The initial report of Prader-Willi syndrome (PWS), published in 1956, described five major morbidities: short stature, hypotonia, obesity, hypogonadism, and cognitive delay. The clinical definition of PWS was fine-tuned over the next 3 decades; reported association with abnormalities in chromosome 15q in the 1980s led to the genetic definition in the 1990s. Human growth hormone (GH) was first purified in the 1950s, followed by increased therapeutic use of preparations purified from human pituitaries, which were emergently replaced by recombinant DNA-produced GH in 1985. Coincident developments in both fields led to trials of GH treatment for PWS and regulatory approval of GH treatment for PWS in 2000. As the only therapeutic agent with worldwide labeling for PWS, GH has shown efficacy for growth and hypotonia. Potential benefits for cognitive function and obesity have also been suggested, particularly with early treatment. A warning added in 2002 to the GH label for the PWS indication regarding use in severe obesity and severe respiratory impairment does not appear to be fully evidence-based; few other adverse effects have been observed. Delayed diagnosis and treatment of PWS continues to be a significant problem. The inclusion of PWS in newborn screening programs, a current area of research, would address the issue of late diagnosis, facilitating earlier initiation of GH treatment. Initial steps toward genetic therapy provide hope for a more complete medical treatment for this condition.

Sickle cell disease (SCD) is a significant global public health issue due to its prevalence and the associated acute and chronic complications. In high-income countries, the infant mortality rate has fallen to below 5%; this enables girls with SCD to reach adulthood and thus (potentially) become mothers. In this context, we address crucial aspects of the pathophysiology and management of pregnancy in women with SCD, since both the mother and the fetus face substantial risks. In France, there is now a shift toward the provision of multidisciplinary, personalized care by specifically trained professionals at hemoglobinopathy reference centers.

Recent advances in the understanding of the molecular and cellular basis of systemic lupus erythematosus (SLE) have challenged the classical view of SLE as the exemplary B cell and autoantibody-mediated disease. While much emphasis has been given to abnormalities on the humoral side of the immune response as essential to disease development, current findings suggest that mechanisms antedating B cell activation and autoantibody production are at the root of SLE initiation. In this review, we delineate key aspects involved with SLE pathogenesis, with a focus on how disturbances in cell death and metabolism may facilitate disease initiation and progression. We expound the relevance of disrupted cell death by non-programmed pathways, such as NETosis and ferroptosis, and of defective clearance of cellular debris, by complement factor and extracellular endonuclease deficiency, to the generation of damage-associated molecular patterns that will ultimately trigger interferon (IFN) production. We also describe how mitochondrial disturbances leading to reduced respiratory capacity, increased reactive oxygen species, and leakage of mitochondrial nucleic acids into the cytosol, underlie the dysfunctional behavior of multiple cell types involved in the immune response. Lastly, we outline the latest findings on how the IFN signature modulates the disease commencement, suggesting a primordial role of the skin stromal cells in producing several subtypes of IFN that will ultimately shape the behavior of infiltrating immune cells, thus constituting a paradigm shift on regards to the directionality of IFN effects between hematopoietic and non-hematopoietic cells. We advance the proposition that, in SLE, type I IFN plays a central role as an informational influence molecule, i.e., while IFN does not, in itself, act as an effector molecule driving SLE manifestations, it primes multiple cell types and misdirects immune responses, thus enabling autoreactivity.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multisystem involvement and various phenotypes. It follows a relapsing-remitting course, marked by alternating periods of relative inactivity and disease flares that can lead to organ damage, significant morbidity, and increased mortality. Approximately half of patients with SLE develop organ damage within 5 years of diagnosis. Potentially modifiable risk factors for damage include uncontrolled disease activity/severe flares, and glucocorticoid exposure. This review outlines a strategy to reduce disease activity and prevent organ damage, emphasizing early diagnosis, maintenance of low disease activity with minimal corticosteroid use, and flare prevention. Early recognition is crucial to avoid disease progression and prevent the development of more severe phenotypes. The 2019 EULAR classification criteria strike a balance between specificity and sensitivity but exclude ANA-negative patients, who may represent up to 20% of cases at diagnosis. To address this limitation, we introduced the SLE Risk Probability Index (SLERPI), a simple, clinician-friendly, machine learning-based model that does not require ANA positivity as a criterion; a score > 7 in SLERPI has shown 94.2% accuracy. Reducing the frequency and severity of flares is a major treatment goal to prevent organ damage and achieve remission or maintain low disease activity. The 2023 EULAR recommendations suggest the early use of biological agents to control disease activity, reduce flares, and facilitate corticosteroid dose reduction and damage prevention. However, incomplete response or refractory disease remains a significant challenge for both patients and clinicians, with evidence suggesting that response rates decline with each subsequent flare. Globally, new approaches are being explored that target various cellular and molecular pathways, including B cells, T cells, and CAR-T cells. The use of CAR-T cell technology to profoundly deplete B cells has shown promising results.

Aim: The absence of dystrophin in patients with Duchenne Muscular Dystrophy (DMD) causes muscle fiber necrosis and fibrosis and eventually muscle weakness and contractures. This study aimed to investigate the timing and extent of lower limb contracture development and to examine how contractures, muscle strength, and kinematic (e.g., limb position or joint movement) deviations relate to longitudinal changes in gait spatiotemporal parameters.

Methods: Seventy-five ambulatory boys with DMD participated in this prospective longitudinal study of contractures, isometric muscle strength, and gait analysis. Nonlinear mixed modeling (NLMIXED) exponential growth curve models were developed to investigate the effects of contractures, muscle strength, and kinematic deviations on longitudinal changes in gait spatiotemporal parameters.

Results: Ankle plantar flexion contractures were present as early as 4 years of age. Hip flexion contractures, assessed by the Thomas test, and knee flexion contractures, assessed by knee extension in supine, developed around 13 years of age and did not exceed ten degrees. Over time, gait speed, stride length, and cadence decreased. Statistically significant covariates for gait speed included hip flexor contracture (limitation in hip extension), hip extensor and ankle plantar flexor strength, and pelvic tilt Gait Variable Score (GVS). Plantar flexor strength was a significant covariate for stride length, while pelvic obliquity GVS significantly correlated with cadence.

Conclusion: Subtle changes in hip extensor and ankle plantar flexor strength, along with pelvic range of motion during gait, are indicators of DMD disease progression. Gait analysis, including easily accessible measures of gait speed and normalized stride length, may provide a more sensitive indicator of DMD disease progression than manual assessments of contractures and muscle strength.

Aim: This study aimed to assess the knowledge, awareness, and clinical practices related to familial hypercholesterolemia (FH) among pediatricians, including certified specialists, in Shizuoka Prefecture, Japan. The objective was to identify key challenges in FH management and propose strategies for improvement.

Methods: A cross-sectional, anonymous survey was conducted from August 2023 to March 2024 among members of the Shizuoka Regional Pediatric Society. The survey included questions about FH screening, diagnostic practices, awareness of guidelines, and treatment strategies. Data were collected via Google Forms and analyzed to evaluate knowledge gaps, adherence to guidelines, and implementation of FH management strategies.

Results: Among 47 respondents, 72.3% supported the implementation of school-age FH screening programs; however, only 8.5% reported conducting such programs in their regions. Awareness of the 2022 Pediatric FH Management Guidelines was limited to 34.8%, and 30.2% of respondents reported adhering to these guidelines in clinical practice. The prevalence of FH in Japan was correctly identified by 45.7% of respondents. Additionally, only 21.3% were aware that FH genetic testing has been covered by health insurance since 2022, highlighting limited awareness of recent advancements in FH management.

Conclusion: The findings underscore critical gaps in pediatric FH management, including insufficient awareness and limited implementation of screening and treatment strategies. Addressing these challenges requires enhanced education, systematic policies, and collaboration between healthcare providers, policymakers, and patient advocacy groups. Establishing centralized care networks and integrating FH screening into routine health checks could significantly improve early detection and management, reducing the future burden of cardiovascular disease.

Neurofibromatosis type 1 (NF1) is a hereditary tumor predisposition syndrome that predisposes patients to tumors derived from the neural crest cell population. One of the most prominent and well-recognized features is the proclivity for nerve sheath tumors of the skin known as cutaneous neurofibromas (CNs). These tumors are benign and have self-limited growth, but they exert a strong negative impact on patients’ quality of life. The only effective treatments currently are procedural, and there are no available medications. This review addresses the cellular and molecular characteristics of cutaneous neurofibromas with a focus on identifying novel therapeutic targets that could complement existing approaches. Preclinical models, tumor evolution throughout the lifespan, genetic associations with tumor phenotype, and a brief history of interventional clinical trials are also discussed.

Our foray into the development of novel therapies for systemic lupus erythematosus (SLE) began several decades ago. This was only possible because of the dissection of the immune system and the identification of key molecules and pathways that appeared to play roles in SLE pathogenesis. For example, although interferon was discovered in the 1950s, its association with SLE was not recognized until the late 1970s. Building upon the early observations made in autoimmune diseases, interferon inhibitors were first tested in SLE in the early 2000s. Another example is the sequencing of neutrophil libraries and the identification of a gene that encodes a protein that was subsequently named B lymphocyte stimulator (BLyS), also known as B cell activating factor. These discoveries eventually led to the development of anifrolumab, an antibody to the interferon alpha receptor, and belimumab, an antibody to BLyS. Their roles in the treatment of SLE are outlined in this article.

Clinical observation and scientific research have established that premature atherosclerotic vascular disease is strongly associated with markedly elevated low-density lipoprotein (LDL) cholesterol levels. Genetic disorders that impair LDL clearance via LDL receptors (LDLRs) are classified into heterozygous and homozygous familial hypercholesterolemia (FH) phenotypes. The heterozygous FH phenotype is characterized by LDL cholesterol levels exceeding 4.9 mmol/L, the presence of tendon xanthomas, and premature heart disease. In contrast, homozygous FH is characterized by LDL cholesterol levels above 13 mmol/L, both cutaneous and tendon xanthomas, and may lead to atherosclerotic vascular disease manifesting in childhood. FH is relatively common and occurs at even higher frequencies in populations founded by small ancestral groups, as documented in South Africa through investigations conducted in tertiary healthcare settings. Despite significant advances in the diagnosis and treatment of lipid and lipoprotein disorders, many of which are part of the differential diagnosis of FH, support for the diagnosis and management of FH has declined. While existing clinical guidelines address most cases of hypercholesterolemia, a subset of individuals with severe dyslipidemias requires more specialized evaluation. Referral criteria are proposed to help identify these patients. Given the high cardiovascular risk associated with severe hypercholesterolemia and the availability of effective treatments, there is an urgent need to strengthen, coordinate, and integrate clinical and laboratory services in South Africa to differentiate among the various causes of these disorders.

Gene therapy for Neurofibromatosis type 1 (NF1), defined as a collection of approaches that restore the quantity and function of neurofibromin, holds promise for treating various NF-associated clinical manifestations by addressing the root cause of the condition. The Gilbert Family Foundation’s Gene Therapy Initiative (GTI) launched one of the first focused research efforts to support a broad array of gene replacement, gene editing, and other strategies aimed at upregulating neurofibromin levels to mitigate symptoms and advance therapies for NF1. Efforts to discover and evaluate novel gene therapies to treat NF1 are hindered by foundational gaps in the field, the absence of quantitative assays, and a lack of robust preclinical models with reliable functional readouts. This perspective begins by shedding light on those key barriers that continue to hinder progress in NF1 gene therapy, outlines some of the strategies being explored to overcome them and offers pointers to additional strategies that merit further exploration. We then highlight several promising gene therapy strategies now in development. Successfully addressing the challenges described earlier is critical to realizing the full potential of these emerging and novel therapeutic approaches, setting the stage for effective and durable NF1 gene therapy interventions.