Tuberous sclerosis is an autosomal dominant disease. The prevalence of tuberous sclerosis is between 1/9000 and 1/6000, with a male to female ratio of approximately 1.44:1. Tuberous sclerosis is associated with two genes, one gene (TSC1) localized on the long arm of chromosome 9 (9q34) and the other gene (TSC2) located at 16P13.3, near the adult polycystic kidney disease gene (APKD1).
I. Pathological changes
Abnormal manifestations can be seen in the brain, skin, eyes, kidneys, bones, heart and lungs. The typical manifestations in the brain are cortical nodules, subventricular nodules and myelin lesions. Cortical nodules are hard, grayish nodules that are elevated on the surface of the cerebral gyrus and vary in size from 1-2 cm in diameter to a number of nodules that are microscopically neuroglial and composed of large multinucleated monomorphic cells. The nodules can thin out the normal cerebral cortex. Subventricular nodules are often found in the anterior horn of the lateral ventricles and are microscopically composed of large, overgrown astrocytes.
In tuberous sclerosis, partial cerebral cortex defects can sometimes be seen, which may be related to the obstruction of neuronal migration during neocortex formation, and insular gray matter ectopia or areas of myelin loss are often seen in the deep part of the defect. In some children with mental retardation, more areas of cortical anterior defects or multiple nodules may be seen.
The nodules can also occur in other organ sites, and in the heart they manifest as rhabdomyosarcomas, which occur in up to 50% of children with tuberous sclerosis, and approximately one quarter of children with tuberous sclerosis with rhabdomyosarcomas die of heart failure within the first few days of life.
Multiple renal swellings, often benign, are present in about 50-80% of cases. The lungs are less commonly affected and may show cystic or fibrous changes. Other organs may be affected.
Clinical manifestations
The main manifestations are: mental retardation, convulsions, skin changes and different parts of the tumor (including the brain).
1.Skin manifestations.
Typical skin changes include depigmented spots, facial angiofibroma, finger (toe) nail fibroma and sharkskin-like spots. Not all of these changes may be present in every child. The disease can also sometimes have coffee milk spots, but the number is not large.
In 90% of children, the skin pigment loss spots are found at birth, white, clearly defined with the surrounding skin, E round, leaf-shaped or irregular in shape, sometimes in clusters of small, confetti-like spots. The pigment loss spots vary in size from a few millimeters to several centimeters in length and diameter. It can be seen on the trunk and extremities, with asymmetric distribution, but rarely on the face. It can also be seen on the scalp, where the hair is also white. Pigment loss spots are easily detected in yellow or black people during physical examinations, and are sometimes more difficult to see in white people, but are easily visible under ultraviolet light.
It is easy to be seen under ultraviolet light. Sometimes 1-2 pigment loss spots can be seen in normal people, which has no diagnostic significance. 0.8% of normal newborns can also see pigment loss spots. The number of depigmented spots can gradually increase within a few years after birth, and the area increases with the growth of body surface area. The pigment loss spots differ from albinism in that the skin of albinism has no pigment cells, while the pigment loss spots of this disease have pigment cells but fewer melanin granules.
It is not a sebaceous gland, but is composed of blood vessels and connective tissues. It is reddish-brown in color or the same color as the skin, raised in the skin, papular or fused into small patches, with a smooth surface without exudation or secretion. They are scattered on both sides of the nose and the cheeks of the nasolabial folds, and in large numbers may extend to the chin and sometimes to the forehead.
Facial angiofibromas are not seen at birth, but appear at the age of 1-5 years, and then gradually increase, and about 12% of children can see angiofibromas at the age of 1 year, this sign has diagnostic value, but not all patients have this manifestation, about 70% -80% of patients can see.
Fibroma of the finger (toe) nail, a small fleshy nodule around or under the finger (toe) nail. They are more common in girls than in boys, but are less common before puberty. Multiple finger (toe) nail fibroids have diagnostic value for this disease.
In some patients, a plate-like malformation of the skin on both sides of the trunk or in the dorsal lumbosacral skin can be seen, called sharkskin-like spots, slightly elevated on the skin, with irregular borders and rough surfaces. In some children, a slightly elevated patch of skin on the forehead can be seen at birth, which is helpful for the diagnosis of the disease.
Coffee milk spots can be seen in 7-16% of cases, and this sign is not used as a diagnostic criterion.
2.Ocular changes.
Tumors can be found in the retina in 50% of patients. Funduscopic examination may reveal mulberry-shaped astrocytomas or plaque-like malignant tumors and anaplastic areas. Retinal malformations are one of the important signs of the disease. Although large retinal lesions can affect vision, complete vision loss is uncommon. Occasionally, patients lose vision due to retinal detachment, vitreous hemorrhage, or large lesions.
3. Neurological symptoms.
The most common symptoms are epilepsy, mental retardation, and occasionally hemiparesis or other limited neurological abnormalities. 80%-90% of children with epilepsy often present with infantile spasms in infancy, and older children may present with complex partial seizures or other limited seizures, or generalized tonic clonic seizures or Lennox-Gastaut syndrome.
About 60% of children have mental retardation, with varying degrees of severity, which often coexists with epilepsy, and some children have only convulsions without mental retardation. The number of neurological nodules varies, and they are often located in the subventricular canal at the base of the lateral ventricle. Calcification can be seen on X-ray plain film, but it takes time to calcify, so it is not common in infants. The pathological histology is a malformation tumor, and nodules are also seen in the cerebral cortex, with an average diameter of 1-2 cm and varying numbers. In some cases, cortical defects can be seen, which may be related to the obstruction of neuronal migration during the formation of the neocortex.
4.Other systems.
Tuberous sclerosis can involve other parts of the body besides skeletal muscle. 50% -80% of patients with tuberous sclerosis have angiomyolipoma in the kidney, which is histologically benign and composed of smooth muscle, adipose tissue and vascular tissue. renal tumors are not as common in pediatric patients as in adults.
Most patients with this type of cardiac tumor are asymptomatic. Typical involvement is heart failure shortly after birth, which can be caused by tumors in the heart chambers. Pulmonary disorders include lymphangioleiomyomatosis of the lungs, which is more common in women.
Diagnosis
The diagnosis of tuberous sclerosis is mainly based on specific skin changes, convulsions, mental retardation or regression, and the main manifestations in infancy are skin depigmentation, infantile spasms, and hair curfew. 1998, the National Institutes of Health proposed the diagnostic criteria for this disease, which were applied with slight modifications by many authors.
The secondary features of the diagnostic criteria for tuberous sclerosis are.
1.Multiple small depressions of enamel destruction
2, rectal polyps
3, bone cystic changes
4, cerebral white matter “migratory scar”
5, gingival fibroma
6.Organ malformation tumor outside the kidney
7.Retinal aphakic plaques
8, Skin “confetti-like” pigment loss spots
9.Polycystic kidney
The main features of tuberous sclerosis diagnostic criteria are
1.Facial angiofibroma of the skin
2.Multiple finger (toe) nail fibroids
3.More than 3 pigmented spots
4, sharkskin-like spots
5.Brain lesions
6.Cortical nodules
7.Subventricular nodules
8.Subventricular giant cell astrocytoma
9.Ocular lesions
10.Multiple retinal malformation tumors
11.Other organ m tumor
12.Heart rhabdomyosarcoma
13.Lymphangioleiomyosarcoma
14.Renal angiomyolipoma
At least 2 major features or 1 major feature and 2 minor features are required to confirm the diagnosis of the disease; 1 major feature and 1 minor feature are required for possible disease; 1 major feature or 2 minor features are required for suspected disease.
Although the disease can be diagnosed genetically, the tests are complex and costly. A more accurate clinical diagnosis of the disease can be made by the manifestations listed in Table 46-1.
Treatment
Antiepileptic drugs can be used for epilepsy. Aminocaproic acid is effective for infantile spasms caused by tuberous sclerosis, but this drug may cause a narrowing of the visual field. For other types of seizures, in addition to sodium valproate and carbamazepine, topiramate, lamotrigine, and oxcarbazepine can be considered.
If the seizures are not satisfactorily controlled by medication, surgery can be considered. Preoperative neuroimaging is required to identify the site of the epileptic focus. If the foci are located in non-functional areas of the cortex, and if the foci are single coherent, surgical excision can result in 78% of patients no longer having seizures and 20% of patients having less frequent seizures.
Kossoff (2005) reported that in 12 children with tuberous sclerosis complicated by epilepsy, after 6 months of treatment with a ketogenic diet, 11 children had more than 50% reduction in seizures.