Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder. TSC consists of a wide variety of clinical manifestations, with neurological and dermatological symptoms being the most frequent. This study aims to describe the clinical characteristics and management of a pregnant patient incidentally diagnosed with TSC.
Keywords: epilepsy, genetic disorders, tuberous sclerosis complex
Tuberous Sclerosis Complex is a rare genetic disorder. Its treatment requires a multidisciplinary team due to its multiple clinical presentations. An early and correct diagnosis will provide adequate treatment and prognosis for the patient's life.
1. INTRODUCTION
Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. 1 , 2 It is mainly characterized by benign hamartomas that mostly occurs in the brain, skin, kidneys, lungs, and heart. 3 TSC affects approximately two million people worldwide with an incidence rate of 1:6,000–1:10,000 among live births regardless of gender. 1 , 4 It was first described in 1862 by von Recklinghausen in a pediatric patient who presented with cardiac lesions (fibroids) and areas of cerebral sclerosis. 3 , 5
Tuberous sclerosis complex is caused by mutations in the genes TSC1 and TSC2, which encodes hamartin (chromosome 9q34.13) and tuberin (chromosome 16p13.3), respectively. 6 More than 60% of cases are caused by sporadic de novo mutations, 30% are transmitted in an autosomal dominant inheritance pattern, and up to 10% have no mutations in these genes. 6 , 7 TSC is diagnosed on the basis of a combination of clinical manifestations, radiological findings, and genetic tests. These follow the criteria established by the International Consensus Conference for the Diagnosis of TSC, and two major criteria or one major criterion and two minor criteria are required for a definitive diagnosis (Table 1). However, detection of mutations in TSC1 or TSC2 is currently considered as a confirmatory diagnosis. 8
TABLE 1.
Diagnostic criteria for tuberous sclerosis complex
| Major features |
| Hypomelanotic macules (≥3 mm, at least 5 mm in diameter) |
| Angiofibromas (≥3) or fibrous cephalic plate |
| Ungual fibromas (≥2) |
| Shagreen patches |
| Multiple retinal hamartomas (≥2) |
| Cortical dysplasias a |
| Subependymal nodules |
| Subependymal giant cell astrocytoma |
| Cardiac rhabdomyoma |
| Lymphangioleiomyomatosis |
| Angiomyolipomas (≥2) |
| Minor features |
| “Confetti” skin lesions |
| Dental enamel pits (≥3) |
| Intraoral fibromas |
| Retinal achromic patch |
| Multiple renal cysts |
| Nonrenal hamartomas |
Includes tubercles and cortical migration lines.
Prognosis of patients with TSC is variable and is related to the multiple clinical presentations. 8 High morbidity and mortality are associated with involvement of the central nervous system, kidneys, and lungs. 5 A multidisciplinary approach mainly directed toward management of symptom is required for the treatment. 9 , 10 Only one case of atypical TSC has been reported in a 22‐month‐old child in a rural area in Honduras. 11 This study aims to describe the clinical characteristics and management of a pregnant patient incidentally diagnosed with TSC.
2. CASE REPORT
A pregnant 20‐year‐old mestizo housewife residing in a rural area of western Honduras was admitted to Hospital de Occidente at 38.4 weeks of gestation with generalized tonic–clonic seizures and sphincter relaxation. The patient had a history of intellectual disability and epilepsy since the age of 6 years and multiple hospitalizations for seizures. A cesarean section was performed on her, followed by antiepileptic treatment with an initial loading dose of 1 g of phenytoin, empirical antibiotic therapy, and advanced airway management. Subsequently, she was referred to Hospital Dr. Mario Catarino Rivas for further specialized management.
The patient was admitted with advanced airway support and features of Richmond Agitation‐Sedation Scale (RASS) +2, tachycardia, right basal crackles, clean Pfannenstiel transverse skin incision, and mild lochia. The patient was placed on mechanical ventilation. Maintenance antiepileptic treatment with 100 mg intravenous (IV) phenytoin administration every 8 h was carried out and titrated until omission, which was subsequently changed to every 8 h administration of 500 mg oral valproic acid. During the substitution, the patient had two epileptic episodes; hence, valproic acid was adjusted to 500 mg at 8 am and 4 pm and to 1000 mg at 12 am as definitive maintenance treatment.
The epilepticus status was initially attributed to the patient's poor adherence to treatment and her subsequent abandonment of treatment. Physical examination revealed facial skin lesions consisting of angiofibromas located in the midfacial region with agglomerates in the nasopharyngeal region (Figure 1A), hypochromic macules in the thoracolumbar region ≥1 cm (Figure 1B,C), and nail fibromas (Figure 1D).
FIGURE 1.
(A) Angiofibromas in the centrofacial region agglomerated in the nasopharyngeal region, (B, C) hypomelanotic macules, (D) ungual fibroma
A simple cranial computed tomography (CT) revealed periventricular and capsular calcifications suggestive of neurocysticercosis (Figure 2A) and a chest CT showed basal infiltrates in the posteroinferior segments (Figure 3A,B). Electroencephalogram reported abnormal recordings caused by generalized dysfunction and epileptiform activity in the right frontal and left temporal regions.
FIGURE 2.
Simple skull CT scan with periventricular and capsular calcifications suggestive of neurocysticercosis
FIGURE 3.
Chest CT with basal infiltrates in posteroinferior segments
Reevaluation of the patient revealed that three major criteria for the diagnosis of TSC (facial angiofibromas, hypochromic macules, and nail fibromas) were met. TSC is an autosomal dominant disorder. Therefore, the patient's father was examined for suggestive signs, which revealed presence of angiofibromas in the midfacial region and hypochromic macules in the chest, both of which are characteristics associated with TSC.
The genetic study of TSC1 and TSC2 was carried out in a laboratory abroad since these tests were unavailable in our country. A positive result with a pathogenic mutation in TSC2 was obtained, which, together with the clinical findings (diagnostic criteria), confirmed the diagnosis of TSC. The patient was evaluated by a multidisciplinary team and discharged together with her newborn without new epileptic episodes and in good general condition. In terms of follow‐up, genetic counseling was suggested to the patient and her relatives.
3. DISCUSSION
Tuberous sclerosis complex is a disorder that mainly affects children, with a minimal incidence in adults. Epilepsy is one of the most frequent neurological manifestations of TSC and occurs in 80–90% of cases. Early onset of seizures is associated with delayed psychomotor development. 8 The patient had a history of epilepsy and intellectual disability since childhood, with poor control and multiple hospitalizations owing to seizures. Although TSC is a disorder diagnosed in childhood, it was incidentally found in this case.
The clinical manifestations of TSC are caused by altered cell growth, proliferation, and migration during embryonic development. 5 The TSC1 and TSC2 genes encode hamartin and tuberin, respectively, and both proteins contribute to the regulation of the mammalian target of the rapamycin (mTOR) pathway. Defects in the regulation of this pathway lead to its hyperactivation and development of benign tumors or hamartomas in various systems. 2 , 3 Mutations in TSC2 are more common and cause greater neurological disability compared to TSC1. The manifestations in cases of familial transmission are mild where TSC1 is the most affected gene. 9 , 12 Genetic tests of the patient revealed a positive result with a pathogenic mutation in TSC2.
Most patients with TSC present with neurological and dermatological manifestations. 9 Dermatological manifestations, which are the most common, are found in more than 90% of patients and include hypochromic macules, confetti‐like lesions, facial angiofibromas, nail fibromas, chagrin plaques, intraoral fibromas, and dental enamel pitting. 6 , 8 The patient presented with three dermatological manifestations, with the first two corresponding to the major criteria: hypochromic macules that are found in 90% of individuals with TSC, facial angiofibromas that are observed in approximately 75% of individuals, and nail fibromas that appear late compared to other dermatological manifestations; thus establishing the definitive clinical diagnosis. 6 , 9 , 11
The diagnostic suspicion for TSC can be based on family history or the presence of clinical criteria. The identification of genetic mutations in one of the parents corresponds to up to a 50% risk for the offspring. Identification of clinical manifestations and genetic testing are the main diagnostic tools for TSC. 1 , 3 Other useful diagnostic tools include magnetic resonance imaging (MRI), electrocardiogram (ECG), echocardiogram (Echo), pulmonary function tests, and computed tomography (CT). In addition to their diagnostic values, MRI and CT have contributed to the reduction in mortality and morbidity rates because of their use as follow‐up tools for patients with TSC. 4 , 9
Multidisciplinary and symptomatic management is necessary because of the wide range of clinical manifestations observed in patients with TSC. 9 Surgical methods, laser therapy, or dermabrasion are among the main treatments for dermatological lesions. Vigabatrin is considered as the first‐line treatment for epileptic spasms, while surgery or vagal stimulation can also be considered as treatment options. However, recent studies have shown that the use of mTOR inhibitors, such as rapamycin or everolimus, can provide promising results for more than one of the affected systems. 5 , 7 , 9 The patient's management was based on the symptoms during her hospital stay and treatment for seizure control was continued upon discharge.
A continuous follow‐up is necessary to avoid complications that can compromise organ functions. Several cases are diagnosed incidentally; therefore, recognizing the clinical criteria and genetic testing are essential for a timely diagnosis. 4 , 13
4. CONCLUSIONS
Tuberous sclerosis complex is a rare disorder with few cases diagnosed in adulthood. Knowing its clinical features can lead to suspecting the disease and establishing an early diagnosis, which with adequate treatment are fundamental for a better prognosis and quality of life. TSC can be discovered incidentally at any age by studying clinical features and medical images.
AUTHOR CONTRIBUTIONS
Rubén D. Cruz‐Zuniga: conceptualization, investigation, resources, writing, reviewing, editing, and approving final draft. César Alas‐Pineda: conceptualization, investigation, resources, writing, reviewing, and editing, Héctor O. Pineda‐Vijil: conceptualization, investigation, resources, reviewing, and approving final draft. Kristhel Gaitán‐Zambrano: investigation, writing, reviewing, editing, and approving final draft. Diana L. Flores‐Reyes: investigation, writing, resources, and approving final draft. Reenie H. Pineda Villeda: investigation, writing, resources, and approving final draft. Marcos A. Quiñonez‐Sánchez: conceptualization, resources, reviewing, and approving final draft.
FUNDING INFORMATION
The authors did not receive support from any organization for the submitted work.
CONFLICT OF INTEREST
The authors have no relevant financial or nonfinancial interests to disclose.
ETHICAL APPROVAL
This study was performed in line with the principles of the Declaration of Helsinki. According to the guidelines for case reports of the Universidad Católica de Honduras ethics committee, this study is exempt from requiring ethics approval.
CONSENT
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
ACKNOWLEDGMENTS
We would like to show our gratitude to the Hospital Dr. Mario Catarino Rivas' Internal Medicine Department who provided insight and expertise that greatly assisted this research.
Cruz‐Zuniga RD, Alas‐Pineda C, Pineda‐Vijil HO, et al. Diagnosis of tuberous sclerosis complex in adulthood: A case report. Clin Case Rep. 2022;10:e06555. doi: 10.1002/ccr3.6555
DATA AVAILABILITY STATEMENT
Patient's files and datasets used to support the findings of this study are restricted to protect the privacy of clinical data. Data are available to investigators who comply the criteria for access to confidential data under request to the Universidad Católica de Honduras ethics committee. Requests for access to these data should be directed to César Alas‐Pineda: cesar_alas10@hotmail.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Patient's files and datasets used to support the findings of this study are restricted to protect the privacy of clinical data. Data are available to investigators who comply the criteria for access to confidential data under request to the Universidad Católica de Honduras ethics committee. Requests for access to these data should be directed to César Alas‐Pineda: cesar_alas10@hotmail.com.