CME INDIA Case Presentation by Dr N.K. Singh, MD, FICP.

CME INDIA Case Study:

For last 3 years, on Oxcarbazepine 300mg bd. and Levetiracetam 500mg bd. For seizure disorder.

Came to me on 04/01/2021 for new onset diabetes detected one week before.

Random sugar 544mg/dl, Hb1ac-10.8%, RFT, LFT-Normal, BMI- 21, No family history of diabetes. Urine Ketone-Negative.

Male with skin lesions

CME INDIA Discussion

Dr Vikash, DNB, Med., Bokaro: Tuberous sclerosis?

Dr Prasun Dev, DM, Endo., KIMS, Hyderabad: Adenoma sebaceum? Keloids?

Dr Amit Kumar, Dermatologist, Ranchi: It is most likely tuberous sclerosis. Can’t be keloids since age of 4. D/D could be dermatofibroma or some epidermal growth.Need to go for excision biopsy.

Dr N K Singh: Why is it not Adenoma sebaceum?It refers to the reddish-brown papular rash found characteristically in a “butterfly” distribution over the face. This rash is a pathognomonic hallmark of tuberous sclerosis . It occurs in over 85% of patients of tuberous sclerosis.

Dr Ravishankar Dwivedi, Dermatologist, Ranchi: Adenoma sebaseum,  the triad part of skin lesion, is more commonly seen as small skin colored papules,  centrofacial location. Location, size and surface texture doesn’t go with Adenoma seb. These appear more as exogenous growth, rather than intra dermal. More likely to be  nervous sebaceous,  however histopathology will be confirmatory.

Dr Rajkamal Chaudhary , Asso.Prof Med Bhagalpur: Tuberose Sclerosis.

Dr N K Singh: See the USG abdomen:

Male with skin lesions

Dr N K Singh:

  • Seizure is well known association. How is it associated with diabetes? Which type of diabetes is it? The literature says – “The TSC1-TSC2 tumor suppressor complex serves as an interface between insulin and nutrient signalling pathways and the cell growth machinery. Recent work has demonstrated that TSC deficiency imposes a negative autoregulatory loop that suppresses insulin signalling at the post-receptor level, effectively resulting in cell autonomous insulin resistance. Exploitation of this insulin signalling deficiency may hold promise among tailored clinical therapies designed to manage tuberous sclerosis.”
  • C peptide will be sent after control of sugar with Insulin Antibodies test. Any role of genetic tests?

 Dr Prasun Dev, KIMS, Hyderabad:

  • Everything else fits in to tuberous sclerosis….skin, kidney lesions, seizures. 👍Not directly linked to diabetes… need to check this, the insulin resistance is at the cell- nutrient usage level, and interfering at that site can help control the lesions. Doesn’t seem to result in diabetes…

Dr Ashok Kumar, Neuro, Ranchi:

  • Shows Brown – red papules and nodules of varying sizes. More on the Left Forehead More interesting findings are in both irises. Pupils have shaggy margins. Irises have hypopigmented spots.
  • In Right eye — the iris shows a papule — is pigmented — at about 10 O’clock. But we need more pictures of eyes.

Male with skin lesions

  • Facial and eye lesions make a definite diagnosis of Tuberose sclerosis.
  • Needs Fundus examination and evaluation for visual problem if any – in addition to evaluation of Brain, heart and kidneys.

Further Inputs:

CT Brain – Cortical or subependymal tubers and white matter abnormalities.

C-peptide – Very Low.

GAD65 – Positive.

Final Clinical Diagnosis: Tuberous Sclerosis with lesions on skin and Brain and Kidneys with Type 1 Diabetes.


CME INDIA Learning Points

  • Tuberous sclerosis (also called tuberous sclerosis complex, or TSC) is a rare, multi-system genetic disease that causes non-cancerous (benign) tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.

  • It usually affects the central nervous system and can result in a combination of symptoms including seizures, impaired intellectual development, autism, behavioural problems, skin abnormalities, and kidney disease.

  • The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify with age and become hard or sclerotic. TSC occurs in all races and ethnic groups, and in both genders.

  • TSC is caused by defects, or mutations, on two genes—TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene is on chromosome 9 and produces a protein called hamartin. The TSC2 gene is on chromosome 16 and produces the protein tuberin. These proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions. most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2—meaning neither parent has the disorder or the faulty gene(s).

  • More than 80% of individuals with tuberous sclerosis develop seizures during childhood.

  • Diagnosing TSC is based upon clinical criteria. The first clue -The presence of seizures or delayed development. In other cases, the first sign may be white patches on the skin (hypomelanotic macules) or the identification of cardiac tumor rhabdomyoma.

  • Diagnosis of the disorder is based (1) careful clinical exam (2) computed tomography (CT) or magnetic resonance imaging (MRI) of the brain (3) an ultrasound of the heart, liver, and kidneys, which may show tumors in those organs. We need to carefully examine the skin for the wide variety of skin features, the fingernails, and toenails for ungual fibromas; the teeth and gums for dental pits and/or gum fibromas; and the eyes for retinal lesions.

  • How to use the major and minor criteria
    1. A definite diagnosis of TSC is made when there are two major features or when there is one major feature with two minor features.
    2. A probable diagnosis of TSC is made when there is one major feature and one minor feature.
    3. A possible diagnosis of TSC is made when there is only one major feature only or when there are two minor features without a major feature.

  • The major features of Tuberous sclerosis complex
    1. Facial angiofibromas or forehead plaque
    2. Nontraumatic ungual or periungual fibroma
    3. Presence of more than three Hypomelanotic macules
    4. Shagreen patch or connective tissue nevus
    5. Multiple retinal nodular hamartomas
    6. Cortical tuber(s)
    7. Subependymal nodule
    8. Subependymal giant cell astrocytoma
    9. Presence of a single Cardiac rhabdomyoma or more
    10. Lymphangioleiomyomatosis
    11. Renal angiomyolipoma

  • The minor features of TSC
    1. Multiple and random dental pits
    2. Hamartomatous gastrointestinal or rectal polyps
    3. Bone cysts
    4. White matter radial migration lines
    5. Gingival fibromas
    6. Non-renal hamartoma
    7. Retinal achromic patch
    8. Confetti skin lesions which are clusters of low melanin lesions with a reticular appearance
    9. Multiple renal cysts
  • Three types of brain lesions are seen in TSC:
    1. Cortical tubers.
    2. Subependymal nodules (SEN).
    3. Subependymal giant-cell astrocytomas (SEGA).

  • Skin abnormalities 
    1. Hypomelanic macules (“ash leaf spots”), which are white or lighter patches of skin that may appear anywhere on the body and are caused by a lack of skin pigment or melanin—the substance that gives skin its color.
    2. Facial angiofibromas (also called adenoma sebaceum) are reddish spots or bumps which appear on the face (sometimes resembling acne) and consist of blood vessels and fibrous tissue.
    3. Forehead plaques are raised, discolored areas on the forehead which are common and unique to TSC and may help doctors diagnose the disorder.
    4. Shagreen patches are areas of thick leathery, pebbly skin, usually found on the lower back or nape of the neck.
    5. Ungual or subungual fibromas 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 usually appear later in life, ages 20-50.
    6. Other skin features that 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 that may appear on the scalp or eyelids.

  • Kidney problems such as cysts and angiomyolipomas (benign growths of fatty tissue and muscle cells) occur in an estimated 70 to 80 percent of individuals with TSC. They usually occur between ages 15 and 30. Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC.

  • Lung lesions are present in about one-third of adult women with TSC and are much less commonly seen in men.  Lung lesions include lymphangioleiomyomatosis (LAM) and multinodular multifocal pneumocyte hyperplasia (MMPH).  

  • No definite association of Tuberous Sclerosis with diabetes has been mentioned in available literature.


CME INDIA Tail Piece

1. Why echocardiography is recommended in this case

A benign tumor known as a rhabdomyoma can develop in the heart of infants and young children. These tumors usually do not cause symptoms and may regress on their own and disappear over time. In some instances, they can interfere or obstruct the flow of blood from the heart (outflow tract obstruction) and/or cause irregular heartbeats (arrhythmias).

2. What is the role of genetic testing?

Molecular genetic testing can confirm a diagnosis of tuberous sclerosis. Molecular genetic testing can detect alterations in one of the two genes known to cause the disorder, and is available as a diagnostic service at specialized laboratories.

3. Which TCS gene is associated with serious disease?

Generally, alterations in the TSC2 gene result in a more severe disease expression.

4. Which 2 drugs are approved by FDA in recent years?

Two drugs have been approved by the U.S. FDA specifically for the treatment of seizures associated with tuberous sclerosis. FDA approved Everolimus(mTOR inhibitor)for the treatment of seizures in adult and pediatric patients aged 2 years and older with tuberous sclerosis in 2018, and Cannabidiol for patients one year and older in 2020.

5. What is the role of mTOR inhibitors?

Individuals taking mTOR inhibitors for internal tumors (e.g. SEGAs or angiomyolipomas) may see improvement in skin lesions. Topical formulations of mTOR inhibitors have shown promise in treating facial angiofibromas. Individuals with no immediate indication for mTOR inhibitor treatment may undergo certain procedures to improve the appearance of skin lesions including dermabrasion, laser therapy, or surgical removal (excision) of a lesion.


Discover CME INDIA: