Artificial Intelligence Portrayals in Orthopaedic Surgery: An Analysis of Gender and Racial Diversity Using Text-to-Image Generators.

BACKGROUND: The increasing accessibility of artificial intelligence (AI) text-to-image generators offers a novel avenue for exploring societal perceptions. The present study assessed AI-generated images to examine the representation of gender and racial diversity among orthopaedic surgeons. METHODS: Five prominent text-to-image generators (DALL·E 2, Runway, Midjourney, ImagineAI, and JasperArt) were utilized to create images for the search queries "Orthopedic Surgeon," "Orthopedic Surgeon's Face," and "Portrait of an Orthopedic Surgeon." Each query produced 80 images, resulting in a total of 240 images per generator. Two independent reviewers categorized race, sex, and age in each image, with a third reviewer resolving discrepancies. Images with incomplete or multiple faces were excluded. The demographic proportions (sex, race, and age) of the AI-generated images were then compared with those of the 2018 American Academy of Orthopaedic Surgeons (AAOS) census. RESULTS: In our examination across all AI platforms, 82.8% of the images depicted surgeons as White, 12.3% as Asian, 4.1% as Black, and 0.75% as other; 94.5% of images were men; and a majority (64.4%) appeared ≥50 years old. DALL·E 2 exhibited significantly increased diversity in representation of both women and non-White surgeons compared with the AAOS census, whereas Midjourney, Runway, and ImagineAI exhibited significantly decreased representation. CONCLUSIONS: The present study highlighted distortions in AI portrayal of orthopaedic surgeon diversity, influencing public perceptions and potentially reinforcing disparities. DALL·E 2 and JasperArt show encouraging diversity, but limitations persist in other generators. Future research should explore strategies for improving AI to promote a more inclusive and accurate representation of the evolving demographics of orthopaedic surgery, mitigating biases related to race and gender. CLINICAL RELEVANCE: This study is clinically relevant as it investigates the accuracy of AI-generated images in depicting diversity among orthopaedic surgeons. The findings reveal significant discrepancies in representation by race and gender, which could impact societal perceptions and exacerbate existing disparities in health care.

The Troubling Rise of Scurvy: A Review and National Analysis of Incidence, Associated Risk Factors, and Clinical Manifestations.

INTRODUCTION: In the era of modern medicine, scurvy has been thought of as a rare disease of ancient times because of improved emphasis on diet and nutrition; however, isolated case reports are plentiful. This investigation presents a comprehensive review of scurvy, including an analysis on its rising incidence, with specific focus on its orthopaedic manifestations and commonly associated diagnoses. METHODS: This comprehensive review includes a retrospective analysis of 19,413,465 pediatric patients in the National Inpatient Sample database from 2016 through 2020. Patients with scurvy were identified by the ICD-10 code, and an estimated incidence of scurvy in the inpatient pediatric population was calculated. Concurrent diagnoses, musculoskeletal reports, and demographic variables were collected from patient records. Comparisons were made using analysis of variance or chi-square with Kendall tau, where appropriate. RESULTS: The incidence of scurvy increased over the study period, from 8.2 per 100,000 in 2016 to 26.7 per 100,000 in 2020. Patients with scurvy were more likely to be younger (P < 0.001), male (P = 0.010), in the lowest income quartile (P = 0.013), and obese (P < 0.001). A majority (64.2%) had a concomitant diagnosis of autism spectrum disorder. Common presenting musculoskeletal reports included difficulty walking, knee pain, and lower limb deformity. Burden of disease of scurvy was markedly greater than that of the average inpatient population, with these patients experiencing greater total charges and longer hospital stays. CONCLUSION: Clinicians should be aware of the increasing incidence of scurvy in modern medicine. In cases of vague musculoskeletal reports without clear etiology, a diagnosis of scurvy should be considered, particularly if risk factors are present. TRIAL REGISTRATION NUMBER: NA.

How Effective Is Phage Therapy for Prosthetic Joint Infections? A Preliminary Systematic Review and Proportional Meta-Analysis of Early Outcomes.

Background and Objectives: Despite the promise of phage therapy (PT), its efficacy in prosthetic joint infection (PJI) management is unknown. Much of the current literature is largely limited to case reports and series. Materials and Methods: In order to help inform power calculations for future clinical trials and comparative analyses, we performed a systematic review and proportional meta-analysis of early PT outcomes to provide a preliminary assessment of early phage therapy treatment outcomes for cases of PJI. Results: In a search of available literature across MEDLINE (Ovid, Wolters Kluwer, Alphen aan den Rijn, The Netherlands), Embase (Elsevier, Amsterdam, The Netherlands), the Web of Science Core Collection (Clarivate, London, UK), and Cochrane Central (Wiley, Hoboken, NJ, USA) up to 23 September 2023, we identified 37 patients with PJIs receiving adjunctive PT. Patients most frequently reported Staphylococcal species infection (95%) and intraarticular phage delivery (73%). Phage cocktail (65%) and antibiotic co-administration (97%) were common. A random-effects proportional meta-analysis suggested infection remission in 78% of patients (95% CI: 39%, 95%) (I2 = 55%, p = 0.08) and 83% with a minimum 12-month follow-up (95% CI: 53%, 95%) (I2 = 26%, p = 0.26). Conclusions: Our study provides a preliminary estimate of PT's efficacy in PJIs and informs future comparative studies.

Asymptomatic Takayasu Arteritis With Critical Multivessel Stenosis.

Takayasu arteritis is characterized by blood vessel inflammation involving the aorta and its branches. We describe a patient with Takayasu arteritis with severe multivessel involvement and classic physical examination findings but virtually no symptoms because of the presence of extensive collateral circulation seen on computed tomography angiography and magnetic resonance angiography imaging.

Bacteriophage therapy and current delivery strategies for orthopedic infections: A SCOPING review.

OBJECTIVES: Interest in phages as adjunctive therapy to treat difficult infections has grown in the last decade. However, phage dosing and delivery for orthopedic infections have not been systematically summarized. METHODS: Following PRISMA-ScR guidelines, we conducted a SCOPING review through September 1st, 2023, of MEDLINE, Embase, Web of Science Core Collection, and Cochrane Central. RESULTS: In total, 77 studies were included, of which 19 (24.7%) were in vitro studies, 17 (22.1%) were animal studies, and 41 (53.2%) were studies in humans. A total of 137 contemporary patients receiving phage therapy are described. CONCLUSIONS: Direct phage delivery remains the most studied form of phage therapy, notably in prosthetic joint infections, osteomyelitis, and diabetic foot ulcers. Available evidence describing phage therapy in humans suggests favorable outcomes for orthopedic infections, though this evidence is composed largely of low-level descriptive studies. Several phage delivery devices have been described, though a lack of comparative and in-human evidence limits their therapeutic application. Limitations to the use of phage therapy for orthopedic infections that need to be overcome include a lack of understanding related to optimal dosing and phage pharmacokinetics, bacterial heterogeneity in an infection episode, and phage therapy toxicity.

Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Authorship Patterns in the Orthopaedic Journals of Low-Income and Lower-Middle-Income Countries.

Background: Extensive research collaborations exist between researchers from high-income countries (HICs) and those from low-income countries (LICs) and lower-middle-income countries (LMICs). Previous research has suggested that authors from LICs and LMICs are underrepresented as first and last authors in the orthopaedic literature on local populations, particularly in LICs. We present a bibliometric analysis of authorship solely in studies published in orthopaedic journals that are based in LICs and LMICs. Methods: The Global Index Medicus was queried, and all articles published from January 1, 2010, to December 31, 2021, in journals with a focus on orthopaedic surgery that were based in an LIC or an LMIC were included. Logistic regressions were calculated to assess the predictors of local authorship. Results: Over 92% of studies included in our analysis had first or last authors from LICs or LMICs. In terms of study type, the majority (89%) of studies were clinical, although largely of low-level evidence (78% of clinical studies were case reports, case series, or descriptive studies). None received funding. LIC or LMIC first authorship and last authorship were less likely for most types of nonclinical studies. LIC or LMIC first authorship was more likely when there were more study authors. LIC or LMIC first authorship and last authorship were less likely when there were more countries affiliated with the study authors. Finally, when compared with studies with only LIC or LMIC authors, those with a combination of HIC and LIC or LMIC authors had significantly lower rates of LIC or LMIC first authorship (93.3% versus 62.5%) and last authorship (97.7% versus 70.8%). Conclusions: Our study presents one of the first analyses to assess authorship patterns in the orthopaedic literature of locally published journals in LICs and LMICs. Future studies are needed to contextualize our findings within a broader bibliometric landscape in order to better address the ongoing challenges to building research capacity in LICs and LMICs. Clinical Relevance: Our study highlights important observations regarding authorship in international, collaborative research in orthopaedics.

Impact of premorbid oral anticoagulant use on survival in patients with traumatic intracranial hemorrhage.

OBJECTIVE: Although oral anticoagulant use has been implicated in worse outcomes for patients with a traumatic brain injury (TBI), prior studies have mostly examined the use of vitamin K antagonists (VKAs). In an era of increasing use of direct oral anticoagulants (DOACs) in lieu of VKAs, the authors compared the survival outcomes of TBI patients on different types of premorbid anticoagulation medications with those of patients not on anticoagulation. METHODS: The authors retrospectively reviewed the records of 1186 adult patients who presented at a level I trauma center with an intracranial hemorrhage after blunt trauma between 2016 and 2022. Patient demographics; comorbidities; and pre-, peri-, and postinjury characteristics were compared based on premorbid anticoagulation use. Multivariable Cox proportional hazards regression modeling of mortality was performed to adjust for risk factors that met a significance threshold of p < 0.1 on bivariate analysis. RESULTS: Of 1186 patients with a traumatic intracranial hemorrhage, 49 (4.1%) were taking DOACs and 53 (4.5%) used VKAs at the time of injury. Patients using oral anticoagulants were more likely to be older (p < 0.001), to have a higher Charlson Comorbidity Index (p < 0.001), and to present with a higher Glasgow Coma Scale (GCS) score (p < 0.001) and lower Injury Severity Score (ISS; p < 0.001) than those on no anticoagulation. Patients using VKAs were more likely to undergo reversal than patients using DOACs (53% vs 31%, p < 0.001). Cox proportional hazards regression demonstrated significantly increased hazard ratios (HRs) for VKA use (HR 2.204, p = 0.003) and DOAC use (HR 1.973, p = 0.007). Increasing age (HR 1.040, p < 0.001), ISS (HR 1.017, p = 0.01), and Marshall score (HR 1.186, p < 0.001) were associated with an increased risk of death. A higher GCS score on admission was associated with a decreased risk of death (HR 0.912, p < 0.001). CONCLUSIONS: Patients with a traumatic intracranial injury who were on oral anticoagulant therapy before injury demonstrated higher mortality rates than patients who were not on oral anticoagulation after adjusting for age, comorbid conditions, and injury presentation.

Long-term outcomes among adults with Langerhans cell histiocytosis.

Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

Epidemiology of Gunshot-Related Spinal Injuries and Related Risk Factors for In-Hospital Mortality in the United States from 2015-2019: A National Trauma Data Bank Analysis.

Firearm injuries in the U.S. pose a significant public health burden, but data on gunshot wounds (GSWs) specifically involving the spine are scarce. We examined epidemiological trends in GSWs to the spine and associated spinal cord injury (SCI) and mortality rates. This was a cross-sectional study of data from level I-III trauma centers in the U.S. participating in the American College of Surgeons National Trauma Data Bank (ACS NTDB) in 2015-2019. We identified adult and pediatric patients presenting with GSW and evaluated those with Abbreviated Injury Scale codes indicating spinal involvement and SCI. We assessed in-hospital mortality and GSW-related SCI. A total of 5,021,316 patients were enrolled in the ACS NTDB. Of the 107,233 patients (2.1% of total) presenting with GSW, 9023 (8.4%) patients had spine involvement. Overall rates of GSW and spinal GSW were similar across years. The most common cause of spinal GSW injury was assault (86.7%). The cervical spine was involved in 24.2% of patients, thoracic spine in 42.8%, and lumbar spine in 39.7%. Cervical SCI was present in 8.7% of all spinal GSW (35.7% of cervical GSW), thoracic SCI in 17.4% (40.6% of thoracic GSW), and lumbar SCI in 8.1% (20.3% of lumbar GSW). The mean patient age was 29.0 ± 12.2 years, 88.5% were male, 62.4% were black, 23.7% were white, and 13.9% were another race. Blood alcohol content was ≥0.08 in 12.1%, and illicit drugs were positive in 24.4%. In-hospital mortality was high in patients with spinal GSWs (8.1%), and mortality was significantly higher with cervical involvement (18.1%), cervical SCI (30.7%), or thoracic incomplete SCI (13.6%) on univariate analysis. On multi-variate analysis of age (excluding patients <16 years of age), sex, Injury Severity Score (ISS), complete SCI, and spinal area of involvement, only greater patient age (age 40-65 years: adjusted odds ratio [aOR] 1.52, 95% confidence interval [CI] 1.09-2.11, p = 0.014; age >65 years: aOR 3.90, 95% CI 2.10-7.27, p < 0.001) and higher ISS (ISS 9-15: aOR 6.65, 95% CI 2.38-18.54, p < 0.001; ISS 16-24: aOR 18.13, 95% CI 6.65-49.44, p < 0.001; ISS >24: aOR 68.44, 95% CI 25.39-184.46, p < 0.001) were independently associated with in-hospital mortality risk after spinal GSW. These results demonstrate that spinal GSW is not uncommon and that older patients with more severe systemic injuries have higher in-hospital mortality risk.

FDG PET/CT and thyroid biopsy leads to neurosarcoidosis diagnosis.

We present a unique case of neurosarcoidosis diagnosed based on thyroid biopsy and FDG PET (Fluorodeoxyglucose positron emission tomography) imaging. A patient presented for a second opinion after being placed in hospice for rapidly progressing dementia, presumed to be due to Creutzfeldt Jakob disease despite negative workup and was unable to perform activities of daily life or communicate with his wife. The patient underwent a workup including whole-body FDG PET, which showed hypermetabolic lymph nodes as well as a hypermetabolic nodule in the thyroid. Biopsy of the lymph nodes was nondiagnostic, but the thyroid biopsy tissue yielded a diagnosis of sarcoid. After ruling out other causes and reviewing the tissue pathology, the patient was diagnosed with systemic sarcoidosis with neurological involvement and started on infliximab with rapid improvement.

BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

Metabolic PET/CT analysis of aggressive Non-Hodgkin lymphoma prior to Axicabtagene Ciloleucel CAR-T infusion: predictors of progressive disease, survival, and toxicity.

PET/CT is used to evaluate relapsed/refractory non-Hodgkin lymphoma (NHL) prior to chimeric antigen receptor T-cell (CAR-T) infusion at two time points: pre-leukapheresis (pre-leuk) and pre-lymphodepletion chemotherapy (pre-LD). We hypothesized that changes in PET/CT between these time points predict outcomes after CAR-T. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and other metrics were calculated from pre-leuk and pre-LD PET/CT scans in patients with NHL who received axicabtagene ciloleucel, and assessed for association with outcomes. Sixty-nine patients were analyzed. While single time point PET/CT characteristics were not associated with risk of PD or death, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p < 0.05 for all). LASSO analysis identified increasing extranodal MTV and increasing TLG of the largest lesion as strong predictors of death (AUC 0.74). Greater pre-LD total MTV was associated with higher risk of grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS) (p = 0.042). Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of progression and death. A two variable risk score stratifies prognosis prior to CAR-T infusion and may inform risk-adapted strategies.

Outcomes of Adolescent T-condylar Fractures: Kids Do Not Always Make You Look Good.

BACKGROUND: Optimal treatment for pediatric and adolescent T-condylar fractures remains poorly understood. We sought to assess how functional outcomes and range of motion (ROM) after surgical fixation of T-condylar fractures are affected by patient and surgical factors. METHODS: This is a retrospective cohort study of 52 patients with operatively treated T-condylar fractures at a single tertiary pediatric referral center between 2003 and 2021. All patients younger than 18 at the time of injury with a radiographically confirmed diagnosis were included. RESULTS: Fifty-two T-condylar fractures were included, with a mean patient age of 12.9 years (SD, 2.8). The cohort was 65% male. Nine (19%) fractures were open, 46% (24/52) were AO type C2, and 33% (17/52) occurred in skeletally mature individuals. The surgical approach was through olecranon osteotomy in 29% (15/52) of patients, and fixation included anatomically specific plates and screws in 42% (22/52) of patients. In our cohort, 46% (24/52) achieved good outcomes based on Jarvis ROM criteria and 42% (22/52) achieved good to excellent results based on Roberts functional criteria. The median loss of ROM was 58 degrees at 6 weeks, 20 degrees at 3 and 6 months, and 8 degrees at 1 year postoperatively. We observed a complication rate of 54% (28/52). Patients undergoing adult-type plate fixation had better postoperative range of motion at 6 weeks (ROM loss 52 vs. 80 degrees, P =0.03) and 3 months (10 vs. 35 degrees P =0.004) compared with pediatric-type fixation and trended towards better functional outcomes. We did not identify significant differences in functional outcome scores or complication rates with respect to surgical approach or skeletal maturity. CONCLUSIONS: Surgical fixation of pediatric and adolescent T-condylar fractures achieved a good to excellent functional outcome in only a minority of patients (46% Jarvis / 42% Roberts) with a high rate of postoperative complications (54%). Future work is needed to elucidate optimal treatment to minimize complications and achieve the best functional outcomes in these challenging fractures. LEVEL OF EVIDENCE: Level-IV.

Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells.

Malignant histiocytoses (MHs), or the 'M group' of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.

Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation.

Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based 'omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.