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Tuberous Sclerosis Complex with PKD and Renal Hemorrhage

Basic InformationName: OAge: 18-year-oldGender: FemaleDate of Admission: 2009/2/24 Underline disease: tuberous sclerosis complex

Underlying DiseaseTuberous sclerosis complexSkin:Facial angiofibromasHypomelanic macules Forehead plaquesCNS: giant cell astrocytoma s/p operation (91-4)Renal: Bilateral multiple huge angiomyolipomas

Present Illness02/245pm Right flank pain Pattern: dullness and persistent aggravated when walk and deep breath Sharp pain since 7 pm02/247pm No trauma No fever, no dysuria/ frequency/ urgencyNCKUH ER

Renal Sonography

Abdominal CT

Abdominal CT

Hemogram & Biochemistry

Estimated blood loss volume: 500-600 ml

Further Condition Transcatheter arterial embolization (TAE) or Nephrectomy bleeding spontaneous ceasedTransferred to general ward on 02/27 & discharged on 03/02

Tuberous Sclerosis ComplexThe majority insults leading to death or disabilityNeurologic disease the commonest cause of death in childhood and adolescenceRenal disease angiomyolipomas (60-80%), leading to renal failure or spontaneous hemorrhageSelective transcatheter arterial embolization (TAE)Nephrectomy Pulmonary manifestation lymphangioleiomyomatosis, a progressive lung disease

Tuberous Sclerosis ComplexA tumor-suppressor syndrome caused by mutations in the tuberin gene (TSC2) or the hamartin gene (TSC1)The hamartintuberin (TSC1-TSC2) complex regulates the activity of the mammalian target of rapamycin (mTOR) mTOR -- lies downstream of cellular pathways controlling cell growth and proliferation (G1S) Abnormal signaling through mTOR is involved in a number of tumor-suppressor syndromes and cancers

Clinical Experience of Rapamycin in Tuberous SclerosisStructure analogous -- SirolimusCCI-779 (Temsirolimus)RAD001(Everolimus) and FK-50Case report of sirolimus-induced reduction in angiomyolipoma size clinically was first reported in 2006 19 y/o female patient with bilateral renal angiomyolipoma (tumor size, 5.2 x 6.8 x 7.3 cm) (Am J Kidney Dis 2006;48(3):e27-e29)38-year-old female with huge angiomyolipoma Left side: 20.5 cm in diameter; right side: 11.5 cm 6 mg of sirolimus once daily for 2 years (Eur J Intern Med 2007;18:76-7)

Treatment EffectBefore Tx1 year2 year6 months after stopping Tx

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex25 patients, 18 to 65 y/o, from May 2003 to November 2004All patients received sirolimus for 1 year; followed up for an additional year after stopping medicationImage survey were performed at months 2, 4, 6, 12, 18, and 24MRI for brain and abdomenCT scan for lung

N Engl J Med 2008;358:140-51

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex0.25 mg/m2 (serum levels prevent rejection in renal transplants)2 weeksAdjust dose to achieve serum sirolimus level between 1 - 5 ng/ml2 monthsAdjust dose to achieve serum sirolimus level between 5-10 ng/mlThe longest coronal-plane dimension 10% of the baseline value YESNOKeep current dosage 410-15N Engl J Med 2008;358:140-51

Result -- AngiomyolipomaN Engl J Med 2008;358:140-51

Result -- Angiomyolipoma70% of the baseline value5 of the 18 patients (28%) remained at least 30% smaller than baseline value 1 year after therapy}N Engl J Med 2008;358:140-51

Adverse Events

Our Patient Start Sirolimus (0.25mg/m2) since 2009/03/02Follow up renal echo03/11: hyperechoic nodules(~5.6cm) in both kidneys04/08: hyperechoic nodules(~4.4cm) in both kidneys 03/1104/08

Thanks for your Attention

CT scan on August, 2008

Physical ExaminationConsciousness: clearAppearance: fair-lookingVital sign:T/P/R:36.4C/ 109 / 14 BP: 135/85 mmHgHead: conj: not anemicsclera: not ictericthroat: not injectedtonsil: not enlargedNeck: supple, LAP(-)Chest: symmetric expansion, subcostal retraction (-) - H.S.: regular heart beat, no audible murmur - B.S.: clear,no cracklesAbdomen: soft, no distended - Tenderness (+) over right flank area and back - No rebounding pain - L/S: impalpable / impalpable - BS: hypoactiveExtremities: pitting edema (-)Skin: turgor fine, rash(+)

Renal hemorrhage occurred in 51% of patients with lesions 4.0 cm or largerCurrent management suggestion:Asymptomatic lesions< 4.0 cm: observation with annual CT scan 4.0 cm, follow-up CT scans every 6 monthsProphylactic embolization of asymptomaticlesions 4.0 cm or larger is recommended in select highriskpatients, including younger women who intendpregnancy or patients in which regularfollow-up is difficult.

http://www.cellsignal.com/reference/pathway/mTor.htmlcomposed of mTOR, Raptor, and GL (mLST8), is inhibited by rapamycin and integrates multiple signals reflecting the availability of growth factors, nutrients, or energy to promote either cellular growth when conditions are favorable or catabolic processes during stress or when conditions are unfavorable. Growth factors (e.g. insulin) signal to mTORC1 via Akt or ERK1/2 which inactivate TSC2, thus preventing its inhibitory action on mTORC1. Alternatively, low levels of ATP lead to the AMPK-dependent activation of TSC2, thus reducing mTORC1 signaling. Amino acid availability is signaled to mTORC1 via a pathway involving the Rag proteins. Active mTORC1 has a number of downstream biological effects including translation of mRNA via the phosphorylation of downstream targets (4E-BP1 and p70 S6 Kinase), suppression of autophagy, ribosome biogenesis and activation of transcription leading to mitochondrial metabolism or adipogenesis. The mTOR complex 2 (mTORC2), composed of mTOR, Rictor, GL, and Sin1, promotes cellular suvival by activating Akt, and regulates cytoskeletal dynamics by activating PKC and/or Rho GTPase. Aberrent mTOR signaling is involved in many disease states including cancer, cardiovascular disease and metabolic disorders