Rare Disease Research Articles

Blue rubber blister nevus syndrome: A case report

BACKGROUND Blue rubber blister nevus syndrome (BRBNS) is a congenital, rare disease characterized by venous malformations of the skin and internal organs, affecting all systems throughout the body. The pathogenesis is unknown. There is no consensus on the treatment of BRBNS. Most of the previously reported cases were mild to moderate with a good prognosis, and this case was a critically ill patient with severe gastrointestinal hemorrhage, disseminated intravascular coagulation (DIC), and severe joint fusion that was different from previously reported cases. CASE SUMMARY An 18-year-old man with early onset of BRBNS in early childhood is reported. He presented with recurrent melena and underwent malformed phlebectomy and partial jejunectomy and ileal resection. The patient had melena before and after surgery. After active treatment, the patient's gastrointestinal bleeding improved. This was a case of atypical BRBNS with severe gastrointestinal bleeding and severe joint fusion, which should be differentiated from other serious joint lesions and provide clinicians with better understanding of this rare disease. CONCLUSION This case of critical BRBNS with gastrointestinal hemorrhage, DIC and severe joint fusion provides further understanding of this rare disease.

The Non-Healing Wound: An Early Clue to Calciphylaxis

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a rare disease that presents as painful, necrotic lesions. While calciphylaxis is most commonly associated with renal insufficiency, calciphylaxis can occur in those without renal impairment. A case of non-uremic calciphylaxis occurring at a below-knee amputation site presenting as a single non-healing wound is provided; this presentation stands in stark contrast to the multiple, exquisitely painful lesions that are typical of calciphylaxis.

Characterization of non‐IgA vasculitis: Demographic, clinical, and treatment‐related features in a retrospective analysis of 28 biopsy‐confirmed cases from a German university hospital

AbstractNon‐IgA vasculitis is a rare disease that belongs to the group of small‐vessel vasculitides. Due to nomenclature and classification changes introduced in 2018, there are few published data under this name. The aim of this study is to characterize non‐IgA vasculitis as an independent vasculitis entity in terms of demographic, clinical, and treatment‐related features. A retrospective data analysis of patients with biopsy‐confirmed non‐IgA vasculitis treated at the Department of Dermatology at the University Medical Center Hamburg‐Eppendorf between January 1, 2018, and December 31, 2022, was performed. A total of 28 patients with non‐IgA vasculitis were included; 53.6% (15/28) were women and 42.9% (12/28) were older than 71 years. Previous infection as a possible triggering factor was found in 42.6% (12/28) of the cases. Palpable purpura was the most common skin finding (78.6%, 22/28) and 28.6% patients (8/28) had skin lesions above the waist. On direct immunofluorescence, C3 (89.3%, 25/28) was the most frequent deposition, followed by fibrinogen (71.4%, 20/28) and IgM (53.6%, 15/28). Hospitalization was required in 85.7% (24/28), with a mean hospital stay of 9.4 ± 4.1 days. No fatal courses were reported. This study is the first characterization of non‐IgA vasculitis based on patient cases from Germany and contributes to a better understanding of non‐IgA vasculitis as an independent entity. Non‐IgA vasculitis primarily affects older patients of both sexes, with most cases having an identifiable trigger. Our results indicate that cutaneous manifestations often extend beyond the lower legs. Treatment is usually required in the inpatient setting and requires a longer stay than other dermatological conditions. With proper treatment, the disease is not expected to be fatal.

Four-weekly dosing intervals with subcutaneous spesolimab appear to be required for optimal prevention of generalized pustular psoriasis flares: Data from the EFFISAYIL® 2 and EFFISAYIL® ON trials

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Spesolimab, an anti-interleukin-36 receptor antibody, is approved in adults and adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as a subcutaneous dosage for treatment of GPP when not experiencing a flare, and as an intravenous dosage for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Sclerotic Fibroma in a Patient with Birt-Hogg-Dubé Syndrome

Birt-Hogg-Dubé syndrome (BHD) is a rare genetic disorder characterized by cutaneous lesions and systemic findings such as renal neoplasms, pulmonary cysts, and spontaneous pneumothoraces. Fibrofolliculomas, trichodiscomas, and acrochordons are the most common cutaneous lesions associated with BHD. Some cases with mucocutaneous lesions have also been reported. We report a sclerotic fibroma that developed over a previous thoracotomy scar of a patient with BHD.

Spatio-temporal quasi-experimental methods for rare disease outcomes: the impact of reformulated gasoline on childhood haematologic cancer

Abstract Although some pollutants emitted in vehicle exhaust, such as benzene, are known to cause leukaemia in adults with high exposure levels, less is known about the relationship between traffic-related air pollution (TRAP) and childhood haematologic cancer. In the 1990s, the US EPA enacted the reformulated gasoline program in select areas of the U.S., which drastically reduced ambient TRAP in affected areas. This created an ideal quasi-experiment to study the effects of TRAP on childhood haematologic cancers. However, existing methods for quasi-experimental analyses can perform poorly when outcomes are rare and unstable, as with childhood cancer incidence. We develop Bayesian spatio-temporal matrix completion methods to conduct causal inference in quasi-experimental settings with rare outcomes. Selective information sharing across space and time enables stable estimation, and the Bayesian approach facilitates uncertainty quantification. We evaluate the methods through simulations and apply them to estimate the causal effects of TRAP on childhood leukaemia and lymphoma.

Utilizing Upadacitinib for the Management of Hailey-Hailey Disease

Hailey-Hailey Disease (HHD) is a rare disease associated with mutation of the ATP2C1 gene characterized by skin blistering and erosion. Here, we report a case of a patient with HHD who significantly improved after treatment with upadacitinib. A 55-year-old male with biopsy-confirmed Hailey-Hailey disease presented with a 20-year history of ill-defined, brightly erythematous, painful patches initially on the neck and subsequently involving the penile shaft. Following treatment with 30mg of upadacitinib, the patients neck ulcers gradually re-epithelized. This case adds to the growing body of literature supporting the use of Janus kinase inhibitors as a therapeutic modality for this condition.

Jordans’ anomaly in Chanarin-Dorfman syndrome

Abstract Objectives Chanarin-Dorfman syndrome is a rare disease inherited in an autosomal recessive pattern whose prevalence does not exceed 130 cases worldwide. Case presentation A 4-year-old patient with generalized erythematous-desquamative ichthyosiform syndrome since birth. The main laboratory finding was persistent hypertransaminasemia. Supplementary studies included peripheral blood smear (PBS), which revealed the presence of multiple cytoplasmatic vacuoles in polymorphonuclear leukocytes (PMN) and platelets. Ichthyosiform lesions concomitant to the presence of lipid vacuoles in peripheral blood PMNs are signs of Chanarin-Dorfman syndrome. Diagnostic suspicion was confirmed by genetic sequencing. Conclusions Chanarin-Dorfman syndrome is characterized by a mutation in the CGI-58 gene. This gene is involved in the catabolism of long-chain triglycerides stored in cytoplasmic lipid droplets. Jordans’ anomaly is a congenital alteration characterized by the presence of multiple vacuoles in the granulocytic series due to defective lipid metabolism. In this syndrome, long-chain triglycerides build up in tissues, thereby causing dermatological manifestations that are controllable through diet.

Exploring 17q12 Deletion Syndrome: A Case Report of Neurodevelopmental, Endocrine, and Genital Anomalies

Objective − 17q12 deletion syndrome is a rare genetic disease characterized by neurodevelopmental disorders, genital and renal abnormalities, and maturity-onset diabetes of the young type 5 (MODY5).Case Report − This case report details the case of a 13-year-old female with moderate intellectual disability, Mayer-Rokitansky-Küster-Hauser syndrome, multicystic dysplastic kidneys, and MODY5. Genetic testing revealed a 1.52-megabase heterozygous deletion on chromosome 17q12, encompassing the HNF1B and LHX1 genes, which was found to be inherited from the mother. Conclusion − This case underscores the importance of early genetic testing and multidisciplinary approach in managing the multisystemic manifestations of 17q12 deletion syndrome. Early diagnosis and appropriate management are crucial for improving the outcomes and quality of life for affected individuals.

External Occipital Protuberance Enlargement in Children: A Benign Anatomic Variant with Rare Associations

Objective − The aim of this study is to raise awareness about External Occipital Protuberance (EOP) enlargement in children, its typically benign anatomical variant, and the importance of considering associated conditions in diagnosis and management.Case Report − We reviewed the cases of four male patients, presenting with EOP enlargement. Among the cases, one involved a newborn diagnosed with Menkes disease, a rare genetic disorder affecting copper transport, which was associated with occipital exostosis. The other three cases involved adolescents with varying degrees of EOP enlargement, linked to factors such as prior trauma and excessive screen time. Conclusion − While EOP enlargement is generally a benign anatomical variant, this study underscores the importance of differential diagnosis, particularly in the pediatric population. Clinicians should be aware of the potential, albeit rare, associations with serious conditions such as Menkes disease. A comprehensive approach to diagnosis and management is recommended, especially in symptomatic cases.

Clinico-histopathological characteristics and management outcome of rare chronic infective granulomatous diseases: A case series study

Granulomatous skin diseases are common cutaneous dermatoses commonly encountered by practicing dermatologist. Granulomatous skin lesions are distinctive pattern of chronic inflammatory response of skin due to reaction against various organic and inorganic antigens. Granulomas are characterized by focal collection of epithelioid cells or histiocytes, admixed with variable number of leucocytes (especially mononuclear cells) and multinucleated giant cells. Granulomatous reaction is a type IV hypersensitivity reaction evoked by poorly soluble reactive substances. Incidence and prevalence of different types of granulomatous dermatitis depend on geographic location. Granulomatous skin lesions are common in the eastern parts of India. Many granulomatous skin lesions have identical histomorphology and conversely a single pathology can produce varied histological features. Some rare suppurative chronic granulomatous skin diseases include Botryomycosis, Actinomycosis, Rhinosporoidosis, Nocardiosis, and Cutaneous Tuberculosis. To describe clinical, histopathological features and treatment outcome of rare chronic infective granulomatous diseases. In this observational case series study, we retrospectively analysed six biopsy proven cases of rare chronic infective granulomatous diseases presented to our department (OPD) of Dermatology, Venereology and Leprosy (DVL) over a period of six months between June 2023 to November 2023 at Great Eastern Medical School and Hospital (GEMS), Srikakulam, Andhra Pradesh, India. The patient’s full clinical history, morphology of lesions, histopathological findings and treatment outcome were analysed. Along with histopathology, other necessary laboratory investigations were performed if required. A total of six patients were involved in the study, of whom four were males and two were females. The male to female ratio was 2:1, with a slight male majority. The most common age group was 31-40 years for both males and females. Painful raised lesion for long duration was the predominant complaint among those patients. Out of these six rare chronic granulomatous diseases, bacterial infections were common than fungal infection. All the cases showed clinical improvement after one month of starting treatment.: Most of the patients had a chronic history with improper treatment. So, it is imperative that the clinical diagnosis has to be confirmed with histopathology for the definitive diagnosis and appropriate treatment of these rare chronic infective granulomatous diseases. All these rare cases showed excellent progress after starting the right treatment.

Technical challenges of intracellular flow cytometry-based assays as a functional complement to diagnosis of signaling defects of inborn errors of immunity: PI3K pathway as a case of study

BackgroundThe use of next-generation sequencing in inborn errors of immunity (IEI) has considerably increased the identification of novel gene variants, many of which are identified in patients without the described clinical phenotype or with variants of uncertain pathogenic significance in previously described genes. Properly designed functional and cellular assays, many necessarily accomplished by research-based laboratories, reveal the pathogenic consequences of the gene variants and contribute to diagnosis. Activated PI3Kδ syndrome (APDS) is a rare disease that can be divided into APDS1, caused by gain of function (GOF) mutations in PIK3CD gene, and APDS2, with loss of function (LOF) variants in the PIK3R1 gene. Both entities present hyperactivation of the PI3K pathway, which can be analyzed through Akt and S6 phosphorylation status.MethodsOur objective was to perform an accurate, robust, and reproducible functional assay to analyze the phosphorylation status of proteins in the PI3K-Akt-S6 pathway by flow cytometry, to contribute to diagnosis, to monitor treatments, and to establish intra-assay standardization.ResultsWe illustrate the robustness and reproducibility of our experimental procedure in patients with APDS who had high Akt and/or S6 phosphorylation levels at baseline, and after anti-IgM stimulation in B cells. We show the relevance of an appropriate cohort of samples from healthy donors, processed within the same conditions as the suspected samples, in particular the time frame for sample processing once blood is collected.DiscussionWe highlight the importance of B cell stimulation through B cell receptor signaling, which is highly recommended, especially for samples that would be processed more than 24 hours after blood extraction. Also, having a defined experimental procedure is important, including the cytometer setup, which allows cytometer reproducibility for a period of time, enabling the comparison of a sample at different times.

Non-infectious mixed cryoglobulinemia as a new clinical presentation of mutation in the gene encoding coatomer subunit alpha: a case report of two adult sisters

Cryoglobulinemia is a rare disease characterized by the presence of cryoglobulins in the blood serum. It is usually caused by autoimmune, lymphoproliferative, or infectious factors. The pathogenesis of cryoglobulinemia is not well understood, therefore, genetic testing is very important. We present the case of two adult sisters with different clinical phenotypes of non-infectious cryoglobulinemic vasculitis associated with a rare genetic variant [(Hg38) 1:160323529 C>G, NP_004362.2:p.(Gly203Ala)]. One of the sisters suffered from essential mixed cryoglobulinemia, while the other suffered from cryoglobulinemia associated with systemic connective tissue disease. In both cases, genetic tests revealed a variant in the COPA gene, encoding coatomer subunit alpha. Mutations in the COPA gene are associated with COPA syndrome, an autoimmune interstitial lung, joint, and kidney monogenic disease, found mainly in children. Only 15 pathogenic COPA variants have been reported thus far which suggests that the full spectrum of disease manifestations remains unknown. Ours is the first report of the association of the COPA gene with non-infectious cryoglobulinemic vasculitis in adults. This unexpected finding may direct research into the pathogenesis of cryoglobulinemia and new treatment strategies for this rare disease.

Economic Burden of Haemophilia from a Societal Perspective: A Scoping Review.

Haemophilia is a rare genetic bleeding disorder that leads to musculoskeletal complications. The high cost of haemophilia treatment necessitates a thorough evaluation of its economic burden. However, due to the difficulty of estimating direct non-medical, indirect, and intangible costs, studies often underestimate the actual economic burden of haemophilia. This scoping review aims to summarise economic studies in haemophilia conducted from a societal perspective. A systematic search across eight scholarly databases, grey literature, and reference lists until the5th of July 2023 was conducted to identify relevant studies. The inclusion criteria encompassed full-text, English-language publications of economic analyses in congenital haemophilia from a societal perspective. Model-based studies and those adopting a payer perspective were excluded. Costs were adjusted to international dollars (I$) and US dollars (US$) in 2022 for comparability. Out of 2993 potential sources identified, 25 studies met the inclusion criteria, covering 7226 persons with haemophilia across 22 countries. All studies reported direct medical costs, with four excluding the cost of haemostatic therapy. Fifteen studies reported direct formal non-medical costs, while eight reported direct informal non-medical costs. All but one study reported the indirect costs. The average annual costs of haemophilia varied widely based on treatment modality, disease severity, geographical location, and included cost categories. When including the cost of clotting factor replacement therapy (CFRT), the total cost for severe haemophilia without inhibitors ranged from 1566 I$ to 700,070 I$ per person per year (lowest value reported in India and highest in the United States). CFRT represented up to 99.9% of the total cost for those receiving prophylaxis and up to 95.1% for episodic treatment. Haemostatic therapies accounted for 82% of the total cost in patients with inhibitors. There is a significant heterogeneity in defining cost categories required for a comprehensive economic analysis from a societal perspective. While haemostatic therapies constitute a substantial portion of the overall cost, direct non-medical and indirect costs are crucial as they are often paid out-of-pocket and may impede access to treatment. It is essential for haematologists and economists to establish a standardised costing framework for future studies, particularly in the era of novel therapies.

Effects of internet-based health education on patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a rare genetic metabolic disorder characterized by acute attacks of neurovisceral symptoms. This disease not only poses a threat to patients' physical and mental well-being, but its frequent acute attacks also have a profound impact on patients' mental state and overall quality of life (QoL). This study aimed to explore the impact of internet-based health education on the acute attacks, mental health, and QoL of patients with AIP. This study employed a pre-post comparison design, recruiting 52 patients diagnosed with AIP and treated at the Second Hospital of Hebei Medical University between September 2021 and May 2023 as the subjects of investigation. All participants underwent a 12-month internet-based health education intervention. Quantitative assessments of the intervention's efficacy in reducing acute attacks, enhancing mental health status, and improving QoL among AIP patients were conducted using various instruments, including measures of acute episode frequency and severity, the Depression Anxiety Stress Scales-21 (DASS-21), the Positive and Negative Affect Schedule (PANAS), and the MOS 36-Item Short Form Health Survey (SF-36). Data were collected at two distinct time points: pre- and post-health education interventions, which were then subjected to comparative analysis. Compared to pre-health education, the frequency of acute attacks among patients with AIP significantly decreased post-health education intervention (p < 0.05). Furthermore, notable improvements were observed in the severity of acute attacks, PANAS scores, DASS-21 scores, and SF-36 scores (p < 0.05). This study validated that health education effectively reduced the frequency and severity of acute attacks in AIP patients while enhancing their mental health status and quality of life. Internet-based health education emerges as a practical and productive strategy for AIP patients.

Magnetic resonance imaging of pulmonary hypertension.

Pulmonary hypertension is a rare but serious disease in children with potentially poor prognosis in the long term. Direct measurement of increased pressure in the pulmonary circulation requires right-heart catheterisation. Echocardiography is the imaging modality commonly used for suggesting the presence of pulmonary hypertension and estimating its severity. Recognition of structural and haemodynamic signs of increased pulmonary arterial pressure and pressure overload of the right ventricle at magnetic resonance (MR) imaging may contribute to the diagnosis of pulmonary hypertension and management of these patients. In this article, the structural, functional, and haemodynamic cardiovascular MR findings of paediatric pulmonary hypertension are reviewed. Typical diagnostic MR scenarios in children with suspected pulmonary hypertension or in children with disease associated with pulmonary hypertension are presented and discussed.

Management of traumatic duodenal rupture in children-case series.

Traumatic duodenal rupture is rare which accounts for only 2-10% of all Blunt abdominal trauma. The purpose of this study was to investigate the experience of diagnosis and treatment of traumatic duodenal rupture in children. This was a retrospective case series study. Clinical data were collected from three children suffering from a traumatic duodenal rupture who received surgical treatment in our hospital from January 2013 to January 2023. Demographic characteristics, trauma mechanism, physical examination, auxiliary examination, operation timing and plan, postoperative management and follow-up of included patients were described. Summarize the importance of early diagnosis and treatment of this type of injury. Three children (1 male and 2 females) with duodenal rupture due to traumatic abdominal injury were included in the study, with average age of 8.2 years (range 2.75-13.25 years). Among them, One child was injured by heavy objects. The other two children had lumbar fracture and seat belt sign. All three patients underwent emergency operation within 24h, and recovered well after surgery. No related complications seen during follow-up. Duodenal rupture is a rare but fatal disease. Early identification and active abdominal exploration can reduce the incidence of related complications and mortality in children with blunt abdominal injury, especially those with seat belt sign. Simultaneously, the standardized postoperative management is significant for the cure of children.

Pathological Examination in Pilonidal Sinus Surgery: Evaluating Necessity and Cost-Effectiveness: A 10-Year Retrospective Analysis.

Malignancy in pilonidal sinus disease (PSD) is rare, with squamous cell carcinoma (SCC) being the most common type. This study aims to assess the incidence of malignancy in PSD and identify risk factors to guide more targeted pathological examination strategies. A retrospective analysis was conducted on 1505 patients who underwent surgical excision of PSD between January 1, 2014, and December 31, 2023. Patients with incomplete or missing histopathological data were excluded, and no imputation methods were used for missing data. All specimens underwent histopathological examination to detect malignancies. Two cases (0.13%) of SCC were identified, both in males aged 50 and 58 years without a history of Crohn's disease, HIV, prior radiation, or other cancers. Significant risk factors for malignancy included age over 40 years (OR 3.2, 95% CI 1.1-9.5) and disease duration over 3 years (OR 2.8, 95% CI 1.0-7.6). Both cases were treated surgically and received adjuvant radiotherapy, with both patients being disease-free at the 2-year follow-up. While malignancy in PSD is rare (0.13%), older age and prolonged disease duration are associated with increased risk. Selective pathological examination based on these risk factors could enhance cost-effectiveness by reducing unnecessary routine examinations.

Expression of activin A in liver tissue and the outcome of patients with biliary atresia

Biliary atresia (BA) is a rare disease of unknown etiology which leads to cirrhosis and death if left untreated. The standard of care is an early hepatoportoenterostomy (HPE). Long-term follow-up is mandatory, during which most patients will require a liver transplant. Activin A belongs to the transforming growth factor-β (TGF-β) superfamily. TGF-β is a central regulator in chronic liver disease. We have studied the expression of activin A in liver tissue collected intraoperatively during the HPE. We included patients who underwent HPE in a single medical center. Clinical, ultrasonographic, and pathohistological data were collected. Activin A immunostaining was performed. Expression in the bile duct epithelium and hepatocytes was scored as either weakly positive, moderately positive, or strongly positive. Patients were then divided into three groups accordingly. We observed the outcome after the HPE at 3 months, 2 years, and at the end of follow-up. The study encompassed 37 patients. At 3 months after HPE, 92.3% of those with a weakly positive activin A reaction (group A) achieved good jaundice clearance, whereas only 44.4% of those with a moderately (group B) and 40% of those with a strongly positive reaction (group C) achieved good jaundice clearance (p = 0.008). Furthermore, 2 years after the HPE, 92.3% of those in group A survived with native liver (SNL), but only 33.3% of those in group B and 46.7% of those in group C had SNL (p = 0.007). At the end of follow-up, 83.3% of those in group A survived with native liver, as did 33.3% in group B and 40% in group C. Activin A is a valuable pathohistological predictor of the outcome of BA after an HPE.

Clinico-radiological correlation in a case of Schuurs–Hoeijmakers syndrome

Schuurs–Hoeijmakers syndrome is a very rare disease entity presenting as a neuro-developmental disorder with dysmorphic facies and a host of non-specific phenotypes. The diagnosis of this autosomal dominant disorder is made by genetic testing based on high clinical suspicion. Little is known about the radiological findings in such children. Here, we show a case of a 7-year-old boy diagnosed by whole exome sequencing and portray the various radiological and clinical findings that he presented with.