Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome that is characterized by a partial deletion of the short arm of chromosome 4 and was first described by Hirschhorn and Cooper in 1965 (1). The majority of cases are de novo deletions of preferential paternal origin (2). In 1997, the critical region of WHS was defined as a 165-kb locus in 4p16.3 (3). Those with WHS often have refractory seizures (4) and easily develop status epilepticus (SE) (5). In this study, we investigated seizure types, clinical courses, and reported effective treatments of epilepsy in WHS.
Summary: Purpose: We investigated the evolution of epilepsy, seizure types, and effective drugs in Wolf-Hirschhorn syndrome, which is a malformation syndrome often with refractory seizures and status epilepticus.
Methods: We reviewed 11 cases of Wolf-Hirschhorn syndrome (age range, 2–25 years; SD, 7.2 years) and who were treated in Osaka University or Osaka Medical Center of Research Institute for Maternal and Child Health.
Results: In all patients, febrile or afebrile convulsions had developed. Epileptic seizures included alternative hemiconvulsions, generalized tonic–clonic seizures, focal clonic seizures, tonic seizures, and epileptic spasms. Seizures were often induced by a high fever or a hot bath. Status epilepticus occurred in all patients, including one patient who died at the first status epilepticus. In some cases, intratracheal intubation was needed because of respiratory insufficiency. The effective antiepileptic drugs for long-term use were sodium bromide (four of four), followed by clorazepate (CLP; one of two), and nitrazepam (NZP; two of four). Sodium bromide was particularly effective for preventing status epilepticus. The mean age of last status epilepticus in patients receiving sodium bromide (1 year 8 months) was significantly younger than that in those not treated with sodium bromide (3 year 4 months).
Conclusions: We identified that, in most patients of Wolf-Hirschhorn syndrome, the frequency of both seizures and status epilepticus decreased gradually after age 5 years. However, during infancy, status epilepticus sometimes resulted in permanent disability or even death. We propose that sodium bromide should be used as the initial treatment for the prevention of the development of status epilepticus associated with Wolf-Hirschhorn syndrome.
PATIENTS AND METHODS
We examined seizure onset and frequency, seizure types, the treatment and evolution of epilepsy in 11 cases of WHS treated at either Osaka University Hospital or Osaka Medical Center and Research Institute for Maternal and Child Health. The subjects included three male and eight female patients. The mean age at the final visit was 10 years (range, 2–25 years; SD, 7.2 years). All of the subjects had partial deletions of the short arm of chromosome 4. Eight cases had de novo deletions. The other three had translocations; two of the subjects were brothers whose father had a translocation of chromosome 4 and 8 (Table 1). We defined SE as prolonged seizures of >30 min. The antiepileptic drugs (AEDs) were defined effective when seizure or SE decreased in frequency to <50% of that observed when untreated. When seizure frequency decreased without any change of AEDs, the change was defined as spontaneous remission.
|Case No.||Br treated||Non-Br treated|
|(p 15.2)||(p 15.2)||(p 15.32)||(p 16.1)||(p 15)||(p 15.32P16.3)||(p 16.1)||(p 15.32; p21.3)||(p16.1; p13.31)||(p16.1; p13.32)|
|Congenital heart anomaly||VSD, ASD, PS, PH||ASD||PS, PDA||ASD, TR||ASD||ASD, PDA||ASD||−||ASD, PS||ASD||ASD, PS, AoV|
|Cleft palate/cleft lip||+||−||−||−||+||−||+||−||−||−||−|
|Other anomaly||Anal atresia, deafness||–||Deafness, finger overlapping, finger stiffness||–||Overlapping, deafness||Hypoplasia of kidney||Hypospadias||Deafness||Finger anormaly, deafness||–||–|
Clinical findings of cases
Clinical findings are listed in Table 1. All of the cases showed a characteristic craniofacial appearance with microcephaly, hypertelorism, a prominence of the nose and mouth with downturned corners (Fig. 1A). All cases were small for gestational age, and the mean birth weight was 1,901 ± 359 g. Ten cases had congenital heart anomalies. Three had cleft palate or cleft lip or both. Five cases displayed deafness. Other abnormalities included anal atresia, hypoplasia of kidney, hypospadias, and finger abnormalities.
Seizure onset, seizure types, and evolution of epilepsy
Figure 1B shows the clinical courses of all cases. The mean age at the first seizure was 13 months (range, 5–24 months; SD, ± 6.7). Thereafter all cases, except one, had febrile seizures, and three had hot bath–induced seizures. Nine cases had afebrile seizures. All cases had SE. In particular, six cases had refractory SE >3 times. Seizure types were generalized tonic–clonic seizures (GTCSs) in eight cases; unilateral convulsions (UCs) in six cases (Fig. 2A), complex partial seizures (CPSs) in five cases; secondarily generalized seizures in four cases; tonic seizures, epileptic spasms, and epileptic myoclonia, each in one case. Despite adequate AED treatments, GTCSs or USs were frequently prolonged for a few hours. The mean age at the first SE was 21 months, and the mean age at the last SE was 3 years and 6 months. The frequency of SE was monthly in three cases, sometimes yearly in four cases, and only once in four cases. The seizure types of SE were classified as GTCSs in four cases, UCs in three cases, focal motor seizures in three cases, and tonic seizures in one case. Case 5 had a permanent hemiparesis after UCs of SE. Case 8 died of pulmonary edema after SE. The frequency of seizures and SE decreased gradually after age 5 years in all cases.
Treatment of seizures and epilepsy
The effective AEDs for cessation of SE were intravenous diazepam (DZP) in 8 cases, intravenous lidocaine in one case, intravenous thiamylal sodium in one case, and intravenous thiopental sodium in one case. In three cases, intratracheal intubation was required because of respiratory insufficiency due to AEDs. In two cases, nonconvulsive SE appeared after the cessation of prolonged convulsions (Fig. 2B).
The most effective treatment for the prevention of GTCSs or UCs was sodium bromide (Br). The efficacy of Br was 100% (four of four; 30–50 mg/kg/day; mean concentration, 564 μg/ml). It was especially effective for the prevention of SE. In seven cases treated without Br, refractory febrile or afebrile seizures recurred and sometimes developed into SE. In cases 1 and 3, convulsive seizures disappeared after the administration of Br (300 μg/ml, 581 μg/ml). At a later time, case 3 had seizures including SE only at the time of decreasing clorazepate (CLP) and at a time of drug incompliance. In case 4, SE disappeared after the administration of Br (585 μg/ml). In case 2, refractory SE, which sometimes required intratracheal intubation, disappeared after the administration of Br (790 μg/ml), but short seizures continued to appear for a few minutes (Fig. 2). No adverse effects were shown with Br treatment. Benzodiazepines (BZDs) such as CLP (one of two) and nitrazepam (NZP; two of four) also are effective after Br. The conventional AEDs for partial seizures such as carbamazepine (CBZ; one of five), zonisamide (ZNS; none of two), and phenytoin (PHT; none of three) or those for febrile seizures such as phenobarbital (PB; one of seven) and valproic acid (VPA; none of four) were rarely effective.
Patients of WHS often have severe mental retardation, motor developmental delay, and other problems, such as failure to thrive, repeated infections, difficulties swallowing, and intractable seizures. In the past reports, the incidence of seizures in WHS was reported as high as 47 to 92%. Battaglia et al. (6) reported that seizures in WHS appeared between ages 5 and 23 months, with unilateral clonic or GTCSs that were often facilitated by fever (6–8). SE was reported to occur in 40% of patients, and the seizures stopped by ages 3 to 8 years. In our study, febrile and afebrile convulsions occurred frequently with an increased tendency to develop SE. SE sometimes ended with hemiparesis or death. Because the frequency of seizures and SE decreased gradually after age 5 years, the prevention of SE during infancy is very important. SE was halted by intravenous DZP or intravenous short-acting barbiturates. Lidocaine and PHT were ineffective. Because SE was prevented dramatically in all cases treated with Br, Br should be introduced for the treatment of epilepsy with WHS at an early stage.
Sgro et al. (9) reported that WHS presented generalized or unilateral myoclonic seizures followed later by atypical absences and could be categorized under UCs. Our patients also had various seizure types such as GTCSs or alternative UCs, often easily induced by high fever. Epilepsy in WHS also is reported to have atypical absences, myoclonic seizures, and complex partial seizures. All of these characteristics are very similar to those of severe myoclonic epilepsy in infancy (SMEI). In 1988 Ernst et al. (10) reported the efficacy of Br in early-onset epilepsy with GTCSs and/or alternation of hemi-grand mal precipitated by fever. In 1994 Oguni et al. (11) also reported that Br had moderate to excellent effects for the prevention of seizures in SMEI. In this study, Br was very effective, especially in preventing SE. The mean age of the last SE in the Br-treated group was much younger than that in the group not treated with Br. Br is the most classic AED and was the principal AED before the introduction of PB in 1912. The anticonvulsive mechanism of Br is still unknown. However, it is considered to have an anticonvulsant action in that both chloride and bromide ions cross the nerve cell membrane in response to inhibitory neurotransmitters through chloride ion channels (12). Recently, the mutations in the sodium-channel gene, SCN1A, were reported to cause SMEI and generalized epilepsy with febrile seizures plus (GEFS+) (13). Conversely, it is unclear why seizures in WHS easily progress to SE and how Br can prevent SE in WHS.
Recently it was reported that critical components of WHS include the leucine zipper/EF-hand–containing transmembrane (LETM1) gene. The LETM1 gene encodes a putative member of the Ca2+-binding protein, which controls Ca2+ signaling and homeostasis (14). In addition, Br was reported to have a concentration-dependent effect to block low Ca2+-induced seizure discharges in rat brain slices (15). Thus Ca2+-binding proteins translated from the LETM1 gene may play an important role in seizures in WHS patients. Further investigations into the mechanisms of Br and Ca2+-binding proteins may further the understanding of the mechanisms of the seizures and may lead to the development of new antiepileptic treatments for WHS patients.