Macaya A(1), Torra R(2); en representación del Grupo Español Multidisciplinar de Expertos en Complejo Esclerosis Tuberosa (GEM-CET). Tuberous sclerosis complex (TSC) involves abnormalities of the skin ( hypomelanotic macules, confetti skin lesions, facial angiofibromas. Download Citation on ResearchGate | On Jan 1, , Carlos Medina-Malo and others published Complejo esclerosis tuberosa }.

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Actualización de los criterios diagnósticos del complejo esclerosis tuberosa

University of Washington, Seattle; July 13, ; Last Update: Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death. The diagnosis of TSC is established in a proband with one of the following:.

For symptomatic cardiac rhabdomyomas: Prevention of secondary complications: For those on vigabatrin therapy, vision testing within four weeks of therapy initiation, at three-month intervals while on treatment, and three to six months after treatment is discontinued. Evaluation of relatives at risk: Identifying affected relatives enables monitoring for early detection of problems associated with TSC, which leads to earlier treatment and better outcomes. TSC is inherited in an autosomal dominant manner.

Two thirds of affected individuals have TSC as the result of a de novo pathogenic variant. If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk and preimplantation genetic diagnosis are possible. Tuberous sclerosis complex TSC should be suspected in individuals with either one major clinical feature or two or more minor features, as listed below. Clinical diagnostic criteria for TSC have been revised [ Northrup et al ] to take into account the results of molecular genetic testing.

The combination of LAM and angiomyolipomas without other features does not meet the clinical diagnostic criteria for a definite diagnosis. Molecular genetic testing approaches can include concurrent gene testing or use of a multigene panel:.

[Recommendations for the multidisciplinary management of tuberous sclerosis complex].

View in own window. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. Sequence analysis esclerosiw variants that are benign, likely benign, of uncertain significancelikely pathogenic, or pathogenic.

For issues to consider in interpretation of sequence analysis results, click here. TSC1 yuberosa variants are primarily small deletions and insertions and pathogenic nonsense variants detected by sequence analysis. Methods used may include: Using MLPA, tubberosa identified large TSC2 exon or whole-gene deletions in four of 15 families in which no pathogenic variant had been esclerpsis by sequence analysis and Southern blotting.

Tuberous sclerosis complex TSC exhibits both inter- and intrafamilial variability in clinical findings. Females tend to have milder disease than males [ Sancak et alAu et al ]. Any organ system can be involved in TSC. Among the skin lesions, the facial angiofibromas cause the most disfigurement. None of the skin lesions results in serious medical problems. These giant cell astrocytomas may enlarge, causing pressure and obstruction and resulting in significant morbidity and mortality.

TSC is a known cause of infantile spasms. The leading cause eclerosis premature death TAND refers to the interrelated functional and clinical manifestations of brain dysfunction common in individuals with TSC, including behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties esclersis de Vries a ].

Autism spectrum disorder ASD. Neurofunctional impairments closely associated with ASD, including impaired language pathways [ Lewis et al ] and atypical face processing [ Spurling Jeste et al ], have been noted in persons with TSC.

Attention deficit hyperactivity disorder ADHD is another common and potentially seriously debilitating condition closely associated with TSC. Deficits in attention particularly in dual-task performanceccomplejo flexibility, and memory have also been noted in neuropsychological studies of children and adults with TSC [ Ridler et alde Vries et alTierney et alCuratolo et alde Vries et al ].


Learning and cognitive impairment.

Disruptive behaviors and emotional problems are another cluster of debilitating conditions associated with TSC. All individuals with TSC should be assessed for the presence of TAND, given that it has been closely associated with clinical outcome and quality of life [ Krueger ]. Given that unaddressed TAND concerns contribute significantly to poor outcome, and that individuals with TSC have a very high health care resource utilization [ Lennert et alRentz et al ], the importance of recognizing and addressing TAND concerns cannot be overestimated.

Renal disease is the second leading cause of early death Five different renal lesions occur in TSC: Benign angiomyolipomas comprise abnormal blood vessels, sheets of smooth muscle, and mature adipose tissue. In children, angiomyolipomas tend to increase in size or number over time. Benign angiomyolipomas can cause life-threatening bleeding and can replace renal parenchyma, leading to end-stage renal disease ESRD.

Renal cysts have an epithelial lining of hypertrophic hyperplastic eosinophilic cells. In these individuals, progressive enlargement of the cysts may compress functional parenchyma and lead to ESRD [ Martignoni et al ]. Malignant angiomyolipoma and renal cell carcinoma RCC may result in death. Although rare, these two tumors are much more common in individuals with TSC than in the general population [ Pea et al ].

Common imaging techniques may not distinguish fat-poor angiomyolipomas from RCC. These tumors have been documented to regress with time and eventually disappear.

The cardiac rhabdomyomas are often largest during the neonatal period. If cardiac outflow obstruction does not occur at birth, the individual is unlikely to have health problems from these tumors later. However, a small number of individuals have arrhythmias postulated to result from rests of persistent cells left after the rhabdomyomas regress.

For information regarding treatment options for obstructive lesions, see Management. Multifocal micronodular pneumonocyte hyperplasia MMPHcharacterized by multiple nodular proliferations of type II pneumocytes, was first described in association with TSC in [ Popper et al ]. While MMPH does not have known prognostic or physiologic consequences, there have been at least two reports of respiratory failure associated with MMPH [ Cancellieri et alKobashi et al ].

MMPH can be confused with atypical adenomatous hyperplasia, which is a premalignant lesion that is not clearly associated with TSC. These lesions are relatively rare in the general population with a recent case series of healthy term newborns identifying only two with these lesions [ Li et al ]. Although these lesions are usually asymptomatic, a few persons with TSC have had progressively enlarging retinal astrocytic hamartomas with total exudative retinal detachment and neovascular glaucoma [ Shields et al ].

Although rare, extrarenal angiomyolipomas have been reported [ Elsayes et al ]. More recently single case reports have included gastrinoma, pheochromocytoma, and carcinoids. Individuals representing simplex cases i.

Individuals with a TSC2 pathogenic variant are at greater esclerosix for:. Terms used in the past to describe findings in tuberous sclerosis that are now outdated or inappropriate but have not yet been eliminated from the medical literature include the following:. The incidence of TSC may be as high as 1: A high mutation rate 1: A contiguous gene deletion syndrome comppejo which PKD1 and the adjacent TSC2 are disrupted by deletion has been described [ Consugar et al ].

In individuals with this syndrome, the phenotype of tuberous sclerosis and severe polycystic kidney disease is usually evident in utero or is diagnosed in infancy. Sporadic tumors including pulmonary lymphangioleiomyomatosis, perivascular epithelioid cell tumors, urothelial carcinomas, and hepatocellular carcinomas occurring as single tumors in the absence of any other findings of TSC harbor somatic variants in TSC1 or TSC that are not present in the germline ; thus, predisposition to these tumors is not heritable.


For more details see Cancer and Benign Tumors.

Many of the features of TSC are nonspecific and can be seen as isolated findings or as a feature of another condition. Hypopigmented macules have been observed in 0. A study by Vanderhooft et al [] determined that three or more hypopigmented macules are much more likely to be seen in an individual who will be diagnosed with TSC.

Other conditions with hypopigmented macules as part of the phenotype include vitiligo, nevus depigmentus, nevus anemicus, piebaldism, and Vogt-Koyanagi-Harada syndrome. Associated findings can usually distinguish these conditions from TSC. On physical examination, acne vulgaris, acne rosacea, or multiple trichoepithelioma can be mistaken for angiofibromas, but biopsy easily distinguishes among them.

The shagreen patch of TSC is quite specific based on location and appearance and was retained as a major diagnostic criteria for TSC. However, the diagnostic criteria has been updated to omit use of the term “connective tissue nevus” because this term encompasses a variety of skin lesions with excessive dermal connective tissue that are not necessarily associated with TSC.

Ungual fibromas can result from trauma, but generally traumatic ungual fibromas are single lesions and their presence can be explained e. Two or more ungual fibromas are now required as a major clinical diagnostic criterion for TSC.

Actualización de los criterios diagnósticos del complejo esclerosis tuberosa

Ungual fibromas must be distinguished from epithelial inclusion cysts, verruca vulgaris, and infantile digital fibromatosis. Renal angiomyolipomas AMLs are rare tumors sometimes observed in individuals tuverosa no other medical problems. Studies have shown that such sporadic AMLs can have loss of heterozygosity for TSC2leading to the conclusion that they occur as a result of loss of function of TSC2 in individuals not affected with tuberous sclerosis complex.

While cardiac rhabdomyomas can be observed as an isolated finding, this is unusual. Potentially, sporadically occurring cardiac rhabdomyomas could also have a mechanism similar to the sporadic AMLs described see Kidneys. Consensus clinical management and surveillance recommendations for individuals with TSC have been published [ Krueger et al a ] full text. To establish the extent of disease and needs in an individual diagnosed with escleroiss sclerosis complex TSCthe evaluations summarized in Table 2 if not performed as part of the evaluation that led to the diagnosis are recommended by the International Tuberous Sclerosis Consensus Conference [ Northrup et al ] full text.

Subependymal giant cell astrocytomas SEGAs. Early identification of an enlarging giant cell astrocytoma permits medical therapy with mTOR inhibitors [ Krueger et al ], which may obviate esclerosks need for neurosurgical intervention in esclerksis individuals.

However, neurosurgery may still be indicated when the size of the SEGA causes life-threatening neurologic symptoms. Early control of seizures is thought to prevent subsequent epileptic encephalopathy and reduce cognitive behavioral consequences [ Bombardieri et al ].

An ongoing study see clinicaltrials. The seizures in Tuberosaa may be resistant to polydrug therapy with anticonvulsants. A number of small tuuberosa have reported excellent results after epilepsy surgery. Initial case reports suggested a potential for mTOR inhibitors to help in the treatment of tjberosa epilepsy in individuals with TSC [ Krueger et al b ].

Topical mTOR inhibitor formulations have been shown to be efficacious in the treatment of facial angiofibromas. Previous standard of care for the treatment of newborns with cardiac rhabdomyomas resulting in life-threatening complications i.