Dermatologic Manifestations of Tuberous Sclerosis Clinical Presentation

• Most individuals with tuberous sclerosis present with parental concern about small raised tumors on the child's face. (In most cases, the parent draws the attention to the cutaneous stigmata.)
• Some tuberous sclerosis cases are detected in child health clinics as whitish spots.
• Children with late-onset tuberous sclerosis and individuals with few skin signs may remain undetected until adolescence.
• Dental pitting and fibromas may be noticed by the parents or an astute dentist.
• Clinical manifestations have a varied penetrance, adding to the delay in diagnosis.

The criteria for diagnosing tuberous sclerosis complex have been revised.^{[7, 8]} The features have been divided into major features and minor features.

• Major features of tuberous sclerosis

  • Facial angiofibromas or forehead plaque^[9]
  • Nontraumatic ungual or periungual fibromas
  • Hypomelanotic macules (≥ 3)
  • Shagreen patch (connective tissue nevus)
  • Multiple retinal nodular hamartomas
  • Cortical tuber
  • Subependymal nodule
  • Subependymal giant cell astrocytoma
  • Cardiac rhabdomyoma, single or multiple
  • Lymphangiomyomatosis
  • Renal angiomyolipoma
• Minor features of tuberous sclerosis

  • Multiple randomly distributed pits in dental enamel
  • Hamartomatous rectal polyps
  • Bone cysts
  • Cerebral white matter radial migration lines
  • Gingival fibromas
  • Nonrenal hamartoma
  • Retinal achromic patch
  • Confetti skin lesions
  • Multiple renal cysts
• Diagnosis of tuberous sclerosis

  • Definite tuberous sclerosis complex is diagnosed by the presence of either 2 major features or 1 major feature plus 2 minor features.
  • Probable tuberous sclerosis complex is indicated by 1 major feature plus 1 minor feature.
  • Possible tuberous sclerosis complex is indicated by either 1 major feature or 2 or more minor features.
• Skin lesions (found in 70-80% of cases) of tuberous sclerosis

  • The characteristic lesions are angiofibromas, previously known by a misnomer, adenoma sebaceum. 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, in the latter location reaching sizes up to several centimeters. In the oral mucosa, they may be observed in the lips, dorsa of tongue, and palate. Dental pitting occurs in about 90% of patients. A hand lens examination aids detection of these pits, which are less obvious in deciduous teeth.
  • Periungual fibromas (Koenen tumors) are smooth, firm, flesh-colored papules emerging from the nail folds. They can be the only manifestation in some individuals. These are noted around puberty and may increase in frequency as the patient ages.
  • 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.
  • White macules are 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. The use of Wood lamp accentuates these macules. The color, even though described as white, lacks the depigmented white appearance of vitiligo. A careful examination is necessary before making any firm diagnosis because hypopigmented macules may be a normal finding in newborn babies. One suggestion is that 3 or more white macules at birth should alert the clinician regarding the possibility of tuberous sclerosis.
  • Other skin signs include guttate leukoderma, café-au-lait macules, and poliosis.
• Neurologic findings of tuberous sclerosis

  • The tuberosclerotic nodules of glial proliferation occur in the cerebral cortex, basal ganglia, and ventricular walls but are rare in the cerebellum, medulla, or spinal cord. Rarely, hydrocephalus may result from obstruction of the foramen of Monro.
  • Subependymal giant cell astrocytomas also may be present, and serial imaging scans are recommended to monitor if growth occurs.
  • The number of tubers in the cortex and subcortex appears to correlate with the clinical severity of tuberous sclerosis disease, as measured by the ease of control of seizures, the appearance of developmental milestones, and school performance.
  • Epilepsy occurs in 80-90% of all patients, with a positive correlation with subnormal intelligence.^[10] Epilepsy requires treatment, preferably with monotherapy. Carbamazepine and sodium valproate are traditionally used in the initial treatment. Vigabatrin, an irreversible inhibitor of GABA transaminase, is reported to be more effective for infantile spasms in tuberous sclerosis complex. Lamotrigine is also used as adjunctive therapy for partial seizures in adults. In many cases, resection of the tuber may result in better control of epilepsy.
  • Mental retardation is observed in 60-70% of cases; however, if mental development is normal throughout childhood, subsequent worsening is uncommon.
  • Other features noted include schizophrenia, autistic behavior, and attention-deficit hyperactivity disorder.
  • The cognitive impairment in tuberous sclerosis complex is related to age of seizure onset.
• Ocular findings of tuberous sclerosis: Ocular involvement includes hypopigmented spots in the iris, equivalent to the ash-leaf macule in the skin. Retinal phakomas are observed as whitish-gray nodular lumps with a lump of mulberries appearance.^[11] These represent hamartomas characterized by proliferation of astrocytes. Every patient with tuberous sclerosis complex should have a thorough ophthalmologic examination at the time of diagnosis.
• Tuberous sclerosis findings in other organs

  • Cardiac rhabdomyomas are observed in over 50% of infants. They may be detected prenatally by fetal echocardiography and are the commonest cardiac abnormality detected in utero. Up to 50-60% of patients with tuberous sclerosis complex have cardiac disease, mainly rhabdomyomas. These may cause mechanical problems because of their size or because of the defects in the conducting system caused by their infiltrating nature. Rhabdomyomas usually undergo spontaneous resolution in the first few years of life in about 80% of patients, even though residual areas of histologically abnormal myocardium may persist.
  • Aneurysms of thoracic and abdominal aortas have also been observed rarely.
  • Renal involvement is usually manifested by angiomyolipomas. Angiomyolipomas are benign tumors of vessels and are seen in up to 75% of patients. Spontaneous bleeding may be fatal, and these tumors are best treated by embolization.^[12] Other features may include renal cysts, polycystic kidneys, and renal carcinoma.
  • Pulmonary changes include lymphangiomatosis with cyst formation. This may be progressive and result in dyspnea, cor pulmonale, recurrent pneumothorax, and respiratory failure.
  • Gastrointestinal tumors may be associated. Microhamartomatous polyps are present in the rectum in 75% of cases. Hepatic hamartomas have also been reported.
  • The bones may show areas of cyst formation, periosteal new bone growth, and areas of sclerosis.
  • Other abnormalities noted include pituitary adrenal dysfunction, thyroid disorders, premature puberty, diffuse cutaneous reticulohistiocytosis, and gigantism.
• Related clinical guideline summaries

  • American Academy of Neurology and the Child Neurology Society - Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society^[13]
  • American Academy of Neurology, American Epilepsy Society, and the American Association of Neurological Surgeons - Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons^{[14, 15]}