About

Shana E. McCormack, M.D., M.T.R., is an Associate Professor of Pediatrics specializing in Endocrinology and Diabetes at the University of Pennsylvania's Perelman School of Medicine. She serves as an Attending Physician at the Hospital of the University of Pennsylvania and The Children's Hospital of Philadelphia. Dr. McCormack is a faculty member at the Center for Mitochondrial and Epigenomic Medicine and the Mitochondrial Medicine Frontier Program at CHOP, as well as the Institute of Diabetes, Obesity, and Metabolism and the Diabetes Research Center at the University of Pennsylvania. Her clinical expertise focuses on caring for children with pediatric endocrine diseases, particularly those with endocrine dysfunctions related to rare neuroendocrine and metabolic disorders. She serves as the scientific director for CHOP's Neuroendocrine Center and collaborates with CHOP's Mitochondrial Medicine Frontiers Program and Friedreich's Ataxia Center of Excellence. Her clinical work includes managing children with endocrine complications of primary mitochondrial disease, Friedreich's Ataxia, hypothalamic and pituitary dysfunctions, hypothalamic obesity, and arginine vasopressin deficiency or central diabetes insipidus. Dr. McCormack's translational research program concentrates on children and adults with rare disorders affecting neuroendocrine and metabolic functions, aiming to improve their quality of life. Her research primarily investigates mitochondrial forms of diabetes associated with genetic disorders like Friedreich’s Ataxia and hypothalamic obesity and pituitary hormone deficiencies resulting from hypothalamic or pituitary tumors, such as craniopharyngioma. Her work involves mechanistic studies and clinical trials to develop new therapeutic approaches, utilizing innovative techniques for in vivo assessments of metabolism, mitochondrial bioenergetics, and neuroendocrine function through non-invasive imaging, stable isotope tracing, and metabolomics. She also develops strategies to assess body composition and pediatric growth, collaborating with colleagues to understand the genetic contributions to metabolic phenotypes. Her research insights into these rare metabolic conditions contribute to a broader understanding of energy balance, obesity, and diabetes.

Research topics

• Medicine
• Internal medicine
• Biology
• Endocrinology
• Pediatrics

Selected publications

• Approach to the patient with acquired hypothalamic syndrome

  The Journal of Clinical Endocrinology & Metabolism · 2026-05-09

  articleOpen accessSenior author

  The hypothalamus integrates signals from the body and the environment and coordinates homeostatic responses in multiple physiologic processes including: water balance, stress response, temperature regulation, energy balance, feeding behavior, sleep-wake cycles, and reproduction. Endocrinologists care for individuals for whom hypothalamic injury, whether from tumors, their treatment, or other causes, impairs pituitary hormone production and secretion. The extent of other symptoms in affected individuals is also influenced the extent of hypothalamic injury. "Acquired hypothalamic syndrome" refers to this broader collection of problems attributable to hypothalamic injury, variably including not only pituitary hormone deficiencies, but also hypothalamic obesity (or rarely, diencephalic syndrome), sleep and circadian disruption, temperature dysregulation, and behavioral issues (including memory problems and impulse control). Our goal is to present a pragmatic guide to the multidisciplinary, collaborative evaluation and management of hypothalamic syndrome.

  PublisherDOI

• Geometry of the proximal femur during growth and its contribution to childhood fractures in healthy children

  Journal of Bone and Mineral Research · 2026-05-08

  articleOpen access

  Hip structural analysis (HSA) of proximal femur scans by dual energy X-ray absorptiometry estimates hip geometry and structural strength, but little is known about how these parameters change during peak bone mass development. We describe age-related changes, precision and long-term stability, and sex and race/ethnic identity differences in hip geometry measures by HSA, and test whether HSA measures predict childhood fractures in healthy children. We used data from the Bone Mineral Density in Childhood Study, a multi-center, longitudinal cohort study of 2,014 healthy U.S. children, ages 5-23y, with up to 7 annual visits. HSA measures included cortical thickness, cross-sectional area, cross-sectional moment of inertia, section modulus, buckling ratio, and bone width at the narrow neck and femoral shaft, and hip axis length. Additional measures included self-identified race and ethnicity, Z-scores for height, BMIZ, appendicular lean soft tissue mass index and fat mass index, and self-reported physical activity, calcium intake, Tanner stage and fractures. Results indicated age-related trends and sex differences in hip geometry. Reference ranges were generated and HSA Z-scores were adjusted for height-for-age Z-score. Femoral shaft measures showed better precision (CV: 1.1 to 3.7%) than narrow neck measures (CV: 2.2 to 7.4%); buckling ratio (both sites) was the least precise. HSA Z-scores tracked well over one year (0.77 to 0.94). Narrow neck buckling ratio (HR 1.16 [95% CI: 1.02, 1.31]) and hip axis length Z-scores (HR 1.20 [95% CI: 1.00, 1.44]) associated with fracture risk. When adjusted for covariates (BMD Z-score, BMIZ, Tanner stage, sex), narrow neck cross-sectional area, cross-sectional moment of inertia, section modulus and bone width, and femoral shaft cross-sectional area and section modulus Z-scores positively associated with fractures (e.g., section modulus Z-score associated with 44% increased fracture risk). These findings provide the foundation for evaluating hip geometry as an indicator of bone strength in children.

  PublisherDOI

• Identification of intranasal oxytocin plasma proteome signatures

  Endocrine · 2026-03-10

  article
  PublisherDOI

• Safety and efficacy of individualised exercise and NAD+ precursor supplementation in patients with Friedreich's ataxia in the USA: a single-centre, 2 × 2 factorial, randomised controlled trial

  The Lancet Neurology · 2026-04-17 · 1 citations

  articleOpen accessSenior author

  BACKGROUND: precursor supplementation with nicotinamide riboside, which have each shown benefits in animal and early clinical studies, on cardiopulmonary fitness in individuals with Friedreich's ataxia. METHODS: . Stage 1 analysis tested the difference between each active treatment versus the control group, and stage 2 analysis (if combination therapy was effective) tested the difference between combination treatment and exercise alone; family-wise type 1 error was maintained <0·05. Analyses were by intention-to-treat. Adverse events were recorded systematically. This trial is registered with ClinicalTrials.gov (NCT04192136) and is complete. FINDINGS: =0·0299) for nicotinamide riboside and exercise in combination. Combination therapy was not statistically different from exercise alone (difference -0·05 ([95% CI -0·10 to 0·21]; p=0·49). Adverse events were all mild or moderate, and included gastrointestinal symptoms, falls, upper respiratory infections, and skin rashes. At least one moderate adverse event of interest in these categories was reported by seven (41%) participants in the control group; six (35%) in the nicotinamide riboside and no exercise group; three (19%) in the placebo and exercise group; and four (25%) in the nicotinamide plus exercise group. INTERPRETATION: The combination of nicotinamide riboside plus exercise for 12 weeks was safe and increased cardiopulmonary fitness in children and adults with Friedreich's ataxia. Longer studies are needed to establish whether adding nicotinamide riboside to exercise could be considered as part of a long-term, comprehensive treatment approach. FUNDING: US National Institutes of Health and Friedreich's Ataxia Research Alliance.

  PublisherDOI

• Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia

  BMJ Neurology Open · 2026-01-01

  articleOpen access

  Background: Novel therapeutics for Friedreich ataxia employ diverse strategies to increase frataxin protein levels, and a better understanding of the relation to clinical outcomes could strengthen their use as pharmacodynamic markers, and potentially as surrogate endpoint in therapeutic development. An elaborate modelling framework was developed to evaluate the suitability of frataxin as a biomarker across assays, tissues and disease stages. Methods: Frataxin levels generated previously through two distinct assay platforms and from two separate clinical cohorts: whole blood frataxin was measured by a lateral-flow immunoassay (LF cohort), and a triple-quadrupole LC-MS/MS method (TQ cohort), which enables separate quantification of mature frataxin (FXN-M) and erythrocyte-specific frataxin (FXN-E). Results were compared descriptively with control and heterozygous carriers, and several distinct modelling strategies were employed to correlate them with clinical function. Results: Both cohorts represented the relevant disease spectrum, with minor differences in both genetic and clinical severity, which correlated with frataxin levels. Heterozygous carriers showed intermediate levels. Modelling confirmed the predictive value of frataxin across multiple clinical assessments, such as age of symptom onset, age at loss of ambulation and long-term progression. GAA1, the shorter repeat expansion, was confirmed as the dominant predictor of frataxin itself, and, in most situations, clinical function. Discussion and conclusion: Although isoform biology and tissue-specific expression remain important considerations, peripheral frataxin quantification provides biologically grounded measure of the pathophysiology and disease progression, with strong potential for application in therapeutic trials. Frataxin is a valid clinical biomarker, and our findings support advancing its candidacy as a surrogate endpoint in Friedreich ataxia.

  PublisherOA PDFDOI

• Neonatal Hypopituitarism

  NeoReviews · 2026-04-01

  articleSenior author

  Neonatal hypopituitarism, a collection of conditions characterized by 1 or more pituitary hormone deficiencies, is associated with various phenotypes, each characterized by specific clinical, hormonal, radiographic, and, sometimes, genetic findings. Signs and symptoms of neonatal hypopituitarism include hypoglycemia, prolonged jaundice, microphallus, midline defects, and feeding difficulties. The initial evaluation of neonates at risk of multiple pituitary hormone deficiencies includes laboratory assessment of all hormone axes and brain magnetic resonance imaging for visualization of the pituitary. Pediatric endocrinologists should be consulted to guide interpretation of laboratory results and management. Prompt initiation of treatment is expected to improve overall clinical outcomes. In this review, we summarize the spectrum of phenotypes associated with neonatal hypopituitarism, the role of genetic testing, and the clinical presentation of hypopituitarism in infancy. We also describe the diagnostic approaches and management strategies for each abnormality of the pituitary axis in neonates.

  PublisherDOI

• OR11-01 Efficacy And Safety Of Setmelanotide In Acquired Hypothalamic Obesity: Results From A Double-blind, Multicenter, Placebo-controlled, Randomized Phase 3 Trial

  Journal of the Endocrine Society · 2025-10-01 · 2 citations

  articleOpen access

  Abstract Disclosure: S.A. Phillips: Rhythm Pharmaceuticals. H.M. van Santen: Novo Nordisk, Pfizer, Inc., Rhythm Pharmaceuticals. J.K. Hamilton: Rhythm Pharmaceuticals, Eli Lilly &amp; Company, Novo Nordisk, Pfizer, Inc. A.H. Shoemaker: Rhythm Pharmaceuticals. S.E. McCormack: Rhythm Pharmaceuticals. M.J. Abuzzahab: Ascendis, Lexicon Pharmaceuticals, Inc., Mannkind Corporation, Medtronic, Novo Nordisk, Pfizer, Inc., Rhythm Pharmaceuticals, Soleno. M.J. Wabitsch: Rhythm Pharmaceuticals. M.T. Dattani: Besins, Novo Nordisk, Pfizer, Inc., Sandoz, Rhythm Pharmaceuticals. T. Tanaka: Boehringer Ingelheim, Eli Lilly &amp; Company, FUJIFILM Toyama Chemical, Mitsubishi Tanabe Pharma, Novo Nordisk, Rhythm Pharmaceuticals. C. Scimia: Rhythm Pharmaceuticals. G. Yuan: Rhythm Pharmaceuticals. H.L. Muller: Ferring Pharmaceuticals, Ipsen, Eli Lilly &amp; Company, Merck Serono, Novo Nordisk, Pfizer, Inc., Rhythm Pharmaceuticals, Sandoz/Hexal. C.L. Roth: Rhythm Pharmaceuticals. J.L. Miller: Rhythm Pharmaceuticals. Background: Hypothalamic melanocortin-4 receptor (MC4R) signaling plays a critical role in the regulation of hunger, satiety, and energy expenditure. Hypothalamic injury from a tumor or its treatment, or following traumatic brain injury, can lead to hyperphagia and acquired hypothalamic obesity (aHO), for which there are no approved treatments. We present results of an international Phase 3 trial of treatment with the MC4R agonist setmelanotide (SET) in aHO (NCT05774756). Methods: Patients (pts) aged ≥4 years (y) with body mass index (BMI) ≥95th percentile (4-&amp;lt;18 y) or ≥30 kg/m2 (≥18 y) with aHO following hypothalamic tumor, lesion, or injury were included. Pts were randomized 2:1 to SET (0.5 mg subcutaneously once daily [QD], titrated up to 1.5-3.0 mg QD based on age, weight, and tolerability) or placebo (PBO) for up to 60 weeks. The primary endpoint was a modified intent-to-treat (mITT) analysis of the percentage change in BMI at 52 weeks. Secondary endpoints included the proportion of pts with a ≥5% BMI reduction and the change in the maximal daily hunger score (scored 0-10 in pts ≥12 y). Safety was also assessed. Results: Of 120 pts included, 81 and 39 received SET or PBO, respectively (female, 60.0%; mean [SD] age, 19.9 [13.8; range: 4-66] y; BMI in pts ≥18 y, 41.2 [9.7] kg/m2; BMI Z score in pts &amp;lt;18 y, 3.61 [1.66]). Fourteen pts discontinued treatment before end of trial (due to adverse events [AEs], n=7 [SET, n=5; PBO, n=2]; withdrew, n=7 [SET, n=4; PBO, n=3]). The primary endpoint was met: mean (standard error) change in BMI at 52 weeks was -16.5% (1.4%) for SET vs +3.3% (2.0%) for PBO, with a significant PBO adjusted–difference of -19.8% (95% CI: -24.6%, -15.1%; P&amp;lt;0.0001). A significantly greater proportion of pts who received SET vs PBO achieved a BMI reduction of ≥5% (79.5% vs 10.4%), ≥10% (63.0% vs 5.2%), ≥15% (50.6% vs 2.6%), and ≥20% (43.2% vs 0%; all P&amp;lt;0.0001). The mean (standard error) change in the weekly average of the maximal daily hunger score (≥12 y) was -2.68 (0.28) for SET vs -1.24 (0.40) for PBO (P=0.0030). Overall, 81 (100%) vs 35 (89.7%) pts receiving SET vs PBO experienced AEs, the most common of which were skin hyperpigmentation (55.6% vs 7.7%), nausea (50.6% vs 30.8%), vomiting (39.5% vs 17.9%), and headache (38.3% vs 30.8%). In the SET arm, there was 1 serious treatment-related AE of hypernatremia due to vomiting and an inability to tolerate their desmopressin. After 2 days, SET was reinitiated upon discharge from the hospital. One death due to seizures in a pt with a history of seizure disorder was reported in the SET cohort and was considered unrelated to treatment. Conclusions: In the largest randomized, PBO-controlled trial in aHO to date, SET demonstrated significant effects over PBO in the primary and all key secondary efficacy endpoints at 52 weeks, with no new safety signals. SET may represent an important treatment option for pts with aHO aged ≥4 y, for which there are no currently approved treatments. Presentation: Saturday, July 12, 2025

  PublisherOA PDFDOI

• Individualized exercise and NAD+ precursor supplementation in Friedreich’s Ataxia: a randomized controlled trial

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• Abstract 4367364: A Multicenter Friedreich Ataxia Registry Identifies Posterior Wall Thickness as a Predictor of Major Adverse Cardiac Events

  Circulation · 2025-11-03

  article

  Background: Cardiac disease is the leading cause of premature mortality in Friedreich Ataxia (FA). However, validated prognostic indicators or early imaging biomarkers that can reliably predict cardiac events are lacking. To address this gap, we created a multicenter FA cardiac registry to characterize disease progression and identify early echocardiographic (echo) predictors of major adverse cardiac events (MACE). Methods: FA subjects from 6 North American centers with at least two echos performed ≥5 years apart were included. Demographics, FA-specific disease characteristics, and MACE (a composite of death, heart failure hospitalization, aborted sudden cardiac death, and/or life-threatening arrhythmia) were abstracted. Digital echo images were re-read at a centralized core lab. Paired T tests were utilized for comparison of the normally distributed first and second echo parameters, and logistic regression models were utilized to evaluate for predictors of MACE. Results: Of 115 subjects, 52 (45%) were female. Mean age at diagnosis was 10 ± 3 years, median GAA1 repeat length (a marker of genetic severity) was 700 (range 66–1200), and median age at first analyzed echo was 12 years (range 4-36). MACE occurred in 35 (30%) of the cohort. Serial echocardiograms demonstrated progressive worsening of multiple cardiac parameters over time, including markers of ventricular thickness and hypertrophy, chamber size, systolic function, and novel markers of atrial and ventricular strain (Table 1). On univariate analysis, several markers of hypertrophy and systolic function from the earliest analyzed echo predicted MACE. However, after adjusting for age of diagnosis, GAA1 repeat length, and collinearity among variables, only posterior wall thickness in diastole (PWTd) remained an independent predictor of MACE (odds ratio 1.8 per mm increase, 95% CI 1.1–3.3, p = 0.028). Conclusions: This multicenter FA registry identifies early posterior wall thickness as a significant and independent predictor of major adverse cardiac events in FA. Each millimeter increase in PWTd on early echo is associated with nearly double the odds of MACE. This commonly acquired parameter is often overlooked and may serve as a powerful early marker of cardiac risk. Further investigation of PWTd as a potential surrogate endpoint for therapeutic trials in FA is warranted.

  PublisherDOI

• The gSOS Polygenic Score is Associated with Bone Density and Fracture Risk in Childhood

  medRxiv · 2025-04-23

  preprintOpen access

  Abstract The polygenic risk score genetic quantitative ultrasound speed of sound (gSOS) was developed using machine learning algorithms in adults of European ancestry and associates with reduced odds of fracture in adults. We aimed to determine if gSOS was associated with bone health in children. Two observational studies of children were evaluated: (1) children enrolled in the Bone Mineral Density in Childhood Study (BMDCS) with genetic data (N=1,727); and (2) children with genetic data for research at the Children’s Hospital of Philadelphia (CHOP; N=10,301). Genetic variants were used to calculate gSOS and genetic ancestry. For the BMDCS, puberty stage, dietary calcium, physical activity and fracture accumulation (none or ≥1 fracture) were self-reported, height and weight were measured and BMI calculated. Areal bone mineral density (aBMD) of the lumbar spine, hip, radius, and whole body were assessed by dual energy X-ray absorptiometry and expressed as Z-scores. The CHOP study paired genetic data with documentation of fracture in the electronic health record (EHR). gSOS associated with higher aBMD Z-scores across 7 skeletal sites [e.g., a 1 SD increase in gSOS associated with 0.17 (95% CI: 0.10-0.24) higher lumbar spine aBMD Z-score]. These associations were consistent for males and females, age, puberty stage, and lifestyle factors, and most consistent among children of European genetic ancestry. A 1 SD increase in gSOS associated with 12% and 16% reduced likelihood of self-reported fracture in the BMDCS (OR=0.84, 95% CI: 0.74, 0.95) and a recorded fracture in the CHOP EHR (OR=0.88; 95% CI: 0.82, 0.95). No sex or genetic ancestry differences were found. A higher gSOS score associated with higher aBMD at multiple skeletal sites and reduced odds of fracture in two independent pediatric samples. This genetic tool may have clinical utility to help enhance bone health in early life and protect against fracture across the lifespan. Lay summary In adults, the polygenic risk score gSOS associates with reduced fracture risk. This study evaluates the relationship of gSOS to bone density and fractures in two groups of children. We found that a 1 standard deviation increase in gSOS was associated with higher bone density at multiple skeletal sites. In our two groups of children, a 1 standard deviation increase in gSOS associated with reduced odds of fracture in children by 12% (95% CI: 0.82, 0.95) and 26% (95% CI: 0.74, 0.95). Having a higher gSOS may enhance bone accretion in early life, and protect against fracture across the lifespan.

  PublisherOA PDFDOI

Recent grants

• NIH Grant F32DK093206

  NIH · $40k · 2012

• Mitochondrial creatine metabolism and glucose utilization in humans.

  NIH · $172k · 2017–2019

• NAD+ precursor supplementation with exercise training to improve aerobic capacity in Friedreich's Ataxia

  NIH · $4.0M · 2020–2025

• NIH Grant K23DK102659

  NIH · $515k · 2018

• Phentermine/Topiramate in children, adolescents, and young adults with hypothalamic obesity: a pilot and feasibility study

  NIH · $690k · 2023–2027

Frequent coauthors

• Babette S. Zemel

  University of Pennsylvania

  98 shared

• Struan F.A. Grant

  95 shared

• Andrea Kelly

  Children's Hospital of Philadelphia

  83 shared

• Jonathan A. Mitchell

  Children's Hospital of Philadelphia

  76 shared

• Marni J. Falk

  72 shared

• John Shepherd

  66 shared

• Alessandra Chesi

  Children's Hospital of Philadelphia

  53 shared

• Diana L. Cousminer

  50 shared

Labs

• McCormack LaboratoryPI