Tuberous sclerosis Q85.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 23.02.2021

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Synonym(s)

Bourneville-Brissaud disease; Bourneville disease; Bourneville M.; Bourneville-Pringle disease; Bourneville-Pringle Disease; Bourneville-Pringle Syndrome; Brain sclerosis; central neurinomatosis (Orzechewski); cerebral sclerosis tuberous; diffuse neurospongioblastosis; Epiloia; Phacomatosis (Bourneville); sclerosis tuberosa; spongioblastosis centralis circumscripta (Bielschowsky); Tuberosclerosis; tuberose; Tuberous sclerosis complex

History
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Bourneville, 1890; Pringle, 1880

Definition
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Rare multifocal neurocutaneous malformation syndrome characterized by variably expressed hamartomas of the skin, CNS, eyes, heart, and kidneys. Clinically suggestive is the DMD triad of:

  • Acne-like centrofacial and periungual angiofibromas.
  • mental retardation and
  • epilepsy.

Tuberous sclerosis is classically counted among the so-called phakomatoses . These are diseases whose common feature is the occurrence of hamartomas in several organ systems.

Other diseases classified as phakomatoses include

Occurrence/Epidemiology
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Worldwide spread. Estimated prevalence is 6.8-12.4 /100,000 inhabitants. It is equally distributed among ethnic groups and both sexes.

Etiopathogenesis
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Autosomal-dominant inherited (new mutations are frequent; in about 70%) mutations of the genes TSC1 (tuberous sclerosis gene 1; gene locus 9q34) and TSC2 (tuberous sclerosis gene 2; gene locus 16p13.3), which lead to disorders of the proteins hamartin (TSC1) and tuberin (TSC2), respectively. The disruption of the physiological function of both proteins as growth regulators of neurons during embryonic development is discussed. Both proteins lead to an inhibition of mTOR (mechanistic target of rapamycin complex 1) and thus to tumor suppression. Mutation of one of these proteins leads to dysfunction of the signaling pathway with consecutive increased cell proliferation and formation of tumors.

The numerous mutations identified are summarized in the Tuberous Sclerosis Complex Variation Database for TSC1 and for TSC2. However, in 10-15% of patients no mutations (no mutation identified) can be detected (NMI patients).

Manifestation
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Discrete hypopigmentations are already present at birth (ash leaf spots). A so-called Adenoma sebaceum usually develops only during puberty. Neurological symptoms appear in the course of the first years of life.

Clinical features
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Integument:

  • Ash leaf spots: Already at birth highly characteristic " vitiligo-like" depigmentation (98%) impress in random distribution (see below Ash leaf spot). The presence of > 5 ash leaf spots is highly suspicious for tuberous sclerosis. Poliosis is considered an alternative expression of hypomelanosis (note: insertion of a Wood lamp may be helpful in detecting ash leaf spots!).
  • Chagrin spots: In addition, skin-coloured to yellow-brownish, plaque-like, punctate, coarsely textured plaques (chagrin spots, also called shagreen spots), which can be found on the trunk and here frequently in the lumbar region, impress. The cause is local collagen thickening. They usually appear after the age of 5.
  • Facial angiofibromas: Only in childhood and at puberty do "acne-typical" facial angiofibromas appear in about 60% of patients (traditional dermatological term: adenoma sebaceum).
  • Fibrous forehead plaques: these plaques histologically diagnosed as angiofibromas occur in 25% of patients (Northrup H et al. 2013).
  • Peri- and subungual (angio-)fibromas of fingers and toes (so-called Koenen tumors) occur as the last dermatological manifestation (are observed in about 20% of patients) and do not appear until adolescence or even adulthood.
  • It is not uncommon to find café-au-lait spots.
  • Very rarely, cutis verticis gyrata develops.

Extracutaneous manifestations:

  • Papular gingival hyperplasia.
  • Epileptiform seizures are typical of tuberous sclerosis (96%). In the first 2-3 years of life, seizures occur focally, later generalized. Usually intellectual retardation, multiple periventricular calcifications in the CNS (98%).
  • Cystic kidney changes up to full-blown poylcystic kidneys occur with so-called large deletions that include the TCS2 (tuberin) gene as well as the PkD1 gene.
  • Multilocular angiomyolipomas of the kidney: 38%
  • Renal cell carcinoma: 3%
  • Adenomas and lipomyomas of the liver
  • Congenital angiomas of the retina; achromatic retinal spot
  • Adenomas of the pancreas
  • Splenic tumors
  • Subependymal giant cell astrocytomas of the CNS: 5-15%
  • Cardiac rhabdomyoma
  • Lymphangioleiomyomatosis of the lung (LAM)

Complex malformations e.g. situs viscerum inversus completus, skeletal changes (bone cysts, periosteal thickening of the diaphysis of the long tubular bones), honeycomb lung, lung cysts, kidney cysts or double kidney have been described.

Therapy
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Causal therapies are not known.

Symptomatic local therapy if necessary is in the foreground.

Everolimus: Everolimus, an mTOR inhibitor, has been shown to have positive effects on subependymal giant cell astrocytoma and renal angiomyolipoma in patients with TSC. Results of the "EXIST study" led to the approval of everolimus for both manifestations. Such effects are also to be expected for Sirolimus.

In the EXIST-study there was also a decrease of neurological symptoms and facial angiofibromas under this therapy. Based on these study results, everolimus is also approved as concomitant therapy for refractory, partial, epileptic seizures, with or without secondary generalization since January 2017 (French JA et al. Lancet 2016).

Genetic counseling is mandatory.

Operative therapie
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Koenensche tumours as well as gum growths are excised if necessary. In the case of subungual Koenens tumours, the corresponding part of the nail plate must be removed first.

For fibroadenomas and trichoepitheliomas of the face, dermabrasion and CO2 laser therapy are possible. Since the results are often unsatisfactory and no standard therapy is recommended, it is left to the treating physician to use further therapy methods such as electrocautery with a sharp needle, laser, cryosurgery, if necessary.

For the treatment of the so-called Adenoma sebaceum s.dort.

Progression/forecast
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Progressive suffering with general developmental delay, increasing behavioural and neurological disorders and increasing mental retardation.

Note(s)
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Diagnostic criteria for tuberous sclerosis (according to Roach ES et al. 1998)

Major criteria

  1. Facial angiofibroma or fibrous forehead plaques (Adenoma sebaceum)
  2. Sub- or periungual fibroids
  3. > 3 hypomelanotic spots (vitiligo-like depigmentation)
  4. Lumbo-sacral connective tissue nevus (shagreen patch)
  5. Multiple nodular hamartomas of the retina
  6. Sclerosing plaque or tumor of the cerebral cortex
  7. Subependymal node or giant cell astrocytoma
  8. cardiac rhabdomyoma
  9. renal angiomyolipoma
  10. Lymphangiomatosis

Minor criteria

  1. Multiple, pit-like enamel defects
  2. Hamartomatous rectal polyp
  3. Bone cysts
  4. Gingival fibroids
  5. Non-renal hamartoma
  6. Achromatic retinal spots
  7. Confetti-like, hypomelanotic spots
  8. Multiple kidney cysts

For the definitive diagnosis of tuberous sclerosis, either 2 major criteria, or 1 major criterion and 2 minor criteria are required. For the probable diagnosis of tuberous sclerosis, 1 major and 1 minor criterion are sufficient.

Literature
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  1. Ammari MM et al (2014) Oral findings in a family with Tuberous sclerosis complex. Spec Care Dentist. doi: 10.1111/scd.12100
  2. Balzer F, Grandhomme (1886) Nouveau cas d'adénomes sébacés de la face. Arch Physiol 8: 93-96
  3. Beltle J, Seaman MD (2003) Computed tomographic findings in Bourneville-Pringle Disease. Eur J Res 8: 292-294
  4. Bourneville DM (1880) Sclérose tubéreuse des circonvolutions cérébrales, idiotie et épilepsie hémiplégique. Arch Neurol (Paris) I: 81-91
  5. Dill PE et al (2014) Topical everolimus for facial angiofibromas in the tuberous sclerosis complex. A first case report. Pediatric Neurol 51:109-113
  6. Ebrahimi-Fakhari D et al (2017) Dermatological manifestations of tuberous sclerosis.J Dtsch Dermatol Ges 15: 695-701
  7. French JA et al (2016) Adjunctive everolimus therapy for treatment-resistant focal-onset seizuresassociated
    with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388:2153-2163.
  8. Liebman JJ et al (2014) Koenen tumors in tuberous sclerosis: a review and clinical considerations for treatment. Ann Plast Surgery 73:721-722
  9. May M et al (2003) Angiomyolipoma of the kidneys as a rare cause of retroperitoneal hemorrhage. Two case reports with tuberous sclerosis Bourneville-Pringle. Urologist 42: 693-701
  10. Northrup H et al (2013) Tuberous sclerosis complex diagnostic criteria update: recommendations of the2012
    Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatric Neurol 49:243-524.
  11. Pringle JJ (1890) A case of congenital adenoma sebaceum. Brit J Derm 2: 1-14
  12. Roach ES, Delgado MR (1995) Tuberous sclerosis. Dermatol Clin 13: 151-161
  13. Roach ES et al (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13:624-628
  14. Trauner MA et al (2003) Segmental tuberous sclerosis presenting as unilateral facial angiofibromas. J Am Acad Dermatol 49: S164-166

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 23.02.2021