Efficacy of Antiseizure Medications in Wolf-Hirschhorn Syndrome.

Wolf-Hirschhorn syndrome (WHS) is caused by deletion of the terminal region of chromosome 4 short arm and is frequently associated with intractable epilepsy. This article evaluates the clinical features of epileptic seizures in WHS and the therapeutic efficacy of oral antiseizure medications (ASMs). Patients with WHS who were treated for epilepsy at the Saitama Children's Medical Center under 5 years of age were included. WHS was diagnosed based on genetic tests and clinical symptoms. Medical records regarding the age of onset of epilepsy, seizure type, treatment of status epilepticus (SE), and effectiveness of ASMs were retrospectively reviewed. Oral ASMs were considered effective when seizures were reduced by at least 50% compared with the premedication level. Eleven patients were included in the study. The median age at the onset of epilepsy was 9 months (range: 5-32 months). Unknown-onset bilateral tonic-clonic seizure was the most common type of seizure, occurring in 10 patients. Focal clonic seizures occurred in four patients. Ten patients exhibited recurrent episodes of SE, and its frequency during infancy was monthly in eight patients and yearly in two. SE occurrence peaked at 1 year of age and decreased after 3 years of age. The most effective ASM was levetiracetam. Although WHS-associated epilepsy is intractable with frequent SE occurrence during infancy, improvement in seizure control is expected with age. Levetiracetam may be a novel ASM for WHS.

Distinct Epileptogenic Mechanisms Associated with Seizures in Wolf-Hirschhorn Syndrome.

Seizures are one of the clinical hallmarks of Wolf-Hirschhorn syndrome (WHS), causing a significant impact on the life quality, still in the first years of life. Even that the knowledge about WHS-related seizure candidate genes has grown, cumulative evidence suggests synergic haploinsufficiency of distinct genes within cellular networks that should be better elucidated. Herein, we evaluated common mechanisms between candidate genes from WHS seizure-susceptibility regions (SSR) and genes globally associated with epilepsy. For this purpose, data from 94 WHS patients delineated by chromosomal microarray analysis were integrated into a tissue-specific gene network with gene expression, drugs, and biological processes. We found functional modules and signaling pathways involving candidate and new genes with potential involvement in the WHS-related seizure phenotype. The proximity among the previous reported haploinsufficient candidate genes (PIGG, CPLX1, CTBP1, LETM1) and disease genes associated with epilepsy suggests not just one, but different impaired mechanisms in cellular networks responsible for the balance of neuronal activity in WHS patients, from which neuron communication is the most impaired in WHS-related seizures. Furthermore, CTBP1 obtained the largest number of drug associations, reinforcing its importance for adaptations of brain circuits and its putative use as a pharmacological target for treating seizures/epilepsy in patients with WHS.

A practical approach to dental care for patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome is a polymalformative chromosomal disorder caused by a deletion in the distal region of the short arm of chromosome 4. The disease is considered rare (1/50,000 births) and predominantly affects females (2:1). In addition to the characteristic facial phenotype ("Greek warrior helmet"), its clinical manifestations include epilepsy, developmental and psychomotor delay, intellectual disability, cardiac and respiratory complications, and eating problems. The most prevalent oral manifestations are hypodontia, delayed tooth eruption, morphological dental abnormalities, dental malocclusions, cleft lip/palate and ogival palate. Based on our clinical experience, Wolf-Hirschhorn syndrome does not represent an absolute contraindication for any type of dental procedure. The feasibility of dental treatment will depend mainly on the degree of epilepsy control and on the level of collaboration, this latter conditioned by the severity of the intellectual disability and communication difficulties.

Hip displacement in Wolf-Hirschhorn syndrome: Report on three cases and review of associated musculoskeletal pathologies.

Wolf-Hirschhorn syndrome is a rare genetic disease caused by a chromosomal deletion of the distal short arm of Chromosome 4. It is associated with multisystem abnormalities, including delayed growth, characteristic facial features, epilepsy, and skeletal abnormalities. We report three patients who developed hip displacement, and describe the occurrence of delayed and nonunion in patients who underwent corrective proximal femoral osteotomy for hip displacement. We also performed a literature review identifying common musculoskeletal presentations associated with the condition. Patients with Wolf-Hirschhorn Syndrome are at risk of hip displacement (subluxation), and we would advocate annual hip surveillance in this patient group.

Nonossified cervical vertebrae in Wolf-Hirschhorn Syndrome: A case report.

RATIONALE: Wolf-Hirschhorn Syndrome (WHS) is a rare disorder caused by the loss of the distal part of the short arm of chromosome 4, and has various phenotypes depending on the deletion size. Although many articles report on urinary tract malformations or ophthalmologic abnormalities, there are few descriptions of the skeletal anomalies. This is an extremely rare case of cervical dysplasia in WHS. PATIENT CONCERNS: A 24-year-old pregnant woman was transferred to our hospital at 21 gestational weeks for intrauterine growth retardation and oligohydramnios and decided to preserve the pregnancy after evaluation. A female was born at full term by normal vaginal delivery, weighing 1791 g. The patient was suspected to have congenital dysplasia of the cervical vertebrae on the routine newborn chest radiograph, and cervical spine magnetic resonance imaging revealed nonossification of the C3 and C4 vertebral bodies. DIAGNOSIS: The newborn had the "Greek warrior helmet" face typical of WHS. A deletion was detected in the distal portion of the short arm of chromosome 4 (p 16.3) by fluorescence in situ hybridization analysis. INTERVENTIONS: She was hospitalized for nutritional management and congenital anomaly evaluation for a month before being discharged with rehabilitation and antiepileptic drugs. OUTCOMES: The patient has been readmitted with seizure attacks 5 times to date. At one year of age, she still shows severe head lag and feeding problems. Her last weight was below the 3rd centile. LESSONS: Although cervical dysplasia is a rarely reported morphology in WHS, it may provide artefacts for diagnosing WHS as cervical anomalies, unlike facial anomalies or developmental delays, are seldom found in congenital disease.

Severe congenital bilateral corneal ulceration due to Wolf-Hirschhorn syndrome: a case-report and review of the ophthalmic literature.

A newborn boy with genetically confirmed Wolf-Hirschhorn syndrome presented with severe bilateral corneal ulceration that required emergency surgical tarsorrhaphies and permanent lower punctal occlusion. The patient healed completely, with no recurrence over 18 months of follow-up.

Hepatic Malignancy in an Infant with Wolf-Hirschhorn Syndrome.

INTRODUCTION: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome involving deletions of the chromosome 4p16 region associated with growth failure, characteristic craniofacial abnormalities, cardiac defects, and seizures. CASE REPORT: This report describes a six-month-old girl with WHS with growth failure and typical craniofacial features who died of complex congenital heart disease. Genetic studies revealed a 9.8 Mb chromosome 4p-terminal deletion. At autopsy, the liver was grossly unremarkable. Routine sampling and histologic examination revealed two hepatocellular nodular lesions with expanded cell plates and mild cytologic atypia. Immunohistochemical staining revealed these nodules were positive for glutamine synthetase and glypican 3, with increased Ki-67 signaling and diffuse CD34 expression in sinusoidal endothelium. These findings are consistent with hepatoblastoma or hepatocellular carcinoma. CONCLUSIONS: A possible association between WHS and hepatic malignancy may be an important consideration in the care and management of WHS patients.

Retraso del crecimiento intrauterino de causa genética: síndrome de Wolf-Hirschhorn / Intrauterine growth retardation of genetic cause: Wolf-Hirschhorn syndrome

El síndrome de Wolf-Hirschhorn es una enfermedad genética rara provocada por la pérdida de material genético en el brazo corto del cromosoma 4. Los individuos afectos presentan un fenotipo característico con apariencia de 'casco de guerrero griego', retraso en el desarrollo y epilepsia. El pronóstico es desfavorable lo que condiciona la importancia de su detección prenatal. Presentamos un caso de síndrome de Wolf-Hirschhorn diagnosticado postnatalmente que en el período prenatal únicamente mostraba un retraso del crecimiento intrauterino severo y polihidramnios. El estudio genético, solicitado de manera urgente a las 33 semanas, señaló un cariotipo 46 XX normal. Destacamos la importancia del estudio genético molecular durante el período prenatal en los casos de retraso del crecimiento intrauterino severo, en los que se sospeche una cromosomopatía, de cara a confirmar el diagnóstico, establecer el pronóstico y realizar consejo genético a los progenitores (AU)

The Wolf-Hirschhorn syndrome is a rare genetic disease caused by the loss of genetic material in the short arm of chromosome 4. The affected individuals have a characteristic 'Greek warrior helmet'-like phenotype, a delay in the development and epilepsy. The prognosis is poor, which determines the importance of prenatal screening. We present a case of postnatally diagnosed Wolf-Hirschhorn syndrome, which during the prenatal period just showed a severe intrauterine growth restriction and polyhydramnios. The requested genetic study, performed urgently at 33 weeks, seemed to show a normal 46, XX karyotype. We stress the importance of the molecular genetic study during the prenatal period in severe intrauterine growth restriction cases where the existence of a genetic disease is suspected, in order to confirm the diagnosis, establish the prognosis and provide parents with genetic counseling (AU)

Neuroblastoma in a Child With Wolf-Hirschhorn Syndrome.

Neuroblastoma is the most common extracranial solid tumor of childhood originating from sympathetic nervous system cells. Neuroblastoma has also been diagnosed in conjunction with other congenital conditions such as Hirschsprung's disease, congenital hypoventilation disorder, and neurofibromatosis type 1. Wolf-Hirschhorn syndrome is a congenital disorder caused by microdeletion of short arm of chromosome 4 encoding MSX1 gene with characteristic facial features. We describe a child with dysmorphic features, developmental delay, mental retardation who developed neuroblastoma at 2 years of age and cytogenetic analysis of blood lymphocytes revealed an interstitial deletion of 4p(15,2). To best our knowledge, this report is the first report of neuroblastoma in a child with Wolf-Hirschhorn syndrome; and the reported association may be an important clue for oncological follow-up of patients with Wolf-Hirschhorn syndrome.

Successful treatment of migrating partial seizures in Wolf-Hirschhorn syndrome with bromide.

A girl with mild psychomotor developmental delay developed right or left hemiclonic convulsion at 10months of age. One month later, clusters of hemiclonic or bilateral tonic seizures with eyelid twitching emerged, resulting in status epilepticus. Treatment with phenobarbital and potassium bromide completely terminated the seizures within 10days. Ictal electroencephalography revealed a migrating focus of rhythmic 3-4Hz waves from the right temporal to right frontal regions and then to the left frontal regions. Genetic analysis was conducted based on the characteristic facial appearance of the patient, which identified a 2.1-Mb terminal deletion on chromosome 4p. This is the first case of Wolf-Hirschhorn syndrome complicated by epilepsy with migrating partial seizures.

[Wolf-Hirschhorn syndrome. A series of 27 patients: their epidemiological and clinical characteristics. The current situation of the patients and the opinions of their caregivers regarding the diagnostic process]. / Sindrome de Wolf-Hirschhorn. Serie de 27 pacientes: caracteristicas epidemiologicas y clinicas. Situacion actual de los pacientes y opinion de sus cuidadores respecto al proceso diagnostico.

INTRODUCTION: Wolf-Hirschhorn syndrome (WHS) is a chromosome pathology produced by a deletion in the distal region of the short arm of chromosome 4. It is characterised by the presence of a peculiar phenotype, delayed growth, delayed psychomotor development and epilepsy. AIMS: To describe the characteristics of a series of children with WHS, including the mean amount of time spent on reaching the diagnosis, and to evaluate the opinion of the families about the diagnostic process. PATIENTS AND METHODS: The researchers contacted the National WHS Association and, through them, contact was established with 29 families affected by the condition. Information was collected about the clinical features of the child and the opinion about the diagnostic process, and the families were asked to present medical reports that confirmed the information they had given. Once a database of information about the patients had been created, it was submitted to a statistical analysis. RESULTS: Information was obtained on 27 families. The mean age of the patients is currently 6.94 ± 6.37 years. The mean age of diagnosis was 14.34 months. Delayed intrauterine growth exists in 92.6% of the pregnancies. Epilepsy is present in 92.6% of patients, 44.4% of them in monotherapy. Delayed psychomotor/cognitive development exists in all the patients. Thirty-three per cent of them can walk unaided. The parents rated the treatment offered by physicians with a mean score of 7.25 ± 2.17 and the information they were provided with was given a score of 6.29 ± 2.11. CONCLUSIONS: No references have been found regarding the mean age of diagnosis for WHS. In our sample there are important variations in this respect, possibly influenced by the phenotype of the case and the doctor's own experience. The clinical characteristics are similar to the ones that were expected. The estimated degree of dependence is high and, in contrast, the quality of the information received by the family is low.

TITLE: Sindrome de Wolf-Hirschhorn. Serie de 27 pacientes: caracteristicas epidemiologicas y clinicas. Situacion actual de los pacientes y opinion de sus cuidadores respecto al proceso diagnostico.Introduccion. El sindrome de Wolf-Hirschhorn (SWH) es una cromosomopatia producida por una delecion en la region distal del brazo corto del cromosoma 4. Se caracteriza por la presencia de un fenotipo peculiar, retraso en el crecimiento, retraso del desarrollo psicomotor y epilepsia. Objetivos. Describir las caracteristicas de una serie de niños con SWH, incluido el tiempo medio empleado para el diagnostico, y valorar la opinion de las familias sobre el proceso diagnostico. Pacientes y metodos. Se contacto con la Asociacion Nacional de SWH y, a traves de ella, con 29 familias afectadas. Se recogio informacion sobre la clinica del niño y la opinion sobre el proceso diagnostico, y se solicitaron informes medicos que confirmaran la informacion facilitada. Constituida una base de datos de pacientes, se procedio a su analisis estadistico. Resultados. Se obtuvo informacion de 27 familias. Los pacientes presentan una edad media actual de 6,94 ± 6,37 años. La edad media de diagnostico fue de 14,34 meses. Existe retraso del crecimiento intrauterino en el 92,6% de los embarazos. Un 92,6% de los pacientes presenta epilepsia, el 44,4% de ellos en monoterapia. Existe retraso del desarrollo psicomotor/cognitivo en todos los pacientes. Camina sin ayuda el 33%. Los padres califican con una nota media de 7,25 ± 2,17 el trato ofrecido por los facultativos y de 6,29 ± 2,11 la informacion recibida. Conclusiones. No se han encontrado referencias a la edad media de diagnostico para el SWH. En nuestra muestra, existen variaciones importantes en este aspecto, posiblemente condicionadas por el fenotipo del caso y la experiencia del medico. Las caracteristicas clinicas son similares a las esperadas. El grado de dependencia estimado es alto y la calidad de la informacion recibida por la familia, baja.

Two cases of hepatic adenomas in patients with Wolf-Hirschhorn syndrome: a new rare complication?

Wolf-Hirschhorn syndrome (WHS) is a rare microdeletion syndrome associated with a characteristic facial appearance, failure to thrive, psychomotor delays, and various major malformations of internal organs; many medical complications have been described (feeding difficulties, epilepsy, hearing problems). Benign or malignant oncologic problems are not a typical feature of the natural history of these patients. We report on two patients with WHS patients in whom hepatic adenoma (HA) were diagnosed during adolescence. The clinical evolution of liver involvement was different between the two. We discuss the possibility of considering HA as a rare medical problem in the follow-up of WHS patients. © 2013 Wiley Periodicals, Inc.

Clinical and polygraphic improvement of breathing abnormalities after valproate in a case of Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome is a rare genetic form of severe psychomotor delay, caused by mutations in transcription cell factor-4 gene and characterized by distinctive dysmorphic features and abnormal breathing pattern. The current report describes the polygraphic features of the syndrome's typical breathing pattern in a patient both in wakefulness and in sleep. The control of these breathing alterations is important to prevent the neurological sequelae linked to chronic cerebral hypoxemia in early ages. No data are available on effective treatment options for breathing abnormalities of Pitt-Hopkins syndrome. The authors polygraphically documented a reduction of apneic and hypopneic phenomena, with a significant improvement in saturation values, after the introduction of sodium valproate.