Diagnostic odyssey of acute disseminated encephalomyelitis in children

We aimed to determine whether acute disseminated encephalomyelitis (ADEM) diagnosis in children is delayed, and if so, to identify the clinical risk factors of delayed diagnosis. Standardised data were collected from children with ADEM from 2003 to 2020. Overall diagnostic delay (time between symptom onset and ADEM diagnosis), physicians’ delay (between the first medical visit and ADEM diagnosis), and patients’ delay (between symptom onset and the first medical visit) were analysed. Thirty ADEM patients were identified, including 16 (54%) with neurological deficits at discharge. Overall, physicians’, and patients’ delays were 9 (interquartile range [IQR] 6–20.5), 5.5 (IQR 3–14), and 4 (IQR 2–8) days, respectively. Overall delay was significantly associated with physicians’ delay, but not with patients’ delay. There were 61 misdiagnoses among 25 (83%) patients, while 5 (17%) were diagnosed correctly at the first visit. The misdiagnoses of common respiratory and gastrointestinal infection and aseptic meningitis were associated with overall and/or physicians’ delay. Later onset of specific neurological features suggestive of ADEM was associated with all three diagnostic delays. A unique diagnostic odyssey exists in ADEM. Several clinical risk factors were associated with the diagnostic delay.

Ending diagnostic odyssey using clinical whole-exome sequencing (CWES)

Objectives Most rare diseases are genetic diseases. Due to the diversity of rare diseases and the high likelihood of patients with rare diseases to be undiagnosed or misdiagnosed, it is not unusual that these patients undergo a long diagnostic odyssey before they receive a definitive diagnosis. This situation presents a clear need to set up a dedicated clinical service to end the diagnostic odyssey of patients with rare diseases. Methods Therefore, in 2014, we started an Undiagnosed Diseases Program in Hong Kong with the aim of ending the diagnostic odyssey of patients and families with rare diseases by clinical whole-exome sequencing (CWES), who have not received a definitive diagnosis after extensive investigation. Results In this program, we have shown that genetic diseases diagnosed by CWES were different from that using traditional approaches indicating that CWES is an essential tool to diagnose rare diseases and ending diagnostic odysseys. In addition, we identified several novel genes responsible for monogenic diseases. These include the TOP2B gene for autism spectrum disorder, the DTYMK gene for severe cerebral atrophy, the KIF13A gene for a new mosaic ectodermal syndrome associated with hypomelanosis of Ito, and the CDC25B gene for a new syndrome of cardiomyopathy and endocrinopathy. Conclusions With the incorporation of CWES in an Undiagnosed Diseases Program, we have ended diagnostic odysseys of patients with rare diseases in Hong Kong in the past 7 years. In this program, we have shown that CWES is an essential tool to end diagnostic odysseys. With the declining cost of next-generation sequencers and reagents, CWES set-ups are now affordable for clinical laboratories. Indeed, owing to the increasing availability of CWES and treatment modalities for rare diseases, precedence can be given to both common and rare medical conditions.

A case of shiitake dermatitis in the United States

ABSTRACT A 65-year-old male presented to our dermatology clinic with a two-day intensely pruritic rash covering his back. The lesions were predominantly on his chest, upper extremity, and back. He denied any prior history of similar rashes and his past medical history was non-contributory. A detailed exposure history revealed the patient had eaten Shiitake mushrooms for dinner 48 hours previously. Physical examination showed a truncal dominant rash. Close-up examination confirmed the papulovesicular nature of the rash with multiple small vesicles grouped both along the breadth and length of each linear streak on an erythematous background. Biopsies showed spongiosis with micro-vesiculation. Blood work showed a nominal CBC and CRP/ESR and serum IgE. The patient was put on topical steroid and the rash resolved in one week. With increasing mushroom consumption [1], cognizance of this etiology avoids a diagnostic ‘odyssey’ and prevents recurrence of this very characteristic rash.

Chudley–McCullough Syndrome: Case Report and the Role of Neuroimaging to Suggest the Diagnosis

Chudley–McCullough syndrome (CMS) is an autosomal recessive condition first described in 1997. The most striking features of this syndrome include sensorineural hearing loss, craniofacial disproportion, and brain abnormalities such as agenesis of the corpus callosum, polymicrogyria, ventriculomegaly, and changes in cerebellar architecture. We describe the case of a 2-year-old patient with CMS confirmed by genetic testing (GPSM2 gene mutation), who presented with global developmental delays and characteristic neuroimaging features including arachnoid cysts, agenesis of the corpus callosum, cerebellar dysplasia, and frontal heterotopia. Early recognition of this rare clinical syndrome may reduce the diagnostic odyssey and ultimately improve the quality of life for affected children. This report will focus on unique clinical and radiographic features of CMS.

Splicing in the Diagnosis of Rare Disease: Advances and Challenges

Mutations which affect splicing are significant contributors to rare disease, but are frequently overlooked by diagnostic sequencing pipelines. Greater ascertainment of pathogenic splicing variants will increase diagnostic yields, ending the diagnostic odyssey for patients and families affected by rare disorders, and improving treatment and care strategies. Advances in sequencing technologies, predictive modeling, and understanding of the mechanisms of splicing in recent years pave the way for improved detection and interpretation of splice affecting variants, yet several limitations still prohibit their routine ascertainment in diagnostic testing. This review explores some of these advances in the context of clinical application and discusses challenges to be overcome before these variants are comprehensively and routinely recognized in diagnostics.