Dareen D. Siri, MD, FAAAAI, FACAAI is a board-certified allergist and immunologist practicing at Midwest Allergy Sinus Asthma, based in central Illinois. She talked with CheckRare about a unique, rare disorder called systemic mastocytosis. 

Systemic mastocytosis involves the proliferation of mast cells, which can accumulate in various areas of the body. The early signs of mastocytosis can be quite variable, said Dr. Siri, and include cutaneous spots or an extensive rash; gastrointestinal symptoms like diarrhea, bloating, or perceived new food intolerance; or even anaphylactic reactions. 

Patients may present with what looks like an allergic reaction, she added, and some patients do not have a very high mast-cell burden. This variability may pose a challenge to accurate diagnosis. Most patients experience some level of fatigue. Patients may also complain of bone pain or “feeling like they have the flu every day.”

Dr. Siri pointed out that these patients may have many symptoms. A convincing allergic reaction that gives a strong gastrointestinal and perhaps an anaphylactic reaction, may suggest to clinicians that mast-cell proliferation is the root of the problem.

Once a clinician suspects systemic mastocytosis as the cause, a key step is obtaining a blood test for increased tryptase levels, which can serve as “a good screener, at least.” However, this is not sufficient alone. A bone marrow biopsy and histology will confirm the diagnosis. An acquired (not inherited) genetic variant (KIT D816V), is present in the stem cells of nearly all patients with systemic mastocytosis.

Systemic mastocytosis comes in two forms—aggressive and indolent. She cautioned that indolent mastocytosis should not necessarily be considered a disorder with a mild course. The rash can be quite extensive and the potential for anaphylactic reactions can result in loss of consciousness and falls. 

Exciting new therapy offers promise to long-suffering patients that this chronic condition can be treated at the source: targeting the genetic mutation responsible. Finally, patients have more than antihistamines and leukotrienes to alleviate their symptoms. 

Dr. Siri concluded that “It’s important for patients to know that this condition is acquired during their lifetime,” and it is not inherited or congenital. Even though the body is now making abnormal mast cells, patients can live a normal, full life.

CHAPTERS
Introduction 00:00
Early Signs and Symptoms 00:36
Indolent SM Variability 1:45
Most Burdensome Symptoms 2:45
Key Steps to Diagnosis 3:38
Approach to Management With Newer Therapies 4:53
What Physicians Should Know 5:20
Take Home Message for Patients 6:41

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Arthur Beisang, MD, Department of Pediatrics at Gillette Children's Specialty Healthcare in Saint Paul, Minnesota, discusses Daybue (trofinetide) Stix, a new formulation of the treatment for Rett syndrome.

Rett syndrome is a neurodevelopmental condition that primarily affects girls. People with the disease appear to have normal psychomotor development during the first 6 to 18 months of life, followed by a developmental "plateau," and then rapid regression in language and motor skills. Additional signs and symptoms may include repetitive, stereotypic hand movements, fits of screaming and inconsolable crying, autistic features, panic-like attacks, teeth grinding, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and slowed head growth. Classic Rett syndrome is most commonly caused by genetic changes in the MECP2 gene.

Trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor-1, approved for treatment of Rett syndrome in 2023. Daybue Stix is an oral, dye- and preservative-free powder formulation of the treatment approved in December 2025 and now available in the US for patients 2 years of age and older.

The new formulation has the same efficacy and safety profile of the original formulation, based on results from the phase 3 LAVENDER (NCT04181723) study, while also giving patients flexibility and choice in dose volume and taste of treatment. The approval of this new formulation was informed by the results of a bioequivalence study, which demonstrated that both the original Daybue oral solution and the new Daybue Stix formulation provide comparable exposure.

Daybue Stix comes as a powder that can be mixed with a variety of water-based liquids to customize to a patient's preference of taste. The product comes in individual packets that are easily portable and do not have to be refrigerated unlike the original formulation.

A recent publication of expert recommendations for real-world use of trofinetide in Rett syndrome emphasized the importance of patient-centered approaches. Experts from International Rett Syndrome Foundation-designated centers of excellence agreed that treatment options that allow for individualized decision making help optimize outcomes for patients, families, and caregivers.

CHAPTERS
Introduction 00:00
Rett Syndrome Overview 00:26
Patient Improvements With Daybue Stix 1:13
Impact on Real-World Outcomes 2:36
Choosing Treatment 4:00
Impact on Caregivers 5:13
Unmet Needs in Rett Syndrome 6:53
Take Home Message 9:08

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Stacey Kallish, MD, Clinical Geneticist at Penn Medicine in Philadelphia, is helping to lead a new wave of innovation at the intersection of artificial intelligence (AI) and rare disease care. With a clinical focus on lysosomal storage diseases (LSDs)—including Fabry disease, Gaucher disease, and Pompe disease—Dr. Kallish is exploring how emerging technologies can improve diagnosis, risk prediction, and long-term management for patients with complex genetic conditions.

AI is increasingly becoming a topic of discussion across healthcare, but in rare diseases, its potential impact may be especially significant. These conditions are often difficult to recognize due to their rarity, variability, and overlap with more common disorders. As a result, patients frequently experience delayed or missed diagnoses. AI offers a powerful opportunity to change that.

By training machine learning models on datasets of patients with confirmed rare diseases, researchers can teach these systems to recognize patterns that distinguish affected individuals from those without disease. These models can then be applied to large-scale datasets, such as electronic health records (EHRs), to flag patients who may otherwise go undiagnosed.
Dr. Kallish explains that one of AI’s greatest strengths lies in its ability to synthesize vast amounts of information. “These models can evaluate countless small data points simultaneously—far more than we can realistically process as clinicians,” she notes. This allows AI to detect subtle signals that may not be immediately apparent, particularly in early or atypical cases.

Beyond diagnosis, AI is also being investigated as a tool for predicting disease progression and guiding treatment decisions. In conditions like Fabry disease, clinicians must often determine when to initiate therapy and how to assess a patient’s risk for complications such as stroke or organ damage. AI-driven models have the potential to analyze longitudinal patient data and generate individualized risk profiles, offering more precise and personalized insights.
However, while these applications are promising, Dr. Kallish emphasizes that the field is still evolving. Diagnostic use cases—such as identifying patients through EHR screening or interpreting genetic variants—are likely to reach clinical utility sooner. More complex applications, like optimizing treatment timing or selecting the most appropriate therapy for an individual patient, will require additional validation and real-world evidence.

Importantly, AI is not intended to replace physicians. Instead, it is best understood as a complementary tool—one that can enhance clinical decision-making and improve access to specialized expertise. This is particularly evident in the field of medical imaging.
Studies have shown that AI models can perform at a level comparable to expert radiologists in interpreting imaging studies such as brain MRIs. In some cases, these models even outperform general radiologists. But rather than viewing this as a threat, Dr. Kallish sees it as an opportunity for collaboration.

“The goal is partnership,” she explains. “AI can help us get to better answers, especially in settings where specialized expertise may not be readily available.” For patients in community hospitals or underserved areas, this could mean more accurate diagnoses and improved care without the need for referral to major academic centers.

Another area where AI may have a transformative impact is biomarker development. Currently, clinicians rely on a combination of enzyme assays, molecular testing, and established biomarkers to diagnose and monitor LSDs. AI has the potential to identify new biomarkers that are more sensitive, more specific, and potentially tailored to individual patients. These insights could help clinicians better determine when to initiate treatment, assess disease progression, and evaluate therapeutic response.

Some AI-driven tools are already making their way into clinical practice. One example is FDrisk, a publicly available platform that uses machine learning to estimate the likelihood of Fabry disease based on a series of clinical inputs. By answering a set of targeted questions, clinicians can generate a dynamic risk score and receive guidance on next steps, including whether to pursue diagnostic testing.

At a broader level, researchers are also leveraging AI to analyze patient journeys within healthcare systems. By studying the clinical trajectories of patients with known rare diseases, machine learning models can identify similar patterns in other patients’ records. This approach has already demonstrated success in detecting conditions such as Rett syndrome and Lowe syndrome, highlighting the potential for earlier identification and intervention.

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Stacey Kallish, MD, Clinical Geneticist at Penn Medicine in Philadelphia, is helping to lead a new wave of innovation at the intersection of artificial intelligence (AI) and rare disease care. With a clinical focus on lysosomal storage diseases (LSDs)—including Fabry disease, Gaucher disease, and Pompe disease—Dr. Kallish is exploring how emerging technologies can improve diagnosis, risk prediction, and long-term management for patients with complex genetic conditions.

This video highlights the critical role of perspective in clinical decision-making, emphasizing how subtle differences in interpretation can impact diagnosis and treatment. Through compelling examples, it encourages healthcare professionals to challenge assumptions, recognize cognitive biases, and consider alternative viewpoints when evaluating patients. The piece reinforces the importance of thoughtful, multidisciplinary thinking to improve diagnostic accuracy and ultimately enhance patient outcomes.

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Stacey Kallish, MD, Clinical Geneticist at Penn Medicine in Philadelphia, is helping to lead a new wave of innovation at the intersection of artificial intelligence (AI) and rare disease care. With a clinical focus on lysosomal storage diseases (LSDs)—including Fabry disease, Gaucher disease, and Pompe disease—Dr. Kallish is exploring how emerging technologies can improve diagnosis, risk prediction, and long-term management for patients with complex genetic conditions.

This video underscores how initial impressions and ingrained assumptions can influence clinical decision-making, sometimes leading to missed or delayed diagnoses. Through illustrative scenarios, it encourages healthcare professionals to pause, reassess, and broaden their differential when evaluating patients. The content reinforces the importance of critical thinking, awareness of cognitive bias, and maintaining diagnostic curiosity—particularly in complex or atypical presentations—to improve accuracy and patient outcomes.

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Stacey Kallish, MD, Clinical Geneticist at Penn Medicine in Philadelphia, is helping to lead a new wave of innovation at the intersection of artificial intelligence (AI) and rare disease care. With a clinical focus on lysosomal storage diseases (LSDs)—including Fabry disease, Gaucher disease, and Pompe disease—Dr. Kallish is exploring how emerging technologies can improve diagnosis, risk prediction, and long-term management for patients with complex genetic conditions.

This video emphasizes how critical details in patient presentation can be overlooked when clinicians rely too heavily on familiar patterns or common diagnoses. It encourages healthcare professionals to take a step back, reassess clinical assumptions, and remain open to less obvious possibilities—particularly in complex or atypical cases. The content reinforces the importance of vigilance, pattern recognition balanced with curiosity, and a broader diagnostic lens to help reduce missed or delayed diagnoses and improve patient care outcomes.

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Richard J. Nowak, MD, global principal MINT investigator and director of the Myasthenia Gravis Clinic at Yale University, discusses a post-hoc analysis of Uplizna (inebilixumab) on the effect of ocular manifestations in generalized myasthenia gravis (gMG).

gMG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. The condition results from a defect in the transmission of nerve impulses to muscles due to the presence of antibodies against the acetylcholine receptor in the neuromuscular junction.

Inebilizumab is a first-in-class, humanized anti-CD19 B-cell depletion therapy for gMG. It was approved for the treatment of gMG in December 2025 based on results from the phase 3 Myasthenia Gravis Inebilizumab Trial (MINT).

At the 2026 NANOS Annual Meeting, a post-hoc analysis of the MINT clinical study was presented. This analysis focused on the ocular manifestations of gMG, which Dr. Nowak explains are present in upwards of 90% of patients.

Treatment with inebilizumab illustrated improvements in Myasthenia Gravis Activities of Daily Living (MG-ADL) and Qualitative Myasthenia Gravis (QMG) ocular domain scores compared to placebo at week 26 in overall AChR+ and MuSK+ populations. Additionally, In the AChR+ population at week 52, inebilizumab improved MG-ADL and QMG ocular domain scores compared to placebo.

CHAPTERS
Introduction 00:00
Myasthenia Gravis Therapeutic Landscape 00:44
MINT Clinical Trial of Inebilizumab 2:07
Ocular Manifestations of MG 4:33
Post-Hoc Analysis 6:39
Next Steps 12:37

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Fernanda Leal-Pardinas, MD, MSc, Global Clinical Development Lead, Rare & Metabolic Disorders at Otsuka Pharmaceutical, discusses the open-label extension data from their study testing repinatrabit for patients with phenylketonuria (PKU).

For more information on Phase 3 PheORD clinical trial (NCT06971731) recruitment, visit https://clinicaltrials.gov/study/NCT06971731?intr=JNT-517&rank=3

PKU is a genetic metabolic disorder that increases the body's levels of phenylalanine to toxic levels. Phenylalanine is a natural part of the foods we eat.. People with PKU lack the enzyme phenylalanine hydroxylase to break down this phenylalanine, causing a build up in the blood, urine, and body. Without treatment, children with classic PKU develop permanent intellectual disability. Light skin and hair, seizures, developmental delays, behavioral problems, and psychiatric disorders are also common. In most cases, PKU is caused by changes in the PAH gene.

At the 2026 American College of Medical Genetics and Genomics (ACMG) meeting, open-label extension data of repinatrabit and the study design for the phase 3 PheORD clinical trial were presented. Repinatrabit is an investigational, selective, small-molecule inhibitor of the Phe transporter SLC6A19 developed to reduce blood Phe levels.

In a long-term, open-label extension, the first cohort of adolescents receiving repinatrabit 75 mg twice daily, evaluated in the Phase 2 adolescent study (NCT06637514), achieved sustained Phe reductions at day 56. At this assessment, adolescents achieved an average –67% reduction from baseline. The scale and consistency of Phe reduction observed in adolescents were comparable to those reported in adult phase 2 studies.

All participants in the cohort demonstrated a clinical response, including adolescents with prior sapropterin experience (both responders and non-responders), as well as one sapropterin-naïve participant. Repinatrabit was well tolerated, with a safety profile consistent with prior phase 2 findings in adults. No new treatment-related adverse events were identified, and no serious adverse events were reported.

This study is ongoing, with patients in the open-label extension advancing to the higher dose (150 mg) of repinatrabit in the second cohort. The pivotal global, randomized, double-blind, placebo-controlled phase 3 PheORD trial in adults with PKU is also advancing, designed to evaluate the efficacy and safety of two oral dose regimens of repinatrabit (75 mg or 150 mg twice daily) compared with placebo.

Completion of the primary endpoint of the adult population in the Phase 3 study is anticipated in late 2026, with full study completion expected in 2028. This trial is actively recruiting.

CHAPTERS
Introduction 00:00
PKU Overview 00:21
Repinatrabit Mechanism of Action 1:33
Clinical Trial Data 3:42
Next Steps 5:53

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Dena Sherwood, mother to a neuroblastoma survivor and Founder of Arms Wide Open Childhood Cancer Foundation, discusses her organization and the CureFest event.

Neuroblastoma is a rare childhood cancer, but it is the most common extracranial solid tumor in children. It is a neuroendocrine tumor that originates in neuroblasts or neural crest progenitor cells. It often appears initially in the adrenal glands, but tumors can be found virtually anywhere in the sympathetic nervous system. Its presentation is highly variable, ranging from a relatively benign palpable tumor to high risk, aggressively metastatic disease.

Ms. Sherwood describes the long diagnostic journey children with neuroblastoma often go through, including struggles with misdiagnosis caused by the heterogeneity of symptoms and presentations. While the majority of patients with neuroblastoma get diagnosed at stage 4, proper monitoring and testing could diagnose and treat these patients earlier. She highlights the importance of physicians digging deeper into patients who return with recurring and/or worsening symptoms.

Her advice to newly diagnosed families is to not rush decisions following diagnosis, stressing the importance of doing research on the best possible treatment options, physicians, and cancer centers. She also wants families to know that there is always hope and to not compare their child’s circumstance and diagnosis with anyone else’s, especially in a disease that is so individualized.

While on the neuroblastoma fight with her son, Ms. Sherwood and her family founded the Arms Wide Open Childhood Cancer Foundation. The organization provides financial and emotional support for families at any stage of the childhood cancer journey. Some of their programs include funding of research and clinical trials, bereavement retreats, survivor retreats, and CureFest.

CureFest is an annual, three-day event that takes place in Washington, DC and is open to families and patients affected by childhood cancer. The goal of CureFest is to raise awareness, build community, and have lawmakers, clinicians, researchers, and families come together in support of the childhood cancer community and amplify their voices.

This year’s CureFest will be held September 18-20, 2026. For more information, visit https://www.curefestusa.org/.

CHAPTERS
Introduction 00:00
Neuroblastoma Diagnostic Odyssey 00:44
Early Signs and Symptoms 3:00
Finally Getting a Diagnosis 4:07
Advice for Newly Diagnosed Families 4:59
Arms Wide Open Foundation 9:37
Encouraging Caregivers to Get Involved 13:08

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