Case- study

1. Case- study

2. 40 yrs old female patient came to medicine OPD with complaints of 5 days H/O pain abdomen, distension of abdomen. • History Of Present illness is preceded by low grade fever • Pain abdomen – sudden onset ,spasmodic, aggravated by intake of food. Associated with 2 episodes of vomitings. • H/O distension of abdomen, increased on taking food. • H/O early morning puffiness of face present. • H/O swelling of lower limbs. • Decreased urinary out put since 3 days.

3. Exertional dyspnoea since 4 days present. No orthopnoea and PND. • Central chest pain radiating to back. • No H/O headache/seizures/vomitings/chest pain/palpitation/fainting. • No history suggestive of cognitive defects. • No history suggestive of old PTB/ Bronchiectasis/epilepsy. • No H/O similar complaints in the past. • Family history;- her mother is having similar complaints.

4. ADENOMA SEBACEUM

5. O/E :- pt conscious, coherent. pallor present, no icterus, no cyanosis, no lymphadenopathy, B/L pitting pedal edema. Facial angiofibroma present, hypopigmentary macules present over left fore arm. subungal fibroma present, Shagreen patches present over back. • Vitals :- Temp-N, PR- 72 / min, regular, good volume, BP- 110/70 mmof Hg. RR- 24bpm.

6. PERI UNGAL FIBROMA

8. Buccal mucosal fibrous plaques

9. SYSTEMIC EXAMINATION • P/A:- Abdomen distended, umbilicus is placed transversely. Liver palpable, no splenomegaly Mass in left iliac fossa hard in consistency. BS- present. • RS- NVBS. • CVS – NAD. • CNS – HMF – normal, cranial nerves examination, motor system, sensory system –normal.

10. HB- 5.7gm%,TC- 4500/cmm, DC- 62/28/03/07. platelet – 2,74,000, ESR- 120 mm/1hr. • Heamogram – microcytic hypochromic anemia. • Urea / creatinine- 32.5/ 1.83 mg/dl. • CUE- albumin- +++,, pus cells- plenty, R.B.C- 20-25/HPF. • RBS- 70 mg%. • Na/K/Cl - 136/4.6/96 meq/L. • Amylase / Lipase – 142 / 36 U/L.

13. U/S abdomen:-hepatomegaly with prominent IVC , congestive changes in liver, B/L enlarged kidneys with gr2 nephropathy with ?multiple angiomyolipoma. • 2DECHO – concentric LVH, EF68%, no RWMA, good LV function. • CT Abdomen:- B/L renal angiomyolipoma, bony sclerotic lesions. • CT brain:- subependymal nodules. • MRI brain:- Normal study.

14. Ophthalmology examination:- Visual acuity – 6/12 with PH 6/9 in both eyes. No hypopigmented patches on iris, no atypical colobomas. Fundus normal study without any astrocytomas. Medical Gastroenterology examination:- colonoscopy – normal study.

15. Dermatology examination:- Adenoma sebaceum+, Ashleaf macules+ , Confeti like macules+, Shagreen patches +, facial fibrous plaques+, Buccal mucosal fibrous plaques+.

16. Histopathology Biopsy shows a thickened reticular dermis with haphazardly arranged thickened collagen bundles. There is no increase in the number of fibrocytes or capillaries. Overlying epidermis shows gentle mammillation. Impression: Collagen nevus Consistent with Shagreen patch To correlate clinically. Dr. UdayKhopkar Consultant Dermatopathologist

17. Diagnostic Criteria Tuberous Sclerosis Complex Consensus Conference (1998)

18. Definite TSC: Either 2 major features or 1 major feature with 2 minor features Probable TSC: One major feature and one minor feature Possible TSC: Either 1 major feature or 2 or more minor features Imp: TUBEROUS SCLEROSIS

19. Discussion

20. History • Latin tuber (swelling) and Greek skleros(hard), refers to the pathological finding of thick, firm and pale gyri, called "tubers," in the brains of patients postmortem. • These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponymBourneville's disease

21. Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. • A combination of symptoms may include seizures,  developmental delay, behavioral problems, skin abnormalities, lung and kidney disease

23. Itis an autosomal dominant disorder that affects 1 in 6000 people. It results from mutations in either the TSC1 gene encoding hamartin or the TSC2 gene encoding tuberin Hamartin and tubulin form a complex that is thought to negatively regulate cell growth and proliferation through inhibition of mTOR. The presence of either mutation produces uncontrolled proliferation in numerous tissues, including the kidneys, skin, central nervous system, and heart.

24. Hamartin and tuberin physically interact, and this interaction is important for their function. . These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation. The complex appears to be a RhebGTPase which suppresses mTOR signalling, part of the growth factor (insulin) signalling pathway. The hamartin/tuberin complex antagonizes an insulin-signaling pathway that plays an important role in the regulation of cell size, cell number, and organ size. In the absence of growth factor stimulation, tuberin /hamartin complexes maintain Rheb (“Ras homolog enriched in the brain”) in an inactive GDP-bound state by stimulating its intrinsic GTPase activity and inhibit downstream signaling from Rheb via mTOR (target of rapamycin). Growth factor stimulation of phosphoinositide 3-kinase (PI3K) signaling leads to Akt-dependent phosphorylation of tuberin, dissociation of the tuberin/hamartin complex, and activation of Rheb and mTOR. Tuberin or hamartin mutations also prevent the formation of tuberin/hamartin complexes and lead to constitutive activation of mTOR.

25. CLINICAL MANIFESTATIONS

26. kidney • The kidneys are affected in 80% of patients. • Renal involvement is second only to the involvement of the central nervous system (CNS) as a cause of death in patients with TSC. • The main renal manifestations include angiomyolipomas, cysts, RCCs with various histological patterns, epithelioidangiomyolipomas, lymphangiomatous cysts, and rarely focal segmental glomerulosclerosis.

27. Angiomyolipomas in TSC are extremely common, are usually multiple and bilateral, and affect both genders • Usually single, and mainly found in middle-age women. • They develop after the first year of age, and by the third decade. • Women have more and larger angiomyolipomas than men. • Small angiomyolipomas are most often cortical and frequently have a wedge-shaped appearance, with the base of the wedge facing the surface of the kidney.

28. As the lesions increase in size, they penetrate deeper into the renal parenchyma or become exophytic extending into the perirenal fat. • The main manifestations relate to their potential for hemorrhage (hematuria, intratumoral or retroperitoneal) and mass effect (abdominal or flank mass and tenderness, hypertension, renal insufficiency). • The diagnosis can be established by sonography, CT, or MRI and requires demonstration of fat in the tumor. • Large lesions, >4 cm, are more likely to be symptomatic and may require transcatheter arterial embolization or surgical excision.

29. Renal cysts may be present in the first year of life, and cystic disease may be the presenting manifestation of TSC. • TSC2 and PKD1 lie adjacent to each other in a tail-to-tail orientation on chromosome 16 at 16p13.3. Deletions inactivating both genes are associated with polycystic kidneys diagnosed during the first year of life or early childhood (TSC2/PKD1contiguous gene syndrome). • Therefore, TSC should be considered in children with renal cysts and no family history of PKD. • Patients with the contiguous gene syndrome usually reach ESRD at an earlier age than that of patients with ADPKD alone. • The renal cysts in TSC can be lined by a very distinct, perhaps unique epithelium of markedly hypertrophic and hyperplastic cells with prominent eosinophilic cytoplasm. • The combination of cystic kidneys and angiomyolipomas has been said to be virtually pathognomonic for tuberous sclerosis.

31. The main clinical problems associated with cystic disease in TSC are hypertension and renal failure. • The treatment consists of strict control of the hypertension. • Bilateral nephrectomy should be considered before transplantation surgery because of the risk of life-threatening hemorrhage and the development of RCC.

32. Renal Cell Carcinoma • The association with RCC is well established. • Compared with sporadic RCCs, there is a female predominance, earlier age of presentation and increased bilaterality. • Early detection is essential. • They should be suspected in cases of enlarging lesions without demonstrable fat and in the presence of intratumoral calcifications.

33. CNS • About 50% of people with TSC have learning difficulties ranging from mild to significant autism, with an even higher proportion showing features of a broaderpervasive developmental disorder. •  A 2008 study reported self-injurious behavior in 10% of people with TSC. •  Other conditions, such as ADHD, aggression, behavioral outbursts andOCD can also occur. • Lower IQ is associated with more brain involvement on MRI.

34. Three types of brain tumours may be associated with TSC: • Giant cell astrocytoma: (grows and blocks the CSF flow leading to dilatation of ventricles causing headache and vomiting) • Cortical tubers: after which the disease is named. • Sub-ependymal nodules: form in the walls of ventricles.

35. Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers. • The tubers are typically triangular in configuration, with the apex pointed towards the ventricles, and are thought to represent foci of abnormal neuronal migration. • The T2 signal abnormalities may subside in adulthood, but will still be visible on histopathological analysis. • On magnetic resonance imaging, TSC patients can exhibit other signs consistent with abnormal neuron migration (radial white matter tracts hyperintense on T2WI, heterotopic gray matter).

36. Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. • There is no interposed neural tissue. These nodules have a tendency to calcify as the patient ages. • A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into a subependymal giant cell astrocytoma (SEGA). • A SEGA typically develops in the region of the foramen of Monro, in which case it is at risk of developing an obstructive hydrocephalus. • A variable degree of ventricular enlargement, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monro) or idiopathic in nature.

40. OCULAR MANIFASTATIONS • Astrocytichamartomas ( phakomas), which appear as a greyish or yellowish-white lesion in the back of the globe on the ophthalmic examination. • Astrocytichamartomas can calcify, and they are in the differential diagnosis of a calcified globe mass on a CT scan. • Multinodular near disc (mulberry appearance); flat, circular at periphery.

41. Non-retinal lesions associated with TSC include • Coloboma • Angiofibromas of the eyelids • Papilledema (related to hydrocephalus)

42. LUNGS • Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts. • This process is identical to another disease called lymphangioleiomyomatosis (LAM). • Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in tuberous sclerosis-related LAM is monoclonal metastasis from a coexisting renal angiomyolipoma. • There have been cases of TSC-related LAM recurring following lung transplant.

43. HEART Rhabdomyomas are benign tumors of striated muscle. • A cardiac rhabdomyoma can be discovered using echocardiography in approximately 50% of people with TSC. • However, the incidence in the newborn may be as high as 90% and in adults as low as 20%. • These tumors grow during the second half of pregnancy and regress after birth. • Many will disappear entirely. Alternatively, the tumor size remains constant as the heart grows, which has much the same effect.

44. skin • Some form of dermatological sign will be present in 96% of individuals with TSC. • Most cause no problems but are helpful in diagnosis. • Some cases may cause disfigurement, necessitating treatment. • The most common skin abnormalities include:

45. Facial angiofibromas ("adenoma sebaceum"): A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distribution. • They consist of blood vessels and fibrous tissue. • This socially embarrassing rash starts to appear during childhood and can be removed using dermabrasion or laser treatment.

46. Periungual fibromas: Also known as Koenen's tumors, these are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. • These are very rare in childhood but common by middle age. • They are generally more common on toes than on fingers, develop at 15–29 years and are more common in women than in men. • Induced by nail-bed trauma.

47. Hypomelanicmacules (ash leaf spots)White or lighter patches of skin that may appear anywhere on the body and are caused by a lack of melanin. • These are usually the only visible sign of TSC at birth. • In fair-skinned individuals a Wood's lamp (ultraviolet light) may be required to see them.

48. Forehead plaques: Raised, discolored areas on the forehead. • Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel,pigmented and usually found on the lower back or nape of the neck. • They can also be scattered across the trunk or thighs. The frequency of these lesions rises with age.

49. Other skin features are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders, café au lait spots or flat brown marks, and poliosis, a tuft or patch of white hair on the scalp or eyelids.

50. Investigations • EEG: may show hypsarrhythmia, focal or multifocal spike or sharp-wave discharges, generalized spike-and-wave discharges. • CT, MRI: calcified subependymal nodules encroach on lateral ventricle; calcified cortical or cerebellar nodules (cortical tubers).