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Recognition of Tuberous Sclerosis in Adult Women: Delayed Presentation With Life-Threatening Consequences

Diane Seibert, PhD, CRNP; Chien-Hui Hong, MD, MS; Fumiko Takeuchi, MD; Cara Olsen, DrPH; Olonda Hathaway, CRNP; Joel Moss, MD, PhD; and Thomas N. Darling, MD, PhD
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From the Uniformed Services University of the Health Sciences and the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, and Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting those of the Department of Defense or the Uniformed Services University of the Health Sciences.

Acknowledgment: The authors thank the LAM Foundation and the Tuberous Sclerosis Alliance for assistance with patient recruitment. They also thank Martha Vaughan for critical review of the manuscript and Angelo M. Taveira-DaSilva and Mary Haughey for assistance in data collection. The authors have listed everyone who contributed significantly to the work.

Grant Support: From the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute, and grants from the National Cancer Institute (R01 CA100907; Dr. Darling) and the Congressionally Directed Medical Research Programs (TS080064; Dr. Darling).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2008.

Reproducible Research Statement:Study protocol: Available from Cardiovascular and Pulmonary Branch/National Heart, Lung, and Blood Institute (contact Dr. Moss: e-mail, mossj@nhlbi.nih.gov). Statistical code: Not available. Data set: Available from Cardiovascular and Pulmonary Branch/National Heart, Lung, and Blood Institute after approval by the institutional review boards of the National Heart, Lung, and Blood Institute and the requesting investigator and completion of a human subjects Material Transfer Agreement (contact Dr. Moss: e-mail, mossj@nhlbi.nih.gov).

Requests for Single Reprints: Thomas N. Darling, MD, PhD, Department of Dermatology, Uniformed Services University of Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; e-mail, tdarling@usuhs.mil.

Current Author Addresses: Drs. Seibert, Olsen, and Darling: Department of Dermatology, Uniformed Services University of Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814.

Dr. Hong: Department of Dermatology, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, Kaohsiung, Taiwan 81362.

Dr. Takeuchi: 2-41-21 Mizutani Higashi-ku, Fukuoka, Fukuoka, 813-0041, Japan.

Ms. Hathaway and Dr. Moss: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892.

Author Contributions: Conception and design: D. Seibert, J. Moss, T.N. Darling.

Analysis and interpretation of the data: D. Seibert, C.H. Hong, F. Takeuchi, C. Olsen, J. Moss, T.N. Darling.

Drafting of the article: D. Seibert, T.N. Darling.

Critical revision of the article for important intellectual content: J. Moss, T.N. Darling.

Final approval of the article: C. Olsen, J. Moss, T.N. Darling.

Provision of study materials or patients: J. Moss.

Statistical expertise: C. Olsen.

Obtaining of funding: J. Moss, T.N. Darling.

Administrative, technical, or logistic support: C.H. Hong, F. Takeuchi, J. Moss.

Collection and assembly of data: C.H. Hong, C. Olsen, O. Hathaway, T.N. Darling.

Ann Intern Med. 2011;154(12):806-813. doi:10.7326/0003-4819-154-12-201106210-00008
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Background: Tuberous sclerosis complex (TSC) is associated with tumor development in the brain, retina, kidney, skin, heart, and lung. Seizures, intellectual disability, and characteristic skin lesions commonly manifest in early childhood, but some findings, notably renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM), emerge later, placing adults with undiagnosed TSC at increased risk for morbidity and mortality.

Objective: To describe the clinical presentation and severity of TSC in adult women.

Design: Retrospective cohort study.

Setting: National Institutes of Health Clinical Center, Bethesda, Maryland, 1995 to 2010.

Patients: 79 women aged 18 years or older who were enrolled in an observational cohort study of TSC to evaluate disease manifestations.

Measurements: History, physical examination, pulmonary function testing, chest radiography, abdominal computed tomography, high-resolution chest computed tomography, and brain magnetic resonance imaging were used to evaluate patients.

Results: Among the 45 patients who received a diagnosis of TSC in adulthood, 21 presented with symptoms due to LAM, 19 with renal angiomyolipomas, and 10 with seizures. Of the 45 patients, 30 met clinical criteria for TSC in childhood that remained undiagnosed for a median of 21.5 years and 15 were older than 18 years before meeting the clinical criteria for TSC. Patients diagnosed in adulthood and those diagnosed in childhood had similar occurrences of pneumothorax, shortness of breath, hemoptysis, nephrectomy, and death.

Limitation: No men were included in the study, and selection was biased toward patients having pulmonary LAM.

Conclusion: Women who received a TSC diagnosis in adulthood had minimal morbidity during childhood but were still at risk for life-threatening pulmonary and renal manifestations.

Primary Funding Source: Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute.


Grahic Jump Location
Figure 1.
Major and minor diagnostic features of tuberous sclerosis complex in adult women.

A. Multiple facial angiofibromas, often scattered symmetrically across the nose and cheeks and concentrated in the nasal groove. B. Forehead plaque, pink to red-brown fibrous plaques that can be located anywhere on the face or scalp, with adjacent white scar from skin biopsy. C. Ungual fibromas, emerging from around or under the nail and more common on the toes than fingers. D. Hypomelanotic macules, with a polygonal or ash-leaf shape, under fluorescent lighting (left) and accentuated with a Wood lamp (right). E. Shagreen patch, a connective tissue nevus usually situated on the lower back. F. Dental pitting, pinpoint to crater-like defects in the enamel. G. Computed tomography scan of multiple renal angiomyolipomas in the left kidney in a patient after right nephrectomy. H. Magnetic resonance image of multiple cortical tubers, including a large cortical tuber in the left parietal lobe (arrow). I. Magnetic resonance image of multiple cortical tubers, calcified subependymal nodules (arrows).

Grahic Jump Location
Grahic Jump Location
Figure 2.
Clinical characteristics of tuberous sclerosis complex with early or late penetrance.

The estimated frequencies of findings (0% to 100%) over time are represented by the filled areas. Patients with tuberous sclerosis complex diagnosed in childhood (dark green) typically experience onset of multiple manifestations of the disease in the first 5 years. Patients with adult penetrance (light green) do not meet clinical criteria for diagnosis in childhood and have lower frequencies of brain and skin involvement in adulthood. The substantial variations in disease severity between patients or the potential for changing disease severity over time for 1 patient are not indicated. Patients at risk for a delay in diagnosis (not shown) have childhood penetrance but minimal illness in childhood.

Grahic Jump Location




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Summary for Patients

Tuberous Sclerosis Complex in Adult Women

The full report is titled “Recognition of Tuberous Sclerosis in Adult Women: Delayed Presentation With Life-Threatening Consequences.” It is in the 21 June 2011 issue of Annals of Internal Medicine (volume 154, pages 806-813). The authors are D. Seibert, C.H. Hong, F. Takeuchi, C. Olsen, O. Hathaway, J. Moss, and T.N. Darling.


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