- Media Sphera Publishers
Tuberous sclerosis (TS) is a genetic disease from the group of phakomatoses, characterized by lesions of the skin, nervous system and internal organs associated with impaired proliferation, migration and differentiation of neuroglia cells [1—3].
The first descriptions of the disease belong to F.D. Von Recklinghausen (1862) and R. Virchow (1863). The involvement of the brain was reported by the French neuropathologist D.M. Bourneville (1880). The priority in identifying the symptom complex as an independent nosology belongs to the English dermatologist J.J. Pringle (1890) .
TS is a rare disease with an incidence of 1 in 5,000—10,000 live births. In about 1/3 of cases the autosomal dominant inheritance with incomplete penetrance and variable expressivity can be traced; in some patients with TS it occurs sporadically as a result of de novo mutations in the TSC1 and TSC2 genes, as a result of mutations in the genes of the tumor suppressors TSC1 (OMIM # 605284) or TSC2 ( OMIM # 191092). Genetic changes in TS in 70% of cases are recorded in the TSC2 gene, the remaining 30% — in the TSC1 gene. Molecular abnormalities in these genes are represented by a wide range of genetic changes. In most cases, these are single nucleotide substitutions — 97.1 and 94.5% in the TSC1 and TSC2 genes, respectively [4—6].
Since skin manifestations are observed in almost 100% of patients and are often presenting signs, the leading role in the diagnosis of TS belongs to dermatologists. The spectrum of dermatological pathology includes angio-fibromas of the face, sub- and periungual angio-fibromas of Kenen, fibrous plaques, "shagreen" spots, vitiligo-like and "coffee" spots, poliosis of tooth enamel [1—4].
The most demonstrative sign of TS is facial angio-fibromas. The rash consists of multiple small (diameter 1—5 mm, sometimes up to 10 mm) oval or round papules with a smooth surface with dense or elastic consistency. The efflorescence color varies from flesh-yellow to brownish-red. First, they appear in the nasolabial folds and then spread to the cheeks, chin, nose, and occasionally to the forehead, scalp and ears. The arrangement of efflorescences is usually bilateral, symmetrical, with no tendency to merge. Oral angiofibromas are found in 20—22% of patients. Rarely reported cases of TS with unilateral localization are presumably the result of postzygotic mutations, a mosaic form of the disease. Rare cases of observation of patients with only angiofibromas or their combination with brain pathology detected on MRI but without pronounced clinical neurological and multi-organ symptoms are described. Angiofibromas in 90—96% of patients appear at the age of 3—7 years, sometimes from the birth. The number of tumors increases until puberty after which their further growth is stabilized and practically does not change until the end of life. In the oral cavity the angiofibromas form on the front surface of the gums, mucous membrane of the lips, less often on the tongue and palate [7—16].
Another cutaneous marker of TS is Kenen's sub- and periungual angiofibromas which occur in the pubertal or post-pubertal period more often in women (50—80% of cases). The predominant lesion of the toes is in the form of pink-meat-red papules 1—10 mm in size; it is dome-shaped with conical in shape sometime. At the same time, longitudinal leukonychia and slit-like sublingual hemorrhages can form. Periungual elements are accompanied by painful sensations sometimes. After the surgical removal the angiofibromas tend to recur [11, 17].
Fibrous plaques are also considered an obligate sign of TS. They are found in 25—36% of patients in the form of solitary (48% of cases) elements; in the remaining 52% of patients 2 or more plaques are recorded, it is slightly elevating and varying in color from beige to red. They are irregular in shape, soft or dense in consistency with a diameter of 1—5 cm or more. In about 65% of cases these manifestations are localized in the forehead or other areas of the face; about 30% in the non-hairy part of the head and also occasionally in the neck. Forming later angiofibromas they often appear in the first year of life; their size increases by aging. According to the histological structure they are connective tissue nevi [4, 18—20].
"Shagreen" spots — connective tissue hamartomas are characteristic manifestations of TS. In patients older than 5 years they are found in 70—80% of cases on any part of the skin but with a particular predisposition to the lumbosacral region. Plaques are usually solitary, slightly elevated, ranging in size from a few millimeters to 10 cm or more with an uneven surface, flesh-yellowish brown, soft or elastic in texture; often have the texture of an orange peel or guinea pig skin. In some cases spots can be a presenting sign of a vehicle. [1—4].
The earliest and most frequent manifestations of TS are hypopigmented spots that often found in infancy and early childhood. According to retrospective analyzes in infants they are recorded in 39% of cases and more; then by puberty their detection rate reaches 92—98%. The spots are of various shapes and sizes. The largest of them (0.5—12 cm) are oval or elongated with pointed ends ("rowan leaves"), the diameter of small confetti-like elements does not exceed 1—3 mm. The number of spots varies from several to 100 or more, predominantly located on the skin of the trunk and extremities. For their better visualization especially in persons with fair skin they resort to irradiation with a Wood lamp [11, 21].
The frequency of pigment spots colored «coffee with milk» in patients with TS does not exceed the average values in the general population. More significant in the diagnosis of the disease are poliosis and point defects of tooth enamel (pits) [13, 22].
Histologically in angiofibromas the proliferation of vessels mainly of the capillary type with the expansion of their lumens located in the fibrous stroma is observed. With Kenen's angiofibromas the picture can be supplemented by the presence of stellate fibroblasts. The structure of fibrous plaques and "shagreen" spots does not differ from connective tissue nevi. In the area of hypopigmented spots the number of melanocytes is normal but the number and size of melanosomes and the content of pigment in them are reduced [1, 4].
Systemic lesions of TS are very diverse and largely determine the prognosis of the disease.
The pathology of the central nervous system is the most significant in the disease. Convulsive syndrome is observed in 80—92% of patients and is manifested by the development of various types of seizures (from focal and tonic to status epilepticus with a fatal outcome). Its debut more often falls on infancy [1, 4]. In the period from 6 to 18 years more than 30% of patients have remission of seizures; after 18 years of remission are recorded in almost 40% of cases. The initial presentation of classic epilepsy is noted only in 15% of patients. At the convulsive syndrome the 40—70% of children have mental retardation impaired cognitive abilities and behavioral deviations. The rest of the intellect remains normal [11, 13, 21]. Psychoneurological symptoms can progress to the development of imbecility and idiocy. EEG changes are sometimes detected even in the absence of neurological pathology. Disturbances in the electrical activity of the brain are recorded in the form of hypsarrhythmia, multifocal epileptiform activity. Psychoneurological disorders are caused by damage to brain tissue primarily by the nodular growth of neuroglia (tubers) in the cortex which is located mainly subtentorially in the frontal lobes. The size of the tubers (single or multiple) varies from a few millimeters to several centimeters. In half of the cases the tumors are calcified. Another CNS lesion is multiple subependymal glial nodes localized more often in the walls of the lateral ventricles and less often in the walls of the III and IV ventricles. In 5—15% of cases these tumors transform into giant-cell astrocytomas which often manifest at the age of 5—10 years and are the cause of occlusive hydrocephalus as a result of obstruction of the Monroe's hole. CTG and MRI are the most important tools for the verification of tumor processes in the brain tissues which make it possible to identify this pathology in 90–95% of TS cases. CNS tumors are a leading cause of morbidity and mortality in TS [6, 13, 21, 23, 24].
Eye lesions in TS are described in the literature relatively rarely. Pathology directly associated with the brain tumors is expressed in the development of congestive nipples of the optic nerves, loss of visual fields (scotomas, hemianopsia) and sometimes atrophy of the optic nerves. An important sign is one- or two-sided hamartomas (phakomas) of the retina that found in 50% of patients. They manifest themselves in three ways. In the first variant the most common phakomas have a flat, smooth surface, oval or rounded, orange-pink in color. In the second variant the white hamartomas calcified with an uneven surface, resemble a mulberry. In the third variant the combination of signs of the first two is observed: a nodular calcified center of white color with a smooth orange-pink periphery. Hamartomas are not prone to significant growth and rarely cause vision loss. In some cases phakomas are the only manifestation of TS. From other eye pathology the strabismus, congenital cataracts, colobomas, depigmentation of the iris, angiofibromas of the eyelids, retinal detachment are possible (sometimes it occurs as an initial symptom). Recently, a new clinical manifestation of TS like bulbar conjunctival lymphangioma was described. [12, 16, 25, 26].
The pathology of the cardiovascular system is manifested primarily by the development of rhabdomyomas which are often the first sign of TS. Ultrasound can detect a heart tumor already during the intrauterine development of the fetus. Especially rapid growth is observed in the second half of pregnancy. By the time of birth the rhabdomyomas reach their maximum size; later they undergo gradual regression and spontaneously disappear at the age of about 6 years; in the absence of such dynamics tumors can persist throughout the life. With massive rhabdomyomas the intrauterine fetal death or premature birth can occur. Lethal outcomes are recorded both in the postnatal and in later periods. Rhabdomyomas occur in 30—60% of TS cases, more often in male children (gender ratio 2: 1). They form mainly in the interventricular septum, very rarely in the interatrial septum and usually do not affect hemodynamics but rhythm disturbances are often observed in the neonatal period. At an older age the tumors are asymptomatic with rare ECG changes in the form of a left bundle branch block, pseudoischemic manifestations. Cases of detection of cardiac angiolipomas, vascular anomalies (aneurysms of the aorta, cerebral arteries, renal artery stenosis) are rare. [27—33].
Lung pathology is observed almost exclusively in women and is characterized by the development of lymphangioleiomyomatosis manifested as cystic formations in the pulmonary parenchyma (cellular, "honeycomb" structure on radiographs). If it was previously thought this process is found in 30—40% of TS cases the results of recent studies indicate that it occurs more often — in 80% of patients under the age of 40. Clinically, patients experience shortness of breath during exercise there may be episodes of hemoptysis and in the III-IV decades of life the development of recurrent pneumothorax is possible. In men, lung pathology is latent [33, 34]. Kidney pathology is the second leading cause of mortality (27.5%) in TS. About 80% of children (average age 10.5 years) have benign angiomyolipomas, epithelial cysts, renal cell carcinoma, malignant angiomyolipomas, or oncocytomas. The most typical for TS are angiomyolipomas developing in the parenchyma of mainly both kidneys their multiplicity is characteristic. They are well identified by ultrasound (including in the fetus). With sizes not exceeding 4 cm the hamartomas are asymptomatic but with their further growth there is a potential for the development of intrarenal or retroperitoneal bleeding, acute or chronic ones with a drop in blood pressure, hematuria and microalbuminuria, pain syndrome. Kidney cysts are caused by hyperplasia of tubular epithelial cells and are most often diagnosed after 10 years although sometimes they are also detected in young children. In general, epithelial cysts occur in 14—47.0% of TS patients. Malignant renal tumors are detected in about 4—4.4% of cases of TS with predominance in middle-aged women (about 30 years): carcinoma is found in about 3% of patients, malignant angiomyolipoma — in about 1%. Unilateral lesion prevails (75%). Oncocytoma (benign adenomatous hamartoma) is recorded in 1% of TS cases. The most common cause of mortality in renal pathology is the development of end-stage chronic renal failure [16, 35—40].
Bone pathology occasionally covered in the literature is manifested mainly by the development of osteolytic foci or cysts, osteosclerosis in various parts of the musculoskeletal system. Even rarer publications describe cases of detection of hamartomas in the liver, spleen, intestines [33, 41].
The clinical phenotype of TS is subject to very variable fluctuations — from cutaneous manifestations only without multi-organ lesions [14, 42] to unusually multiple involvements of organs and systems in various combinations.
Some reports relate to the association of TS with other phakomatoses (type I neurofibromatosis, Klippel-Trenone, Sturge-Weber-Krabbe syndromes, multiple endocrine neoplasia type I), diffuse lipomatosis [43—48].
In the diagnosis of TS the skin manifestations are of great importance; so, the doctors’ knowledge of various specialties especially dermatologists can contribute to the earliest recognition of phakomatosis. In many cases, the classic clinic of these stigmas does not require histological studies. However, to confirm the diagnosis it is necessary to be examined by a wide range of specialists using X-ray, CTG and MRI technologies and sometimes molecular genetic research.
Currently, diagnostic signs of TS are presented by modified main and minor criteria of the disease .
The main criteria include:
1) angiofibromas (≥3) or fibrous plaques;
2) hypomelanotic spots (3 or more with a diameter of more than 5 mm);
3) peri- and sublingual fibroids (2 or more);
4) "pebbled" spots;
5) sub-epidermal nodes;
6) sub-epidermal giant cell astrocytoma;
7) dysplasia of the cerebral cortex (tubers);
8) rhabdomyomas of the heart;
9) renal angiomyolipomas;
10) multiple retina hamartomas;
11) lymphangioleiomyomatosis of the lungs.
Small sings include:
1) hypopigmented spots like confetti;
2) intraoral fibroids;
3) point defects of tooth enamel;
4) achromatic retina spots;
5) multiple kidney cysts;
6) extra-genital hamartomas.
The diagnosis of TS is considered established when 2 main signs or 1 main and 2 minor ones are detected. Detection of small signs should raise suspicion about vehicle capability.
The prognosis is determined by the severity and localization of visceral pathology. With severe lesions the mortality is high in childhood and young age as a result of cerebral pathology, heart, renal or pulmonary failure.
Dermatological manifestations do not correlate with the symptoms of hamartomas of internal organs and are a purely cosmetic problem (if necessary, angiofibromas and fibrous plaques can be removed using cryo- or laser destruction).
Specific therapy for TS consists in prescribing mTOR inhibitors (an intracellular signaling system that is activated by mutations in the TSC1 and TSC2 genes) — rapamycin (sirolimus) and its derivative everolimus. These drugs have immunosuppressive and anti-proliferative effects. Separately, according to few reports, sirolimus in doses from 1 to 7 mg / day (2 mg on average) when taken orally for 12 months it had a significant effect on angiofibromas and "shagreen" spots and reduced neurological, pulmonary and renal symptoms. Positive dynamics of the skin manifestations of TS was also noted when the drug was applied for 6 months in the form of a 0.1—1% cream or ointment daily or 3 times a week with the greatest efficiency in children. However, local therapy does not guarantee the absence of relapses. Oral administration of everolimus at a dose of 4.5 mg / m2 / day for various periods (up to 14 months) was accompanied by noticeable positive dynamics of both cutaneous and visceral hamartomas (including a significant decrease in astrocytoma volume). At the same time, no effect on cognitive abilities and behavioral characteristics was revealed [13, 20, 50—53].
With life-threatening hamartomas and their severe complications the main method of treatment is surgical intervention. In milder cases, patients are subject to interdisciplinary therapy using anticonvulsants, antihypertensive and other drugs.
As an illustration of disease we present a retrospective analysis of our own 15-year observation of boy A., born in 1995.
Anamnesis of the disease: the child was observed from birth by a neurologist with a diagnosis of perinatal encephalopathy of mixed genesis, motor dysfunction syndrome. From 2 years of age there was retardation in speech and psychomotor development, multiple episodes of convulsive syndrome. From the age of 5, papular rashes began to appear on the skin of the face in the paranasal area which was regarded by a pediatric dermatologist as flat warts. Cryotherapy prescribed was ineffective.
At the age of 7 years (Fig. 1.) the child was diagnosed with TS confirmed by the data of molecular genetic research — a mutation in the TSC2 gene with an autosomal dominant inheritance phenotype was found. The boy was registered with a neurologist, dermatologist, geneticist, cardiologist at his place of residence. From this age the boy's parents noted an increase in the clinical manifestations of TS — an increase in episodes of convulsive syndrome, the appearance of new rashes (Pringle's adenoma on the forehead, angiofibromas of the nasolabial triangle, multiple freckles), fibromas and hypo- and hyperpigmented spots on the skin of the trunk.
Fig. 1. Patient A., 7 years old. Face — Pringle adenoma of the forehead skin, angiofibroma of the nasolabial triangle, multiple ephelids of the nose and cheeks.
At the age of 10 the single cystic enlargements of the subarachnoid space of the brain, angiopathy of the retina, pyramidal syndrome — spastic paraparesis with cognitive impairment, rhabdomyoma with lesions of the interventricular septum of the heart were diagnosed.
Later, at puberty (13 years old) according to the X-ray examination of the right knee joint, osteochondropathy of the tibial tuberosity (Osgood-Schlatter disease) was diagnosed. At the age of 16 the patient was diagnosed with II disability group, also diagnosed with angiolipoma of the left kidney and multiple calcifications of the brain. General clinical blood and urine tests, biochemical analysis of the patient's blood corresponded to age norms. From the age of 17 to the present the patient is registered with a dermatovenerologist, geneticist, neuropathologist, cardiologist, ophthalmologist, therapist at the place of his residence. The patient is examined annually and receives treatment in medical institutions of a therapeutic profile including an examination of the disability group at the Bureau of Medical and Social Expertise.
Life history: a child from the VII pregnancy, burdened by an obstetric and gynecological history (threat of yearly pregnancy termination, gestosis, polyhydramnios, feto-placental insufficiency).
Allergic history has no specifics. Heredity is aggravated — when examining all family members the elder sister (born in 1986) was diagnosed with 2 "shagreen" spots on the skin of the lumbar region; also, it was depigmented the spot on the skin of the right thigh.
Concomitant diagnosis: gallstone disease. Concretion in the gallbladder; focal formation of the pancreas at the border of the body and tail; fixed kink of the gallbladder; reactive changes in the pancreas were detected.
Status localis: cutaneous pathological process is widespread, symmetrical, represented by multiple small nodules 2—6 mm in diameter, round and oval in shape, from flesh to yellow-pink color with single telangiectasias on the surface. There are rashes with a smooth surface, dense elastic consistency, which localized in the paranasal area with the spread of the nasolabial triangle to the skin (Fig. 2, 3). On the skin of the forehead there is an asymmetrically located large soft fibroma, irregular in shape, towering above the skin surface, colored yellowish (Fig. 4). On the skin of the face there are multiple small hyperpigmented spots (ephelids) sized up to 0.4 cm. On the skin of the trunk there are multiple dense flesh-pink fibroids with a diameter of 1—1.5 cm. The larger spots, no more than 5, like «coffee with milk», irregular forms, with clear edges, up to 10 cm in diameter are located on the skin of the trunk. In addition, on the skin there are hypopigmented oval-shaped spots, elongated with pointed ends like rowan leaves, 5—9 cm in diameter, and multiple (up to 15) small confetti-like spots, mainly on the skin of the trunk which were better visualized in the rays of a Wood lamp.
Fig. 2. Patient A., 22 years old. On the skin of the face are multiple freckles and angiofibromas.
Fig. 3. Patient A., 22 years old. On the skin of the nasolabial triangle there are multiple small, round and oval nodules, flesh and yellow-pink in color with a smooth surface, without a tendency to merge.
Fig. 4. Patient A., 22 years old. On the skin of the forehead, an asymmetrically located large soft towering fibroma, irregular in shape, yellowish in color.
The patient underwent a biopsy of a fibroma on the skin of the trunk; as a result of pathomorphological examination a thickening of the epidermis with hyperkeratosis and acanthosis was established. Proliferation of capillary vessels with perivascular lymphohistiocytic infiltration was noted subepidermally among dense fibrous tissue. The vascular endothelium is swollen. This type of infiltration has also been noted around the hair follicles. Sebaceous and sweat glands are not changed.
The given clinical observation is a case of TS a rare genetically determined disease from the group of phakomatoses which we have observed for 15 years. The dermatological manifestations of the disease fully corresponded to the detailed clinical picture of the severe TS phenotype which was confirmed by the specific signs of the disease identified over the past years: rhabdomyoma of the heart, angiolipoma of the left kidney, angiopathy of the retina, multiple cysts and calcifications of the brain. Neurological disorders such as retardation of speech and psychomotor development, multiple episodes of convulsive syndrome, signs of pyramidal and extrapyramidal syndromes, multiple areas of calcification and cystic components of the brain, confirmed by CT, MRI, EEG data are comparable to the most significant clinical manifestations of TS [1, 11, 13, 21]. The detected mutation in the TSC2 gene with an autosomal dominant phenotype of inheritance, also the data of pathomorphological and other laboratory and instrumental examination methods confirm the established diagnosis. Despite the fact that the neurological and psychomotor status of the patient remains stable for a number of years of the development of the disease the choice of profession, mode of work and other activities in the patient is limited.
The presented clinical observation indicates the need for medical genetic counseling of families in cases of TS detection. In addition, such patients should be regularly monitored by doctors and be registered with neurologists, dermatologists, neurosurgeons, therapists, cardiologists, ophthalmologists and surgeons in order to diagnose systemic lesions in a timely manner and correct the identified pathology.
The concept and design of the study: T.G. Sedova, V.D. Elkin
Collecting and interpreting the data: A.A. Zhukova, M.Y. Kobernik
Drafting the manuscript: T.G. Sedova
Revising the manuscript: V.D. Elkin
The authors declare no conflict of interest.