ankle arthrodesis has been proposed. A follow-up of 30 years with a median of ten years of the said procedure has been reported. The procedure provides a long-lasting plantigrade and painless foot that has sensation and proprioception. An amputation at any level has not been recommended.

Was thalidomide a placebo hypnotic?

Six decades ago the world learned that thalidomide, a seemingly non-toxic sedative and hypnotic, caused severe birth defects including the flipper-like deformity of the arms known as phocomelia. When thalidomide was tested against placebo by the trialist Louis Lasagna in 1960 (while the drug was banned from the U.S. marketplace), he found the 100-mg dosage equivalent to placebo, as well as greatly inferior to the 200-mg dosage, in producing sleep. Even as these findings were made known, a 100-mg dose of thalidomide was in general use as a sleep aid for pregnant women. It appears that unbeknownst to themselves, an untold number of pregnant women around the world who were prescribed thalidomide incurred the risks of a teratogen in return for the benefits of a sugar pill.

Radiological Insight into the Mermaid Syndrome: An Exploration of a Rare Anomaly.

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Impact of source water quality on total organic carbon and trihalomethane removal efficiency in a water treatment plant: A case study of Upper Awash, Ethiopia.

This study addresses the limited understanding of factors affecting the efficiency of water treatment plants in reducing trihalomethane (THM) formation through total organic carbon (TOC) removal, highlighting significant challenges in improving treatment effectiveness. The aim of this study was to examine the influence of water quality on the efficiency of water treatment plants to remove TOC and reduce THM formation. Linear regression and correlation analyses were conducted to examine the relationship between water quality parameters and THM concentrations. The results showed that there was a negative relationship between turbidity, metals, and TOC concentration with TOC removal efficiency. Positive correlations were found between parameters and the formation of THMs in water. Of these parameters, water temperature was observed to have relatively less influence on THM formation. It was observed that seasonal variations in water quality affect the efficiency of TOC removal and THM content in treated water. THM levels in chlorinated water were found to be within the permissible range of the World Health Organization's drinking water quality guidelines. However, it is still important to maintain continuous monitoring and take measures to reduce THMs. The model demonstrated a strong correlation (R2 = 0.906) between predicted and measured THM values.

Sirenomelia: An anatomical assessment and genetic sex determination of two cases.

The etiology of sirenomelia is currently unknown. Data are limited in comparing external and internal abnormalities using modern imaging technologies and molecular genetic analysis. The purpose of the current study was designed to compare external and internal anatomical defects in two cases of sirenomelia and Potter's sequence. Considered rare, Potter's sequence is a fetal disorder with characteristic features of bilateral renal agenesis, obstructive uropathy, atypical facial appearance, and limb malformations. The internal and external malformations of two term fetuses with sirenomelia and Potter's sequence were compared using assessment of external features, radiography and MRI on internal structures, and molecular genetic studies on sex determination. Data reveal that both fetuses were male and manifested with an overlapping but distinct spectrum of abnormalities. Principal differences were noted in the development of the ears, brain, urogenital system, lower limbs, pelvis, and vertebral column. Defects of the axial mesoderm are likely to underlie the abnormalities seen in both fetuses. The first one, which had only caudal defects, was found to have a spectrum of abnormalities most similar to those associated with more severe forms of the small pelvic outlet syndrome, although the structure and orientation of the sacrum and iliae were different from previously reported cases. The other had both caudal and cranial defects, and was most similar to those described in the axial mesodermal dysplasia syndrome. Defects associated with sirenomelia can be evaluated with standard gross anatomy examination, radiology, MRI, and modified PCR techniques to determine anatomical abnormalities and the sex of preserved specimens, respectively. Evidence indicated that sirenomelia could be developed via various etiologies.

The Frontal Phocomelia in a 3-Year-Old Girl.

Background: Phocomelia is a congenital limb deformity in which the proximal part of the upper or lower limb does not develop. Occasionally the malformed limb may be located ectopically. Case report: We present a frontal phocomelia in a three-year-old girl with right-hand phocomelia and thoracoschisis. The patient's arm was connected directly from the front of the chest, with a rudimentary thumb and two fingers. The truncated arm was not functional. The acromioclavicular joint was abnormal and ectopic, the limb articulated with the medial side of sternum. The thoracoschisis manifested as eventration of the right liver lobe and right side of chest wall. Conclusion: Ectopic phocomelia can be associated with thoracoschisis, it can be nonfunctional, and can articulate with the sternum.

Novel prosthesis with proximity sensor for upper extremity phocomelia.

We herein report on the application of a novel motorized prosthetic hand in a child with upper extremity phocomelia.

Simultaneous femoral and tibial lengthening for severe limb length discrepancy in fibular hemimelia.

BACKGROUND: Fibular Hemimelia (FH) is the most common longitudinal limb deficiency. Significant limb length discrepancy (LLD) will necessitate long treatment times and multiple settings to compensate for LLD when associated with femoral shortening. This study evaluates the outcome of simultaneous femoral and tibial lengthening using the Ilizarov frame. METHODS: This retrospective study included the cases of 12 children with severe limb length discrepancy caused by combined FH and ipsilateral femoral shortening from May 2015 to August 2022. The total LLD ranged from 7 to 14.5 cm. All patients underwent single-session femoral and tibial lengthening using the Ilizarov ring external fixator technique. Additional procedures were performed in the same setting, including Achilles tendon lengthening, fibular anlage excision, peroneal tendons lengthening, and iliotibial band release. Follow-up ranged from 2 to 4 years. RESULTS: The planned limb lengthening was achieved in ten cases (83%). No cases of joint subluxation or dislocation were encountered. No neurovascular injury has occurred during the treatment course. In all cases, the bone healing index was better on the femoral side than on the tibia. Poor regeneration and deformity of the tibia occurred in two cases (16.6%). CONCLUSION: Simultaneous femoral and tibial lengthening using the Ilizarov fixator is a relatively safe procedure with the result of correction of total LLD in one session in a shorter time and less morbidity.

Cardiomyopathy associated 5 (CMYA5) implicated as a genetic risk factor for radial hemimelia in Siamese cats.

OBJECTIVES: The present study aimed to determine the inheritance pattern and genetic cause of congenital radial hemimelia (RH) in cats. METHODS: Clinical and genetic analyses were conducted on a Siamese cat family (n = 18), including two siblings with RH. Radiographs were obtained for the affected kittens and echocardiograms of an affected kitten and sire. Whole genome sequencing was completed on the two cases and the parents. Genomic data were compared with the 99 Lives Cat Genome data set of 420 additional domestic cats with whole genome and whole exome sequencing data. Variants were considered as homozygous in the two cases of the siblings with RH and heterozygous in the parents. Candidate variants were genotyped by Sanger sequencing in the extended pedigree. RESULTS: Radiographs of the female kitten revealed bilateral absence of the radii and bowing of the humeri, while the male kitten showed a dysplastic right radius. Echocardiography suggested the female kitten had restrictive cardiomyopathy with a positive left atrial-to-aortic root ratio (LA:Ao = 1.83 cm), whereas hypertrophic cardiomyopathy was more likely in the sire, showing diastolic dysfunction using tissue Doppler imaging (59.06 cm/s). Twenty-two DNA variants were unique and homozygous in the affected kittens and heterozygous in the parents. Seven variants clustered in one chromosomal region, including two frameshift variants in cardiomyopathy associated 5 (CMYA5) and five variants in junction mediating and regulatory protein, P53 cofactor (JMY ), including a missense and an in-frame deletion. CONCLUSIONS AND RELEVANCE: The present study suggested an autosomal recessive mode of inheritance with variable expression for RH in the Siamese cat family. Candidate variants for the phenotype were identified, implicating their roles in bone development. These genes should be considered as potentially causal for other cats with RH. Siamese cat breeders should consider genetically testing their cats for these variants to prevent further dissemination of the suspected variants within the breed.

Outcomes of Limb Lengthening With Computer-assisted Hexapod External Fixators in the Treatment of Fibular Hemimelia.

BACKGROUND: Fibular hemimelia (FH) represents the most common deficiency of the long bones and is associated with multiple deformities. Reconstructive treatment with external fixators in FH restores normal lower extremity alignment and length with plantigrade feet for a balanced and effective gait. The aim of this study is to evaluate the outcomes of lower limb lengthening and simultaneous tri-plane deformity correction with a computer-assisted hexagonal external fixator in children with FH. METHODS: A retrospective review was performed for FH cases treated with a computer-assisted hexagonal external fixator in a tertiary referral center. Leg length discrepancy (LLD), interphyseal angles, tibiocalcaneal distances, healing index (HI), and callus shapes were analyzed for radiologic evaluation, and the Pediatric Quality of Life Inventory (PedsQL) was used for functional assessment. Limbs with HI <50 days/cm, PedsQL >75, and without regenerate fractures were considered successful lengthenings. RESULTS: Twenty-four limbs of 23 patients were included. The limbs were lengthened for a mean of 7.24 cm (range, 4.7 to 15.6). The initial LLD of 5.6 cm (range, 0.5 to 19 cm) increased to 1.7 cm (range, 0.1 to 6 cm), and the mean interphyseal angle was 12.7 degree (range, 1.5 to 54.2 degree), tibiocalcaneal distance was 0.85 cm (range, 0.1 to 1.7) at final follow-up. The most common regenerated bone morphology was cylindrical, as seen in 11 limbs (45.8%). The average PedsQL score was 83.5 (range, 69.5 to 96.7). Sixteen limbs (66.7%) had successful lengthening at their first, and 4 limbs (80%) had successful lengthening at their second surgeries. Seven limbs had complications requiring surgical intervention (29.1%), with 3 (12.5%) regenerate fractures after external fixators removal. CONCLUSIONS: Limb reconstruction with computer-assisted hexapod fixators is a successful and reliable option for the treatment of LLD in FH, and patients demonstrate good functional outcomes. Surgeons should be aware of potential complications and should utilize prophylactic measures when necessary. LEVELS OF EVIDENCE: Level III, retrospective comparative study.

Mermaid syndrome: Rare genetic anomaly.

Mermaid syndrome (Sirenomelia) is a rare fatal congenital anomaly. The prevalence is reported to be 1 in 100,000 births. The baby appears to have a fish-like tail and joined legs featuring a mermaid at the time of birth or during antenatal screening. Most of these patients die shortly after birth, denoting rare survival rate. Gastrointestinal and genitourinary obstruction with single umbilical artery are the clinical symptoms. Two important hypotheses support the Sirenomelia disorder: the artery steal hypothesis, called the vitelline artery, and the blastogenesis defect hypothesis. There is no known reason for MS, but certain risk factors need to be identified, which include mother aged more than 40 years or less than 20 years at the time of giving birth, cousin marriage, exposure to teratogenic agents, and family history. A case of this rare congenital disorder was seen in Civil Hospital Faisalabad, Pakistan, which was referred from Duniyapur, District Lodhran, Pakistan. The neonate presented with fused lower limbs, congenital heart disease, and high-grade fever. The mother had a history of gestational diabetes mellitus and hypertension. The baby had fused legs, unidentified internal and external genital system, thumbs anomaly, bile in vomit, and despite life-saving efforts, the patient expired after five days of birth. There is lack of information regarding symptoms and a lack of prenatal screening for MS. Hence, there is a need to create awareness among health care professionals to identify the disease on screening for early diagnosis.

Re-examining the nomenclature of congenital failure of formation in the upper limb: a historical perspective.

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 (n = 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.Level of evidence: IV.

Fibular hemimelia and risk of patellar dislocations: A case series.

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.