Surgical Correction of Ischiopagus Tripus Conjoined Twins with Fused Pelvis: Enhancing Quality of Life through Orthopedic Intervention.

BACKGROUND The rarity of ischiopagus tripus conjoined twins complicates the surgical separation, owing to the lack of cases and high complexity. We aim to report our experience in performing orthopedic correction for ischiopagus tripus twins. CASE REPORT A pair of 3-year-old conjoined boys presented with a fused body at the pelvis region and only 1 umbilicus. There were 2 legs separated by shared genitalia and an anus at the midline, and 1 fused leg, which could be felt and moved by both of the patients. The twins also shared internal organs of the bladder, intestine, and rectum, as visualized through angiography computerized tomography scan. After several team discussions with the institutional review board, the hospital ethics committee, and both parents, it was agreed to perform disarticulation of the fused third limb, followed by correction of the trunk alignment by pelvic closed wedge osteotomy and internal fixation. We successfully reconstructed the pelvis using locking plates and additional 3.5-mm cortical screws and 1.2-mm stainless steel wire. CONCLUSIONS This report describes the presentation and surgical management of a case of ischiopagus tripus conjoined twins. It highlights the challenges involved in surgery and the importance of investigating these infants for other congenital abnormalities. Although surgical approaches for different sets of twins should be individually tailored, interventions aimed to provide optimal outcomes should consider ethical issues and parental/patient expectations. Even in situations in which the twins are inseparable, there is still room for surgical correction to be performed.

Identification and Functional Evaluation of a Novel TBX4 Mutation Underlies Small Patella Syndrome.

Small patella syndrome (SPS) is a rare autosomal dominant disorder caused by mutations in TBX4 gene which encodes a transcription factor of FGF10. However, how TBX4 mutations result in SPS is poorly understood. Here, a novel TBX4 mutation c.1241C>T (p.P414L) was identified in a SPS family and series of studies were performed to evaluate the influences of TBX4 mutations (including c.1241C>T and two known mutations c.256G>C and c.743G>T). Results showed that mesenchymal stem cells (MSCs) with stable overexpression of either TBX4 wild-type (TBX4wt) or mutants (TBX4mt) were successfully generated. Immunofluorescence study revealed that both the overexpressed TBX4 wild-type and mutants were evenly expressed in the nucleus suggesting that these mutations do not alter the translocation of TBX4 into the nucleus. Interestingly, MSCs overexpression of TBX4mt exhibited reduced differentiation activities and decreased FGF10 expression. Chromatin immunoprecipitation (ChIP) study demonstrated that TBX4 mutants still could bind to the promoter of FGF10. However, dual luciferase reporter assay clarified that the binding efficiencies of TBX4 mutants to FGF10 promoter were reduced. Taken together, MSCs were firstly used to study the function of TBX4 mutations in this study and the results indicate that the reduced binding efficiencies of TBX4 mutants (TBX4mt) to the promoter of FGF10 result in the abnormal biological processes which provide important information for the pathogenesis of SPS.

Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic SNV in a lung-specific enhancer in trans to the frameshifting TBX4 variant.

Variants involving TBX4 are associated with a wide variety of disorders, including pulmonary arterial hypertension, ischiocoxopodopatellar syndrome (ICPPS)/small patella syndrome (SPS), lethal lung developmental disorders (LLDDs) in neonates, heart defects, and prenatally lethal posterior amelia with pelvic and pulmonary hypoplasia syndrome. The objective of our study was to elucidate the wide variable phenotypic expressivity and incomplete penetrance in a three-generation family with a truncating variant in TBX4. In addition to exome and genome sequencing analyses, a candidate noncoding regulatory single nucleotide variant (SNV) within the lung-specific TBX4 enhancer was functionally tested using an in vitro luciferase reporter assay. A heterozygous frameshift variant c.1112dup (p.Pro372Serfs*14) in TBX4 was identified in patients with mild interstitial lung disease (1), bronchiolitis obliterans (1), recurrent pneumothorax (1), ICPPS/SPS (1), LLDD (2), and in unaffected individuals (4). In two deceased neonates with LLDD, we identified a noncoding SNV rs62069651-C located in trans to the mutated TBX4 allele that reduced the TBX4 promoter activity by 63% in the reporter assay. Our findings provide a functional evidence for the recently reported model of complex compound inheritance in which both TBX4 coding and in trans noncoding hypomorphic variants in the lung-specific enhancer of TBX4 contribute to LLDD.

Volumetric Evaluation of Dead Space in Ischial Pressure Injuries Using Magnetic Resonance Imaging: A Case Series.

OBJECTIVE: To establish a preoperative evaluation procedure by measuring the volume of dead space using MRI in patients with ischial pressure injuries. METHODS: Patients with spinal cord injury and ischial pressure injuries who underwent treatment between August 2016 and November 2019 were included in the study. Preoperative MRI scan was conducted on all patients. The volume estimation and three-dimensional (3D) reconstruction were performed based on MRI data using a 3D Slicer. Based on the resulting volume, a muscle flap that could fit the dead space was selected. Surgery was performed with the selected muscle flap, and a fasciocutaneous flap was added, if necessary. RESULTS: A total of eight patients with ischial pressure injuries were included in the study. The mean patient age was 59.0 ± 11.0 years. The mean body mass index was 26.62 ± 3.89 kg/m2. The mean volume of dead space was 104.75 ± 81.05 cm3. The gracilis muscle was the most selected muscle flap and was used in four patients. In five of eight cases, a fasciocutaneous flap was used as well. The mean follow-up period was 16 months, and by that point, none of the patients evinced complications that required surgery. CONCLUSIONS: To the authors' knowledge, this is the first report on volumetric evaluation of dead space in ischial pressure injuries. The authors believe that the 3D reconstruction process would enable adequate dead space obliteration in ischial pressure injuries. The authors propose that preoperative MRI scans in patients with ischial pressure injury should become an essential part of the process.

Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation.

INTRODUCTION: TBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown. METHODS: We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network. RESULTS: 20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (D LCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma. CONCLUSION: PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.

Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.

Identifying pathogenic variants in the Follistatin-like 1 gene (FSTL1) in patients with skeletal and atrioventricular valve disorders.

BACKGROUND: Follistatin-like 1 (Fstl1) is a glycoprotein expressed throughout embryonic development. Homozygous loss of Fstl1 in mice results in skeletal and respiratory defects, leading to neonatal death due to a collapse of the trachea. Furthermore, Fstl1 conditional deletion from the endocardial/endothelial lineage results in postnatal death due to heart failure and profound atrioventricular valve defects. Here, we investigated patients with phenotypes similar to the phenotypes observed in the transgenic mice, for variants in FSTL1. METHODS: In total, 69 genetically unresolved patients were selected with the following phenotypes: campomelic dysplasia (12), small patella syndrome (2), BILU (1), and congenital heart disease patients (54), of which 16 also had kyphoscoliosis, and 38 had valve abnormalities as their main diagnosis. Using qPCR, none of 69 patients showed copy number variations in FSTL1. The entire gene body, including microRNA-198 and three validated microRNA-binding sites, were analyzed using Sanger sequencing. RESULTS: No variants were found in the coding region. However, 8 intronic variants were identified that differed significantly in their minor allele frequency compared to controls. Variant rs2272515 was found to significantly correlate (p < 0.05) with kyphoscoliosis. CONCLUSION: We conclude that pathogenic variants in FSTL1 are unlikely to be responsible for skeletal or atrioventricular valve anomalies in humans.

Quantitative ultrasound imaging over the ischial tuberosity: An exploratory study to inform tissue health.

BACKGROUND: Characterization of ischial tissue health using a standardized diagnostic ultrasound protocol capturing thickness and gray scale analysis has not been established. OBJECTIVES: This study evaluates inter-participant and inter-trial reliability of thickness and gray scale analysis of ultrasound images of tissues overlying the ischial tuberosity. It provides recommendations for the number of images required to minimize the standard error of measurement (SEM) and determines the number of images required for thickness, gray scale and contrast values that exceed an a-priori minimal detectable change (MDC) for repeated tissue assessment. METHODS: Brightness mode ultrasound images using a 12 MHz linear probe were collected on the dominant limb in the side lying position for ten healthy participants and partitioned into three regions of interest: skin, subcutaneous tissue and muscle. Thickness and gray scale measures of skin, muscle and subcutaneous tissue were calculated using a customized MATLAB program. Contrast of each region of interest was calculated using the Gray Scale Level Co-Occurrence Matrix. Generalizability theory was used to quantify indices of dependability and corresponding SEMs and MDCs with 90% Confidence Intervals. RESULTS: Participants accounted for most of the total variance (75.56% to 94.78%). Coefficient of dependability (ϕ) for thickness, grey scale and contrast measures was greater than 0.80 when more than two images were averaged. In order to detect a MDC of 21% in thickness and echogenicity measures, at least three images are required, while at least 5 images are required for a MDC of 25% for contrast measures. CONCLUSIONS: Obtaining reliable thickness, echogenicity and contrast measures of tissue overlying the ischial tuberosity can be achieved from two ultrasound images by a single therapist on an individual participant however three and five images are required to use a MDC of 21% for thickness measures and MDC of 25% for contrast measures respectively.

Genetics of patella hypoplasia/agenesis.

The patella is a sesamoid bone, crucial for knee stability. When absent or hypoplastic, recurrent knee subluxations, patellofemoral dysfunction and early gonarthrosis may occur. Patella hypoplasia/agenesis may be isolated or observed in syndromic conditions, either as the main clinical feature (Nail-patella syndrome, small patella syndrome), as a clue feature which can help diagnosis assessment, or as a background feature that may be disregarded. Even in the latter, the identification of patella anomalies is important for an appropriate patient management. We review the clinical characteristics of these rare diseases, provide guidance to facilitate the diagnosis and discuss how the genes involved could affect patella development.

Ischiovertebral dysplasia: a retrospective analysis of 30 consecutive cases pointing out the specifics and risks of the spine management.

STUDY DESIGN: A review of clinical publications, current knowledge, and recent developments regarding the etiology of ischiovertebral dysplasia was combined with a clinical review of the condition. OBJECTIVE: To acquaint orthopedic spine surgeons with identification patterns of ischiovertebral dysplasia in order to provide them with guidelines about spine management and which complications to expect. SUMMARY OF BACKGROUND DATA: Ischiovertebral dysplasia is a rare skeletal dysplasia that may appear in a sporadic fashion or be inherited with an autosomal dominant inheritance pattern. It is defined by the association of an ischiopubic ramus hypoplasia and a vertebral dysplasia. It leads to a specific spine deformity whose management and complications should be clarified. METHODS: Thirty consecutive patients from 0 to 31 years of age with ischiovertebral dysplasia were included from 5 centers specialized in congenital spinal deformities. Frontal and sagittal Cobb angles before treatment, natural history of the curves, therapeutic options, and their complications were systematically analyzed. RESULTS: All the patients had a vertebral dysplasia and 28 of them developed a spinal deformity. This deformity was an extremely severe thoracic kyphoscoliosis in 25 cases. The other deformities were a thoracolumbar scoliosis in 1 case and a thoracolumbar kyphosis in 2 cases. The management of the thoracic kyphoscoliosis was always challenging and complications included death by respiratory failure (3 cases) and neurological impairment (9 cases). CONCLUSION: Recognizing the occurrence of ischioverterbral dysplasia is very important to allow for dedicated treatment. The authors advocate preoperative distraction and circumferential fusion to prevent progression of the curve and to avoid the potentially fatal sequelae associated with this disorder. LEVEL OF EVIDENCE: 4.

Medial and lateral retinaculum plasty for congenital patellar dislocation due to small patella syndrome.

The objective of this study was to explore the clinical effect of medial and lateral retinaculum plasty for congenital patellar dislocation due to small patella syndrome. Twelve patients with congenital patellar dislocation due to small patella syndrome treated at the authors' hospital between January 2005 and February 2010 were enrolled in the study. The study group comprised 4 men (4 knees) and 8 women (8 knees) with an average age of 10.58±6.91 years. All patients underwent medial and lateral retinaculum plasty. Clinical evaluation included the number of patellar redislocations, patellar apprehension sign, Kujala score, subjective questionnaire score, and patella lateral shift and patellar tilt angle measured using a cross-sectional computed tomography scan. All patients were followed up, and the shortest follow-up time was 2 years. Kujala scores improved from 49.20±6.20 preoperatively to 80.10±5.80 postoperatively. Subjective questionnaire scores indicated that the excellent and good rate was 75%. In addition, a significant difference existed in the patellar tilt angle and patella lateral shift between pre- and postoperative results (P<.05). Medial and lateral retinaculum plasty for patients with congenital patellar dislocation due to small patella syndrome can be effective to correct the tracking of the patellofemoral joint and improve knee function.

A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome.

The phenotypic similarities have been demonstrated between non-lethal campomelic dysplasia (CD) and small patella syndrome (SPS), in which different genetic defects have been identified. We report on a familial case of skeletal dysplasia with overlapping phenotype of mild CD and SPS, including defective ischio-pubic ossification, elongated femoral neck, hypoplastic patellae, and increased space between the first and the second toes (sandal gap). Direct sequencing analysis demonstrated a novel missense mutation (p.H169Q) within the coding region of the SOX9 gene and negative for TBX4 mutations. Functional analysis of the p.H169Q mutant revealed reduced but not fully abolished transactivation capacity of the mutated protein. Retained residual SOX9 function might contribute to an extremely mild CD phenotype in the present cases. © 2013 Wiley Periodicals, Inc.

TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension.

BACKGROUND: Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene, BMPR2, were reported to cause PAH in only 10-16% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH. METHODS: We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2. TBX2 and TBX4 were selected from this area as candidate genes and sequenced in all 20 children. After identifying TBX4 mutations in these children, we subsequently sequenced TBX4 in a cohort of 49 adults with PAH. Because TBX4 mutations are known to cause small patella syndrome (SPS), all patients with newly detected TBX4 mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH. RESULTS: TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with TBX4 mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one TBX4 mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH. CONCLUSIONS: These data indicate that TBX4 mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult TBX4 mutation carriers is low.

Van neck disease: osteochondrosis of the ischiopubic synchondrosis.

BACKGROUND: Van Neck disease (VND) is a benign skeletal abnormality of children involving a hyperostosis of the ischiopubic synchondrosis (IPS) seen on radiographs. Patients typically complain of vague groin or buttock pain. Few descriptions of this disorder exist and it easily can be mistaken for other entities, particularly osteomyelitis or tumor. It is often considered a diagnosis of exclusion as laboratory values are usually normal and routine radiographic workup may be nonspecific. We present a series of patients with VND and we compare them with a similar cohort of patients with acute hematogenous ischiopubic osteomyelitis (IPOM). We also draw attention to a new magnetic resonance imaging (MRI) finding that seems to support the theory that VND results from an excessive pull of the hamstring tendon on the ischial tuberosity. METHODS: All patients presenting to our institution for the evaluation of groin or buttock pain during an 8-year period (August 2001 to May 2009) were retrospectively identified. Twenty-five patients demonstrated enhancement of the ischiopubic area on MRI. Five patients were excluded for lack of sufficient laboratory data. Ten patients were diagnosed and treated with culture proven IPOM and 10 patients were diagnosed with VND and treated with observation. History, physical examination, laboratory values, plain films, and MRI were compared to identify the diagnostic differences between these 2 entities. RESULTS: The age range for both groups was between 4 and 12 years old. The mean age was 7 years for the VND group and 7.6 years for the IPOM group. The VND group tended to have more distinct hyperostosis of the IPS on radiographs. The factors that were characteristic of IPOM were: fever, limp, pain with rotation of the hip, elevated erythrocyte sedimentation rate, elevated C-reactive protein (CRP), and positive blood culture. MRI showed obvious myositis, abscess, and free fluid surrounding the IPS in all patients with IPOM, but not in the VND patients. Enhancement was seen in the ischial tuberosity, near the hamstring origin, in nearly all Van Neck patients; this pattern of edema may support stress reaction and callus formation as a mechanism for IPS hypertrophy. CONCLUSIONS: VND is a little-known entity characterized by enlargement of the IPS and should be in the differential of groin or buttock pain in children from the age of 4 to 12 years. IPOM may present similar to VND. Absence of fever, limp, pain with rotation of the hip, elevated C-reactive protein/erythrocyte sedimentation rate, and negative blood culture can help to differentiate VND from IPOM. Presence of marrow edema around the IPS and in the ischial tuberosity, along with absence of surrounding myositis, abscess, and free fluid on MRI are reliable findings that can confirm the diagnosis of VND. The absence of these characteristics can eliminate the need for admission, aspiration, or biopsy. The treatment for VND is observation and the symptoms should abate over time with expectant management. LEVEL OF EVIDENCE: Comparative Diagnostic, Level IV.

Pregnancy in a woman with treated bladder extrophy, split pelvis and hypoplasia of ischial bones. Case report.

We present a case of a pregnancy in a 24 year old woman who was born with ectopia vesicae, split pelvis and hypoplasia of ischial bones. From childhood to adulthood she had undergone reconstructive surgeries of the abdomen and perineum, as well as urine diversion surgery. During pregnancy she experienced recurrent urinary tract infections which were treated with antibiotics. In spite of tocolysis, she delivered by cesarean section a premature baby boy at 35th week of gestation due to premature uterine contractions. The postoperative period was uneventful and they were discharged from the hospital in a good general condition.

A new and a reclassified ICF patient without mutations in DNMT3B and its interacting proteins SUMO-1 and UBC9.

The ICF syndrome (immunodeficiency, centromeric instability, facial anomalies) (OMIM#242860) is a rare autosomal, recessively inherited disorder. Another rare condition, ischiadic hypoplasia, renal dysgenesis, immunodeficiency, and polydactyly (IHRDIP, OMIM#243340), displays features that resemble those of the ICF syndrome. Due to the overlapping symptoms in both syndromes, we asked whether a shared underlying molecular defect exists. Two patients, each with the clinical characteristics of one of these syndromes, were subjected to conventional cytogenetic analysis and the determination of the methylation state of satellite II DNA. We found that both displayed the two hallmark features of the ICF syndrome, namely hypomethylation and centromeric instability of chromosomes 1 and 16. Therefore, we reclassified the patient previously diagnosed with the IHRDIP syndrome as an ICF patient. Since the majority of ICF patients are carriers of mutations in the methytransferase gene DNMT3B, we determined the sequence of its coding, splice site, and putative promoter region and analyzed its transcripts in both patients, without detecting any alterations. Similarly, the coding region of two DNMT3B-interacting proteins, SUMO-1 and UBC9, did not reveal mutations. With this study, the published number of patients that lack mutations in DNMT3B coding region increases to almost 40% of all ICF patients reported. It is, therefore, implied that a significant subset of ICF patients will have a yet unknown, alternative alteration, which may include the involvement of DNMT3B-interacting factors or aberrations of an independent pathway.