Seizure and EEG patterns in Wolf-Hirschhorn (4p-) syndrome

doi:10.1016/j.braindev.2004.02.017

Brain and Development

Volume 27, Issue 5, August 2005, Pages 362-364

https://doi.org/10.1016/j.braindev.2004.02.017 Get rights and content

Abstract

Wolf-Hirschhorn syndrome (WHS) is a well-characterized chromosomal disorder that occurs due to partial deletion of the short arm of chromosome 4 (4p-). Although, about 300 cases have been reported to date, limited data are available on electroclinical findings. Information given to parents at the time of diagnosis tends to be skewed to the extreme negative. To delineate the natural history of seizures and EEG patterns in WHS, and obtain better information on diagnosis or outcome in a clinical setting, we reviewed the available literature on electroclinical findings of WHS. 4p- syndrome is characterized by distinctive seizure and EEG patterns that facilitate the early diagnosis and management of such patients.

Introduction

Wolf-Hirschhorn syndrome (WHS) is a well known multiple congenital anomalies/mental retardation syndrome initially described by Cooper and Hirschhorn in 1961 [1]. The disorder occurs due to partial loss of material from the distal portion of the short arm of chromosome 4. The minimal deleted segment causing the phenotype is 4p16.3 [2]. The majority of cases (87%) comprises de novo deletions [2] of preferential paternal origin [3], [4]. WHS was brought to the attention of the genetics community in 1965 [5], [6].

The frequency of this disorder is estimated as one per 50,000 births with a female predilection of 2:1 [2], [7]. However, this rate may be an underestimation in view of the frequency of missed diagnosis due to lack of recognition or inadequate cytogenetic analysis [8]. The most striking features of WHS are the typical ‘Greek warrior helmet appearance of the nose’, pre- and post-natal growth delay, congenital hypotonia, mental retardation and seizures [8].

Although several cases have been published [9], [10], [11], [12], [13], [14], [15], [16], very little information is available on the seizures, their natural history and electroencephalographic (EEG) findings in WHS. There is a tendency of skewing of information to the extreme negative, with families usually being informed that their child will have refractory epilepsy [12], [15], [17], [18], [19].

Since accurate information is of paramount importance to pediatricians and child neurologists who provide health care for many years in several cases [20], [21],we present an update on the types of seizures and EEG findings in WHS, and their natural history.

Section snippets

Seizures/epilepsy in WHS

Detailed and comprehensive descriptions of seizures in association with 4p- syndrome are very rare in the literature. Furthermore, almost all articles only provide descriptions of the first seizure(s), and stress the initial difficulty in controlling seizures in some cases. No information is provided on the evolution of seizures/epilepsy. As a consequence, the reader may get the impression that these patients have refractory epilepsy [10], [12], [15], [17], [18], [19], [22], [23], [24], [25].

EEG findings in WHS

Until recently, very little was known on the EEG findings in WHS, due to the paucity of reported cases in each article, poor description of these findings, and lack of serial EEG studies [10], [17], [32]. In a recent report, Battaglia and Carey [8], [31] observed distinctive EEG abnormalities in 70% of 48 patients. The children participating in this study received serial electroencephalographic investigations during wakefulness and sleep over a long period of time. Most patients were subjected

Discussion

WHS displays a distinctive electroclinical pattern resembling both ‘severe myoclonic epilepsy in infancy (Dravet syndrome)’ [37] and ‘myoclonic status in non-progressive encephalopathies’ [38]. However, a few significant differences are evident between WHS and the two epileptic syndromes. Seizures in WHS are easier to treat after the first few years of life and thereafter well controlled by anti-epileptic drugs, whereas all the ‘Dravet syndrome’ seizure types are drug resistant. The myoclonic

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Cited by (33)

Clinical and epilepsy characteristics in Wolf-Hirschhorn syndrome (4p-): A review
2024, Seizure
Citation Excerpt :
These were followed by tonic spasms (20%); focal seizures with impaired awareness (12%) and clonicseizures in 7% of patients [1,4]. Over 1/3 of children can develop atypical absences by age 1–6 years, accompanied by a mild myoclonic component, mainly involving the eyelids and hands [1,54]. These seizures were very frequent and prolonged throughout the day.
Wolf–Hirschhorn syndrome (WHS) is araredisorderwithan estimated prevalence being around 1 in 50,000 births. The syndrome is caused by the deletion of a critical region (Wolf–Hirschhorn Syndrome Critical region- WHSCR) on chromosome 4p16.3. WHS is clinically characterized by pre-and postnatal growth restriction, hypotonia, intellectual disability, craniofacial dysmorphismand congenital fusion anomalies. The clinical aspects are variable due to the deletion size.Consistently, epilepsy is one of the major concerns for parents and professionals caring for children with WHS. Seizures tend to occur in over 90% of patients, with onset within the first 3 years of life, and a peak incidence at around 6–12 months of age. Approximately 20% of patients had the first seizure onset within the first 6 months of age, almost 50% at 6 to 12 months of age and about 25% later than 12 months of age. The main types of epileptic seizures occurring in patients with WHS were generalized tonic–clonic seizures (around 70%). These were followed by tonic spasms (20%); focal seizures with impaired awareness (12%) and clonicseizures in 7% of patients.Seizures are often triggered by fever, followed by infections of various systems. Particularly, half of WHS patients experience status epilepticus in the first years of life, which can be fatal. Due to limited number of reports on the topic of EEG abnormalities in epilepsy among WHS patients, it is difficult to determine whether there are any characteristic deviations for WHS. Although more than 300 persons with WHS have been reported in the literature, there is sparse knowledge about epilepsy and methods of its anti-seizure medication (ASM) management with an assessment of their effectiveness. The purpose of this systematic review is to briefly summarize achievements and advances in the field of epilepsy in Wolf-Hirschhorn syndrome.
Pediatric diagnosis not made until adulthood: A case of Wolf-Hirschhorn syndrome
2013, Gene
Citation Excerpt :
People with WHS show pathognomonic dysmorphic facial features (including prominent glabella and nose, hypertelorism, high-arched eyebrows, micrognathia and downturned mouth corners) (Battaglia et al., 1999), associated with multiple organ defects (bilateral cleft lip or palate, congenital heart defects, urogenital, skin and skeletal anomalies) (Battaglia et al., 1999), and varying degrees of neurological impairment (Battaglia and Carey, 2005; Battaglia et al., 1999). Almost all people with WHS have seizures, with seizure onset usually being in the first year of life (Battaglia and Carey, 2005; Battaglia et al., 2003; Kagitani-Shimono et al., 2005; Zankl et al., 2001). Seizures are often triggered by fever and tend to be refractory: status epilepticus may be frequent.
Wolf–Hirschhorn syndrome is a well-known clinical entity caused by a terminal deletion of the short arm of chromosome 4 (4p-). The diagnosis is usually made in childhood because of the pathognomonic facial dysmorphism, multi-organ involvement and seizures. Epilepsy is a major medical complication during the first years of life, with seizures typically being frequent, although they tend to improve or cease with age. We report on a woman diagnosed with WHS in her thirties by array-CGH. She presents with milder dysmorphic features, recognized by stereophotogrammetry and seizures persistent in adulthood.
Partial monosomy Xq(Xq23 → qter) and trisomy 4p(4p15.33 → pter) in a woman with intractable focal epilepsy, borderline intellectual functioning, and dysmorphic features
2008, Brain and Development
Studies of epilepsy associated with chromosomal abnormalities may provide information about clinical and EEG phenotypes and possibly to identify new epilepsy genes. We describe a female patient with intractable focal epilepsy, borderline intellectual functioning, and facial dysmorphisms, in whom genetic study (i.e., karyotype and array-CGH analysis) revealed a distal trisomy 4p and distal monosomy Xq. Although any genetic hypothesis remains speculative, several genes are located in the 4p chromosome segment involved in the rearrangement, some of which may be related to epilepsy.
A Case of Wolf-Hirschhorn Syndrome Progressing to Resistant Epilepsy
2007, Pediatric Neurology
Citation Excerpt :
Wolf-Hirschhorn syndrome is a well-characterized chromosomal disorder that occurs because of partial deletion of the short arm of chromosome 4 (4p−). The 4p− syndrome is characterized by distinctive seizure and electroencephalograph patterns that facilitate the early diagnosis and management of such patients [2]. Here we describe, and discuss in terms of the related literature, a 3-year-old girl with Wolf-Hirschhorn syndrome who initially presented with myoclonic seizures but then underwent a progression toward resistant epilepsy.
Wolf-Hirschhorn syndrome is defined by a collection of core characteristics that include mental retardation, epilepsy, growth delay, and craniofacial dysgenesis. The disorder is caused by subtelomeric deletions in the short arm of chromosome 4. The syndrome, as described in the literature, may have a progression to resistant seizures and status epilepticus, which may then exhibit specific electroencephalographic findings. This study investigates a 3-year-old girl presenting with the classic phenotype for Wolf-Hirschhorn syndrome, confirmed by fluorescence in situ hybridization. Here we describe and discuss this patient, who initially presented with myoclonic seizures but then had a progression toward resistant epilepsy, along with electroencephalographic findings specific to Wolf-Hirschhorn syndrome.
Genotype-phenotype correlation of deletions and duplications of 4p: case reports and literature review
2023, Frontiers in Genetics
Natural history study of adults with Wolf–Hirschhorn syndrome 2: Patient-reported outcomes study
2021, American Journal of Medical Genetics, Part A

View all citing articles on Scopus

^☆: The paper is based on the lecture given at the sixth annual meeting of the Infantile Seizure Society,Tokyo, March 15–16, 2003.

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Mini-reviewSeizure and EEG patterns in Wolf-Hirschhorn (4p-) syndrome☆

Abstract

Introduction

Section snippets

Seizures/epilepsy in WHS

EEG findings in WHS

Discussion

Adv Pediatr

J Pediatr

J Pediatr

Am J Ophthalmol

Electroencephalogr Clin Neurophysiol

Neuron

Genomics

Am J Hum Genet

Apparent deletion of short arms of one chromosome (4 or 5) in a child with defects of midline fusion

Mamm Chrom Newslett

The Wolf-Hirschhorn syndrome I. Genetics

Clin Genet

Paternal origin of the de novo deleted chromosome 4 in Wolf-Hirschhorn syndrome

J Med Genet

Parental origin of chromosome 4p deletion in Wolf-Hirschhorn syndrome

Am J Med Genet

Baitsch Defizienz am den kurze Armen eines Chromosomes nr. 4

Humangenetik

Deletion of short arms of chromosome 4–5 in a child with defects of midline fusion

Humangenetik

Syndromes of the head and neck

The 4p- syndrome

Am J Dis Child

Translocation 4p- syndrome

Am J Dis Child

Clinical atlas of human chromosomes

Familial Wolf's syndrome with a hidden 4p deletion by translocation of an 8p segment Unbalanced inheritance from a maternal translocation (4;8)(p15.3;p22). Case report, review and risk estimates

Clin Genet

Familial Wolf-Hirschhorn syndrome resulting from a cryptic translocation: a clinical and molecular study

J Med Genet

Epileptic seizures in the 4p- syndrome: report of two cases

Jpn J Psychiatry Neurol

The Wolf-Hirschhorn syndrome: deletion of the short arm of chromosome 4

Acta Paediatr Belg

Mini-review
Seizure and EEG patterns in Wolf-Hirschhorn (4p-) syndrome☆