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Keywords:

  • Wolf–Hirschhorn syndrome;
  • Electroclinical patterns;
  • Epileptic evolution

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary: Background: Wolf–Hirschhorn syndrome (WHS) is a well-known clinical entity caused by partial deletion of the short arm of one chromosome 4 (4p– syndrome). Seizures occur in almost all the cases, but studies on the electroclinical disorder and its evolution are still scarce. We present a longitudinal study of the electroclinical features in 10 children with WHS.

Methods: Ten patients (five boys and five girls) underwent a detailed clinical assessment and a prolonged EEG study. Six of the 10 also had video-polygraphy.

Results: Nine of the 10 patients had seizures; they were generalized or unilateral clonic and tonic–clonic, and atypical absences associated with myoclonic jerks. Age at onset of seizures varied from 1 day to 2.5 years. In all the patients, including the only one without seizures, two stereotyped EEG patterns were observed, consisting of (a) bursts of rhythmic (3–5 Hz), high-voltage slow waves located in the posterior regions and increased by sleep, or bursts of rapid spike–wave complexes in the centroparietal and parietooccipital regions; and (b) repetitive rapid posterior spikes. Sleep organization was constantly absent or very poor. The evolution of epilepsy was frequently good, with four seizure-free cases at the end of follow-up, two of them weaned from antiepileptic drugs (AEDs).

Conclusions: Seizure onset in WHS also can occur at neonatal age. At least two electrical stereotyped patterns of the epileptic disorder are associated with a relevant disorganization of the sleep states. Prognosis of epilepsy is generally good both for the seizure control and for its evolution.

Wolf–Hirschhorn syndrome (WHS) is a well-known clinical entity caused by partial deletion of the short arm of one chromosome 4 (4p– syndrome). Clinical manifestations include a typical craniofacial appearance with microcephaly, hypertelorism, large and protruding eyes, high nasal bridge, short philtrum, and micrognathia, associated with major malformations (congenital heart defects, midline defects, and renal and skeletal anomalies), intrauterine and postnatal growth retardation, and neurologic abnormalities (hypotonia, mental retardation, and epilepsy).

Seizures occur in practically all the cases (1–3). Only a few studies have reported electroclinical features (4–10) in WHS, stressing the similarities to EEG findings in Angelman syndrome (AS) (8). Several points concerning the mechanism of seizures, their age at onset, and their evolution, however, have not been investigated.

We report the results of a serial electroclinical study of 10 patients with WHS.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Our series consists of 10 patients (five boys and five girls) with partial deletion of the short arm of chromosome 4. Prometaphase chromosome analysis (600–800 bands) was performed on peripheral lymphocyte by the R(RBG) banding method. A minimum of 20 metaphases were scored in each patient. Fluorescent in situ hybridization (FISH) analysis was carried out in all patients with the subtelomeric probe pC847.351 and with probes 190b4 and 174g8, delimiting, distally and proximally, the first defined WHS critical region (WHSCR) (10,11). The proximal breakpoint of the deletion varied from p15.1 to p16.2. By FISH, the deletion was demonstrated to be terminal, and to include the WHSCR on each occasion. The newly defined critical region, WHSCR-2 (12), also was included in the deletion interval in all patients.

All the children had a complete clinical examination. The EEG study consisted of at least one awake and one nap-sleep EEG in our unit and an evaluation of other EEG recordings performed elsewhere. In six cases (cases 2, 3, 4, 6, 7, and 9), we performed a serial video-polygraphic study, by using 21 EEG electrodes according to the 10/20 International System, and deltoid surface electromyogram (EMG). In three patients with frequent seizures (cases 2, 4, and 5), it was possible to record and evaluate the ictal electroclinical features. Magnetic resonance imaging (MRI) was performed in six cases, and computed tomography (CT) scan in one. The children were examined approximately every 6 months; in the cases followed up elsewhere, our evaluations were less frequent. In six cases, the EEG had been routinely performed since the first year of life.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Main clinical data are summarized in Tables 1 and 2. Cases 1, 2, 4, 9, and 10 were previously described (3). The mean age at the end of follow-up was 4.6 years, with a range between 1.8 and 9 years.

Table 1. Clinical data
CasesSexGrowth retardationCraniofacial characteristicsMicrocephalyCardiac heart diseaseMidline defectsRenal defectsLast observation (yr)Karyotype
  1. ASD, atrial septal defect; PS, pulmonary stenosis; PDA, patent ductus arteriosus; BAV, bicuspid aortic valve; VSD, ventricular septal defect.

  2. a4q33qter Trisomy also present, due to a recombinant chromosome 4.

 1M–2 SD  ++ASD, PS,HypospadiasHypoplasia2.4/1246,XY,del(4) (p15.32)
      PDA, BAV    
 2F–5 SD  ++ASDCleft palateKidney pelvis546,XX,del (4) (p16.1)
        dilatation  
 3F– 6 SD  ++VSD, ASDIris colobomaHypoplasia646 XX, del (4) (p15.3)
 4F–2 SD  ++VSD, ASD,Cleft palateNo746, XX, del (4) (p15.1)
      PDA    
 5F–4 SD  ++NoNoNo446,XX, del (4) (p16.2)
 6M–4.5 SD++PDAHypospadiasKidney pelvis4.7/1246, XY, del(4) (p16.1)
        dilatation  
 7M–6.5 SD++PDA, ASDHypospadias,Hypoplasia,3.2/1246, XY del (4) (p15.3)a
       cleft palate, kidney pelvis  
       retrobulbar cyst, dilatation  
       iris colobomas   
 8M–6 SD++PSHypospadias,No4.10/1246, XY, del (4) (p 16.2)
       cleft palate.   
 9F–4.5 SD++ASDNoNo246, XX, del (4) (p16.3)
10M–2 SD  ++NoHypospadiasKidney pelvis946, XY, del (4) (p16.3)
        dilatation  
Table 2. Neurologic data
CasesMental retardHypotoniaMRIInterictal myocloniaSeizures
OnsetTypeFrequencyTreatmentRefractoryOutcome
  1. CC, corpus callosum; PB, phenobarbital; VPA, valproate; ESM, ethosuximide; CLB, clobazam; ACTH, adrenocorticotropic hormone.

 1+++++Atrophy cortical and subcortical?<12 moGeneralized clonicSporadicPBNoSporadic
 2+++++Normal+2 yr, 5 moa) Partial complex: vomit, drooling, drowsiness b) Absences or myoclonias and myoclonias without absence c) Astatica) Monthly b) Daily c) WeeklyVPANoNo more seizures
 3+++++++(CT scan) atrophy?<1 mo1) Infantile spasms 2) At 2 yr, generalized clonicSporadicPBNoNo more seizures; weaned from AED
 4+++++++Normal+1 d1) Neonatal: clonic–tonic 2) at 1.4 yr, febrile generalized clonic 3) at 2.5 yr, daily absences with myoclonias, sometimes unilateral; atypical absence statusSporadic/dailyPB PB+VPA ACTH VPA+PB+  ESM+CLBYesMajor improvement
 5++NoNoNo2 mo1) at 2 mo, myoclonias 2) at 8 mo, clonic 3) at 1 yr, absences or myoclonias: myoclonic statusDaily/sporadicVPA VPA+PB VPA+CLB VPA+ESM+CLBNoNo more seizures
 6++++NoNo6 mo1) at 6 mo, tonic 2) at 1 yr, tonic–clonic and hemiclonic 3) at 1.10 yr, convulsive status 4) at 3 yr, long-lasting absences with myoclonias and salivationSporadicPB VPA+PB VPA?Sporadic
 7+++++++Atrophy, CC hypoplasiaNo0No0000
 8+++++No?12 moGeneralized convulsive (?)SporadicVPA+PBNoNo more seizures
 9++++CC hypoplasia+13 moGeneralized clonic with or without feverSporadicVPA PBNoSporadic
10++++Atrophy, CC hypoplasia?12 moGeneralized convulsive with feverSporadicPBNoNo more seizures: weaned from AED

As expected, mental retardation was always present, with various (moderate to severe) degrees of severity, whereas diffuse hypotonia was observed in all the cases but one, in whom persistent axial hypotonia was, however, present in the first months of life.

An interictal myoclonus was found in three cases (2, 4, and 9). It always consisted of small segmentary myoclonic jerks of low amplitude, mainly in the hands.

Neuroimaging was normal in only two patients (2 and 4), whereas the other cases had aspecific changes (cortical and/or subcortical atrophy and corpus callosum hypoplasia). Seizures were present in all the cases but one. Their onset varied from 1 day to 2 years 5 months, with a mean onset age of 9 months.

The association of convulsive seizures (CSs; either generalized or unilateral, tonic–clonic or clonic), atypical absences, and myoclonias was present in four patients (2, 4, 5, and 6). In four patients (1, 8, 9, and 10), only CSs were found, sometimes triggered by fever. Moreover, in case 2, frequent partial complex seizures and drop attacks were noted; in case 3, transient infantile spasms occurred in the first month; and in case 6, transient tonic seizures occurred at age 6 months.

One isolated epileptic status was observed in three patients: myoclonic status (case 5), atypical absence status (case 4), and convulsive status (case 6), respectively. Patients 3 and 4 had their first seizures during the first month of life. In patient 3, the EEG was similar to that usually found in early epileptic encephalopathy, such as a hypsarrhythmic-like pattern (Fig. 1), whereas seizures included infantile spasms and generalized CS. She is now seizure free without treatment. In patient 4, several generalized CSs appeared in the neonatal period, and severe epileptiform abnormalities were present in EEGs. After a short seizure-free period with EEG normalization and an isolated febrile generalized clonic seizure at 1 year 4 months, the epileptic pattern, as in the other cases, was characterized by the association of different types of seizures: generalized or unilateral CSs, atypicalabsences, sometimes with eyelid or perioral myoclonias, and erratic and asynchronous myoclonias, both ictal and interictal.

image

Figure 1. Case 3: at age 6 months, sleep EEG showed a hypsarrhythmic pattern interrupted by decremental activity heralded by a spasm (arrow).

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Epilepsy was generally well controlled, with monotherapy alone; in only one patient (case 4) could epilepsy be defined as refractory. Phenobarbital (PB) was the most efficient drug against tonic–clonic seizures, whereas valproate (VPA) or ethosuximide (ESM) succeeded in absence and myoclonic seizures.

There was evidence of a general improvement of epileptic disorders with age: at the end of the follow-up, five cases were seizure free, two of them (cases 3 and 10) weaned from AEDs. In one case (case 4), definite improvement was found, whereas in the other three cases, sporadic occurrence of seizures persisted practically unchanged. However, follow-up of two of them (cases 1 and 9) was short (<2 years).

In all cases, including the one without seizures, interictal EEG (Table 3) showed a generally slow background with characteristic bursts of rhythmic (3–5 Hz) high-voltage slow waves located in posterior regions or, less frequently, in frontocentral areas (Fig. 2). Sometimes the bursts acquired a paroxysmal aspect with diffusion and superimposed spikes, notched appearance of the waves, or atypical spike-and-wave discharge. The same aspect was observed in the ictal paroxysms (Fig. 3) associated with atypical absences or myoclonias consisting of diffuse discharges of slow (2–3 Hz) spike–waves or waves with superimposed spikes, with onset in central or posterior regions, sometimes preceded by rhythmic high-voltage slow waves.

Table 3. Electrophysiological data
 Interictal EEG 
  Epileptiform abnormalities  
Cases BackgroundMorphology distribution Sleep Ictal EEG follow-up
  1. WHS, Wolf–Hirschhorn syndrome.

 1Diffuse theta + bursts of high-voltage, rhythmic (2–3 Hz), slow wavesBursts of high-voltage, rhythmic (2–3 Hz), slow waves with superimposed spikesDiffuse, with posterior onsetNo organizationNot performedWHS pattern only after 1 yr
 2Bursts of asynchronous, high-voltage, rhythmic, theta slow waves, in frontal central areasBursts of high-voltage, rhythmic (2–3 Hz), slow waves with superimposed spikes + posterior repetitive spikesDiffuseNo organizationNotched, rhythmic (2–3 Hz) slow waves, in bursts (2–4 s), clinically expressed as myoclonias + vomit during sleep and followed by postictal slow wavesWHS pattern only after 1 yr
 3Monomorphic theta + bursts of rhythmic slow waves in parietal regions.Hypsarrhythmia before 6 mo, posterior repetitive spikesRight, posteriorNo organizationNot performedSevere abnormalities in the first 6 mo of life, followed by WHS pattern
 4Central or posterior bursts of rhythmic slow wavesBursts of high-voltage, rhythmic (2–3 Hz), slow waves with superimposed spikesDiffuseNo organizationNotched, rhythmic (2–3 Hz) slow waves in bursts lasting 5–10 s, expressed as absences with eyelid and/or limb myocloniasSevere abnormalities in the first month of life; after 2 yr, WHS pattern
 5Diffuse, rhythmic slow wavesPosterior repetitive spikesLeft, posteriorNo organizationMyoclonias, absences with or without myoclonias. Rhythmic (2–3 Hz) slow waves with superimposed spikes, in bursts lasting 2–4 sWHS pattern only after 5 mo of life
 6Generally normal + rhythmic bursts of posterior slow wavesBursts of high-voltage, rhythmic (2–3 Hz), slow waves, sometimes with superimposed spikesDiffuse with posterior onsetPoorly organizedNot performedNo information concerning the first year. WHS pattern during year 2
 7Diffuse thetaBursts of high-voltage, rhythmic (2–3 Hz), slow waves, sometimes with superimposed spikesDiffuse, predom. centralNo organizationNot performed1st EEG at 2 yr: WHS pattern
 8Theta rhythmic bursts of slow waves + sporadic posterior slow wavesNoDiffuse with left posterior onset?Not performed1st EEG at 3 yr: WHS pattern
 9Diffuse theta1) Bursts (2–3 s) of high-voltage, rhythmic (2–3 Hz) slow waves with superimposed spikes 2) Rare isolated spikes1) Diffuse, asynchronous 2) Right fronto centralNo organizationNot performedWHS pattern only after 1 yr
10Theta rhythmic bursts of slow waves + sporadic rhythmic posterior slow wavesNoNoNo organizationNot performed1st EEG at 5 yr: no typical WHS pattern
image

Figure 2. Case 2: (left) at 4 years, awake EEG showed diffuse, rhythmic slow-wave discharges followed by slow-wave bursts in the frontocentral regions; they were preceded by posterior spikes; (right) synchronous and asynchronous spikes and slow waves with superimposed spikes on the posterior regions.

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image

Figure 3. Case 4: awake EEG showing an atypical absence characterized by diffuse, rhythmic, high-voltage slow waves with superimposed spikes with onset on centroposterior left regions.

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Besides these more frequent EEG findings, in three cases (cases 2, 3, and 5), we observed another pattern characterized by rapid posterior repetitive spikes (Fig. 4); in one of them, posterior spikes were associated with diffuse discharges (Fig. 2).

image

Figure 4. Case 3: at 6 years, awake EEG showed slow background activity and repetitive right posterior spikes.

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EEG evolution showed the typical patterns in four of the six patients studied since the first year of life: the pattern appeared only during the second year of life, and generally persisted until the last observation; after seizure control, however, a progressive reduction of paroxysmal activities was found. In the other two patients, we observed a fluctuation of paroxysmal abnormalities that was severe in early recordings, disappeared after few months, and presented again with the typical appearance of WHS EEG after 2 years.

Electrical organization of sleep appeared thoroughly abnormal. Frequently activation of EEG epileptiform abnormalities occurred, and physiological patterns were hardly recognizable.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In our series, nine of 10 patients had seizures, most commonly convulsive (generalized or unilateral), typically associated with segmental, asynchronous myoclonias and atypical absences (sometimes with eyelid or oral myoclonias). These findings are consistent with those previously reported in the literature (7–10). In our patients, however, we did not observe the repetition of myoclonic status, as reported by Sgro et al. (8). EEGs showed two different patterns of paroxysmal activity. The first pattern consisted of focal or diffuse discharge of slow (2–3 Hz), high-voltage, rhythmic, notched waves or waves with superimposed spikes, often with asynchronous onset in frontocentral or posterior regions. This pattern, similar to that observed in both interictal and ictal EEGs, was associated with atypical absences or myoclonias. In interictal EEGs, these bursts of slow (3–5 Hz) high-voltage waves sometimes heralded an electroclinical seizure. These abnormalities also were found in patient 7, who did not have seizures. The similarity of ictal and interictal EEG in these patients raises the question whether case 7 was really nonepileptic.

The second pattern consisted of bursts of posterior rapid repetitive spikes, observed in three cases, so far not described in the literature. As case 2 can suggest, these posterior spikes could represent a fragment of the complete pattern of slow waves superimposed by posterior spikes. A wider and more precise study of the relation between the two patterns is required to support this hypothesis.

The EEG patterns observed in our patients are similar to that observed in Angelman syndrome (AS) (8). WHS and AS also share similar clinical epileptic features, but a greater variety of seizure types, more pervasive and persistent EEG abnormalities, and a more severe evolution (13) characterize AS epilepsy. The interictal myoclonus also is much less severe in WHS than in AS, as in the latter, this occurs in clusters and triggers clonic seizures (14,15).

Another quite peculiar EEG feature in our series of WHS was the marked disorganization of sleep with absence or poor presence of spindles, at least in the first stages of sleep, because we did not perform complete nocturnal recordings. In two patients, only clinical sleep disturbances were known to be present. Clinical sleep disturbances were reported by Battaglia et al. (16), who did not study sleep EEG findings in their patients. Only Sgro et al. (8) reported a delay in the appearance of rapid-eye-movement (REM) stage. Conversely, in AS, frequent clinical sleep problems were observed, but, similarly, at the best of our knowledge, no sleep EEG data are available except for the activation of abnormalities. It is well known that brainstem and thalamic structures play a role in modulating sleep–wake cycles, even though there is increasing evidence that the hemispheres also are involved (17). Abnormal sleep patterns are reported in other syndromes such as Down syndrome and Prader–Willi syndrome (18,19) and in other different types of encephalopathy, especially in mentally retarded children (20). They have been used as prognostic factor in many early or acquired encephalopathies, but the role played by sleep disorganization in child development is still not clear, and, in particular, it is not easy to speculate about its presence in WHS. According to our experience, although never described, it seems a peculiar aspect of electroclinical disorder in the 4p– syndrome.

The evolution of epilepsy deserves some comments. It is known that seizures in 4p– syndrome tend to disappear with age (1), but so far no detailed reports on the epileptic outcome are available. Battaglia et al. (1) indicated that seizures stopped in 33% of their cases by age 2–13 years. Half of these cases were already off medication. In our series, five patients were seizure free, two of these without antiepileptic drugs (AEDs); three had sporadic seizures, and the last one still had seizures but had definitely improved. Even though mean age at seizure onset was 9 months, as generally described, two cases had seizures in the first weeks of life, one of them in the first day, an occurrence never reported in the literature. Intriguingly, both patients belonged to the group of patients associated with the most extensive deletion (p15.1).

Although the electroclinical features of epilepsy in AS are clearly different from those in West and Lennox–Gastaut syndromes, Minassian et al. (21) noted the persistence of the age-specific modality of seizure presentation (as brief tonic spasms as in West and Lennox–Gastaut syndromes) in AS beyond infancy; this could be considered a way of retaining in the CNS networks normally expressing infancy or early childhood epilepsy. Differently, in 4p– syndrome, it seems that no delay occurs in epileptic age-correlated phenotypes, with a general trend toward seizure regression. Epilepsy improvement during childhood concerned several patients of our series; all the subjects older than 5 years were seizure free for ≥2 years, and two of them with no more AEDs.

Electroclinical phenotype–genotype correlation

The similarities of electroclinical patterns in WHS to those found in AS and the involvement of γ-aminobutyric acid (GABA)A-receptor genes of chromosome 15 in the latter syndrome, drew attention to the GABA-receptor subunits mapped in the short arm of chromosome 4. Unfortunately, its location on chromosome 4 (p12-p13) out and far from the usual locus involved in 4p deletion prevents consideration of the possible role of chromosome 4 GABA-receptor gene in determining WHS epilepsy.

The usual broad size of deletion in WHS may explain the complexity of the phenotype, probably correlated with the contribution of more contiguous genes. It also could account for the generally homogeneous electroclinical patterns in WHS epilepsy.

However, the use of molecular techniques allowed the study of even narrower submicroscopic terminal or interstitial deletions that could provide the detection of candidate genes for single symptoms such as seizures. Recently a new gene (LETM1) was characterized as a candidate gene for seizures. The indication is stressed by the fact that LETM1 encodes a putative member of the EF-hand family of Ca2+-binding proteins, involved in Ca2+ signaling and/or homeostasis (22).

By overlapping deletion analysis, the critical regions for WHS (WHSCR) was initially considered to be restricted to a 165-kb interval in 4p 16.3, defined by the loci D4S166 (including cosmid 174g8) and D4S3327 (including cosmid 19h1) (11). LETM1 is not included in WHSCR, and haploinsufficiency of this region results in an atypical WHS phenotype, with no seizures (23,24).

The newly characterized critical region, WHSCR-2 (12), is distally contiguous to WHSCR, and it includes LETM1. At a molecular level, the candidate gene WHSC1 (25) overlaps the two regions; however, its haploinsufficiency accounts for some facial dysmorphisms, providing evidence that WHS is a contiguous gene syndrome.

Deletion of WHSCR-2 thus results in a typical WHS phenotype that includes psychomotor retardation, growth delay, characteristic facial appearance, and seizures. All these signs are considered minimal diagnostic criteria for WHS (12), fulfilled by all our patients. According to the model of a contiguous gene syndrome, the degree of both mental retardation and growth delay varied in individual patients, mostly depending on the extent of the deletion.

In conclusion, according to our experience, seizures seem to be an almost invariable feature of the 4p– syndrome phenotype, with a mean onset at between ages 6 and 12 months, but with possible neonatal onset. At least one electrical stereotyped pattern occurs, and perhaps a second one (characterized by repetitive posterior spikes) of the epileptic disorder in WHS. A relevant disorganization of the sleep states also is frequently observed. Prognosis of epilepsy is generally good, both for the seizure control by AEDs and for its evolution. The pathogenesis of the epileptic disorder might be explained by the genetic individuation of candidate genes to seizures inside the deleted short arm of chromosome 4.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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