Pseudohypoaldosteronism type 1 (PHA1) is characterized by aldosterone resistance in the kidneys and other target tissues.This results in excessive renal salt loss, poor potassium excretion, severe volume depletion, hyponatremia, hyperkalemia, and metabolic acidosis, with markedly elevated plasma renin and aldosterone levels. PHA1 is a potentially life-threatening condition in neonates and infants, necessitating prompt diagnosis and management. However, due to its rarity and nonspecific symptoms, the diagnosis of PHA1 may be delayed. Genetic tests are valuable for differential diagnosis and to establish appropriate management strategies. We present the clinical manifestations and molecular analyses of two infants with autosomal dominant PHA1, highlighting the importance of early diagnosis and genetic testing.

Purpose: Artificial intelligence has been applied across various fields of medicine, with large language models (LLMs) demonstrating potential to assist in clinical decision-making for rare diseases. This study assessed the performance of LLMs in aiding the phenotyping process and guiding the identification of correct genetic conditions. Materials and Methods: Clinical images from 10 Korean individuals with genetically confirmed rare diseases were collected through a literature review. Using identical prompts, the top 10 Human Phenotype Ontology (HPO) terms and suspected genetic conditions were queried across three LLMs: generative pre-trained transformers (GPTs) models GPT-4o and GPT o1, and Claude 3.5 Sonnet. Concordance between 5 manually curated key HPO terms and the top 10 predicted terms were assessed, and the accuracy of genetic diagnoses among the LLMs was analyzed. Results: Clinical images, ranging from 3 to 9 per case, were used as input for 10 Korean rare disease cases. The average number of key HPO terms correctly matched among the top 10 predictions was 3.0 (1.99-4.01) for GPT-4o, 2.8 (2.06-3.54) for GPT o1, and 1.7 (0.80-2.60) for Claude 3.5 (mean, [95% confidence interval]). GPT models provided more specific HPO terms than Claude in these cases. The accuracy of genetic diagnosis within the top 10 predictions was 2/10 for GPT-4o, 3/10 for GPT o1, and 0/10 for Claude 3.5, with frequent hallucination events observed. Conclusion LLMs demonstrate potential as a supportive tool for image-based rare disease phenotyping, while the frequent hallucinations highlight the need for further investigation and caution in clinical application.

Infantile cortical hyperostosis, or Caffey disease, is a rare genetic disorder characterized by subperiosteal hyperostosis, primarily affecting the long bones, mandible, clavicle, and ribs. It presents with painful swelling in infancy and typically resolves spontaneously by two years of age. The disease follows an autosomal dominant inheritance pattern and is associated with the c.3040C>T (p.Arg1014Cys) mutation in the COL1A1 gene. We report Korean male twins diagnosed with Caffey disease, both developing painful swelling of the lower extremities before six months of age, with the second twin presenting symptoms two months after the first. Radiographic examinations revealed periosteal hyperostosis in the tibiae, femurs, and upper extremities, with progressive mandibular involvement. Laboratory findings showed elevated serum phosphorus, while other biochemical markers remained normal. Single gene sequencing confirmed the c.3040C>T (p.Arg1014Cys) mutation in the COL1A1 gene, inherited from their asymptomatic mother. Conservative pain management led to gradual symptom resolution, with radiographic improvements observed by 27 months of age. Caffey disease should be considered in infants presenting with acute painful limb swelling, and genetic testing, including parental screening, is crucial for diagnosis. This case provides valuable insights into the familial occurrence, genetic basis, and natural progression of Caffey disease, contributing to a deeper understanding of this rare condition.

Purpose: HLA-DR(–) is a well-known characteristic of acute promyelocytic leukemia (APL), but also observed in some acute myeloid leukemia (AML) patients without PML::RARA fusion gene. We investigated the prevalence of clonal hematopoiesis of indeterminate potential (CHIP), immunophenotypic and cytogenetic abnormalities of HLA-DR(–) AML patients by comparing with those of APL patients. Materials and Methods: Thirteen patients diagnosed with HLA-DR(–) AML were enrolled. Twenty patients diagnosed with APL were assigned as a control group. Next-generation sequencing of CHIP genes (58 genes) was performed. Bone marrow or peripheral blood samples were used for flow cytometry to immunophenotype the leukemic blasts according to the laboratory protocol. Results: In HLA-DR(–) AML patients, CD117 positivity was less frequent. CD13 showed lower expression level. The median number of variants was three per patient, which was significantly higher than in the APL group. NPM1 variants were found in five patients. FLT3-ITD was frequently co-existed with NPM1 variant. Conclusion HLA-DR(–) AML patients exhibit a higher frequency of complex genetic abnormalities (three or more), which may explain why their prognosis is worse than that of APL patients, despite the frequent observation of NPM1. It is necessary to gather the results for each gene and conduct further evaluation.

This article critically examines the regulatory framework governing human biobanks in Korea, with particular attention to the 2024 revision of the Standard Operating Guidelines for Human Biobanks. It analyzes how the revised guidelines reflect the evolving legal and institutional landscape of human biological material governance. Special emphasis is placed on the four legally recognized pathways for collecting human biological materials under the Bioethics and Safety Act (BioAct), which have been further clarified in the revised guidelines to ensure greater clarity and consistency. The article argues that it is essential, on the one hand, for practitioners to clearly understand each collection pathway and its procedural requirements, and on the other hand, for normative safeguards to be in place to protect donors—without undermining the efficiency of biobank operations. In this context, the guidelines also offer illustrative guidance on how the current Donation Consent Form under the BioAct may be supplemented. The article further discusses concerns related to the independence and ethical competence of Institutional Review Board (IRB), as well as the potential need for a dedicated “provision review board” to enhance procedural rationality—issues that appear to have been reflected in the revised guidelines. In particular, as non-medical organizations increasingly engage in establishing biobanks, it becomes critical to establish robust operational governance to ensure accountability in the processes of collection, storage, and provision. It is within this context that the revised guidelines underscore the need to strengthen IRB independence and mandate the creation of a provision review committee.

Infantile nystagmus syndrome (INS) refers to congenital forms of nystagmus that are present at birth or during infancy. This syndrome may be caused by afferent visual system disorders or abnormal development of the ocular motor system. INS is a genetically heterogeneous disorder for which there are more than 100 causative genes. Since applying clinical tests for the differential diagnosis of INS can be challenging in early infancy and children, genetic testings such as next-generation sequencing are becoming more important for achieving accurate diagnoses. An improved understanding of the molecular mechanisms of INS may also lead to the development of gene-based therapies for INS. These advantages of genetic testing have the potential to change the diagnostic paradigm of patients with INS. However, the diagnostic pathway based on genetic testing still has several limitations in terms of the therapeutic effect and methodology. This review summarizes genetic and clinical features of INS, and discusses the promise and pitfalls of genetic testing in INS.

Despite advances in the diagnosis and management of rare diseases (RDs), there remains a tendency to overlook adult RD patients. In addition to the considerable number of adult-onset RDs, advances in the diagnosis and management of pediatric RDs have led to an increase in the survival of these patients into adulthood. Adult RDs exhibit distinct features from pediatric counterparts, necessitating careful consideration during medical assessments. Given the extended life expectancy of adult RD patients, precise diagnosis and management strategies can significantly enhance patient outcomes. This review aims to provide an in-depth exploration of the characteristics unique to adult RDs. Special emphasis will be placed on the importance of cascade screening and prenatal genetic testing in the context of adult RDs, highlighting the need for a comprehensive understanding of these aspects in clinical practice.

Purpose: Neurofibromatosis 1 (NF1) is one of the most common autosomal dominant diseases caused by heterozygous mutation in the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of a high number of partial pseudogenes, and the great variety of mutations. We aimed to study the mutation spectrum of NF1 gene in Korean patients with NF1. Materials and Methods: We have analyzed total 69 unrelated patients who were clinically diagnosed with NF1. PCR and sequencing of the NF1 gene was performed in all unrelated index patients. Additionally, multiplex ligation-dependent probe amplification (MLPA) test of the NF1 and SPRED1 gene analysis (sequencing and MLPA test) were performed in patients with negative results from NF1 gene sequencing analysis. Results: Fifty-five different variants were identified in 60 individuals, including six novel variants. The mutations included 36 single base substitutions (15 missense and 21 nonsense), eight splicing mutations, 13 small insertion or deletions, and three gross deletions. Most pathogenic variants were unique. The mutations were evenly distributed across exon one through 58 of NF1, and no mutational hot spots were found. When fulfilling the National Institutes of Health criterion for the clinical diagnosis of NF1, the detection rate was 84.1%. Cafe-au-lait macules were observed in all patients with NF1 mutations. There is no clear relationship between specific mutations and clinical features. Conclusion This study revealed a wide spectrum and genetic basis of patients with NF1 in Korea. Our results aim to contribute genetic management and counseling.

Rare diseases are characterized by a low prevalence, which often means that patients with such diseases are undiagnosed and do not have effective treatment options. Neurodevelopmental and neurological disorders make up around 40% of rare diseases and in the past decade, there has been a surge in the identification of genes linked to these conditions. This has created the need for model organisms to reveal mechanisms and to assess therapeutic methods. Different model animals have been employed, like Caenorhabditis elegans, Drosophila, zebrafish, and mice, to investigate the rare neurological diseases and to identify the causative genes. While the zebrafish has become a popular animal model in the last decade, mainly for studying brain development, understanding neural circuits, and conducting chemical screens, the mouse has been a very well-known model for decades. This review explores the strengths and limitations of using zebrafish as a vertebrate animal model for rare neurological disorders, emphasizing the features that make this animal model promising for the research on these disorders.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome is a maternally inherited mitochondrial disorder that usually affects the cerebral cortex and prevents high-energy demands from being met. Herein, we present the case of a male patient who rapidly developed multiple seizures, headaches, and altered mentality accompanied by severe metabolic acidosis and lactic acidosis. Initially, a brain imaging study confirmed stroke-like lesions (SLLs) only in the cerebellum. During follow-up, newly developed SLLs with lactic acidosis were observed in the basal ganglia (BG), cerebellum, and occipital lobe. The m.3243A>G variant had been found in the patient and MELAS was diagnosed, despite the BG and cerebellum being atypical locations for SLLs in MELAS. Since most cases of m.3243A>G variant MELAS show SLLs in the cerebral cortex, this case is unusual considering the location of the lesion. We emphasize that in the case of lactic acidosis accompanied by neurological symptoms, such as seizures, as in this case, MELAS should be included in the differential diagnosis, even if SLLs are observed in areas other than the cerebral cortex.