Genetics of Tuberous Sclerosis Clinical Presentation

Updated: Sep 16, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Presentation

History

Clinical features

Children with tuberous sclerosis complex (TSC) may have a broad range of symptoms and signs, ranging from subclinical findings to severe handicaps, because of variable expression.

CNS symptoms

The most common and severe CNS manifestations of tuberous sclerosis complex include seizures, including infantile spasms and mental retardation. These relate to cortical/subcortical glioneuronal tubers, subependymal glial nodules, and subependymal giant cell astrocytomas (SEGA). The cortical tubers in the brain are typically located at the gray-white matter interface, commonly in the frontal and parietal lobes. [19] Seizures may develop during infancy or later. Infantile spasms or a hypsarrhythmia pattern on EEG findings may be present in infants with tuberous sclerosis complex. Other common seizure types in patients with tuberous sclerosis complex are complex partial and tonic-clonic seizures. As previously mentioned, high rates of infantile spasms have been linked to TSC2 mutation. [93]

TSC2 mutations, and especially TSC2/PKD1 mutations, tend to develop SEGA earlier in childhood and should be screened for SEGA from birth (Kotulska et al, 2014).

All patients with tuberous sclerosis complex who have mental retardation have seizures, but not all patients with seizures have mental retardation. Intelligence may be normal, or children may have mild, moderate, or severe mental retardation.

Other symptoms include autism or pervasive developmental disorder (PDD), aggressive behavior, schizophrenia, and sleep disturbances. Sleep disturbances may be displayed by decreased overall sleep time and frequent nocturnal awakenings.

Dermatologic symptoms

Skin findings are very common in tuberous sclerosis complex and should be regarded as signs of this pivotal systemic disease.

Hypomelanotic macules are overwhelmingly the most common early finding in tuberous sclerosis complex. [20] . These hypopigmented lesions are described as ash-leaf spots. These are best observed using a Wood lamp. A Fitzpatrick patch or ash-leaf spot may be observed in the general population, but the presence of at least 3 spots constitutes one of the major diagnostic criteria. These macules often come in other shapes, although most are polygonal, usually 0.5-2 cm in diameter, and resemble a thumbprint. In honor of their deceased describer, Thomas Fitzpatrick, they are termed Fitzpatrick patches. [21]

Infants with seizures or other stigmata of tuberous sclerosis complex should be evaluated for these hypomelanotic macules and for other associated findings. Confetti lesions are also hypomelanotic lesions that cluster and have a reticulated or network appearance. They may develop anywhere on the skin.

Facial angiofibromas and forehead plaques usually present in patients older than 2 years. Facial angiofibromas are erythematous lesions located on the cheeks, nose, and chin, often sparing the upper lip. Growth is often increased during puberty, and angiofibromas are sometimes confused with acne. The presence of one or both of these lesions constitutes one of the major diagnostic criteria. The relationship between the presence of a forehead plaque and CNS involvement may be statistically significant in patients with tuberous sclerosis complex. [22] If true, forehead plaque may be considered as a novel cutaneous marker of CNS involvement in tuberous sclerosis complex at an early stage.

A shagreen patch is a connective tissue hamartoma located in the lower back region. A shagreen patch has an orange peel or leathery texture and often presents in children aged 2-6 years but may not appear until puberty. See the image below.

A shagreen patch is a connective tissue hamartoma A shagreen patch is a connective tissue hamartoma with a leathery texture and is found most commonly in the lower back region.

Ungual or periungual fibromas (see the image below) may appear in adolescents or adults with tuberous sclerosis complex. Fibromas may cause distortion of the nail or nailbed. They can occur as an isolated sign of tuberous sclerosis complex with TSC1 germline mutation. [23]

Periungual fibroma on the thumb of a patient with Periungual fibroma on the thumb of a patient with tuberous sclerosis complex (TSC).

Periungual fibromas may bleed and may produce pain and nail distortion. [24]

Café au lait spots occasionally develop in patients with tuberous sclerosis complex, although they are usually less common in patients with tuberous sclerosis complex than in those with neurofibromatosis.

Renal symptoms

Renal angiomyolipomas are considered one of the major diagnostic features of tuberous sclerosis complex. Angiomyolipomas are mesenchymal neoplasms that occur sporadically or are associated with tuberous sclerosis complex; they are generally considered to be benign. Malignant angiomyolipomas are rare; most are found to be epithelioid upon histopathological examination. A renal angiomyolipoma with a malignant epithelioid component was recently described in a patient with tuberous sclerosis complex. [25] Renal cysts are also common, and 40-80% of patients with tuberous sclerosis complex have either renal angiomyolipomas or renal cysts. The presence of hypovolemic shock may result from bleeding angiomyolipomas. Renal failure may also be evident.

Flank pain is the most common renal symptom. Other symptoms include hematuria, hypertension, and, rarely, hemorrhagic shock or renal failure, which may develop in severe cases. Renal symptoms are rare during childhood and are not present in all patients with renal disease.

Cardiac symptoms

Cardiac rhabdomyomas are often present at birth or during infancy but may be detected as early as 20 weeks' gestation using fetal ultrasonography. These are usually multiple and intramural, may cause abnormal valve function, outflow obstruction, decreased contractility, cardiomyopathy, and arrhythmias. Usually they are asymptomatic and spontaneously regress as the child ages. However, they may cause cause outflow tract obstruction during the neonatal period. Cardiac rhabdomyomas may cause heart failure or arrhythmia, even in the presence of normal echocardiogram findings.

A case report of molecular confirmation identified multiple cardiac rhabdomyomas as a sole symptom of tuberous sclerosis complex. A child was described with multiple cardiac rhabdomyomas that were identified using routine fetal ultrasonography. [26] Molecular genetic studies identified a TSC2 gene missense mutation. At age 6 years, he had no skin manifestations of tuberous sclerosis complex, although CT scan of the brain revealed 2 periventricular calcifications consistent with the molecular diagnosis. Molecularly confirmed tuberous sclerosis complex in a child with multiple cardiac rhabdomyomas and no other clinical manifestations of the disease had not been previously described. All infants with multiple cardiac rhabdomyomas were proposed to be given a tentative diagnosis of tuberous sclerosis complex.

Pulmonary symptoms

Lymphangiomyomas (LAM) and pulmonary cysts develop almost exclusively in women in the third or fourth decade of life, and are present in fewer than 1% of females with tuberous sclerosis complex. LAM produces cystic lung disease adroitly characterized as a type of perivascular epithelioid cell tumor. [27]

Symptoms include dyspnea, hemoptysis, and development of spontaneous pneumothorax. Pulmonary fibrosis and hypertension may lead to cor pulmonale.

Oral symptoms

Most oral fibromas in tuberous sclerosis complex are gingival. [28] Asymptomatic pitting of dental enamel is common in the permanent teeth of patients with tuberous sclerosis complex. Nearly all patients have dental pits. They are more easily detected when teeth are stained.

Miscellaneous manifestations

A retinal hamartoma or astrocytoma may cause an abnormal red reflex that is sometimes confused with retinoblastoma. Visual acuity is typically not affected.

A rectal hamartoma or polyp is occasionally detected using a digital rectal examination.

A low-grade hypothalamic papillary tumor recently described may extend the spectrum of neoplasms with tuberous sclerosis complex. [29]

Children with tuberous sclerosis complex may rarely develop a chordoma, a cancer that arises from notochordal remnants. [30] TSC1 and TSC2 mutations have been postulated to contribute to chordoma etiology.

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Physical

Diagnosis

The diagnosis of tuberous sclerosis complex is made on the clinical basis. In 1998, the National Institutes of Health Consensus Conference on Tuberous Sclerosis Complex developed revised diagnostic criteria, as follows: [31]

  • Definitive diagnosis - The presence of 2 major features or 1 major feature plus 2 minor features

  • Probable diagnosis - The presence of 1 major feature plus 1 minor feature

  • Possible diagnosis - The presence of 1 major feature or 2 minor features

Diagnostic criteria for tuberous sclerosis complex have been revised. [32] Recognize that individuals with isolated lymphangioleiomyomatosis (LAM) who have associated renal angiomyolipomas do not have tuberous sclerosis complex.

Major features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), 3 or more ash-leaf spots (see the first image below), facial angiofibromas or forehead plaques (see the second image below), shagreen patches, ungual or periungual fibromas in the absence of trauma, cardiac rhabdomyomas, lymphangioleiomyomatosis (LAM), renal angiomyolipomas, or retinal hamartomas.

Ash-leaf spots are hypomelanotic lesions that are Ash-leaf spots are hypomelanotic lesions that are observed more easily with the use of a Wood lamp.
Forehead plaque in a patient with tuberous scleros Forehead plaque in a patient with tuberous sclerosis complex (TSC). The presence of either a forehead plaque or a facial angiofibroma constitutes one of the major diagnostic criteria for TSC.

Minor features include dental pits, gingival fibromas, confetti skin lesions (see the image below), bone cysts, hamartomatous rectal polyps, multiple renal cysts, other nonrenal hamartomas, achromic lesions of the retina, and radial migration lines of cerebral white matter.

Confetti skin lesions are hypomelanotic lesions th Confetti skin lesions are hypomelanotic lesions that cluster and appear reticulated.

Many findings regarded as highly specific for tuberous sclerosis complex are not apparent until late childhood or adulthood. [33] Physicians should be aware of the criteria frequency at different stages of tuberous sclerosis complex in children.

Molecular analysis can detect mutations in about 85% of cases and the rest do not have a detectable mutation. Molecular analysis is also complicated by the fact that the genes are large and many different disease causing mutations occur. It can be used to confirm diagnosis in clinically diagnosed cases and is quite useful for genetic counseling and prenatal diagnosis when a mutation in an affected parent is known. Information regarding gene testing is available online from GeneTests.

Phenotypic variation is observed even with the same genotype (same genetic mutation). Clinical symptoms of tuberous sclerosis complex in 4 patients with an identical TSC2 mutation were assessed. [34] Epilepsy, depigmented spots, and periventricular calcification and cortical tubers were evident in all 4 patients; cardiac rhabdomyoma and angiomyolipoma of the kidneys were evident in 3 patients; and mental retardation and forehead fibroma were evident in 2 patients. Thus, tuberous sclerosis complex symptoms varied in patients with the identical type of TSC2 mutation. The main symptoms were present in all or most patients; the clinical picture also differed based on age.

Tuberous sclerosis complex is most often diagnosed in children, with an average age at diagnosis of 7.5 years (range, birth to 73 y) in one retrospective study. [35] Eighty-one percent were diagnosed with tuberous sclerosis complex before age 10 years in this retrospective evaluation of 243 patients at Massachusetts General Hospital in Boston.

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Causes

Tuberous sclerosis complex is inherited in an autosomal dominant pattern. Therefore a detailed family history should be obtained when a child is diagnosed with tuberous sclerosis complex, looking for subclinical symptoms and bearing in mind the major and minor clinical features. This should be followed by a detailed clinical examination to look for major/minor criteria of tuberous sclerosis complex. A parent affected with tuberous sclerosis complex has a 50% chance of transmitting the disease to each offspring.

About two thirds of cases are sporadic as a result of new mutations. If the parents are determined to be unaffected after careful evaluation, they still have a recurrence risk of 1-2% in subsequent pregnancies due to possible gonadal mosaicism. Incidence of gonadal mosaicism is approximately 10-25%.

Criteria for germline mosaicism have recently been outlined. Parents without evidence of either major or minor criteria of tuberous sclerosis complex who have 2 or more children with tuberous sclerosis complex meet the criteria for germline mosaicism.

Mutations in two genes, TSC1 and TSC2, have been identified as causes of tuberous sclerosis complex. Approximately 50% of familial cases are due to mutations in TSC1, and the remaining 50% are due to TSC2. A mutation in the TSC2 gene is responsible for 75% of sporadic cases.

Currently, tuberous sclerosis complex is a clinical diagnosis but genetic testing is useful for prenatal diagnosis if the affected parent has a detectable mutation. It may be useful in suspected cases of gonadal mosaicism.

The family should be referred to a genetics clinic for genetic counseling of all of the above issues.

The genetic counselor can provide information to the patient and the family about the natural history, inheritance, recurrence risk and resources.

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