Tuberous Sclerosis

• 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. A recent publication indicates that topical rapamycin is helpful for treatment of facial angiofibromas.[71
• 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.
• Hypomelanic macules (“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.
• Forehead plaques: Raised, discolored areas on the forehead.
• Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel, usually found on the lower back or nape of the neck.

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, cafe au Tait spots or flat brown marks, and poliosis, a tuft or patch of white hair on the scalp or eyelids.

Ash leaf spot REF: Harrison’s 18^th ed chapter 53

Repeat in December 2011

“The earliest manifestation of tuberous sclerosis is Ash leaf spot”

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:

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. A recent publication indicates that topical rapamycin is helpful for treatment of facial angiofibromas.

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.

• Hypomelanic macules (“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.

• Forehead plaques: Raised, discolored areas on the forehead.
• Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel, usually found on the lower back or nape of the neck.

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 laft spots or flat brown marks, and poliosis, a tuft or patch of white hair on the scalp or eyelids.

Angiomyolipomas are present in 25% to 50% of patients with tuberous sclerosis, a disease caused by loss-of-function mutations in the TSC1 or TSC2 tumor suppressor genes.

This is a benign tumor consisting of vessels, smooth muscle, and fat.

It is characterized by lesions of the cerebral cortex that produce epilepsy and mental retardation, a variety of skin abnormalities, and unusual benign tumors at other sites, such as the heart.

Essentials of Diagnosis & Typical Features of Tuberous sclerosis:

• Facial angiofibromas or subungual fibromas.
• Often hypomelanotic macules, gingival fibromas.
• Retinal hamartomas.
• Cortical tubers or subependymal glial nodules, often calcified.
• Renal angiomyolipomas.

Ash leaf spots are white, ovoid, hypopigmented, ash leaf–shaped macules that can be found on the trunks or limbs. White macules offer an excellent opportunity for early diagnosis because they may be found at birth or early infancy.

Shagreen patches are flesh-colored soft plaques that are frequently found in the lumbosacral area but may occur anywhere on the trunk. The surface may be pebbly (resembling pigskin or untanned leather) with prominent follicular openings. They are usually noticed during the first decade.

The characteristic lesions are angiofibromas. These are pink or skin-colored telangiectatic papules commonly observed in the nasolabial folds and on the cheeks and chin. They usually appear in children younger than 10 years and increase in size and number until adolescence, remaining unchanged thereafter.

Other areas in which they may be observed include in and around nails (ungual fibromas), scalp, and forehead, lips, dorsa of tongue, and palate. 

Diagnostic triad of Tuberous sclerosis includes epilepsy, mental retardation and adenoma sebaceum (facial angiofibroma).

Internal manifestations of tuberous sclerosis include seizures, mental retardation, central nervous system (CNS) and retinal hamartomas, pulmonary lymphangioleiomyomatosis (women), renal angiomyolipomas, and cardiac rhabdomyomas.

Ans. is ‘d’ i.e. germline mosaicism

Inheritance of Tuberous sclerosis

o Tuberous sclerosis is a genetic condition which is transmitted either through inheritance or as a spontaneous genetic mutation.

o Mutation in one of the two genes TSC₁ and TSC₂ have been identified as a cause for tuberous sclerosis.

o Approximately 33% or one third of people with Tuberous sclerosis inherit it from a parent who also has tuberous sclerosis. This occurs via dominance inheritance.

o Thus there is 50 per cent chance with each pregnancy for a parent with Tuberous sclerosis to have a child with Tuberous sclerosis.

o In the remaining 66 % or two thirds of the people with Tuberous sclerosis, neither parent has tuberous sclerosis. o It appears that one of the normal genes from either parent changes to the abnormal form, leading to a new (or

sporadic), occurrence of tuberous sclerosis in the child. Normally these parents do not have another child with

tuberous sclerosis because the mutation was sporadic not inherited. However, some families have more than one

child with Tuberous sclerosis even though neither parent showed symptoms or findings of Tuberous sclerosis.

How does this occur?

o Scientists have determined that small number of physically unaffected parents of a child with TSC have mutations in some of their cells.

o Because the mutation is limited to a small portion of all of the body’s cells, these individuals show no signs of Tuberous sclerosis.

o But if a portion of the egg or sperm cells of a parent carries the tuberous sclerosis mutation, that parent can have

more than one affected child, possibly at the same 50/50 chance that people with Tuberous sclerosis have.

o A person who carries cells with Tuberous sclerosis mutation in her egg or his sperm supply has germline

mosaicism.

o “Mosaicism” means that the person’s body is made up of a combination of cells with and cells without a Tuberous sclerosis mutation.

o ‘Germline mosaicism’ refers to the presence of cells with Tuberous sclerosis mutations in the egg or the sperm cell supply.

o Germline mosaicism is relatively rare and this explanation does not apply to most families with a sporadically affected child. However, the occurrence of germline mosaicism has geneticists to estimate a recurrence risk (or chance that a family with a sporadically affected child will have anohter child with TSC) ranging from 1 to 3%. At this time there is no way to determine whether an unaffected parent of a child with TSC has germline mosaicism.

Ans. is ‘a’ i.e., Autosomal dominant

Ans. is ‘a’ i.e., Vigabatrin

Ans. is ‘b’ i.e., Tuberous sclerosis

Tuberous sclerosis :

o It is an autosomal dominant neurocutaneous syndrome.

o Pathology

• Characteristics brain, lesion, consists of tubers in the brain.
• They are typically present in subependyneal region where they undergo calcification producing candle dripping appearance.

Ans. is ‘b’ i.e., Tuberous sclerosis

History of seizures and multiple hypopigmented macules over the back (ash leap patch) suggest the diagnosis of tuberous sclerosis.

A i.e. Tuberous sclerosis

C i.e. Tuberous sclerosis

A i.e. Iris nodule

B i.e. Tuberous sclerosis

B i.e. Tuberous sclerosis

A i.e. Tuberous sclerosis

A i.e. Tuberous sclerosis

C i.e. Cafe au lait macules exclude the diagnosis.

Tuberous sclerosis is autosomal dominant disorderQ presenting with classical Vogt’s triad of epilepsy, low intelligence/mental retardation/ delayed mile stones and adenoma sebaceum (arjgiofibroma of face)Q and ashleaf (stippled or Confetti) hypomelanotic offwhite macules mostly on trunk & buttockQ. (Acronym-Epiloia)

Answer is A (Tuberous Sclerosis):

The presence of hvopigmented macules in the background of seizures and mental retardation suggests the diagnosis of Tuberous Sclerosis.

Often hypopigmented macules are the initial clue to tuberous sclerosis, a neurocutaneous disorder inherited in an autosomal dominant manner. Any child with unexplained seizures should be examined carefully for cutaneous clues, particularly hypopigmented macules. The hypopigmented lesions are small, ovoid and scattered and their number varies.’ — Oski’s Pediatrics 4th/861

The off white hypomelonotic macules are seen more easily in tanned or dark skinned individuals. The macules often are oval or ‘ash leaf’ in shape and follow dermatomes. In infancy the presence of these macules accompanied by seizures is virtually diagnostic of Tuberous Sclerosis’

Tuberous Sclerosis

Autosomal Dominant Neurocutaneous Disorder

Answer is B (Tuberous Sclerosis):

Neurological features of seizures and mental retardation together with cutaneous manifestations in the form of sebaceous adenomas are characteristic of the neurocutaneous syndrome of Tuberous sclerosis.

The answer is D (Hydrocephalus):

The characteristic triad in tuberous sclerosis includes epilepsy, mental retardation, and Adenoma Sebacium.

Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumors to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin.

A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease.

Ans. B: Tuberous Sclerosis

TSC is caused by mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively.

These proteins act as tumour growth suppressors, agents that regulate cell proliferation and differentiation.

The physical manifestations of tuberous sclerosis are due to the formation of hamartia (malformed tissue such as the cortical tubers), hamartomas (benign growths such as facial angiofibroma and subependymal nodules) and, very rarely, cancerous hamartoblastomas.

Central nervous system

Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/ subcortical tubers.

Kidneys

Between 60 and 80% of TSC patients have benign tumors (hamartomas) of the kidneys called angiomyolipomas (AML) frequently causing hematuria.

Lungs

Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts. This process is identical to another disease called lymphangioleiomyomatosi (LAM).

Heart

Rhabdomyomas are benign tumors of striated muscle.

Skin

The most common skin abnormalities include:

– Facial angiofibromas (“adenoma sebaceum”): A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distribution.

– Ungual or subungual fibromas: Small fleshy tumors that grow around and under the toenails or fingernails.

– Hypomelanic macules (“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.

–  Forehead plaques: Raised, discolored areas on the forehead.

– Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel, usually found on the lower back or nape of the neck.

Eyes

Retinal lesions, called astrocytic hamartomas, appear as a greyish or yellowish-white lesion in the back of the globe on ophthalmic examination.

Ans. Wegener’s granulomatosis

Ans. Ependymoma

Ans. is ‘b’ i.e., Tuberous sclerosis

Periungual fibromas (Koenen’s tumors) :‑

• Present in 20% of patients of tuberous sclerosis.
• Develop in adult life.
• Small, pink, sausage-shaped growths arising from under the nail folds; may distort the nail plate.

Ans. is ‘d’ i.e., All the above

• Tumors associated with tuberous sclerosis are subependymal giant cell astrocytoma, ependymoma, rhabdomyomas of heart, angiomyomas of kidney, liver, adrenal and pancreas.

Ans. is ‘c’ i.e., McCollon Plaques

Ans. c. Tuberous sclerosis

• Most probable diagnosis in a child with seizures, oval hypo-pigmented macules on the trunk, and sub-normal IQ is Tuberous sclerosis.

Ans. d. Ependymoma

Ependymoma is typically a feature of neurofibromalosis 2, but it can be seen in tuberous sclerosis as well, though it is
much less common.
Seizuresa
– Seizures are the MC presenting symptom
– Infantile spasms may be the presenting feature during infancy
Mental Retardation
Mental Retardation occurs in up to 50% of patients referred to tertiary care
Characteristic brain lesion is a cortical ‘Tuber’.
MC neurological manifestations: Seizures, cognitive impairment and behavioral abnormalities including autism.
Patients with seizures are more prone to mental retardationo
Subependymal nodules which may calcify
Hydrocephalus

Ans. is ‘d’   i.e., Blue white 

Wood lamp

• This is a source of ultraviolet light (320-400nm) from which virtually all visible rays have been excluded by a Wood’s (nickel oxide) filter.
• Primarily emits 360nm.
• UV light, when absorbed by certain substances, fluorescences in dark and color produced, is useful in diagnosis of the certain conditions

Ans. is ‘d’ i.e., All the above

Differential diagnosis of congenital disorders of pigmentation

• Waardenburg syndromes types 1-4
• Tietz syndrome
• Piebaldism
• Woolf’s syndrome
• Generalized vitiligo
• Segmental vitiligo
• Vogt-Koyanagi-Harada syndrome
• Chemical leukoderma
• Tuberous sclerosis (hypopigmented macules and patches)
• Ziprkowski-Margolis syndrome (X-linked albinism-deafness syndrome)

Ans. is ‘a’ i.e., Tuberous sclerosis

• Koenen’s periungual fibroma is seen in tuberous sclerosis

Ans. is ‘a’ i.e., Autosomal dominant