Publications by authors named "James T Bennett"

60 Publications

Pre-operative nutrition assessments do not improve outcomes in cerebral palsy patients undergoing varus derotational osteotomy.

Medicine (Baltimore) 2021 Nov;100(47):e27776

Children's Orthopaedic Center, Children's Hospital Los Angeles, Los Angeles, CA.

Abstract: Pre-operative nutritional assessments have been used as a "cornerstone" to help optimize nutritional status and weight in children with cerebral palsy (CP) to lower the risk of postoperative complications. However, the potential value of nutritional assessments on surgical outcomes in patients with CP undergoing major orthopedic surgery remains unproven.Do pre-operative nutritional assessments reduce complication rates of varus derotational osteotomy surgery in children with CP? Are complication rates higher in patients with a gastrostomy tube (G-tube) and can they be decreased by pre-operative nutritional assessment?One-hundred fifty-five patients with CP who underwent varus derotational osteotomy from January 1, 2012 through December 31, 2017 at a tertiary pediatric hospital with minimum 6 months follow-up were retrospectively identified. One-hundred-ten (71%) were categorized as "non-ambulatory" (Gross Motor Function Classification System [GMFCS] IV-V), and 45 (29%) as "ambulatory" (GMFCS I-III). Variables assessed included age, GMFCS level, G-tube, body mass index (BMI) percentile, complications, and if patients underwent pre-operative nutritional assessment.One-hundred-eleven patients (71.6%) underwent pre-operative nutritional assessment. Sixty-two of 155 patients (40.0%) had G-tubes. In non-ambulatory patients with G-tubes, BMI percentile changes were not significantly different between patients with a pre-operative nutritional assessment compared to those without at 1 (P = .58), 3 (P = .61), 6 (P = .28), and 12 months (P = .21) postoperatively. In non-ambulatory patients who underwent pre-operative nutritional assessment, BMI percentile changes were not significantly different between those with and without G-tubes at 1 (P = .61), 3 (P = .71), 6 (P = .19), and 12 months (P = .10). Pulmonary complication rates were significantly higher in non-ambulatory patients with G-tubes than in non-ambulatory patients without G-tubes (20% vs 4%, P = .03). Pre-operative nutritional assessments did not influence postoperative complication rates for non-ambulatory patients with or without a G-tube (P = .12 and P = .16, respectively). No differences were found in postoperative complications between ambulatory patients with and without G-tubes (P = .45) or between ambulatory patients with or without nutritional assessments (P = .99).Nutritional assessments, which may improve long term patient nutrition, should not delay hip surgery in patients with CP and progressive lower extremity deformity. Patients and their families are unlikely to derive any short-term nutritional improvement using routine pre-operative evaluation and surgical outcomes are unlikely to be improved.Level of Evidence: III, retrospective comparative.
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http://dx.doi.org/10.1097/MD.0000000000027776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615376PMC
November 2021

Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in .

Cold Spring Harb Mol Case Stud 2021 12 9;7(6). Epub 2021 Dec 9.

Seattle Children's Hospital, Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA.

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K-RAS-MAPK pathway (Padia et al., 4: 170-173 [2019]). Activating pathogenic variants in the gene , which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., 16: 51 [2013]; Luks et al., 166: 1048-1054.e1-5 [2015]; Al-Olabi et al., 128: 1496-1508 [2018]). These vascular malformations are part of the -related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic pathogenic variants (Keppler-Noreuil et al., 167A: 287-295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet-Dechaume-Blanc syndrome, and Wyburn-Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., 7: 5-17 [2001]; Krings et al., 17: 245-258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., 39: 2103-2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene We propose that CVMS be recognized as part of the -related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.
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http://dx.doi.org/10.1101/mcs.a006147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751408PMC
December 2021

Acetylsalicylic acid suppression of the PI3K pathway as a novel medical therapy for head and neck lymphatic malformations.

Int J Pediatr Otorhinolaryngol 2021 Dec 5;151:110869. Epub 2021 Aug 5.

Division of Pediatric Otolaryngology, Seattle Children's Hospital, Seattle, WA, USA; Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA, USA. Electronic address:

Objectives: Head and neck lymphatic malformations (HNLM) are caused by gain-of-function somatic mutations in PIK3CA. Acetylsalicylic acid (ASA/aspirin) is thought to limit growth in PIK3CA-mutated neoplasms through PI3K pathway suppression. We sought to determine if ASA could be beneficial for HNLM.

Methods: Retrospective case series of patients (0-18 years) offered ASA (3-5 mg/kg/day) for HNLM treatment (2010-2018). Clinical and treatment characteristics, patient-reported symptom improvement, medication tolerance, compliance, and complications were recorded. Treatment response was determined by change in patient/caregiver-reported symptoms, or HNLM size [complete (resolved), partial (decreased), or stable].

Results: Fifty-three patients were offered ASA, 23 (43%) accepted (median age 10 years, IQR 6-14). Compared to patients who declined, patients receiving ASA were more likely to have extensive malformations: ex-utero intrapartum treatment procedure, bilateral malformations, oral cavity location, ≥2 invasive treatments, or tracheotomy (p < 0.05). All patients with tissue available had PIK3CA mutations (13/23). Treatment indications included oral pain/blebs (12, 52%), recurrent pain/swelling (6, 26%), or sudden/persistent swelling (5, 22%). Treatment plan was commonly one 81 mg tablet daily (19, 83%) for 3-12 months (8, 42%). Therapeutic adherence was reported by 18 patients (78%). Symptoms improved in 18 patients [78%; decreased pain (9, 39%) and swelling (8, 35%)]. Treatment resulted in partial (14, 61%) or complete response (4, 17%). Three patients developed oral bleb bleeding, which resolved with medication discontinuation.

Conclusion: ASA seems to be a well-tolerated, low-risk medication for HNLM treatment. This pilot study suggests that it often improves symptoms and reduces HNLM size. Further prospective, randomized studies are warranted to comprehensively assess indications, safety, and efficacy.

Level Of Evidence: Level 4.
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http://dx.doi.org/10.1016/j.ijporl.2021.110869DOI Listing
December 2021

Targeted long-read sequencing identifies missing disease-causing variation.

Am J Hum Genet 2021 08 2;108(8):1436-1449. Epub 2021 Jul 2.

Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387463PMC
August 2021

Computational fluid dynamics modeling aiding surgical planning in a toddler with Parkes Weber syndrome.

J Pediatr Surg Case Rep 2021 Mar 6;66. Epub 2021 Jan 6.

Division of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Parkes Weber syndrome is a fast-flow and slow-flow vascular anomaly with limb overgrowth that can lead to congestive heart failure and limb ischemia. Current management strategies have focused on symptom management with focal embolization. A pediatric case with early onset heart failure is reported. We discuss the use of computational fluid dynamics (CFD) modeling to guide a surgical management strategy in a toddler with an mutation.
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http://dx.doi.org/10.1016/j.epsc.2021.101780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978412PMC
March 2021

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

Am J Hum Genet 2021 01;108(1):8-15

Molecular Medicine & Pathology and Pediatrics, McMaster University, Hamilton, ON L8S 3K9, Canada.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820621PMC
January 2021

CHRNB1-associated congenital myasthenia syndrome: Expanding the clinical spectrum.

Am J Med Genet A 2021 03 9;185(3):827-835. Epub 2020 Dec 9.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.

CHRNB1 encodes the β subunit of the acetylcholine receptor (AChR) at the neuromuscular junction. Inherited defects in the neuromuscular junction can lead to congenital myasthenia syndrome (CMS), a clinically and genetically heterogeneous group of disorders which includes fetal akinesia deformation sequence (FADS) on the severe end of the spectrum. Here, we report two unrelated families with biallelic CHRNB1 variants, and in each family, one child presented with lethal FADS. We contrast the diagnostic odysseys in the two families, one of which lasted 16 years while the other, utilizing rapid exome sequencing, led to specific treatment in the first 2 weeks of life. Furthermore, we note that CHRNB1 variants may be under-recognized because in both families, one of the variants is a single exon deletion that has been previously described but may not easily be detected in clinically available genetic testing.
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http://dx.doi.org/10.1002/ajmg.a.62011DOI Listing
March 2021

Immune dysfunction in MGAT2-CDG: A clinical report and review of the literature.

Am J Med Genet A 2021 01 12;185(1):213-218. Epub 2020 Oct 12.

Department of Pediatrics, School of Medicine, University of Washington, Seattle, Washington, USA.

Glycosylation is a critical post/peri-translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N-acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N-glycans. Complex N-glycans are essential for immune system functionality, but only one individual with MGAT2-CDG has been described to have an abnormal immunologic evaluation. MGAT2-CDG (CDG-IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4-year old female with MGAT2-CDG due to a novel homozygous pathogenic variant in MGAT2, a 4-base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2-CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2-CDG.
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http://dx.doi.org/10.1002/ajmg.a.61914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098812PMC
January 2021

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Brain 2020 10;143(10):2929-2944

Division of Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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http://dx.doi.org/10.1093/brain/awz307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780481PMC
October 2020

Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations.

Genet Med 2021 01 4;23(1):123-130. Epub 2020 Sep 4.

Vascular Anomalies Program, Seattle Children's Hospital, Seattle, WA, USA.

Purpose: Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients with isolated VM.

Methods: cfDNA was isolated from plasma or cyst fluid from patients with arteriovenous malformations (AVM), venous malformations (VeM), or lymphatic malformations (LM), and assayed for known pathogenic variants using droplet digital polymerase chain reaction (ddPCR). Cyst fluid cfDNA from an independent cohort of LM patients was prospectively screened for variants using a multiplex ddPCR assay.

Results: Variants were detected in plasma cfDNA in patients with AVM (2/8) and VeM (1/3). Variants were detected in cyst fluid cfDNA (7/7) but not plasma (0/26) in LM patients. Prospective testing of cyst fluid cfDNA with multiplex ddPCR identified variants in LM patients who had never undergone surgery (4/5).

Conclusion: Variants were detected in plasma from AVM and VeM patients, and in cyst fluid from patients with LM. These data support investigation of cfDNA-based molecular diagnostics for VM patients, which may provide opportunities to initiate targeted pharmacotherapies without prior surgery.
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http://dx.doi.org/10.1038/s41436-020-00943-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796969PMC
January 2021

The Impact of Rapid Exome Sequencing on Medical Management of Critically Ill Children.

J Pediatr 2020 11 15;226:202-212.e1. Epub 2020 Jun 15.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA; Brotman Baty Institute for Precision Medicine, Seattle, WA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA. Electronic address:

Objectives: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population.

Study Design: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES.

Results: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days.

Conclusions: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise.
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http://dx.doi.org/10.1016/j.jpeds.2020.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736066PMC
November 2020

Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.

Hum Mol Genet 2020 01;29(2):320-334

Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.
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http://dx.doi.org/10.1093/hmg/ddz310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001721PMC
January 2020

A child with autism, behavioral issues, and dysmorphic features found to have a tandem duplication within CTNND2 by mate-pair sequencing.

Am J Med Genet A 2020 03 8;182(3):543-547. Epub 2019 Dec 8.

Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, Washington.

We describe a 5-year-old male with developmental delay, behavioral problems, and dysmorphic features who was found by microarray to have a 93-kb duplication of uncertain significance that fully encompasses the third exon of CTNND2 (delta catenin). Mate-pair sequencing was used to determine that the duplication is tandem and is predicted to lead to CTNND2 haploinsufficiency. Haploinsufficiency for CTNND2 has been shown to result in developmental delay and intellectual disability, providing a unifying diagnosis for this patient. His features overlap those associated with the larger cri-du-chat deletion of this region, expanding the clinical phenotype of isolated CTNND2 variants. The use of mate-pair sequencing to determine the orientation of the small duplication was essential to the diagnosis and avoided the use of exome sequencing, which would not have defined the arrangement of the duplication. This is only the second reported patient, to our knowledge, with a single exon duplication of CTNND2.
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http://dx.doi.org/10.1002/ajmg.a.61442DOI Listing
March 2020

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

Hum Mutat 2020 01 26;41(1):299-315. Epub 2019 Oct 26.

Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
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http://dx.doi.org/10.1002/humu.23929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973139PMC
January 2020

Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations.

JCI Insight 2019 11 1;4(21). Epub 2019 Nov 1.

Center For Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.

Lymphatic malformations (LMs) are congenital, nonneoplastic vascular malformations associated with postzygotic activating PIK3CA mutations. The mutation spectrum within LMs is narrow, with the majority having 1 of 3 hotspot mutations. Despite this relative genetic homogeneity, clinical presentations differ dramatically. We used molecular inversion probes and droplet digital polymerase chain reaction to perform deep, targeted sequencing of PIK3CA in 271 affected and unaffected tissue samples from 81 individuals with isolated LMs and retrospectively collected clinical data. Pathogenic PIK3CA mutations were identified in affected LM tissue in 64 individuals (79%) with isolated LMs, with variant allele fractions (VAFs) ranging from 0.1% to 13%. Initial analyses revealed no correlation between VAF and phenotype variables. Recognizing that different mutations activate PI3K to varying degrees, we developed a metric, the genotype-adjusted VAF (GVAF), to account for differences in mutation strength, and found significantly higher GVAFs in LMs with more severe clinical characteristics including orofacial location or microcystic structure. In addition to providing insight into LM pathogenesis, we believe GVAF may have broad applicability for genotype-phenotype analyses in mosaic disorders.
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http://dx.doi.org/10.1172/jci.insight.129884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948764PMC
November 2019

Redefining the Etiologic Landscape of Cerebellar Malformations.

Am J Hum Genet 2019 09 29;105(3):606-615. Epub 2019 Aug 29.

Genetic Services, Kaiser Permanente Washington, Seattle, WA 98112, USA.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731369PMC
September 2019

Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia.

Am J Hum Genet 2019 05 11;104(5):936-947. Epub 2019 Apr 11.

Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address:

Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1r) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1 neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1 neurons. Since a large fraction of CUX1 neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1 neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1r fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506793PMC
May 2019

Rapid clinical exome sequencing in a pediatric ICU: Genetic counselor impacts and challenges.

J Genet Couns 2019 04;28(2):283-291

Department of Laboratories, Seattle Children's Hospital, Seattle, Washington.

Exome sequencing (ES) has revolutionized molecular diagnosis in children with genetic disease over the past decade. However, exome sequencing in the inpatient setting has traditionally been discouraged, in part due to an increased risk of providers failing to retrieve and act upon results, as many patients are discharged before results return. The development of rapid turn-around-times (TATs) for genomic testing has begun to shift this paradigm. Rapid exome sequencing (rES) is increasingly being used as a diagnostic tool for critically ill infants with likely genetic disease and presents significant challenges to execute. We implemented a program, entitled the Rapid Inpatient Genomic Testing (RIGhT) project, to identify critically ill children for whom a molecular diagnosis is likely to change inpatient management. Two important goals of the RIGhT project were to provide appropriate genetic counseling, and to develop protocols to ensure efficient test coordination- both of which relied heavily on laboratory and clinic-based genetic counselors (GCs). Here, rES was performed on 27 inpatient trios from October 2016 to August 2018; laboratory and clinical GCs encountered significant challenges in the coordination of this testing. The GCs involved retrospectively reviewed these cases and identified three common challenges encountered during pretest counseling and coordination. The aim of this paper is to define these challenges using illustrative case examples that highlight the importance of including GCs to support rES programs.
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http://dx.doi.org/10.1002/jgc4.1116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481675PMC
April 2019

Identification of a deletion containing TBX4 in a neonate with acinar dysplasia by rapid exome sequencing.

Am J Med Genet A 2019 05 3;179(5):842-845. Epub 2019 Mar 3.

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington.

We describe a neonate with severe respiratory failure due to acinar dysplasia found by rapid exome sequencing (rES), to have a deletion containing the TBX4 gene. rES can affect patient management in the intensive care unit and should be considered in concert with lung biopsy in neonates with undifferentiated respiratory failure.
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http://dx.doi.org/10.1002/ajmg.a.61096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738195PMC
May 2019

Minimal mosaicism, maximal phenotype: Discordance between clinical and molecular findings in two patients with tuberous sclerosis.

Am J Med Genet C Semin Med Genet 2018 09 27;178(3):374-378. Epub 2018 Sep 27.

Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by hamartomatous growths in the brain, kidneys, lungs, skin, heart, and retina. TSC is caused by loss of function mutations in one of two tumor suppressor genes, TSC1 or TSC2. Two-thirds of individuals with TSC have de novo mutations, and individuals with postzygotic pathogenic variants in both TSC1 and TSC2 have been reported. The development of sensitive molecular methods, such as next generation sequencing, has led to an increased ability to detect low-level mosaic variants, which are typically thought to have milder phenotypes because a smaller fraction of cells in the body harbor the mutation. Here, we describe two patients with TSC who had severe phenotypic involvement, but only low-level mosaicism in TSC2. Given this apparent discrepancy and concern about a missed constitutional variant, we sampled multiple tissues in both cases to confirm these mosaic mutations. Sampling of multiple tissues can be crucial in molecular diagnosis of mosaic TSC. These cases highlight, in general, challenges in molecular diagnosis of genetic conditions due to postzygotic mutations.
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http://dx.doi.org/10.1002/ajmg.c.31656DOI Listing
September 2018

A comprehensive review of the diagnosis and management of congenital scoliosis.

Childs Nerv Syst 2018 11 4;34(11):2155-2171. Epub 2018 Aug 4.

Shriners Hospitals for Children-Philadelphia, 3551 N Broad Street, Philadelphia, PA, 19140, USA.

Purpose: To provide the reader with a comprehensive but concise understanding of congenital scoliosis METHODS: We have undertaken to summarize available literature on the pathophysiology, epidemiology, and management of congenital scoliosis.

Results: Congenital scoliosis represents 10% of pediatric spine deformity and is a developmental error in segmentation, formation, or a combination of both leading to curvature of the spine. Treatment options are complicated by balancing growth potential with curve severity. Often associated abnormalities of cardiac, genitourinary, or intraspinal systems are concurrent and should be evaluated as part of the diagnostic work-up. Management balances the risk of progression, growth potential, lung development/function, and associated risks. Surgical treatment options involve growth-permitting systems or fusions.

Conclusion: Congenital scoliosis is a complex spinal problem associated with many other anomalous findings. Treatment options are diverse but enable optimization of management and care of these children.
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http://dx.doi.org/10.1007/s00381-018-3915-6DOI Listing
November 2018

Characterization of a severe case of PIK3CA-related overgrowth at autopsy by droplet digital polymerase chain reaction and report of PIK3CA sequencing in 22 patients.

Am J Med Genet A 2018 11 31;176(11):2301-2308. Epub 2018 Jul 31.

Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington.

PIK3CA-related overgrowth spectrum (PROS) refers to a group of disorders of segmental overgrowth of a wide variety of tissues as well as venous and lymphatic malformations. Clinical and molecular diagnosis can be challenging due to phenotypic heterogeneity and difficulties detecting low-level mosaicism using standard methods. Here, we report a patient with a severe presentation of PIK3CA-related overgrowth with analysis of 27 posthumously collected tissues by droplet digital polymerase chain reaction (PCR) at autopsy. This patient had a complicated medical course, with coagulopathy, ischemic brain injury, and sepsis resulting in multi-organ failure and death at age 2 months despite sirolimus therapy. Five of the 27 tissues analyzed possessed a mosaic PIK3CA mutation (p.E545K), with mutation levels ranging from 3 to 20% across affected tissues. We found no correlation between tissue-specific disease severity and mutation levels, likely reflecting sampling limitations. We also tested a series of 22 individuals with somatic overgrowth and/or vascular-lymphatic malformations using a targeted next generation sequencing panel and found PIK3CA mutations in nine individuals, identifying three novel PIK3CA variants. This report expands the clinical and molecular spectrum of PROS, emphasizes that different molecular methods can be complimentary in the diagnosis of these disorders, and highlights the risk of coagulopathy in a subset of patients with PIK3CA-related overgrowth.
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http://dx.doi.org/10.1002/ajmg.a.40487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290925PMC
November 2018

Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.

Genet Med 2018 11 19;20(11):1354-1364. Epub 2018 Apr 19.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.

Purpose: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

Methods: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.

Results: The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.

Conclusion: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.
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http://dx.doi.org/10.1038/gim.2018.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195491PMC
November 2018

Clinical and genetic characterization of AP4B1-associated SPG47.

Am J Med Genet A 2018 02 28;176(2):311-318. Epub 2017 Nov 28.

Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, and Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated.
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http://dx.doi.org/10.1002/ajmg.a.38561DOI Listing
February 2018

Evaluation and management of adolescent idiopathic scoliosis: a review.

Neurosurg Focus 2017 Oct;43(4):E2

Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.

Adolescent idiopathic scoliosis (AIS) is a 3D spinal deformity affecting children between the ages of 11 and 18, without an identifiable etiology. The authors here reviewed the available literature to provide spine surgeons with a summary and update on current management options. Smaller thoracic and thoracolumbar curves can be managed conservatively with observation or bracing, but corrective surgery may be indicated for rapidly growing or larger curves. The authors summarize the atypical features to look for in patients who may warrant further investigation with MRI during diagnosis and review the fundamental principles of the surgical management of AIS. Patients with AIS can be managed very well with a combination of conservative and surgical options. Outcomes for these children are excellent with sustained longer-term results.
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http://dx.doi.org/10.3171/2017.7.FOCUS17297DOI Listing
October 2017

Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction.

Genet Med 2018 02 10;20(2):250-258. Epub 2017 Aug 10.

Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.

PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.
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http://dx.doi.org/10.1038/gim.2017.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846811PMC
February 2018

Loss of function in is associated with tetralogy of Fallot and septal defects.

J Med Genet 2017 12 7;54(12):825-829. Epub 2017 Jun 7.

Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, Maryland, USA.

Background: Congenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model.

Methods: Four hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections.

Results: Loss of function variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model.

Conclusion: Our findings identify Slit-Robo as a significant pathway in human heart development and CHD.
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http://dx.doi.org/10.1136/jmedgenet-2017-104611DOI Listing
December 2017

Outcomes of patients with syringomyelia undergoing spine deformity surgery: do large syrinxes behave differently from small?

Spine J 2017 10 13;17(10):1406-1411. Epub 2017 Apr 13.

Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA, 19129, USA.

Background Context: A paucity of data exists studying outcomes of patients with syringomyelia undergoing spinal deformity correction. The literature does not stratify patients by syrinx size, which is likely a major contributor to outcomes.

Purpose: The study aimed to compare differences in outcomes between patients with large (≥4 mm) and small syrinxes (<4 mm) undergoing spinal deformity correction.

Design: This is a retrospective review.

Patient Sample: The sample included 28 patients (11 with large syrinx [LS, >4 mm] and 17 with small syrinx [SS, <4 mm]).

Outcome Measures: The outcome measures were radiographic, operative, and neurophysiological measures.

Methods: We retrospectively reviewed 28 patients with syringomyelia who underwent spine deformity surgery with 2-year follow-up. Demographic, surgical, and radiographic data were collected and compared preoperatively and at 2 years.

Results: The LS group (11 patients) trended toward more left-sided thoracic curves (36% vs. 18%, p=.38) and was more likely to have had a Chiari decompression (45% vs. 12%, p=.08). The LS patients had larger preoperative major curves (LS=66° vs. SS=57°, p=.05), more thoracic kyphosis (LS=42°, SS=24°, p<.01), and greater rib prominences (LS=16°, SS=13°, p=.04). The LS patients had more levels fused (LS=12.2, SS=11.2, p=.05), higher estimated blood loss (EBL) (LS=1068 cc, SS=832 cc, p=.04), and a trend toward less percent correction of the major curve (LS=57%, SS=65%, p=.18). Four of 11 LS patients (36%) did not have somatosensory evoked potentials, and one of these also did not have motor evoked potentials. Neuromonitoring changes occurred in 3 of 11 (27%) LS patients and in none of the SS patients, with no postoperative deficits.

Conclusions: Outcomes of patients with syringomyelia undergoing spine deformity surgery are dependent on the size of the syrinx. Those with large syringomyelia are fused longer with more EBL and less correction. Spine surgeons should be aware that these patients are more likely to have less reliable neuromonitoring, with a higher chance of experiencing a change.
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http://dx.doi.org/10.1016/j.spinee.2017.04.006DOI Listing
October 2017

Factors affecting the outcome in appearance of AIS surgery in terms of the minimal clinically important difference.

Eur Spine J 2017 06 9;26(6):1782-1788. Epub 2016 Dec 9.

Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: The minimal clinically important difference (MCID) of the Appearance domain of the SRS-22 questionnaire is an increase ≥1.0 in surgically treated patients with adolescent idiopathic scoliosis (AIS). However, no study has sought to identify the factors associated with an SRS-22 Appearance score increase greater than the MCID at 2 years.

Methods: A retrospective analysis was performed on a prospectively collected multicenter database of 1020 surgically treated AIS patients with a minimum 2-year follow-up. Patients were divided into two cohorts: "I" = Improved after surgery (Δ Appearance ≥1.0) and "NI" = Not improved after surgery (Δ Appearance <1.0). Univariate regression was used to find a significant difference between the cohorts for individual measures. Multivariate logistic regression was used to find continuous predictors.

Results: 663 (65%) patients were improved greater than the MCID, and 357 were not improved (35%). The improved cohort trended toward a greater percentage of underweight patients (p = 0.074) with lower preoperative SRS Appearance scores (p < 0.001) and larger preoperative trunk shifts (p = 0.033). Postoperatively, those patients with greater percent correction of thoracic (p = 0.021) and lumbar (p = 0.003) Cobb angles, smaller apical lumbar translation (p = 0.006), and a greater correction in trunk shift (p = 0.003) were most likely to attain the MCID.

Conclusion: Several factors influence which patients are most likely to attain the MCID following surgery for AIS. Factors such as preoperative appearance scores and body weight are patient specific; other factors such as percent correction of the thoracic and lumbar Cobb angles, trunk shift, and lumbar apical translation may be influenced by the surgeon.

Level Of Evidence: II.
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http://dx.doi.org/10.1007/s00586-016-4857-xDOI Listing
June 2017
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