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Keywords:

  • Sotos syndrome;
  • Seizures;
  • Epilepsy;
  • Cerebral gigantism;
  • Overgrowth syndrome

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Sotos syndrome (SS) is an overgrowth syndrome characterized by typical facial appearance, learning disability, and macrocephaly as cardinal diagnostic features. Febrile (FS) and afebrile seizures are reported in 9–50% of cases. There is no evidence that patients with SS and FS later develop epilepsy, and no studies have investigated the electroclinical features and the long-term outcome in epileptic SS patients. The authors report a series of 19 SS patients with FS and/or epilepsy during childhood and a long-term follow-up. More than half of FS evolved to epilepsy. Temporal lobe seizures were recorded in 40% of patients with SS. Seizures were easy to control with common antiepileptic drugs in almost all patients. A careful neurologic evaluation is useful for SS patients, since seizures are an important finding among people with this overgrowth syndrome.

Sotos syndrome (SS) (OMIM #117550) is an autosomal dominant disease characterized by three cardinal features: distinctive facial appearance, learning disability, and overgrowth resulting in tall stature and macrocephaly. Typical facial features include high, broad forehead, frontotemporal sparse hairs, malar flushing, down-slanting palpebral fissures, and a pointed chin. In addition, a range of major and/or minor anomalies may occur, such as advanced bone age, neonatal problems, scoliosis, joint laxity, tumors, auditory/visual disturbances, and behavioral problems (Tatton-Brown et al., 2005).

SS is caused by mutations in or deletions of the nuclear receptor set domain containing protein 1 gene (NSD1), located at 5q35.2–q35.3 (Kurotaki et al., 2002; Douglas et al., 2005). More than 400 patients with SS have been reported (Fickie et al., 2011).

Most SS patients have nonprogressive neurologic dysfunction and brain anomalies. Neurologic disturbances associated with SS are hypotonia, feeding difficulties, clumsiness, poor coordination, delayed language and motor development, behavioral anomalies, and seizures. The degree of learning impairment is estimated to be extremely variable, although it is present in almost all patients (Tatton-Brown et al., 2005).

Several studies affirm that seizures may appear in about 15–50% of patients, and they are estimated to be febrile in half of cases (Tatton-Brown et al., 2005; Baujat & Cormier-Daire, 2007; Tatton-Brown & Rahman, 2007). A recent review of 21 SS adults described seizures as rare (9%) (Fickie et al., 2011). However, no data are available on whether patients with SS and febrile seizures (FS) later develop epilepsy, and no studies have investigated the electroclinical features and the long-term outcomes of epilepsy in these patients.

The aim of this study is to analyze the neurologic profile of 19 Caucasian patients with SS, with particular regard to epileptic phenotype and outcome.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

This multicenter, retrospective study was carried out at the Division of Pediatric Neurology, Umberto I Hospital, Sapienza University, Rome, Italy. To be eligible for this study, patients had to have been clinically diagnosed with typical SS (e.g., presence of all the cardinal features in the same patient) (Tatton-Brown & Rahman, 2007) and had to present with at least one FS or afebrile seizure (AF). All the patients had to have undergone full neurologic examination, brain magnetic resonance imaging (MRI), electroencephalography (EEG) recording, and long-term clinical and EEG follow-up. Age at onset of seizures, seizure semiology, EEG characteristics, brain MRI findings, and therapy with antiepileptic drugs (AEDs) were analyzed for each case. Genetic analysis of exons 2–23 of the NSD1 gene was performed in the reported patients by means of denaturing high performance liquid chromatography (HPLC; Transgenomics, Omaha, NE, U.S.A.), and direct sequencing of the chromatographic variant on 3130xl sequencer (Applied Biosystems, Foster City, CA, U.S.A.). Seizures were classified according to criteria of the International League Against Epilepsy (ILAE) (Engel, 2001). Written informed consent was obtained from parents or guardians of all recruited people.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Data from 19 Caucasian patients (15 male, four female) were collected from a cohort of patients referred to eight Italian Pediatric Neurology Divisions. The mean age at time of first evaluation was of 5 years 2 months (range 4 months–15 years), and the mean age at time of last follow-up was of 11 years 2 months (range 6–20 years). Minimum follow-up period was of 5 years (range 5–19 years). Febrile and afebrile seizures were recorded in 11 and 15 patients, respectively; seven children with FS developed generalized and/or focal AF. Clinical, neurologic, neuroradiologic, and genetic features of the 19 patients are summarized in Table 1.

Table 1.   Summary of the 19 reported patients with SS
  1. TLS, Temporal Lobe Seizures; GTCS, generalized tonic–clonic seizures; LV, lateral ventricles; SAS, subarachnoid spaces; VRS, Virchow Robin spaces; CC, corpus callosum.

  2. aOne patient had TLS + GTCS, one patient had TLS + GTCS + absence seizures.

  3. bBehavioral disturbances included: attention deficit hyperactivity disorder, aggressiveness, poor social behavior, pyromania, tics, obsessive-compulsive disorders, temper tantrum.

  4. cOcular anomalies included: nystagmus, strabismus, optic disk pallor.

  5. dOther anomalies included: dysplastic fornix, Chiari type II malformation, pineal gland cyst, subarachnoid cyst, and periventricular nodular heterotopia.

Cardinal Sotos syndrome features and genetic analysis   
Facial gestalt NSD1 analysis 
 Yes19 (100%)NSD1-mutated SS patients14 (74%)
 No Non-NSD1-mutated SS patients5 (26%)
Overgrowth with macrocephaly Type of NSD1 point mutation 
 Yes19 (100%)Missense10 (71%)
 NoFrameshift4 (29%)
Learning disability   
 Yes19 (100%)  
 No  
Seizures’ features   
Seizures [Mean age of onset]   
 Only febrile4 (21%) [1 year 6 months]
 Only afebrile8 (42%) [6 years 2 months]
 Febrile[RIGHTWARDS ARROW]Afebrile7 (37%) [1 year 5 months[RIGHTWARDS ARROW]4 years 9 months]
Seizure type EEG pattern 
 Febrile (11 pts) Febrile seizures 
  Only simple6 (55%)Normal4 (36%)
  Only complex1 (9%) Diffuse anomalies (slow waves)4 (36%)
  Simple + complex4 (36%)Focal anomalies 
 Afebrile (15 pts) Centrotemporal area3 (28%)
  Only GTCS5 (33%)Afebrile seizures 
  Only TLS4 (27%)Diffuse anomalies1 (7%)
  Only atonic seizures2 (13%)Focal anomalies 
  Only frontal lobe epilepsy1 (7%)Frontotemporal area5 (33%)
  Only absence seizures1 (7%)  Parietotemporooccipital area9 (60%)
  Multiple seizures typea2 (13%)Response to AED therapy 
Patients requiring AED therapy Febrile seizures3 (100%)
 Febrile seizures4 (36%)Afebrile seizures 
 Afebrile seizures15 (100%)Monotherapy12 (87%)
  Polytherapy1 (6.5%)
  Drug-resistant epilepsy1 (6.5%)
Nonepileptic neurologic features and neuroimaging   
Congenital hypotonia Developmental delay 
 Yes17 (89%)Yes19 (100%)
 No2 (11%)No
Other neurologic signs/symptoms Neuroimaging 
 Behavioral disturbancesb9 (47%)LV enlargement14 (74%)
 Poor coordination4 (21%)SAS enlargement7 (37%)
 Ocular anomaliesc2 (10%)Periventricular leukomalacia6 (32%)
 Vasovagal syncope1 (5%)Cavum septum pellucidum4 (21%)
 Poor feeding1 (5%)Cavum vergae4 (21%)
 Neonatal seizures1 (5%)Thinning of the CC3 (16%)
  VRS enlargement2 (10%)
  Brain2 (10%)
  Other anomaliesd1 (5%)

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Febrile seizures, infantile spasms, absence, tonic–clonic, and myoclonic seizures have been all associated with SS (Tatton-Brown & Rahman, 2007). Furthermore, a wide spectrum of behavioral and emotional disturbances may occur in SS patients, such as attention-deficit-hyperactivity disorder, aggressiveness, irritability, pyromania, social inhibition, psychosis, and autistic features (Mauceri et al., 2000; Tatton-Brown et al., 2005; de Boer et al., 2006). The patients with SS reported herein had FS and/or epilepsy. Mean age of onset of FS was consistently before the onset of epilepsy (1 year 6 months vs. 5 years 5 months). The 64% of SS patients with FS developed epilepsy, a much higher percentage if compared with patients with nonsyndromic FS (3–5%). We noticed that in some of the reported patients the diagnosis of SS was suspected only after they came to our attention for the first seizure, which was febrile in all cases. This may be related to the mild-to-moderate general and neurologic impairment of these patients in the first years of life, in which the typical cardinal features of SS had not aroused suspicion until that moment.

Generalized tonic–clonic seizures were the most frequent type among generalized AF, with a prevalence of 47%. Notably, the 40% of patients had temporal lobe seizures (TLS). Clinical symptomatology of TLS may include olfactory, gustatory, or auditory hallucinations, automatisms, fear, auras (e.g., abdominal aura) with/without behavioral arrest, déjà vu– or jamais vu–like sensations. In two patients, TLS presented with abdominal aura and bursts of aggressiveness, thus being initially confused with behavioral disorders. Ictal EEG recording allowed for the differential diagnosis between TLS and behavioral problems in these two patients (see legend of Fig. 1). Interictal EEG studies in patients with FS revealed normal background activity or anomalies fitting with the epileptic manifestations. Notably, anomalies in the temporal areas were recorded in a majority of patients with epilepsy at interictal EEG.

image

Figure 1.  Ictal EEG recording (20 s) of temporal lobe seizure in a 7-year-old boy with SS. Spikes start in the right temporal region (first 5 s), then high-voltage spikes and spike and waves complexes appear and remain for the duration of seizure in bilateral temporal areas (80 s). During seizure, the patient wanted to go home because he felt hungry and complained of stomachache, and manifested his feelings with a burst of aggressiveness. The patient did not lose consciousness. Parents reported numerous similar episodes, which were confused with behavior disturbances. Before the onset of temporal lobe seizures, the patient experienced FS and febrile status epilepticus, which presented with tonic–clonic seizures of the right side of the body and lasted 50 min at the age of 2 years.

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Seizures appeared easy to control with the common AEDs at standard doses, such as valproic acid, oxcarbamazepine, carbamazepine, lamotrigine, levetiracetam, topiramate. In this case series, monotherapy with valproic acid was the most frequent used treatment. In general, AED administration resulted in progressive reduction and disappearance of seizures. Recurrence of seizures required dose correction; only two patients needed polytherapy. At the time of last follow-up, 4 of 15 epileptic patients discontinued AED therapy (mean seizure-free period: 5 years; seizure-free period range 2–10 years); the other 11 patients still receive AEDs with good clinical control in all cases but one (patient with periventricular nodular heterotopia 0.

The pattern of brain abnormalities in SS suggest delayed or disturbed maturation, in particular of midline structures. In a study of 40 SS cases, ventricular anomalies (90%), enlargement of supratentorial extracerebral fluid spaces (70%), and anomalies of corpus callosum (64%) and other midline structures (40%) were the typical findings. Periventricular nodular heterotopias were reported in three patients (8%) (Schaefer et al., 1997). In the present series 17 patients had central nervous system anomalies, which were similar to the previous alterations described in children with SS. Periventricular nodular heterotopia was observed in one case (5%). In general, we found a lower incidence of midline brain anomalies compared with the series of Schaefer et al.

We cannot clarify the reason for the clinical and EEG involvement of temporal lobe in our patients, since no abnormalities were found in the temporal areas by MRI examination. Furthermore, studies on the role of the NSD1 gene on the brain (or temporal lobe) development are missing, although it is known that the transcript of the NSD1 gene is expressed in brain tissue (Favarelli, 2005).

Conclusions

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

This is the first study investigating the electroclinical features and the long-term follow-up of seizures in patients with SS. More than half of FS in these patients evolved to epilepsy. Generalized tonic–clonic seizures were the more frequent type of generalized seizures, whereas TLS were recorded in the 40% of SS with epilepsy in this series. Because patients with SS may have both behavior disorders and seizures such as TLS, and since TLS may be confused with some behavior disorders, ictal EEG recording may be helpful for differential diagnosis. Seizure control seems to be easy to obtain with monotherapy, or, less frequently, polytherapy with AED. A careful neurologic evaluation is useful in SS because seizures are an important finding among people with this overgrowth syndrome.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

Dr. Marina Grasso and Dr. Massimiliano Cecconi are acknowledged for NSD1 gene testing performed on patients followed at the Department of Pediatrics, Sapienza University of Rome.

Disclosures

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflict of interest to disclose.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. Disclosures
  9. References