Multisystem Presentation Research Articles

Case Report: A male newborn with occipital horn syndrome

Occipital horn syndrome (OHS) is a rare genetic disease and copper transport disorder caused by a faulty ATP7A gene with multisystemic presentations, most originally related to musculoskeletal and connective tissue affections. In our case, a male neonate with OHS presented soon after birth with pathognomonic occipital exostosis, cutis laxa at the nape region, and widely opened skull sutures and fontanels. A skeletal survey showed occipital exostosis projecting from the line of insertion of the trapezius muscle and wide fontanels on skull X-ray films with no exostoses or deformities elsewhere. In addition to our case report being the second reported case for the condition detected early in the neonatal period, it also emphasizes the importance of investigating any sign thoroughly, as it may be an early alarming sign of a progressive disease that may affect the patient’s quality of life. In addition, it highlights the value of early diagnosis and multidisciplinary management of these patients.

Multisystemic Presentation of Disseminated Renal Cell Carcinoma

Multisystemic Presentation of Disseminated Renal Cell Carcinoma

Psoriasis management tree based on comorbidity.

Psoriasis, a common chronic inflammatory skin disorder, encompasses various subtypes, including guttate, pustular, erythrodermic, and the most common type, plaque psoriasis. Irrespective of the subtype, psoriasis can manifest with multisystemic presentations, including psoriatic arthritis, metabolic disorders, cardiovascular disease, malignancies, chronic kidney disease (CKD), psychiatric illness, and inflammatory bowel disease (IBD). Many comorbidities and concomitant conditions must be considered when selecting the most appropriate therapy for a patient (Kaushik etal., 2019 and Monks etal., 2021) . Ongoing clinical trials and the development of new therapeutic targets contribute to the continuous improvement of available treatment options. Given the dynamic landscape of therapies, particularly when managing complex patients with multiple comorbidities, dermatologists are constantly challenged with the task of adeptly tailoring treatments to each psoriasis patient. This article systematically reviews the current evidence, presenting it as an updated Psoriasis Decision Tree to assist physicians in selecting tailored treatment options.

Haemato-radiology: the role of the radiologist at MDT.

Haemato-radiology represents a relatively newly emerging, vast, and complex area of diagnostic imaging. Its complexity arises from the multimodality nature of patient assessment, the multisystem presentation of haematological malignancies and their complications, and the volume of imaging required for diagnosis and follow-up of the fifth most common malignancy type in the United Kingdom. Decisive and accurate assessment of disease by radiologists is at the heart of the haemato-oncology multidisciplinary team (MDT) and therefore essential for providing optimal patient care. We hope to support radiologists leading the MDT by streamlining the vast information in this field, emphasizing the most recent, evidence-based guidelines, and internationally accepted criteria for reporting imaging of lymphoma and myeloma. We also cover the various disease and treatment complications frequently presented to the MDT.

Neurodevelopmental profiles of 14 individuals with phosphomannomutase deficiency (PMM2-CDG).

PMM2-CDG (formerly CDG-1a), the most common type of congenital disorders of glycosylation, is inherited in an autosomal recessive pattern. PMM2-CDG frequently presents in infancy with multisystemic clinical involvement, and it has been diagnosed in over 1000 people worldwide. There have been few natural history studies reporting neurodevelopmental characterization of PMM2-CDG. Thus, a prospective study was conducted that included neurodevelopmental assessments as part of deep phenotyping. This study, Clinical and Basic Investigations into Known and Suspected Congenital Disorders of Glycosylation (NCT02089789), included 14 participants (8 males and 6 females ages 2-33 years) with a confirmed molecular diagnosis of PMM2-CDG. Clinical features of PMM2-CDG in this cohort were neurodevelopmental disorders, faltering growth, hypotonia, cerebellar atrophy, peripheral neuropathy, movement disorders, ophthalmological abnormalities, and auditory function differences. All PMM2-CDG participants met criteria for intellectual disability (or global developmental delay if younger than age 5). The majority never attained certain gross motor and language milestones. Only two participants were ambulatory, and almost all were considered minimally verbal. Overall, individuals with PMM2-CDG present with a complex neurodevelopmental profile characterized by intellectual disability and multisystemic presentations. This systematic quantification of the neurodevelopmental profile of PMM2-CDG expands our understanding of the range in impairments associated with PMM2-CDG and will help guide management strategies.

Case Report: A male newborn with occipital horn syndrome

Occipital horn syndrome (OHS) is a rare genetic disease and copper transport disorder caused by a faulty ATP7A gene with multisystemic presentations, most originally related to musculoskeletal and connective tissue affections. In our case, a male neonate with OHS presented soon after birth with pathognomonic occipital exostosis, cutis laxa at the nape region, and widely opened skull sutures and fontanels. A skeletal survey showed occipital exostosis projecting from the line of insertion of the trapezius muscle and wide fontanels on skull X-ray films with no exostoses or deformities elsewhere. In addition to our case report being the second reported case for the condition detected early in the neonatal period, it also emphasizes the importance of investigating any sign thoroughly, as it may be an early alarming sign of a progressive disease that may affect the patient’s quality of life. In addition, it highlights the value of early diagnosis and multidisciplinary management of these patients.

Retrospective Analysis of the Outcomes of Genetic Testing in Patients Suspected to Have Hereditary Hearing Loss or Deafness.

Uncorrected hearing loss can result in detrimental sequelae. Research addressing clinical presentation and genetic testing would inform clinical decision making. A retrospective chart review of 96 patients aged 1 month to 46 years (median age = 6 years) diagnosed with hearing loss or deafness and who underwent genetic testing at University of Rochester Medical Center from 2011 to 2021. Chi-square and Fisher's exact tests examined the relationship between a diagnostic positive genetic test result and various characteristics of hearing loss, including congenital (n = 52), noncongenital (n = 34), prelingual (n = 53), postlingual (n = 33), progressive (n = 13), not progressive (n = 47), bilateral (n = 67), unilateral (n = 26), sensorineural (n = 68), conductive (n = 14), mixed (n = 5), syndromic (n = 10), and nonsyndromic (n = 87) hearing loss. We also examined the number of patients with presence of developmental disabilities (n = 35), having a first-degree relative with hearing loss (n = 19), having hearing aids or cochlear implants (n = 45), and having a multisystem presentation prior to diagnosis (n = 45). Patients with sensorineural hearing loss (44.1%) had significantly more diagnostic positive results than those with mixed (0%) or conductive hearing loss (21.4%), p = .004. However, significantly fewer patients with disabilities (19.4%) had diagnostic positive tests than those without disabilities (43.3%), p < .05. More patients with a multisystem presentation were also found to have syndromic causes of hearing loss (23.3%) than patients who did not have a multisystem presentation, p < .05. Our study suggests a significant association between sensorineural type of hearing loss and a diagnostic positive genetic test result, while the presence of disabilities was significantly associated with a nondiagnostic genetic test result. Knowledge of these findings is critical for understanding the cause of the hearing loss, identifying other associated symptoms, and determining risk to family members.

ERBIN and phosphoglucomutase 3 deficiency.

ERBIN and phosphoglucomutase 3 (PGM3) mutations both lead to rare primary atopic disorders characterized by allergic disease and connective tissue abnormalities, though each disorder has its own rather unique pattern of multisystem presentations. Pathway studies show how ERBIN mutations allow for enhanced TGFb signaling, and prevent STAT3 from negative-regulating TGFb signaling. This likely explains many elements of clinical overlap between disorders of STAT3 and TGFb signaling. The excessive TGFb signaling leading to increased IL-4 receptor expression also provides the rationale for precision-based therapy blocking the IL-4 receptor to treat the atopic disease. The mechanism by which PGM3 deficiency leads to atopic phenotypes is not well understood, nor is the broad variability in disease penetrance and expressivity, though preliminary studies suggest an overlap with IL-6 receptor signaling defects.

Multisystem presentation of Late Onset Pompe Disease: what every consulting neurologist should know.

Pompe disease is a rare, autosomal recessive, lysosomal disorder caused by deficiency of alpha glucosidase (GAA). It leads to the accumulation of glycogen in body tissues, with severe myopathy and cardiomegaly as a hallmark of the classic infantile form. Non-classical, or late onset, Pompe disease (LOPD) manifests after 12 months of age or in adulthood. The clinical heterogeneity of LOPD causes delay in diagnosis and pharmacological treatment. In the Polish population, it is still underdiagnosed, and the time from onset to diagnosis remains a cause for concern. Although typically patients present with proximal muscle weakness, high CK or early respiratory insufficiency, they can also suffer from multiple symptoms from other organs. Patients may present with arrhythmias, vascular abnormalities including aneurysms or dilative arteriopathy, gastric or urinary symptoms, or musculoskeletal pathologies. A high index of suspicion among neurologists consulting internal medicine wards would aid early diagnosis of LOPD, while a multidisciplinary approach with the involvement of other specialists can reduce the risk of complications and improve the prognosis for LOPD patients. Patients who manifest with musculoskeletal and respiratory symptoms are prone to be diagnosed sooner than individuals with non-muscular symptoms, and therefore it is important to raise awareness of other manifestations of this disease.

Identifying Neuroimaging Patterns in Mitochondrial Leukoencephalopathies (P8-4.001)

<h3>Objective:</h3> To identify patterns of white matter involvement in mitochondrial disease. <h3>Background:</h3> Mitochondrial disease has been estimated to affect 1 in 4300 individuals. Primary mitochondrial diseases (PMD) are caused by pathogenic variants in &gt;300 genes. PMD can present at any age with an average of 16 multi-systemic symptoms per patient and often involves the neurological system due to its high metabolic demand. There is limited knowledge regarding mitochondrial leukoencephalopathies. In this study, we reviewed patterns of white matter involvement on MRI in patients with genetically confirmed PMD. <h3>Design/Methods:</h3> Retrospective chart review of 186 patients with genetically confirmed PMD was conducted. MRI studies available for 153 patients were analyzed to identify presence of white matter involvement. Neuroimaging patterns were delineated based on location, type of involvement (leukodystrophy vs hypomyelination), T1 and T2 appearance, cystic changes, volume loss, atrophy, restricted diffusion, contrast enhancement and associated brain structure involvement. Information was collected regarding CSF protein level, plasma lactate level, and lactate peak on magnetic resonance spectroscopy. <h3>Results:</h3> White matter involvement was observed in 61 out of 153 patients with MRI studies available to review. Genetic diagnosis of these patients included genes involved in mtDNA translation (<i>C12ORF65, MRPS34, RMND1</i>), mtDNA depletion (<i>FBXL4</i>), oxidative phosphorylation (<i>AIFM1, EARS2, CARS2, FARS2, VARS2</i>), complex I function (<i>NDUFS1, NUBPL</i>), complex II function (<i>SDHB</i>), complex IV function (<i>SURF1</i>), single large scale mtDNA deletion, mtDNA transcription (<i>MT-TL1</i>), pyruvate dehydrogenase complex (<i>PDH, ECHS1, PDHA1</i>) and thiamine transport (<i>SLC19A3</i>). Leukodystrophy pattern was seen in 14 while hypomyelination was observed in 16 patients. Location was periventricular in 23, diffuse in 15 and involving corpus callosum in 25 patients. Restricted diffusion was observed in 18, cystic changes in 10, volume loss in 14 and associated cerebral/cerebellar atrophy in 11 patients. <h3>Conclusions:</h3> Leukoencephalopathy with specific imaging patterns in neurologically complex patients with multisystemic presentations should warrant detailed evaluation for mitochondrial disease. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. James Peterson has nothing to disclose. CESAR ALVES has nothing to disclose. Dr. Goldstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reneo Pharmaceuticals .

Identifying Lesions of the Corpus Callosum in Patients with Neurofibromatosis Type I (P8-13.004)

<h3>Objective:</h3> To investigate the rate of lesions of the corpus callosum, including both unidentified bright objects (UBOs) and gliomas, in a large cohort of NF1 patients. <h3>Background:</h3> Neurofibromatosis type I is an autosomal dominant disorder with a multisystem presentation. Patients with NF1 are frequently found to have intracranial lesions, including areas of increased T2 signal intensity known as UBOs, as well as tumors known as gliomas. The presence of these lesions in the corpus callosum has not been studied in a large cohort. <h3>Design/Methods:</h3> We reviewed the medical records of 1373 patients (aged 3 months to 86 years) with NF1 followed at our institution over 2012–2021. Patients with UBOs or gliomas found on MRI in the corpus callosum were identified and recorded. <h3>Results:</h3> Of the 1373 patients analyzed, 34 were reported to have UBOs in the corpus callosum. This represents 6.3% of the 538 patients with any UBO. The majority of corpus callosum UBOs were in the splenium (41%), followed by the body (18%), and genu (12%). Nine patients were reported with corpus callosum gliomas, representing 5.6% of the 161 patients with any glioma. Of these, 7 (78%) were in the splenium. Over the course of follow-up imaging, 5/7 remained stable, 2/7 decreased in size and then stabilized, and 1/7 increased in size. <h3>Conclusions:</h3> Our study indicates a 2.5% and 0.7% prevalence of corpus callosum UBOs and gliomas, respectively. The majority of lesions are present in the splenium, and frequently remain stable over time. This adds to growing data regarding imaging findings in NF1 patients to better inform appropriate follow-up. <b>Disclosure:</b> Ms. Jandhyala has nothing to disclose. Dr. Garcia has nothing to disclose. Miss Kim has nothing to disclose. Dr. Segal has nothing to disclose. Dr. Yohay has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Astra Zeneca. Dr. Yohay has received publishing royalties from a publication relating to health care. An immediate family member of Dr. Yohay has received publishing royalties from a publication relating to health care.

Chapter 8 - Complex neurological and multisystem presentations in mitochondrial disease

Mitochondrial diseases typically involve organs highly dependent on aerobic metabolism and are often progressive with high morbidity and mortality. In the previous chapters of this book, classical mitochondrial phenotypes and syndromes are extensively described. However, these well-known clinical pictures are more the exception rather than the rule in mitochondrial medicine. In fact, more complex, unspecified, incomplete, and/or overlap clinical entities may be even more frequent, with multisystem appearance or progression. In this chapter, we describe some complex neurological presentations, as well as the multisystem manifestations of mitochondrial diseases, ranging from the brain to the other organs.

RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders.

Unmet Cardiac Clinical Needs in Adult Mucopolysaccharidoses.

The Mucopolysaccharidoses (MPSs) are a group of heterogenous disorders with complex multisystemic presentations. Although Haematopoietic Cell Transplantation (HCT) and Enzyme Replacement Therapy (ERT) have extended the lifespan of individuals affected with MPS well into adulthood, reversal of pre-existing cardiac, skeletal and neurocognitive deficits does not occur, so there are no truly curative treatments available to these patients at present. The medical and surgical management of cardiovascular problems in adults with MPS is complicated by these pre-existing comorbidities, requiring the involvement of multidisciplinary and multispecialty perioperative teams. This review sets out to describe the unmet cardiac needs in adults with MPS disorders including the lack of effective treatments, monitoring guidelines, and the challenges regarding expertise and training, and psychosocial support.

Gastrointestinal Features of 22q11.2 Deletion Syndrome Include Chronic Motility Problems From Childhood to Adulthood.

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome and has a multisystemic presentation including gastrointestinal features that have not yet been fully described. Our aim was to examine lifetime gastrointestinal problems in a large cohort of patients with 22q11.2DS. All patients followed in the 22q and You Center at the Children's Hospital of Philadelphia (n = 1421) were retrospectively screened for: 1) age ≥ 17 years, 2) documented chromosomal microdeletion within the 22q11.2 LCR22A-LCR22D region, and 3) sufficient clinical data to characterize the adult gastrointestinal phenotype. Gastrointestinal problems in childhood, adolescence, and adulthood were summarized. Statistical association testing of symptoms against other patient characteristics was performed. Included patients (n = 206; 46% female; mean age, 27 years; median follow-up, 21 years) had similar clinical characteristics to the overall cohort. Genetic distribution was also similar, with 96% having deletions including the critical LCR22A-LCR22B segment (95% in the overall cohort). Most patients experienced chronic gastrointestinal symptoms in their lifetime (91%), but congenital gastrointestinal malformations (3.5%) and gastrointestinal autoimmune diseases (1.5%) were uncommon. Chronic symptoms without anatomic or pathologic abnormalities represented the vast burden of illness. Chronic symptoms in adulthood are associated with other chronic gastrointestinal symptoms and psychiatric comorbidities ( P < 0.01) but not with deletion size or physiologic comorbidities ( P > 0.05). One exception was increased nausea/vomiting in hypothyroidism ( P = 0.002). Functional gastrointestinal disorders (FGIDs) are a common cause of ill health in children and adults with 22q11.2DS. Providers should consider screening for the deletion in patients presenting with FGIDs and associated comorbidities such as neuropsychiatric illness, congenital heart disease, and palatal abnormalities.

Multisystemic Presentation of Iliac Venous Compression disease (May-Thurner Syndrome) that Improves or Resolve after Intervention: A Single-Center Experience of a 189-Patient Analysis of Nonthrombotic Compression Intervention and Outcome

We present analysis of about 200 patient out of 500+ nonthrombotic iliac venous compression interventions to demonstrate that patients symptoms are far ranging that includes cardiovascular (postural orthostatic tachycardia syndrome), pulmonary, gastrointestinal, genitourinary, gynecological, orthopedic, and neurologic manifestations that improve or resolve after intervention. Awareness and inclusion of multisystemic symptoms in evaluating May-Thurner Syndrome patients is paramount in understanding venous diseases.

Immunophenotypical and pathological changes in dogs experimentally infected with Ehrlichia canis.

Canine monocytic ehrlichiosis (CME) is one of the most important tick-borne diseases worldwide, with multisystemic presentations. Immune dysregulation has been proposed as the primary mechanism involved in its pathogenesis and in tissue injury in dogs with CME. Experimental infection of German Shepherd dogs in the present study demonstrated that CME caused marked pathological changes in their lymph nodes and spleen, and also gave rise to mononuclear infiltration in organs and tissues. Immunophenotyping of cells in lymph nodes, spleen and injured tissues highlighted differences in lymphocyte subsets, local expression of immunoglobulin subclasses and MHCII molecules between infected and control dogs. These findings suggest that the immunophenotypic and immunopathological changes in dogs with acute experimental CME are related to Th1 bias and compartmentalized immune response.

"CNS MELIOIDOSIS" IN YOUR ESTEEMED JOURNALAS A CASE REPORT

CNS Melioidosis is a rare and complicated form of Melioidosis with a mortality rate of up to 50%. We hereby present a case of CNS Melioidosis with bacteremia and pulmonary manifestations of Melioidosis based on CT Chest imaging ndings, who on prompt initiation of appropriate IV antibiotic therapy along with craniotomy and drainage of cerebral abscess showed drastic recovery. This indolent multi systemic presentation along with the rarity of CNS Melioidosis in general, makes this case report note-worthy.

A clinical registry of multisystemic presentation of hypovitaminosis D in hospital attendees in Kolkata

Background: Vitamin D (Vit D) is a steroid hormone essential for maintaining functional homeostasis in the body. Hypovitaminosis D has been a recognized worldwide problem affecting all age groups and sex. Its prevalence is very high in South Asia. Aims and Objectives: Therefore, this study was aimed to determine the spectrum of presentation of biochemical levels of hypovitaminosis D in Indian population in terms of age, sex, and multisystemic disorders. Materials and Methods: A cross-sectional study carried out on selective study population attending a tertiary care hospital from July 2019 to December 2020 with clinical presentations suspected to arise due to Vit D deficiency. Serum 25OH Vit D level was estimated by chemiluminescence method. Data were analyzed using GraphPad Prism 8. Results: Of the study population (n = 685), average serum 25(OH)D level in females and males was 24.13 ng/ml and 28.59 ng/ml, respectively. Significant difference in mean value of Vit D existed in males and females in the 21–40 years age group (p = 0.0048). Females in the Vit D deficient group (Vit D level&lt;20) mostly presented with mastalgia (20.45%), low back pain (17.61%), and joint pain (11.36%). Common clinical presentation in males with Vit D levels less than 20 ng/ml was diabetes mellitus without CKD (18.34%), non-diabetic CKD (19.27%), and low back pain (16.51%). Conclusion: Low Vit D levels manifest itself as signs and symptoms involving various multisystemic disorders involving different age groups in both sexes. Early recognition and replacement can prevent the progress of complications which Vit D deficiency makes us prone to develop.

Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations

SummaryHuman mitochondrial RNase P (mt-RNase P) is responsible for 5′ end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.