Tuberous sclerosis complex in a young woman diagnosed incidentally on the basis of pregnancy ultrasonography.

Abstract: Tuberous sclerosis complex (TSC) is more prevalent than previously believed and most cases result from new mutations and, hence, do not have affected relatives. Many patients who meet the new diagnostic criteria have unrecognized skin lesions and/or occult lesions in internal organs. As early diagnosis and appropriate intervention can reduce morbidity and mortality from the neurologic, renal, and pulmonary complications of TSC, physicians should be alert for the dermatological signs of the condition and for the incidental finding of TSC lesions during diagnostic testing. Patients with TSC may be asymptomatic and of normal intelligence. We report a case of TSC diagnosed by the incidental finding of renal lesions in a young woman during pregnancy ultrasonic examination.

Key Words: tuberous sclerosis complex

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Tuberous sclerosis complex (TSC) was previously believed to be a rare genetic condition characterized by seizures, mental retardation, and facial angiomas ("Vogt's triad"). (1) New understandings of the inheritance and pathophysiology of TSC led to revised diagnostic criteria in 1998 (Table) and the recognition that the condition has a wide range of clinical features, covering the spectrum from profound physical and mental abnormalities to completely asymptomatic cases. The true incidence of TSC is thought to be much higher than the estimated 1 per 6,000 to 10,000 on the basis of the classic definition. (2) As early intervention may reduce mortality and morbidity from the brain, renal, and pulmonary lesions of TSC, physicians should be alert for the characteristic skin manifestations on which the diagnosis is usually based. (8) Less commonly, lesions characteristic of TSC may be detected in other organs during diagnostic procedures. We present a case of asymptomatic TSC diagnosed incidentally during a pregnancy ultrasonographic examination.

Case Report

A 20-year-old primigravida presented with vaginal bleeding, abdominal cramping, and low back pain at 12 weeks' gestation. Physical assessment was unremarkable and the birthmark on her forehead (Fig. 1) was not believed to be clinically significant. She gave no significant personal or family medical history; specifically, no family members suffered from mental retardation, seizures, skin lesions, or renal diseases. Ultrasound showed a single live intrauterine pregnancy, but multiple echogenic foci were noted in the maternal kidneys (Fig. 2). As these lesions were suggestive of a neurocutaneous syndrome, magnetic resonance imaging of the brain was performed to identify any additional lesions. A cortical tuber in the right frontal lobe of the brain and a subependymal hamartoma in the right lateral ventricle were detected (Fig. 3), confirming the diagnosis of TSC. The patient successfully completed her pregnancy and her child has no evidence of TSC.

Discussion

TSC is one of the neurocutaneous syndromes, a group of congenital disorders characterized by dysplastic/neoplastic lesions ("tubers") primarily involving the skin and nervous system. More than 40 neurocutaneous syndromes have been described, the most common of which are neurofibromatosis I and II, tuberous sclerosis, Sturge-Weber syndrome, and von Hippel-Lindau syndrome. Tuberous sclerosis complex is an autosomal dominant disorder carried on two genes. The gene, located on chromosome 9 (TSC1, 9q34), produces a protein product called hamartin and usually affects the brain. The other gene, TSC2, located on chromosome 16 (16p 13.3), produces a protein product called tuberin that preferentially affects the kidneys. Both TSC1 and TSC2, however, are associated with manifestations in multiple organ systems. Although TSC is an autosomal dominant disorder, most cases (65-75%) result from new mutations and hence do not have a positive family history.

[FIGURE 1 OMITTED]

The clinical features of TSC depend on the target organ (mainly brain, skin, kidneys, lungs, and heart) or organs affected and the extent of damage due to the lesions. The characteristic brain lesions of TSC are benign areas of dysplastic brain development that commonly cause seizures but rarely become malignant. Blockages of cerebrospinal fluid circulation or focal neurologic defects are less common effects. Occasionally, enlarging benign tumors (subependymal giant cell astrocytomas) develop. Retinal phakomas or astrocytomas may be confused with retinoblastomas in infants. Most TSC lesions of the brain can be easily identified on computed tomographic scanning and may also be seen on radiography as they calcify over time.

Most TSC patients have multiple nonspecific hypomelanotic macules, but the characteristic skin lesions are hypomelanotic macules, shagreen patches, facial angiofibromas, forehead plaques, and ungual fibromas. "Ash leaf" spots are often described in TSC and are hypopigmented macules in the shape of a leaf that illuminate intensely under a Wood's lamp. Shagreen patches are connective tissue hamartomas that resemble rough orange-peel textured skin patches, and are usually found on the lower back. Facial angiofibromas were once considered to be pathognomonic for TSC; they may be misdiagnosed as acne in teenagers or their significance overlooked as in our case. Teenagers also commonly show fleshy papules under the nails (ungual fibromas).

Renal cysts and angiomyolipomas are significant causes of morbidity and mortality in TSC due to renal failure or acute bleeding. (3) Regular screening of TSC patients with renal ultrasound or computed tomographic scanning has been recommended to facilitate early surgical removal of enlarging lesions before they can cause hemorrhage or potentially dangerous distortion of renal architecture. (1) Malignant change has been reported in renal TSC lesions. (4)

Cardiac rhabdomyomas have been found in half of TSC patients but they rarely cause symptoms; this depends on their size and location. (1) Pulmonary lesions are less common and occur mainly as lymphangiomyomatosis and/or multifocal micronodular pneumocyte hyperplasia. Pulmonary manifestations are more common in women. (5,6) Regular chest x-ray and pulmonary function testing are recommended to detect this potentially fatal condition, as hormonal manipulation may impact the pathologic process.

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Conclusion

Under the new criteria, definite TSC complex may be diagnosed if either 2 of 11 major features are confirmed or the patient shows 1 major feature plus 2 of 9 minor features. (7) More importantly, the revision emphasizes that dermatologic manifestations may be the only diagnostic clue to this disorder. As illustrated by our case, other incidental findings can be diagnostic. Prompt recognition of TSC and its potential complications can be lifesaving. Bleeding or renal failure due to renal angiolipomas are the major cause of mortality and morbidity in TSC, and renal ultrasonography is recommended every 1 to 3 years in all age groups, as at least 75% of TSC patients have renal lesions. (7) At some stage, 85% of TSC patients develop epilepsy, (7) and other neurologic problems may arise, depending on the site and size of lesions. Cranial imaging is recommended every 1 to 3 years in children to monitor neurologic lesions. (8) Other common lesions include retinal ("mulberry lesions") astrocytoma (50-75%), cardiac rhabdomyomas (50%), and pulmonary lymphangiomyomatosis (1-6% of women). (1)

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at work worth doing.
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Table. Diagnostic criteria for tuberous sclerosis complex (a,b)

Major Features                    Minor Features

Facial angiofibromas or forehead  Multiple random pits in dental enamel
  plaque
Ungual or periungual fibroma      Hamartomatous rectal polyps
More than three hypomelanotic     Bone cysts
  macules
Shagreen patch                    Cerebral white matter radial migration
                                    lines
Multiple retinal nodular          Gingival fibromas
  hamartomas
Cortical tuberous lesion          Nonrenal hamartoma
Subependymal nodule               Retinal achromic patch
Subependymal giant cell           "Confetti" skin lesions
  astrocytoma
Cardiac rhabdomyoma(s)            Multiple renal cysts
Lymphangioleiomyomatosis
Renal angiomyolipoma

(a) Diagnosis (based on Rbach ES, Gomez MR, Northrup H. Tuberous
sclerosis complex consensus conference: Revised clinical diagnostic
criteria. J Child Neurol 1998;13:624-628).
Definite TSC: Either two major features or one major plus two minor
features.
Probable TSC: One major plus one minor feature.
Possible TSC: Either one major or two or more minor features.
(b) Adapted from Hurst JS, Wilcoski S. Recognizing an index case of
tuberous sclerosis. Am Fam Physician 2000;61:703-708, 710; and Behrman
RE, Jenson HB, Kliegman RM (eds): Nelson Textbook of Pediatrics.
Philadelphia, W.B. Saunders Co., 2001, ed 16 p 1837.

Accepted January 5, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9705-0512

References

1. Hurst JS, Wilcoski S. Recognizing an index case of tuberous sclerosis. Am Fam Physician 2000;61:703-708, 710.

2. Behrman RE, Jenson HB, Kliegman RM (eds): Nelson Textbook of Pediatrics. Philadelphia, W.B. Saunders Co., 2001, ed 16, p 1837.

3. Shepherd CW, Gomez MR, Lie JT, et al. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991;66:792-796.

4. Al-Saleem T, Wessner LL, Scheithauer BW, et al. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 1998;83:2208-2216.

5. Weiner DM, Ewalt DH, Roach ES, et al. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 1998;187:548-561.

6. Muir TE, Leslie KO, Popper H, et al. Micronodular pneumocyte hyperplasia. Am J Surg Pathol 1998;22:465-472.

7. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13:624-628.

8. Roach ES, DiMario FJ, Kandt RS, et al. Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation--National Tuberous Sclerosis Association. J Child Neurol 1999;14:401-407.

RELATED ARTICLE: Key Points

* New diagnostic criteria have been established for tuberous sclerosis complex (TSC).

* Tuberous sclerosis complex may be much more prevalent than formerly believed, and many patients with TSC may be asymptomatic and of normal intelligence.

* The diagnosis should be suspected if a patient has characteristic skin lesions and/or findings on diagnostic testing consistent with renal, brain, lung, or heart lesions of TSC.

* Early diagnosis and regular screening of affected individuals can impact mortality and morbidity due to seizures, renal failure, renal hemorrhage, and pulmonary complications.

Cassandra Caprez, MD, Anne D. Walling, MD, and Christina M. Reimer, MD

From the Department of Internal Medicine, University of Kansas School of Medicine-Wichita, Wichita, KS.

We have no financial support or proprietary interest relevant to this article.

Reprint requests to Christina M. Reimer, MD, Department of Internal Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214-3199. Email: [e-mail]