About

Alexandra M. Dumitrescu, MD, PhD, is an associate professor of medicine at the University of Chicago, specializing in endocrinology with a focus on thyroid diseases. Her research concentrates on identifying inherited genetic mutations that cause thyroid conditions, working closely with experts such as Dr. Refetoff. Dr. Dumitrescu has contributed to several leading textbooks on thyroid diseases and is frequently invited to present her work at national and international conferences. She serves as an ad hoc reviewer for scientific journals and is a member of the editorial board of the Journal of Molecular Endocrinology of the European Society of Endocrinology.

Research topics

• Biology
• Internal medicine
• Endocrinology
• Medicine
• Pathology
• Biochemistry
• Genetics
• Psychiatry

Selected publications

• Prevalence of pendrin defects in sudanese families with congenital hypothyroidism

  Endocrine · 2025-09-16

  articleOpen access

  Pendred syndrome (PDS) is an autosomal recessive disease caused by variants in SLC26A4 manifesting thyroid dyshormonogenesis. Patients typically present with goiter and sensorineural hearing loss (SNHL). The prevalence of PDS in non-African populations is estimated to be between 7.5 and 10 per 100,000, while its occurrence in African populations has not been reported with molecular analysis. This study, conducted at a university research center in Miami, USA and Khartoum, Sudan, to investigate PDS in Sudanese families with congenital hypothyroidism (CH). It involved 32 Sudanese families with children diagnosed with CH between 2016 and 2023. Patients underwent clinical evaluation, thyroid function tests, and genetic sequencing. Two disease-causing SLC26A4 variants were identified in two consanguineous families with first-cousin parents. One homozygous nonsense variant causing premature termination, p.Trp482*, previously reported as part of a compound heterozygous defect together with p.Gly102Arg, while the other homozygous defect was a previously reported missense variant, p.Thr410Met. In 32 families (72 individuals) whole exome sequencing data revealed 56.3% of families or 45.8% individuals harbored the SLC26A4 variants either in hetero or homozygous state. Of the 33 subjects who tested positive for the variants, 12 (36.4%) harbored more than one SLC26A4 variant. This report extends our understanding of the severity of the phenotypes caused by deleterious bi-allelic variants in SLC26A4. Recurrent SLC26A4 variants observed in our cohort likely reflect high consanguinity rather than a founder effect. SLC26A4 screening could be a part of the molecular testing for children presenting with congenital or early-onset SNHL in Sudan.

  PublisherOA PDFDOI

• Functional Domain Mapping of TPO: Insights From 6 Variants in Sudanese Kindreds With Congenital Hypothyroidism

  The Journal of Clinical Endocrinology & Metabolism · 2025-09-25 · 1 citations

  articleOpen access

  CONTEXT: Congenital hypothyroidism (CH) is a leading cause of preventable intellectual disability worldwide if left untreated. Thyroid peroxidase (TPO) is a key enzyme that uses hydrogen peroxide from the DUOX/DUOXA system to oxidize iodide for thyroid hormone synthesis. OBJECTIVE: This work aimed to identify the pathogenic TPO variants responsible for CH. METHODS: Variants identified by whole-exome sequencing were analyzed using in silico tools and structural modeling for pathogenicity. TPO function was assessed through in vitro studies on intracellular trafficking, enzymatic activity, and interaction with DUOX/DUOXA proteins. RESULTS: Six TPO variants were identified: p.G395D, p.V618M, p.M706V, and p.T725P in family 1, and p.R648G and p.G771R in families 2 and 3, respectively. Affected individuals in family 1 exhibited compound heterozygous or homozygous variants for the 4 variants. In silico analyses showed incomplete concordance in predicting pathogenicity. In vitro studies confirmed p.G395D as the primary pathogenic variant in family 1, and p.R648G and p.G771R in families 2 and 3. Notably, p.V618M, p.M706V, and p.T725P did not impair TPO function, either individually or in combination, suggesting that these regions are not critical for enzymatic activity. Further functional analyses revealed that p.G771R is essential for proper membrane insertion, whereas p.R648G is necessary for enzymatic activity. CONCLUSION: When multiple TPO variants occur within the same family, a combination of in silico and in vitro analyses can help identify the variant responsible for the phenotype. In silico methods, however, cannot predict the different mechanisms of impairment, such as enzyme activity vs cellular localization, where the protein's topology is essential for normal function.

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• Combined Levothyroxine and Propylthiouracil Treatment in Children with Monocarboxylate Transporter 8 Deficiency: A Multicenter Case Series of 12 Patients

  Thyroid · 2024-09-16 · 2 citations

  articleOpen access

  Objective: To evaluate the combined administration of propylthiouracil (PTU) and levothyroxine (LT4) in managing monocarboxylate transporter 8 (MCT8) deficiency and identify optimal therapeutic dosages. Methods: This multicenter case series involved 12 male patients with MCT8 deficiency whose parents/guardians consented to PTU and LT4 treatment. Data were collected from January 2008 to June 24, 2024. The study focused on treatment safety and outcomes, analyzing baseline and last encounter biochemical, metabolic, and anthropometric parameters. Statistical analyses included Wilcoxon signed ranks tests and generalized estimated equations to assess effects on thyroid and metabolic markers, and receiver operating characteristics curves to predict optimal dose. Results: Patients showed a significant reduction in serum total triiodothyronine (TT3) concentration and TT3/TT4 ratio, with increased serum TT4 and free T4 (fT4) concentrations. The use of PTU effectively reduced TT3 concentration by 25% at an average dose of 6.8 mg/kg/day, while LT4 increased fT4 concentration by 40% from baseline at an average dose of 4.3 µg/kg/day. Thyrotropin concentration was undetectable on treatment. No statistical differences were observed in metabolic and physical parameters between baseline and last encounter overall for the group, but six of eight patients for whom these data were available had an increase in weight ( z -score). There were no adverse effects on liver function or granulocyte numbers noted throughout the period of observation. Conclusion: Combined treatment with PTU and LT4 normalized serum T3, fT4, and TT4 in patients with MCT8 deficiency. Individualized dose adjustments were crucial for achieving therapeutic goals, indicating the need for personalized treatment plans.

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• 6398 Activating Mutations in a Primate-Specific Enhancer of MIR7-2/MIR1179 Are a Common Cause of Resistance to Thyrotropin

  Journal of the Endocrine Society · 2024-10-01

  articleOpen access

  Abstract Disclosure: H. Grasberger: None. A. Dumitrescu: None. X. Liao: None. E. Swanson: None. R.E. Weiss: None. P. Srichomkwun: None. T. Pappa: None. J. Chen: None. T. Yoshimura: None. P. Hoffmann: None. M. Franca: None. K. Onigata: None. S. Costagliola: None. J. Ranchalis: None. M.R. Vollger: None. A.B. Stergachis: None. J.X. Chong: None. M.J. Bamshad: None. G. Smits: None. G. Vassart: None. S. Refetoff: None. We previously identified a novel form of dominantly inherited resistance to TSH (RTSH), without TSH or TSH receptor mutations, that was linked to a locus on chromosome 15q (Grasberger et al., Hum. Genet. 2005). At birth, affected individuals present with nongoitrous euthyroid hyperthyrotropinemia that persists into adulthood and is frequently associated with high serum thyroglobulin levels not correlated with the degree of TSH elevation. Using whole genome sequencing we now report that noncoding mutations in an intergenic (TTTG)4 short tandem repeat (STR) underlie this form of RTSH in all 82 affected subjects from 12 unrelated families of different ethnic origins. Affected were heterozygous for the deletion of one repeat unit (10 families), or a single nucleotide change within the STR (two families). The STR maps to a primate-specific retrotransposon (AluSx1) with weak thyroid-specific enhancer-like chromatin signature. Paradoxically, some affected individuals appear prone to manifest proliferative thyroid disease since three of the affected subjects in our cohort required thyroidectomy for large nodular goiters in middle age. To investigate the consequence of these noncoding mutations we performed single-molecule chromatin fiber sequencing (Fiber-seq) and RNA-seq on thyroid specimens from subjects representing the two different mutations, and control thyroid tissues (healthy and nontoxic multinodular goiter) without STR mutation. Studies revealed that the mutant STRs stabilize transcription factor (TF) occupancy over the STR site, altering the spacing of adjacent FOXE1 binding elements. Increased TF occupancy at the mutated STR site actuates a complete enhancer cluster that selectively upregulates a bicistronic micro-RNA locus 35 kb downstream. The miRNA primary transcript is specifically overexpressed from the mutant STR allele leading to marked overexpression of the mature miRNA products, MIR7-5P and MIR1179. This was not observed in primary skin fibroblasts from RTSH subjects, consistent with thyroid specific regulation of the enhancer and lack of an extrathyroidal phenotype. An imbalance in signaling pathways targeted by MIR7-5P provides a working model for this novel cause of RTSH. These findings broaden our current knowledge of genetic defects altering pituitary-thyroid feedback regulation and highlight the function of this locus as primate-specific modulator of thyroid function. Presentation: 6/1/2024

  PublisherOA PDFDOI

• Severe neurodevelopmental phenotype, diagnostic, and treatment challenges in patients with SECISBP2 deficiency

  Genetics in Medicine · 2024-09-21 · 8 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Resistance to Thyroid Hormone (RTH) and Resistance to TSH (RTSH)

  Pediatric Endocrinology · 2024-01-01

  book-chapterOpen accessSenior author

  Resistance to thyroid hormone (RTH) is a syndrome characterized by variable tissue hyporesponsiveness to thyroid hormone (TH). Mutations in both TH receptor (TR) isoforms have been identified, which manifest different phenotypes of RTH, RTH-α, and RTH-β. Patients with the RTH-β phenotype seek medical attention for goiter and abnormal thyroid function tests (TFTs). Biochemically, RTH-β is characterized by elevated TH values in the setting of non-suppressed thyrotropin (TSH) levels. Resistance at the level of the hypothalamus and pituitary leads to elevated TSH, which stimulates TH production; however, reduced action elsewhere results in variable degrees of compensated TH hyporesponsiveness depending on the predominant TH receptor (TR) isoform in the tissue, alpha (α) or beta (β). THRA gene mutations have remained elusive until recently. The first case of RTH-α was identified through whole genome sequencing. Because TRα is not involved in the feedback regulation of the hypothalamic-pituitary-thyroid axis, TFTs are different from patients with RTH-β, namely low or normal T4, high normal T3 and normal or slightly elevated TSH. These mild thyroid abnormalities lead patients to present themselves in non-endocrinological clinical departments. Also, defects in TH transmembrane transport, and metabolism manifest as reduced sensitivity to TH. The phenotype of resistance to TSH is characterized by high serum TSH in the absence of goiter. Patients are often identified at birth through neonatal screening for congenital hypothyroidism Affected individuals have normal or hypoplastic thyroid glands, high serum TSH, and normal or low serum T4 and T3, and symptoms range from euthyroid hyperthyrotropinemia to overt hypothyroidism.

  PublisherDOI

• Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie Allan-Herndon-Dudley syndrome

  JCI Insight · 2024-02-20 · 16 citations

  articleOpen access

  Patients with mutations in the thyroid hormone (TH) cell transporter monocarboxylate transporter 8 (MCT8) gene develop severe neuropsychomotor retardation known as Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired triiodothyronine (T3) transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3 inducibility of TH-regulated genes. In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3',5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for patients with AHDS.

  PublisherOA PDFDOI

• P229: Non-coding variants create an enhancer cluster that causes resistance to thyrotropin via long-range interactions with a microRNA promoter

  Genetics in Medicine Open · 2024-01-01

  articleOpen access

  Resolving whether and how rare noncoding genetic variants cause Mendelian conditions remains challenging owing to the diverse mechanisms by which they cause disease. Here we demonstrate the utility of single-molecule chromatin fiber sequencing (Fiber-seq) for resolving the mechanistic basis of the Mendelian condition autosomal dominant resistance to thyrotropin (RTSH), which had previously been linked to noncoding variants within a short tandem repeat (STR) variant on chromosome 15.

  PublisherOA PDFDOI

• STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179

  Nature Genetics · 2024-05-01 · 24 citations

  articleOpen access
  PublisherOA PDFDOI

• OR14-02 The Thyroid Hormone Analogs DITPA And TRIAC Triggered T3-signalling In Human MCT8-deficient Brain Organoids

  Journal of the Endocrine Society · 2023-10-01

  articleOpen access

  Abstract Disclosure: F. Salas Lucia: None. A.M. Dumitrescu: None. S. Refetoff: None. Patients with mutations in the X chromosome-linked thyroid hormone (TH) cell transporter MCT8 gene have brain hypothyroidism, resulting in severe neuro-psychomotor retardation for which treatment remains very challenging. Potential new treatments using the TH-analogues 3,5-diiodothyropropionic acid (DITPA) and 3,3’,5-triiodothyroacetic acid (TRIAC) have been explored in Mct8-deficient mice. However, given species differences in brain TH transporters, in vitro models using human cells are needed. Here, we generated human brain organoids (BOs) from 4 lines of human induced pluripotent stem cells (hiPSCs). Two lines were derived from MCT8-deficient patients. The other two lines were used as controls: one isogenic line in which the MCT8 mutation has been corrected using CRISPR/Cas9, and a line derived from the unaffected father. Control BOs showed multiple large and continuous neuroepithelia surrounding a ventricle and expressed forebrain markers (FOXG1, and LHX2) at 10-fold higher levels than the hiPSCs. After 20 days in culture, BOs expressed TH transporters; the most abundant being MCT8, trailed by LAT2, LAT1, and MCT10. In contrast, the MCT8-deficient BOs exhibit a 3-fold decrease in the relative expression of LAT2, compared to controls. All BOs showed a similar expression of the deiodinase type 3 (DIO3), and the TH nuclear receptor beta (THRB) genes; the DIO2 and THRA expression were undetectable. Additionally, all four BOs expressed the neuronal and glial markers NEUN and GFAP (5.1±2.0, and 7.3±3.8-fold expression, respectively). Immunohistochemistry using fluorescent antibodies confirmed the presence of postmitotic neurons (TUJ1+) expressing MCT8 in the BOs. Next, we measured the D3 activity. BOs were incubated with T3I125, which resulted in a prominent peak of T2I125 measured using an ultra-high-performance liquid chromatography linked to a gamma counter. The peak of T2I125 indicates the uptake of T3I125 into the neural cells residing in the BOs, its metabolism, and the release of T2I125 in the medium. MCT8-deficient BOs exhibited a D3 activity of 5.3±3.1 pmol/mg/h, a 70% less when compared to the 18.4±7.7 pmol/mg/h of controls. When control BOs were incubated with the MCT8 inhibitor Silychristin 2µM, they exhibited 4.4±3.0 pmol/mg/h D3 activity, like MCT8-deficient BOs. Next, BOs were incubated for 24h with either 10nM L-T3, 10nM TRIAC, or 3.5μM DITPA and T3-responsive genes were studied. Treatment with L-T3 upregulated by 2-fold the gene KLF9 in all four BOs, suggesting that the T3-signalling in the MCT8-deficient BOs might not be compromised. The genes HAIRLESS and DIO3 were unresponsive. In parallel, incubation with DITPA and TRIAC also upregulated KLF9 by 1.5-fold, representing a proof of concept for these thyromimetic molecules to act in human neural cells. This human cell model may be used as a platform to screen therapeutic drugs for MCT8 deficiency. Presentation: Friday, June 16, 2023

  PublisherDOI

Recent grants

• Mouse Sbp2 deficiency models the multi-system syndrome of human SBP2 defects

  NIH · $1.8M · 2016–2022

• Thyroid Physiology Studies of Inherited Disorders

  NIH · $10.0M · 1979–2027

• NIH Grant F32DK091016

  NIH · $57k · 2012

Frequent coauthors

• Samuel Refetoff

  University of Chicago

  107 shared

• Roy E. Weiss

  52 shared

• Juan Bernal

  Consejo Superior de Investigaciones Científicas

  25 shared

• Xiao-Hui Liao

  University of Chicago

  18 shared

• Jiao Fu

  18 shared

• Manassawee Korwutthikulrangsri

  University of Chicago

  16 shared

• Xiao-Hui Liao

  University of Chicago

  14 shared

• Antônio C. Bianco

  11 shared

Labs

• Alexandra Dumitrescu LabPI