Tuberous sclerosis complex (TSC) is a disease of varying presentations characterised by the presence of multiple hamartomas in various organ systems in the body. This is an Autosomal dominant disease with damages in two suppressor genes namely TSC1 and TSC2 located on chromosome 9 (9q34-hamartin) and chromosome 16 (16p13.3-tuberin). It is a lifelong disease with neurological manifestations, for example, epilepsy, mental retardation and autism and major dermatological features like facial fibromas (adenoma sebaceum), periungual fibromas, shagreen patches and hypopigmented macules. Some conditions, for example, autosomal dominant polycystic kidney disease can co-exist with TSC as a result of concurrent deletion of both polycystic kidney disease 1 and TSC2 genes present on chromosome 16p13.3. We present a cluster of three families with TSC having varied presentations.
Keywords: Angiofibroma, ash leaf macules, rhabdomyoma
Tuberous sclerosis complex (TSC), a neurocutaneous disorder with an incidence of 1 in 6,000,[1],[2],[3],[4] is a heterogeneous illness with wide clinical manifestations ranging from serious scholarly handicap with unmanageable epilepsy to normal knowledge and absence of seizures. The illness affects numerous organs other than the skin and brain which include the heart, kidney, eyes, lungs and bone [Figure 1]. Youngsters with TSC have heart rhabdomyoma which is the most widely recognized cardiovascular tumour in its early stages. Significant appearances of TSC incorporate skin lesions in over 95%, seizures in 85%, kidney disorders in 60%, mental hindrance in 50%, and cardiovascular rhabdomyoma in 35%. Mental retardation and autism are more in patients of TSC who present with seizures in the initial two years of life. We present here a case arrangement of three families influenced by TSC, showing disease associations with infantile rhabdomyoma and autosomal dominant polycystic kidney disease (ADPKD) in adults.
Case I
A 12-year-old boy with seizure disorder presented with recurrent loin pains for three months. On examination, he was having facial angiofibromas and hypomelanotic macules on his body [Figure 2]b. Per abdomen examination revealed bilateral palpable enlarged kidneys. The possibility of TSC was kept. Renal function tests and electrolytes were normal. The patient's cardiac and eye evaluations were normal. Ultrasound and CT scan of the abdomen revealed bilateral enlarged lobulated kidneys studded with multiple cysts with cortical thinning [Figure 2]d and [Figure 2]e. MRI brain revealed cortical tubers and multiple subependymal nodular lesions [Figure 2]c. His father was having similar angiofibromas [Figure 2]a with an ultrasound abdomen revealing cystic changes in the kidney without any symptoms. Presently child is on antiepileptic drugs and monthly follow-up for renal status.
Figure 2: Family cluster I. (a) Father with facial angiofibromas; (b) patient with facial angiofibromas; (c) MRI (patient) brain cortical tuber; (d) NCCT abdomen (patient) suggestive of multiple cysts in kidneys (d and e) Computed TomographyCase II
This was a nine-month-old male child, a product of non-consanguineous marriage, with an uneventful antenatal, natal and postnatal period, second in order of two. He presented with myoclonic jerks 8–10 episodes/day for one month. Developmental history revealed global developmental delay with DQ 64%. Family history revealed Ash leaf macules in the elder brother, mother, and maternal grandmother while the mother had facial angiofibromas [Figure 3]a, [Figure 3]b, [Figure 3]c. All of them were symptom-free. On examination, the patient had multiple ash leaf macules all over the body along with a hypopigmented patch over the left buttock [Figure 3]d while systemic and eye examinations were normal. 2D echocardiography showed a mass 25 × 30 mm in the left ventricular apex of the heart suggestive of rhabdomyoma [Figure 3]e. CECT brain revealed multiple subependymal calcified nodules in the bilateral lateral ventricle with a large calcified nodule at the Foramen of Munro of the right lateral ventricle measuring up to 12 × 9 mm [Figure 3]f. EEG and USG abdomen were normal. Keeping in view the disease presentation, a diagnosis of TSC was made. The patient was conservatively managed and started on Vigabatrin @ 60 mg/kg/day. On follow-ups, the child is seizure free and thriving.
Figure 3: Family cluster II. (a) Mother with facial angiofibromas; (b) freckles on mother; (c) mother with ash leaf macules over back MRI; (d) hypopigmented macule on the left buttock of the child; (e) 2D echocardiography (patient) cardiac rhabdomyoma; (f) NCCT brain (patient) subependymal tubers in lateral ventriclesCase III
Another patient was a one-month-old child, the second product of a non-consanguineous marriage, who came to us with complaints of generalised tonic-clonic movements of limbs involving five to six episodes per day for one week. On examination, the patient had ash leaf macules on the forehead and back [Figure 4]a. His elder sibling had epilepsy and neurocutaneous manifestations of TSC like ash leaf macules, adenoma sebaceum [Figure 4]b and shagreen patch. Father was a known case of epilepsy and had Ash leaf macules, adenoma sebaceum, shagreen patch, cortical tubers and periungual fibromas [Figure 4]c, [Figure 4]d, [Figure 4]e, [Figure 4]f, [Figure 4]g. Based on history and clinical examination, a diagnosis of TSC was made. The patient was conservatively managed and started on levetiracetam. The child is seizure free on subsequent follow-ups.
Figure 4: Family cluster III. (a) Patient with hypomelanotic macule on the forehead; (b) angiofibromas in brother; (c) angiofibromas in father; (d) freckles on the neck of the father; (e) shagreen patch in father; (f) periungual fibroma in the father; (g) NCCT brain (father) subependymal tubers in lateral ventricles DiscussionTSC is an autosomal dominant neurocutaneous syndrome with a high incidence of sporadic cases and variable clinical expression.[1],[2],[3] The first complete description of TSC was given by Bourneville in 1880.[4] Abnormal neuronal migration plays a major role in neurological dysfunction.[1] The TSC mutation results in abnormal cellular proliferation and differentiation, regulated by mTOR (mammalian target of rapamycin)—A protein kinase that regulates the abnormal cellular proliferation and differentiation; this is responsible for hamartomatous lesions that affect the brain, kidney, heart and lungs.
Diagnostic criteria include major, minor and genetic [Table 1]. The most widely recognized and regular skin finding in TSC is numerous hypopigmented ash leaf macules. Ash leaf macules have an incidence of >90% in early childhood TSC. Another lesion, that is, adenoma sebaceum is a hamartoma made out of connective and vascular components which is pathognomonic of TSC and is hence named angiofibroma. While rhabdomyoma is the most common cardiac tumour of infancy and prenatal life, constituting 89% of fetal cardiac tumours.[5] The incidence of TSC is as high as 59%–80% in patients with confirmed fetal rhabdomyomas.[6] The ability to detect cardiac rhabdomyomas prenatally, as early as 20 weeks of gestation, makes the determination of the frequency of association with TSC important from a pregnancy management and genetic counselling point of view.[7] Most cardiac rhabdomyomas regress early in life.[8] Surgical resection is not usually considered unless they cause severe intractable arrhythmias, valvular obstruction, or congestive heart failure. Patients with TSC can build up a number of renal injuries, the most widely recognized being angiomyolipomas and cysts accounted for up to 80% of grown-up patients. Patients with TSC and ADPKD develop the end-stage renal disease at an earlier age and have an increased risk of malignancy. The intracranial highlights of TSC are cortical or subcortical tubers, subependymal cysts, and subependymal giant cell astrocytomas. Tubers are most regularly found in the cerebrum, 90% being available in the frontal projections. Less regularly tubers are available in the cerebellum, brainstem and spinal cord. Seizures are widely recognized neurologic side effects of TSC happening in 92% of patients.[9]
While retinal lesions in the eye are known as astrocytic hamartomas non retinal injuries incorporate coloboma, angiofibroma of the eyelid and papilledema. All three family clusters of TSC presented the varied status of this lifelong disease.
Topical 0.1% Rapamycin for facial angiofibromas and everolimus, mTOR inhibitors have been tried to treat the subependymal astrocytomas, renal angiomyolipomas and cardiac rhabdomyomas with significant regression. This promises a likely novel therapy in patients with TSC. Moreover, the patients of TSC should also undergo cardiac evaluation [Table 2] apart from other investigations like MRI, USG Abdomen and EEG once every 3 years.[10] Diagnosed cases of TSC should be followed up for neuro-developmental and radiological assessments. Genetic testing will facilitate early identification and provide opportunities for disease stratification and early intervention. Dermatologists should be aware of this condition and be able to arrive at an early diagnosis based on clinical signs; in the newborn period and early infancy, before age four months. Early diagnosis helps initiate epileptogenic treatment before the onset of seizures which can improve cognitive outcomes.
Table 2: New cardiology-specific recommendations for tuberous sclerosis complexDeclaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients/parents have given their images and other clinical information to be reported in the journal. The patients and parents understand that their/their children's names and initials will not be published and due efforts will be made to conceal their identity.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
留言 (0)