Abstract
Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Diagnosis of early onset TSC in newborn infants is usually made by cardiac ultrasound because of circulatory problems due to cardiac rhabdomyoma. Early appearance of cortical tubers on cerebral ultrasound in newborn infants is very rare. Mostly TSC is diagnosed on MRI and not by cerebral ultrasound. Subependymal nodules are the usual presenting sign of TSC on cerebral ultrasound in neonates, which are often misdiagnosed as subependymal hemorrhage, calcifications or ischemic lesions after intrauterine germinal matrix hemorrhage. In this case report, multiple cortical and subcortical tubers are demonstrated in an extremely preterm infant, which were not observed on antenatal ultrasound. Together with cardial rhabdomyoma and the identification of the TSC2 pathogenic mutation in DNA from normal tissue the diagnosis of TSC has been confirmed. To our knowledge this is the first case report of early appearance of disseminated cortical tubers on cerebral ultrasound postnatal in an extremely preterm infant with TSC.
Introduction
Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder, with a wide clinical spectrum. The diagnosis in fetal and neonatal age is usually made by the presence of rhabdomyoma on cardial ultrasound. We present a case of an extremely preterm infant where the diagnosis of TSC was made first by cerebral ultrasound due to the presence of multiple cortical and subcortical tubers.
Case report
A 680-g infant male was born at 27 weeks and 2 days gestational age by a cesarean section because of fetal distress as expressed by fetal deceleration during cardiotocography. The pregnancy was complicated by severe preeclampsia and intra-uterine growth restriction. The Apgar scores were 2, 6 and 8 after respectively 1, 5 and 10 minutes. He was intubated because of respiratory distress. The chest x-ray showed signs of hyaline membrane disease. Surfactant instillation was performed three times. Nevertheless intensive mechanical ventilation was still needed. There was also a lactate acidosis due to fetal distress. On the second day a routine cerebral ultrasound investigation was performed, which showed multiple disseminated echo dense lesions in the cortical and subcortical regions (see Fig. 1). The lesions were heterogeneous in aspect, and were initially interpreted as possible ischemic lesions. Due to clinical suspicion of patent ductus arteriosus (PDA) a cardiac ultrasound was performed later on the same day, which revealed a PDA with left to right shunting. There were also multiple intracardiac echogenic structures visible which are suggestive for myocardial tumors, probably rhabdomyomas (see Fig. 2). With this cardiac finding the intracerebral echo dense lesions are also suggestive for cortical tubers in the context of TSC.
Cerebral ultrasound on day 2: multiple echogenic lesions in cortical and subcortical regions, suspicious for tubers.
Long axis and four-chamber view of cardiac ultrasound showing multiple intracardiac echogenic structures which are suggestive for myocardial tumours.
During the course of intensive mechanical ventilation he developed recurrent bradycardias and hypoxemia. Malposition of tube and central venous catheter were excluded. The subsequent cardiacultrasound showed that the intracardial tumors were rapidly growing, obstructing the outflow tract and causing pulmonary congestion. Because of the rapid clinical deterioration, the fact that he was too small for cardiac surgery and the bad prognosis of TSC, continuing intensive mechanical ventilation was considered futile medical treatment. The patient died after cessation of the mechanical ventilation. As post mortem investigation, a skin biopsy and material for DNA were taken. Also a total body MRI scan was performed. In the brain there were multiple focal lesions with high signal on TIR sequence and low signal on T2TSE sequence, which were suggestive of cortical tuberous hamartoma. There were no subependymal nodules (see Fig. 3). On both sides there was a long focal lesion in the paraventricular region with high signal on TIR sequence and low signal on the T2TSE sequence, which were suggestive of paraventricular hemorrhages. The heart showed myocardial hypertrophy of the left and right ventricles with focal high signal intensity on T2TSE sequence, which could be matching with rhabdomyoma. There were also multiple small cysts in both kidneys. Genetic analysis showed a change on the TSC2-gene called the 5238del18, which genetically confirmed thediagnosis of TSC. This genetic disorder was not found in the parents, so it was a de novo mutation.
Postmortem brain MRI showing multiple corticale located focal lesions with high signal on TIR sequence and low signal on T2TSE sequence, very suggestive for cortical tubers.
Usually the diagnosis of TSC in the neonatal period is made by the symptoms caused by cardial rhabdomyoma which cause problems of the circulation. Sometimes a subependymal nodule on cerebral ultrasound is the first presenting symptom of TSC in newborn infants. However, subependymal nodules in neonates are often diagnosed as subependymal hemorrhage, calcifications or ischemic lesions after intrauterine hemorrhage, especially when there is a history of fetal distress and prematurity [1]. The finding of extensive subcortical and cortical tubers by cerebral ultrasound in a neonate with TSC is rare. The children who are diagnosed antenatal have cardiac tumors (rhabdomyoma) as first presentation on routine antenatal ultrasound [2]. Some cases of prenatal detection of cerebral lesions were described, but these patients also had cardiac rhabdomyoma detected earlier on prenatal ultrasound [3, 4].
Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder; first described by Bourneville in 1880 [5]. It is an autosomal dominant genetic disorder with an incidence of approximately 1 in 6000 live births. It is caused by a mutation in either the TSC1 gene or the TSC2 gene. TSC often causes disabling neurological disorders, dermatological manifestations and manifestations in internal organs such as heart, lungs and kidneys. There is a wide clinical spectrum of this disease. The diagnosis of TSC is made when two major features, or one major and two minor features can be shown and there is an identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue [6]. So according to these criteria the diagnosis of TSC of our patient was clear. Seizures in infancy or early childhood are the most common first presenting clinical symptom in children, widely varying between 79% –96%. Studies show that cardiac rhabdomyoma occur in 50% –67% of children [2, 7]. Patients with a TSC2 mutation were more likely to present earlier in life and with cardial rhabdomyoma [8].
Perinatal morbidity and mortality are mostly caused by cardiac, central nervous system and renal lesions [2]. Normally the cardiac rhabdomyoma tends to regress and commonly rhabdomyoma do not cause any symptoms. In our case however the rhabdomyoma were rapidly growing. This could be because the child was born preterm. It is known that the rhabdomyoma can still grow in the third trimester of gestation and regress after birth. However multiple disseminated subcortical and cortical tubers on cerebral ultrasound in a preterm newborn with TSC that were not observed on antenatal ultrasound, was not demonstrated earlier. The possibility of TSC diagnosis should be considered when multiple cortical and subcortical echogenic lesions are seen in the cerebral ultrasound in newborn infants. It should not be confused with focal ischemic or hemorrhagic lesions. In such cases an additional cardiac ultrasound could be helpful to make the right diagnosis of TSC.