Atypical Variants Research Articles

Cats: The New Challenge for Rabies Control in the State of Yucatan, Mexico.

The growing population in Yucatan has led to the expansion of construction in the Mayan jungle for tourist spaces, residential areas, and agriculture. Recently, rabies cases in cats (Felis catus) have increased in the state. This study aimed to perform antigenic and genetic characterization of the rabies viruses in felines and to present the spatial distribution and environmental features of the areas where these cases were reported. The ArcGIS software and R were employed to generate maps depicting the geographic locations of rabies cases in cats. A total of nine feline rabies cases occurred during the period 2003-2022. Three antigenic variants were detected: dog-related RVV1 (n = 1); vampire bat variant RVV3 (n = 1); and the canine-originated atypical variant (n = 7). Cases reported in Merida (n = 4) and Muna (n = 4) were localized to urban areas, while Cuncunul (n = 1) was rural. This study highlights the concerning resurgence of rabies infections in cats, emphasizing the looming threat of its reintroduction in dogs should vaccination rates diminish. The genetic affinity between the atypical variant and the canine virus underscores the urgent need for vigilance in maintaining high vaccination coverage across all susceptible species.

8623 Atypical VHL Genetic Variant Causing Paraganglioma

Abstract Disclosure: G. Mangu: None. J.J. Faria Briceno: None. R. Yatavelli: None. Abstract: Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell tumors that originate from the adrenal medulla and extra-adrenal paraganglia respectively. Previous studies have shown that incidental PPGLs are seen in older patients with mild symptoms. They have lower levels of plasma catecholamines and lower incidence of malignancy than patients with nonincidental PPGLs. We report a case of an incidental paraganglioma in a young female with atypical pathogenic variant in the VHL gene which is known to cause familial erythrocytosis but NOT VHL syndrome or PPGL. Case Presentation: A 33-year-old African American female with no significant medical history presented to the emergency room with the chief complaint of right lower quadrant pain for 2 days, which started with her menstruation. The vitals were BP 128/67, pulse 67 and physical examination was unremarkable. CT showed a 4.0 x 3.0 cm heterogenous enhancing left adrenal mass and MRI with adrenal protocol revealed 3.4 x 3.1 cm mass consistent with pheochromocytoma. Labs revealed elevated plasma nor metanephrines and 24-hour urine normetanephrines were 1020 mcg. She was asymptomatic without hypertension, palpitations, or chest pain. She underwent laparoscopic left adrenalectomy after appropriate alpha blockade. The pathology report showed left periadrenal paraganglioma with immunohistochemistry staining significant for Carbonic anhydrase IX (CAIX) membranous expression which is mostly seen in paragangliomas associated with von Hippel-Lindau syndrome. Clinically, she did not have any stigmata for hereditary PPGL syndrome. Her genetic testing revealed a pathogenic heterozygous variant in the VHL gene, Exon 3, c.598C.T (pArg200Trp), which is a missense variant expected to disrupt VHL protein function. Although she has a germline mutation in VHL, it is not the garden variant which is associated with classic VHL syndrome. It has been reported to cause autosomal recessive erythrocytosis but not PPGL. Conclusion: The pathogenic heterozygous variant in VHL gene, Exon 3, c.598C.T (pArg200Trp) is known to cause autosomal recessive familial erythrocytosis type 2 in the Chuvash population, termed as Chuvash Polycythemia. Our patient did not have polycythemia but had iron deficiency anemia from menorrhagia. Several studies have reported that this variant does not cause VHL syndrome, however it has been reported in a single family with VHL syndrome but WITHOUT pheochromocytoma. To our knowledge, incidental adrenergic paraganglioma associated with this mutation has not been reported in the literature. Presentation: 6/3/2024

Clinical case of an atypical variant of Labbe's vein structure in a patient with pharmacoresistant temporal epilepsy

Among the commonly recognised structural lesions that cause drug-resistant temporal lobe epilepsy, such as mesial temporal sclerosis, focal cortical dysplasia, benign intracerebral tumors, arteriovenous malformations and cavernous angiomas, researchers have recently noted other pathologies, such as, encephalocele. There are a number of publications on the connection between epilepsy and cerebral venous angiomas. However, there are no published cases of the influence of the abnormal structure and location of normal cerebral vessels on the development of epilepsy. This article presents a case of an atypically large and unusually located vein of Labbe that may have been involved in epileptogenesis and also complicated an anteromedial temporal lobectomy. Forced coagulation and excision of the Labbe vein during surgery did not lead to venous infarction and neurological deficit.

Variants of the Architectonics of the Internal Iliac Vein and Their Applications

The aim was to study the variants of the formation and architectonics of the internal iliac vein (IIV) using postvital and vital methods of research. Material and methods. Typical and atypical variants of the trunk formation, architectonics and skeletotopy of the IIV were studied on the postvital material (n=70) and with the help of three-dimensional modeling of the IIV according to the computer tomographic angiography data (n=400). Results. According to the three-dimensional modeling data, in 90,25% of observations the fusion of the IIV and the external iliac vein (EIV) was typical, when the trunk of the common iliac vein (CIV) was formed. In 9,75% - atypical, when the IIV did not participate in the formation of the trunk of the CIV, but flowed into the opposite CIV, into the confluence of the inferior vena cava, separate trunks of the IIV flowed into the EIV. Based on the evaluation of the whole material under study, the IIV architectonics was typical in 48,3% and atypical in 51,7%. In a typical variant of the IIV architectonics, the main trunk is supplied by the iliolumbar vein (ILV), the posterior trunk is supplied by the superior lateral sacral vein (LSV), superior gluteal vein (SGV), and in the anterior trunk - the obturator vein (OV), lower LSV, internal pudendal vein (IPV) and inferior gluteal vein (IGV). Atypical variants of the IIV architectonics can be divided into 5 groups depending on the peculiarities of the influx of its main tributaries: 1 - atypical influx of the IGV (2,9%), 2 - SGV (2,1%), 3 - OV (16,8%), 4 - ILV (9,9%), 5 - LSV (20%). In 2% of cases anastomoses between IIV and EIV were revealed, in 30,6% - between anterior and posterior trunks of IIV. In the majority of cases, the fusion of the IIV and EIV was located at the level of the first sacral vertebral body, while the fusion of the anterior and posterior trunks of the IIV was at the level of the S1-S2 intervertebral disc. Conclusion. The obtained data should be used when planning and performing surgical interventions on pelvic organs, especially in evisceration.

Laparoscopic transabdominal preperitoneal repair for a patient with Laugier’s and inguinal hernia

BackgroundLaugier’s hernia is a very rare atypical femoral hernia and is challenging to diagnose preoperatively. Herein, we report a rare case of inguinal and Laugier’s hernias treated with laparoscopic transabdominal preperitoneal repair.Case presentationA 63-year-old man was admitted to our hospital with right groin swelling for 4 years. Computed tomography revealed an indirect inguinal hernia with protrusion of the small intestine. The preoperative diagnosis was right indirect inguinal hernia; Laugier’s hernia was unknown. The patient underwent laparoscopic transabdominal preperitoneal repair. During the surgery, part of the perivesical adipose tissue penetrated the lacunar ligament. It was located medial to the typical site of a femoral hernia. Thus, Laugier's hernia was diagnosed. Finally, laparoscopic transabdominal preperitoneal repair was performed for Laugier's hernia and inguinal hernia. The postoperative course was good, without recurrence.ConclusionsTo our knowledge, this is the first reported case of inguinal and Laugier’s hernia treated with laparoscopic transabdominal preperitoneal repair. Surgeons should be mindful that inguinal hernias can occur concurrently with other types of hernias, such as femoral hernias, including atypical variants like Laugier's hernia. Additionally, they should actively consider laparoscopic approaches such as transabdominal preperitoneal for femoral hernias. These approaches are beneficial for precise diagnosis, confirming the presence of other hernias, and simultaneously treating all coexisting inguinal hernias.

Atypical dermatofibroma simulating hansenoma

Introduction: dermatofibroma is a benign mesenchymal lesion of uncertain etiology, centered in the dermis, with fibroblastic and histiocytic differentiation. The atypical variant can mimic superficial sarcoma histologically. Objective: to describe the clinical and histopathological findings of atypical dermatofibroma in a patient undergoing treatment for leprosy with multiple therapeutic failures. Case Description: the report concerns a 39-year-old woman with multiple therapeutic failures for Virchowian leprosy, who developed an atypical dermatofibroma on the upper limb, which clinically resembled a leproma. Discussion: molecular analyses suggest dermatofibroma may be associated with a neoplastic process. However, several studies correlate it to trauma, insect bites, folliculitis, immunological changes, and treated or reactive leprosy. The association of dermatofibroma and leprosy, especially in the Virchowian pole, is documented in the literature. However, there are no reports of atypical dermatofibroma associated with leprosy. Final Considerations: this case adds to other studies regarding a possible association between the pathogenesis of dermatofibroma and the immunological aspects present in leprosy.

Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines. The pathogenic role of cysteine-sparing NOTCH3 mutations with typical clinical CADASIL syndrome is still debated. This review aimed to characterize NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL. Articles on NOTCH3 cysteine-sparing mutations with clinical suspicion of CADASIL were reviewed. Clinical and radiological cerebral phenotypes data were extracted and characterized across regions and compared with phenotypes of typical CADASIL patients. We screened 298 NOTCH3 cysteine-sparing mutation individuals from 20 publications, and mutations in exon 3 were the most frequently reported (21.46%). Gait impairment (76.47%), cognitive impairment (67.47%), and stroke (62.37%) were the three most common clinical phenotypes; the most frequent radiological cerebral phenotypes were lacunes (74.29%) and cerebral microbleeds (72.73%). Compared with CADASIL patients, cognitive impairment and cerebral microbleed frequencies were significantly higher in patients with NOTCH3 cysteine-sparing mutations, while the white matter hyperintensities in anterior temporal polar and external capsule were rarely observed. Compared with Western patients, radiological phenotypes were more common than clinical phenotypes in cysteine-sparing Asian patients. More than half of cysteine-sparing patients had positive granular osmiophilic material deposits. NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL mainly manifested with gait and cognitive impairment but rare white matter hyperintensities in anterior temporal pole and external capsule. Further studies are warranted to pay attention to atypical NOTCH3 variants, which could guide specific diagnosis and help unravel underlying mechanisms.

Towards novel classification of infants’ movement patterns supported by computerized video analysis

BackgroundPositional preferences, asymmetry of body position and movements potentially indicate abnormal clinical conditions in infants. However, a lack of standardized nomenclature hinders accurate assessment and documentation of these preferences over time. Video tools offer a safe and reproducible method to analyze and describe infant movement patterns, aiding in physiotherapy management and goal planning. The study aimed to develop an objective classification system for infant movement patterns with particular emphasis on the specific distribution of muscle tension, using methods of computer analysis of video recordings to enhance accuracy and reproducibility in assessments.MethodsThe study involved the recording of videos of 51 infants between 6 and 15 weeks of age, born at term, with an Apgar score of at least 8 points. Based on observations of a recording of infant spontaneous movements in the supine position, experts identified postural-motor patterns: symmetry and typical asymmetry linked to the asymmetrical tonic neck reflex. Deviations from the typical postural-motor system were indicated, and subcategories of atypical patterns were distinguished. A computer-based inference system was developed to automatically classify individual patterns.ResultsThe following division of motor patterns was used: (1) normal patterns, including (a) typical (symmetrical, asymmetrical: variants 1 and 2); and (b) atypical (variants: 1 to 4), (2) positional preference, and (3) abnormal patterns. The proposed automatic classification method achieved an expert decision mapping accuracy of 84%. For atypical patterns, the high reproducibility of the system’s results was confirmed. Lower reproducibility, not exceeding 70%, was achieved with typical patterns.ConclusionsBased on the observation of infant spontaneous movements, it is possible to identify movement patterns divided into typical and atypical patterns. Computer-based analysis of infant movement patterns makes it possible to objectify and satisfactorily reproduce diagnostic decisions.

Lemierre’s syndrome as a rare cause of septic pulmonary embolism (case report)

Objectives. The purpose of this work is to provide a clinical case study of Lemierre’s syndrome (LS) in order to raise awareness amongst doctors of various medical specialties regarding this rare cause of septic pulmonary embolism (SPE).Materials and methods. The patient in clinical case is a 25-year-old female who was hospitalized due to SPE, which had been complicated by respiratory distress, pneumothorax and septic shock. The initial source of embolus lung damage was the septic thrombosis of both the internal and external jugular veins. This thrombosis occurred against the backdrop of a carbuncle of the lower lip, an inflammatory infiltrate at the bottom of the mouth, an abscess in the soft tissue of the chin and neck cellulitis, which correspond to the diagnostic criteria for Lemierre Syndrome.Results. The literature data of the epidemiology, etiology, pathogenic mechanisms of the venous thrombosis, embolic and septic complications among patients with LS are presented. The article discusses the clinical features and course of the disease, as well as key aspects of diagnosis, including current diagnostic criteria, with regard to the typical and atypical variants of LS. The principles of antibiotic therapy and the possibility of anticoagulation therapy in cases of septic pulmonary emboli associated with head and neck vein thrombosis are also considered.Conclusion. LS is a rare, but clinically significant condition characterized by the development of septic thrombosis in the internal jugular vein in response to acute suppurative inflammation of the head and neck. In typical cases, the causative organism is Fusobacterium necrophorum, or other anaerobic bacteria. This pathological condition is often accompanied by multiple other septic complications, with the most significant being the development of septic pulmonary embolism. Clinical observation indicates the necessity for including LS in the differential diagnosis among causes of the septic pulmonary embolism, and for adopting a multidisciplinary approach in the treatment of these patients in a specialized multifield hospital. Identification and diagnosis of Lemierre Syndrome can be challenging due to its low incidence and variable clinical presentation. Although the condition is not widely recognized among physicians, an understanding of the basic principles of its diagnosis and management can significantly improve treatment outcomes and patients prognosis.

Coinfection of cotton plants with cotton leafroll dwarf virus‐atypical and a novel cotton begomovirus

AbstractCotton is a commercial crop of global importance whose versatile fibre is widely used in the textile industry. Cotton is vulnerable to infectious pathogens, including viruses, that are a major threat to cotton production. Cotton blue disease is caused by cotton leafroll dwarf virus (CLRDV), a polerovirus transmitted by aphids. This virus is controlled by sowing cotton varieties resistant to CLRDV, although, in recent years an atypical variant (CLRDV‐at), that breaks the resistance, has been identified. An outbreak of a disease occurred in cotton fields of the province of Chaco, in the north‐west of Argentina, in the 2014–2015 growing season. NuOpal cotton plants (a variety resistant to CLRDV and susceptible to CLRDV‐at) showed mosaic symptoms and had virus‐transmitting insect vectors, such as aphids and whiteflies (Bemisia tabaci). The symptoms were common for virus infections but different from those caused by CLRDV or CLRDV‐at. According to a reverse transcription‐PCR analysis with polerovirus primers and sequencing, the plants contained CLRDV‐at. To identify the complete virome of these plants, we performed a massive RNA‐based deep sequencing assay using Illumina technology. As a result, a new begomovirus that infects cotton in Argentina was identified. Structural and functional annotation indicated that its sequences corresponded to complete DNA components A and B of a novel New World bipartite begomovirus. Genetic distance and evolutionary analyses support that the detected sequences correspond to a new virus, which we propose to name cotton mosaic virus (CoMV). In addition, we report the first begomovirus and polerovirus coinfection in cotton.

XBB.1, BQ1.1 and atypical BA.4.6/XBB.1 recombinants predominate current SARS-CoV-2 Wavelets with flu-like symptoms in Cameroon: A snapshot from genomic surveillance.

As of December 2022, Cameroon had observed a slight resurgence of COVID-19, raising concerns on genomic surveillance of related-SARS-CoV-2 variants under circulation. Following a laboratory-based survey, positive SARS-CoV-2 samples detected from December-2022 through March-2023 were processed for targeted sequencing at the Chantal BIYA International Reference Centre (CIRCB) in Yaoundé-Cameroon. From all positive cases detected, 13 were successfully sequenced (mean age 34 years, 70% female); the majority of the cases were unvaccinated (70%, 9/13) and symptomatic (92%, 12/13); all with flu-like symptoms (100%, 12/12). Following RT-PCR, the median cycle threshold was 22.23 [18-24] for the N gene; and 24.09 [20-26] for the ORF gene, underscoring high viral loads. Phylogenetic analysis of nucleotide sequences identified four major sub-variants in circulation, of which BA.5 (3/13), the recombinants BQ.1.1 (4/13), XBB.1 (4/13) and novel atypical variant of BA.4.6/XBB.1 (2/13). This snapshot surveillance indicates the introduction/emergence and circulation of new Omicron sub-variants, all accompanied by minor/mild symptoms. However, these new sub-variants and recombinants call for continuous genomic surveillance to prevent further resurgence of Covid-19 epidemiological wave.

Comparing clinical profiles, in-hospital complications and one-year cerebrovascular events in typical and midventricular TTS-results from a retrospective study between two third-level centers

Abstract Funding Acknowledgements None. Background Apical ballooning is considered the typical form of Takotsubo syndrome (TTS) and occurs in about 75-80% of cases. Midventricular (MV) is the most frequent atypical variant and represents about 15% of TTS. Clinical and analytical characteristics, early complications and the risk of cerebrovascular events (CVEs) between these two specific groups are poorly studied. Purpose of the study To investigate the clinical profile, laboratory variables, in-hospital complications and one-year CVEs between typical and MV variants of TTS. Methods we retrospectively examined the patients admitted to two third-level hospitals with a diagnosis of TTS. A total of 248 TTS met InterTAK diagnostic criteria. Clinical features, myocardial enzymes, echocardiographic variables, early complications and one-year CVEs were assessed. Results Of 248 patients diagnosed with TTS, a total of 205 (83%) patients presented with typical and 43 (17%) with MV variant of TTS. Patients with MV form were younger (age mean ± SD 68 ± 12 vs 74 ± 11 years, p value = 0.002) and had a lower incidence of hypertension (46% vs 73%; p value < 0.001) than those with apical variant. On admission, patients with MV form presented a lower degree of left ventricular dysfunction (EF mean ± SD, 44 ± 9% vs 41 ± 9%, p value = 0.018) and a tendence not to present left ventricular outflow tract obstruction (LVOTO) (0 vs 9%, p value = 0.049). Lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels on admission (median [IQR], 881 [99 – 3049] pg/mL vs 3466 [677 - 9067] pg/mL, p value <0.001) and at peak (3150 [947- 4437] pg/mL vs 4622 [1886 - 13163] pg/mL, p value = 0.005) were observed in MV group compared to the typical form. In-hospital cardiovascular (CV) complications were frequently observed (46% in the overall population) and appeared to be more frequent in the typical variant (51% vs 33%, p value= 0.035); in particular, we reported a higher prevalence of AF (16% vs 2%, p value = 0.022). The number of CS and VT cases is remarkable in both the subgroups (13% vs 7%; 5% vs 2%), with a higher prevalence in the typical form, even if not reaching a statistically significant difference between the two groups (p= 0.437; p= 0.695). No significant differences were observed in LV thrombosis, and in on admission and one-year CVEs between the two groups, although with a higher prevalence in the typical variant (respectively 3 vs 0, 10 vs 1 and 5 vs 0). Conclusions MV TTS presents some differences in clinical characteristics, analytical values and echocardiographic parameters compared to the typical variant. In-hospital CV complications are remarkable, and more frequently observed in typical variant, although not reaching a statistically significant difference in CS and VT. Similarly, more CVE were observed in the typical TTS group, although in the absence of a statistical significance. The importance of close monitoring in the acute phase is confirmed for both variants under study.

When mycosis fungoides seems not to be within the spectrum of clinical and histopathological differential diagnoses.

The most prevalent primary cutaneous T-cell lymphoma, mycosis fungoides (MF), is characterized by the development of plaques and nodules after an erythematous patchy phase that is non-specific. An infiltrate of atypical small- to medium-sized cerebriform lymphocytes in the superficial dermis, with variable epidermotropism, is the histopathological hallmark of the disease. In more advanced stages of the illness, large-cell transformation may be seen. Early diagnosis of MF can be very challenging based only on histopathologic or clinical findings, so it is critical to have a clinical-pathological correlation. Many atypical variants of MF that deviate from the classic Alibert-Bazin presentation of the disease have been described over the past 30 years, sometimes with different prognostic and therapeutic implications. Clinically or histopathologically, they can mimic a wide range of benign inflammatory skin disorders. To make a conclusive diagnosis in these cases, it is recommended to take multiple biopsies from various lesions and to carefully correlate the clinical and pathological findings. We have outlined the various facets of the illness in this review, positioning MF as a "great imitator", with an emphasis on the more recently identified variations, differential diagnosis, and its benign mimics.

Systemic lupus erythematosus in dermatological practice

Despite significant advances in the study of the etiology and pathogenesis of systemic lupus erythematosus, the diagnosis of this disease is currently still causing certain difficulties. The active role of dermatologists in the early detection of systemic indicators of the process can be of key importance and be a consequence of a more favorable course of the disease with timely interdisciplinary interaction. A competent approach to monitoring patients, constructive interaction in tandem between a dermatologist and a rheumatologist is the key to reliable diagnosis and early initiation of pathogenetic treatment. With such a variety of clinical manifestations, especially in atypical variants of the disease, verification of the diagnosis is difficult. In this regard, the article presents descriptions of two clinical cases of systemic lupus erythematosus in dermatological practice.

Clinical laboratory characteristics and gene mutation spectrum of Ph-negative MPN patients with atypical variants of JAK2, MPL, or CALR.

To evaluate the incidence, clinical laboratory characteristics, and gene mutation spectrum of Ph-negative MPN patients with atypical variants of JAK2, MPL, or CALR. We collected a total of 359 Ph-negative MPN patients with classical mutations in driver genes JAK2, MPL, or CALR, and divided them into two groups based on whether they had additional atypical variants of driver genes JAK2, MPL, or CALR: 304 patients without atypical variants of driver genes and 55 patients with atypical variants of driver genes. We analyzed the relevant characteristics of these patients. This study included 359 patients with Ph-negative MPNs with JAK2, MPL, or CALR classical mutations and found that 55 (15%) patients had atypical variants of JAK2, MPL, or CALR. Among them, 28 cases (51%) were male, and 27 (49%) were female, with a median age of 64 years (range, 21-83). The age of ET patients with atypical variants was higher than that of ET patients without atypical variants [70 (28-80) vs. 61 (19-82), p = 0.03]. The incidence of classical MPL mutations in ET patients with atypical variants was higher than in ET patients without atypical variants [13.3% (2/15) vs. 0% (0/95), p = 0.02]. The number of gene mutations in patients with atypical variants of driver genes PV, ET, and Overt-PMF is more than in patients without atypical variants of PV, ET, and Overt-PMF [PV: 3 (2-6) vs. 2 (1-7), p < 0.001; ET: 4 (2-8) vs. 2 (1-7), p < 0.05; Overt-PMF: 5 (2-9) vs. 3 (1-8), p < 0.001]. The incidence of SH2B3 and ASXL1 mutations were higher in MPN patients with atypical variants than in those without atypical variants (SH2B3: 16% vs. 6%, p < 0.01; ASXL1: 24% vs. 13%, p < 0.05). These data indicate that classical mutations of JAK2, MPL, and CALR may not be completely mutually exclusive with atypical variants of JAK2, MPL, and CALR. In this study, 30 different atypical variants of JAK2, MPL, and CALR were identified, JAK2 G127D being the most common (42%, 23/55). Interestingly, JAK2 G127D only co-occurred with JAK2V617F mutation. The incidence of atypical variants of JAK2 in Ph-negative MPNs was much higher than that of the atypical variants of MPL and CALR. The significance of these atypical variants will be further studied in the future.

A Rare Concurrence of Polymorphic Pityriasis Rosea: Two Atypical Variants Along with a Classical Plaque Variant in the Pediatric Age Group

Pityriasis rosea, is an acute self-limiting papulosquamous inflammatory disorder. It usually starts with a herald patch on the trunk and proximal extremities, followed by scaly oval patches that give them a “Christmas tree” appearance. The lesions may be associated with fever a rash. The disease can present as numerous morphologies such as papular, urticarial, lichenoid, and generalized that may be confused with other conditions such as secondary syphilis, seborrheic dermatitis, nummular eczema, pityriasis lichenoides chronica, tinea corporis, viral exanthems, lichen planus, and PR like eruption linked to particular drugs. We report a rare case of polymorphic pityriasis rosea in paediatric age group.

Novel Synonymous and Deep Intronic Variants Causing Primary and Secondary Pyruvate Dehydrogenase Complex Deficiency

Pyruvate dehydrogenase complex deficiency (PDCD) is a defect of aerobic carbohydrate metabolism that causes neurological disorders with varying degrees of severity. We report the clinical, biochemical, and molecular findings in patients with primary and secondary PDCD caused by novel atypical genetic variants. Whole-genome sequencing (WGS) identified the synonymous variants c.447A&gt;G, p.(Lys149=) and c.570C&gt;T, p.(Cys190=) in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), the deep intronic variants c.1023+2267G&gt;A and c.1023+2302A&gt;G in pyruvate dehydrogenase complex component X (PDHX), and c.185+15054G&gt;A in thiamine pyrophosphokinase (TPK1). Analysis by Sanger and RNA sequencing of cDNA from patient blood and/or cultured fibroblasts showed that the synonymous variants in PDHA1 lead to aberrant splicing and skipping of exons 5 and 5-6 in one of the patients and transcripts lacking exon 6 in the other. The deep intronic variants in PDHX and TPK1 lead to insertion of intronic sequence in the corresponding transcripts. The splice defects in PDHA1 were more pronounced in cultured fibroblasts than in blood. Our findings expand the spectrum of pathogenic variants causing PDCD and highlight the importance of atypical variants leading to aberrant splicing. The severity of the splice defects and resulting biochemical dysfunction varied between tissues, stressing the importance of performing biochemical and transcript analysis in affected tissues. The two males with hemizygous synonymous PDHA1 variants have a mild phenotype and higher PDH enzyme activity than expected, which is consistent with aberrant but leaky splicing with a proportion of the transcripts remaining correctly spliced.

Abstract 950: Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort

Abstract The generation and widespread sharing of large somatic mutation datasets has revolutionized our understanding of genetic mechanisms driving cancer initiation and progression. For well-understood mutations, this has created the opportunity for individualized therapeutic intervention in a wide range of malignancies. Beyond these well-characterized mutations, there exists a wide range of alterations that remain poorly understood and which require some kind of functional genomics analysis to determine whether such patients are eligible for the targeted therapy used for more typical mutations in that gene, whether these alterations are passenger mutations that don’t affect throughput on the associated signaling pathway, or reflect another more nuanced phenomenon. Whether using ectopic overexpression in cell lines or generation of genetically modified mice, addressing this problem at scale using functional genomics approaches is challenging. A key limitation is the absence of the original tissue context in which that variant co-evolved with other genetic alterations as well as data on the clinical response of the patient to successive lines of therapy. This can be addressed, in part, by the banking of tissue from patient cohorts who have had comprehensive genomic profiling as part of their routine clinical care. The Gundersen Precision Oncology Cohort is a growing dataset of FFPE specimens and longitudinal clinical data from more than 750 patients who have had comprehensive cancer genome profiling using assays from a wide range of diagnostic companies. We use this resource for biomarker discovery and functional classification of many atypical cancer variants. Current subgroups include atypical point mutations in BRAF, ERBB2 and ERBB3, as well as fusions affecting BRAF, PIK3CA and ROS1. We present examples illustrating the value of this approach for classification of variants detected in a range of tumor types. Citation Format: Peter Feiszt, Paraic A. Kenny. Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 950.

Atypical clinical variants of Alzheimer's disease: are they really atypical?

Alzheimer's disease (AD) is a neuropathological disorder defined by the deposition of the proteins, tau and β-amyloid. Alzheimer's disease is commonly thought of as a disease of the elderly that is associated with episodic memory loss. However, the very first patient described with AD was in her 50's with impairments in multiple cognitive domains. It is now clear that AD can present with multiple different non-amnestic clinical variants which have been labeled as atypical variants of AD. Instead of these variants of AD being considered "atypical," I propose that they provide an excellent disease model of AD and reflect the true clinical heterogeneity of AD. The atypical variants of AD usually have a relatively young age at onset, and they show striking cortical tau deposition on molecular PET imaging which relates strongly with patterns of neurodegeneration and clinical outcomes. In contrast, elderly patients with AD show less tau deposition on PET, and neuroimaging and clinical outcomes are confounded by other age-related pathologies, including TDP-43 and vascular pathology. There is also considerable clinical and anatomical heterogeneity across atypical and young-onset amnestic variants of AD which reflects the fact that AD is a disease that causes impairments in multiple cognitive domains. Future studies should focus on careful characterization of cognitive impairment in AD and consider the full clinical spectrum of AD, including atypical AD, in the design of research studies investigating disease mechanisms in AD and clinical treatment trials, particularly with therapeutics targeting tau.

Late-life mood disorder as the initial presentation of progressive supranuclear palsy: A case series.

Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder characterized by Parkinsonism, supranuclear ophthalmoplegia, postural instability, and cognitive impairment. This case series describes three patients initially diagnosed with late-life mood disorders (depression and bipolar disorder) who were later diagnosed with PSP because of the development of typical neurological symptoms. The diagnostic challenge of PSP is highlighted in this case report, particularly in the early stages, when characteristic symptoms may not be present. The importance of considering PSP in the differential diagnosis of late-life mood disorders, especially in the absence of response to standard antidepressant therapy, is also emphasized. The heterogeneity of PSP is described, with various subtypes and atypical variants presenting with different clinical features. The psychiatric symptoms of PSP include apathy, disinhibition, depression, and anxiety, whereas hallucinations and delusions are less frequent. Tau positron emission tomography imaging is discussed as a potential biomarker for atypical PSP. Early diagnosis and intervention are crucial for improved outcomes in PSP, necessitating further research to enhance the diagnostic and treatment strategies for PSP and other neurodegenerative diseases.