Molecular confirmation of Wolf-Hirschhorn syndrome with a subtle translocation of chromosome 4.

Wolf-Hirschhorn syndrome is a clinically recognizable, multiple congenital anomaly syndrome usually associated with terminal deletion of the short arm of chromosome 4. A girl with clinical features of Wolf-Hirschhorn syndrome did not show an obvious deletion of chromosome 4, and a molecular defect was suspected. RFLPs of genomic DNA from the proband and her parents were studied using DNA probes from the distal region of chromosome 4p. Fluorescence in situ hybridization using a cosmid p847.351 containing the fragment 847 E-C was performed to investigate the possibility of a subtle translocation. Cytogenetic analyses done on the child and on both parents did not conclusively reveal abnormalities of chromosome 4. Molecular studies using two probes mapped to distal 4p showed the absence of the maternal haplotype in the child. These findings are thus consistent with a molecular deletion of 4p and confirm the diagnosis of Wolf-Hirschhorn syndrome. Cytogenetic experiments involving fluorescence in situ hybridization showed that the mother carried a subtle translocation between chromosomes 4 and 19, 46,XX,t(4,19)(p16.3; p13.3), which resulted in an unbalanced form in the child. Chorionic villus sampling for prenatal diagnosis in a subsequent pregnancy showed the fetus to be unaffected. This provides the first evidence, in chromosome 4p, of a molecular deletion due to a subtle, inherited translocation leading to the Wolf-Hirschhorn phenotype. Such subtle translocations may become an important mechanism for some recurrent genetic defects.     

Wolf-Hirschhorn (4p-)syndrome in a near adult with major depression; successful treatment with citalopram

The Wolf-Hirschhorn Syndrome (WHS) or 4p-deletion syndrome is characterized by mental retardation, growth retardation, microcephaly and typical facial features. In addition, a wide spectrum of somatic abnormalities can be associated that may cause comorbidity. The syndrome has been extensively described in children, but less information is available about adult patienis. In this case report a near adult female WHS patient is described who developed a major depression with atypical symptoms that was successfully treated with citalopram. Treatment for one year in the effective dose prevented recurrence of depressive symptomatology.     

Growth retardation in Wolf-Hirschhorn syndrome

Summary Postnatal growth records of 13 patients with Wolf-Hirschhorn syndrome indicate that the syndrome is associated with continuing severe growth retardation and marked microcephaly. In spite of severe retardation, these patients (with one exception) survived beyond infancy.     

Genetic and clinical studies in 13 patients with the Wolf-Hirschhorn syndrome [del(4p)]

Summary Clinical and cytogenetic studies are reported on 13 patients with Wolf-Hirschhorn syndrome. The oldest of the living twelve probands is 24 years of age. Three of these patients has a translocation involving the short arm of chromosome 4, and in one of these the anomalous chromosome was inherited from the father. Another three patients were believed, on the basis of GTG-staining, to have a translocation although the origin of the translocated chromatin could not be identified. In the remaining seven patients the anomalous chromosome appeared to be a simple deletion, although in two cases a translocation could not be reled out. Cytogenetic studies in these patients suggest that the critical deletion involved in Wolf-Hirschhorn syndrome is within 4p 16.Supported in part by Grant No. 286 from the Maternal and Child Health Service, United States Public Health Service.     

Wolf-Hirschhorn syndrome: A case demonstrated by a cytogenetic study

We present a case with a 4p terminal deletion, evidenced in GTG-banded chromosome study. Phenotypic signs described in the classical Wolf-Hirschhorn syndrome were found on clinical examination of our patient.     

1.5 Mb deletion of chromosome 4p16.3 associated with postnatal growth delay,psychomotor impairment,epilepsy, impulsive behavior and asynchronous skeletal development

Several Wolf-Hirschhorn syndrome patients have been studied, mouse models for a few candidate genes have been constructed and two WHS critical regions have been postulated, but the molecular basis of the syndrome remains poorly understood.     

Microdeletion 4p16.3 in three unrelated patients with Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome caused by partial monosomy of 4p16.3. Pitt-Rogers-Danks syndrome, first thought to be a distinct entity, is a similar condition associated with a microdeletion overlapping the WHS critical region. In this paper we evaluate three WHS patients showing a microdeletion of 4p and remarkable development with respect to the clinical spectrum of WHS.     

Wolf-Hirschhorn and Cri du Chat syndromes resulting from familial translocations: 3 further examples of the Bp monosomy epistatic effect

Two malformed newborns with the typical Wolf-Hirschhorn syndrome (WHS) resulting from familial balanced translocations t(4;11)(p153;p154) and t(4;18)(p152;q23) respectively, are presented. A third child with the Cri du Chat syndrome and der(5), t(2;5)(q333;p141) is reported. These three cases give further support to the epistatic hypothesis at the chromosomal level of the Bp monosomies over other partial autosomal trisomic syndromes.     

Wolf-Hirschhorn (4P-) syndrome in adults

Wolf-Hirschhorn syndrome (WHS) or 4p-deletion syndrome has been extensively described in children. Knowledge on adult WHS patients is still limited due to the small number of published cases. We present 4 adults and review the literature. The phenotype of adult WHS is in general similar to that of childhood WHS. Growth retardation, microcephaly and mental retardation are the rule in both adults and children. Facial dysmorphism also remains similar. The main difference lies in the absence of serious internal (cardiac) abnormalities in adult WHS. Mental retardation ranges from moderate to severe. The nosological overlap between WHS and Pitt-Rogers-Danks syndrome (PRDS) is discussed. More extensive data on adult WHS are needed for appropriate counselling of families with affected young children.     

De novo inv del(4) in an infant with the Wolf-Hirschhorn syndrome

An infant was found to have a de novo complex rearrangement of one chromosome 4. Her karyotype was interpreted as 46,XX,inv del(4)(pter::p16.3::q31.2----p15.2::q31.2----qter). Clinically she showed the features of the Wolf-Hirschhorn syndrome.     

Interstitial deletion of the short arm of chromosome 4. A phenotype distinct from the Wolf-Hirschhorn syndrome

In this paper we report a 3-month-old male newborn with marked hypotonia and an interstitial deletion of the short arm of chromosome 4 but with preservation of the 4p16 band (karyotype 46,XY,del(4)(pter----p15.3::p14----cen----qter). In contrast to patients with a pure 4p16 deletion this patient presented dysmorphic stigmata which were much more discrete than those found in the typical Wolf-Hirschhorn syndrome.     

The etiology of Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is defined by a collection of core characteristics, which include mental retardation, epilepsy, growth delay and cranio-facial dysgenesis. The disorder is caused by sub-telomeric deletions in the short arm of chromosome 4. The severity of the core characteristics is highly variable, and additional problems, including midline fusion defects, occur at lower frequency. Only one gene, WHSC1, is deleted in every case. However, recent evidence, from patient studies and mouse models, indicates that deletion of WHSC1 alone is insufficient for full-blown WHS. Instead a model is emerging in which deletion of WHSC1 is essential for pathogenesis, but deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems. In this article, we outline the progress being made in patient studies and in the development of mouse models, and relate the implications of this work for a broad group of sub-telomeric deletion syndromes.     

Microdeletion on 17p11.2 in a Smith-Magenis syndrome patient with mental retardation and congenital heart defect: first report from China

Smith-Magenis syndrome (SMS) is a rare syndrome with multiple congenital malformations, including development and mental retardation, behavioral problems and a distinct facial appearance. SMS is caused by haploinsufficiency of RAI1 (deletion or mutation of RAI1). We describe an eight-year-old female Chinese patient with multiple malformations, congenital heart defect, mental retardation, and behavioral problems (self hugging, sleeping disturbance). High-resolution genome wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in chromosome region 17p11.2. This chromosome region contains RAI1, a critical gene involved in SMS. To the best of our knowledge, this is the first report of an SMS patient in mainland China.     

Localization of the D5 dopamine receptor gene to human chromosome 4p15.1-p15.3, centromeric to the Huntington's disease locus.

Genes encoding G-protein-coupled receptors, including dopamine, serotonin, muscarinic cholinergic, and adrenergic receptors, play an important role in neurotransmission and may be involved in the pathophysiology of diseases such as Alzheimer's disease, Parkinson's disease, or Huntington's disease (HD). We mapped the gene encoding the D5 dopamine receptor (DRD5) to human chromosome 4p, an area implicated in HD and the Wolf-Hirschhorn syndrome, using gene-specific amplification with the polymerase chain reaction on a panel of somatic cell hybrids carrying different human chromosomes. Further localization of the DRD5 gene was carried out through the isolation and analysis of yeast artificial chromosomes, fluorescence in situ suppression hybridization to human metaphase chromosomes, and analysis of a panel of somatic cell hybrids subdividing human chromosome 4 into nine regions. The human DRD5 gene is located at 4p15.1-p15.33, centromeric to the location of the Huntington's disease locus although not in the obligate area containing the HD gene. The localization of the DRD5 gene to 4p15.1-p15.33 suggests the possibility that cis-position effects could be responsible for the altered D1-type dopamine receptor number observed in HD tissues or that the DRD5 gene could be a candidate for some of the abnormalities associated with the Wolf-Hirschhorn syndrome.     

Cytogenetic genotype-phenotype studies: improving genotyping, phenotyping and data storage

High-resolution molecular cytogenetic techniques such as genomic array CGH and MLPA detect submicroscopic chromosome aberrations in patients with unexplained mental retardation. These techniques rapidly change the practice of cytogenetic testing. Additionally, these techniques may improve genotype-phenotype studies of patients with microscopically visible chromosome aberrations, such as Wolf-Hirschhorn syndrome, 18q deletion syndrome and 1p36 deletion syndrome. In order to make the most of high-resolution karyotyping, a similar accuracy of phenotyping is needed to allow researchers and clinicians to make optimal use of the recent advances. International agreements on phenotype nomenclature and the use of computerized 3D face surface models are examples of such improvements in the practice of phenotyping patients with chromosomal anomalies. The combination of high-resolution cytogenetic techniques, a comprehensive, systematic system for phenotyping and optimal data storage will facilitate advances in genotype-phenotype studies and a further deconstruction of chromosomal syndromes. As a result, critical regions or single genes can be determined to be responsible for specific features and malformations.     

Three young children with Smith-Magenis syndrome: their distinct, recognisable behavioural phenotype as the most important clinical symptoms

We report on the development and behaviour of three young children with Smith-Magenis syndrome (SMS), del 17p11.2. The behaviour problems and the psychomotor delay in preschool children with SMS are often more striking than the dysmorphic features and can serve as a useful clue to the diagnosis. We compare the behaviour with reported data. The behaviour problems in the three four year olds include very demanding behaviour, severe temper tantrums, hyperactivity, aggressive behaviour, self injurious behaviour, sleeping problems and stereotypic behaviour. Head banging, hand, wrist or finger biting are present. Onychotyllomania is not observed. Insertion of objects in the mouth as well as excessive nose picking is very frequent, although polyembolokoilomania is not present. The so called self hug when excited is present in one child. The behaviour problems and psychomotor delay represent a major management problem for the parents.     

Sleeping Patterns of Afghan Unaccompanied Asylum-Seeking Adolescents: A Large Observational Study

Unaccompanied asylum-seeking children (UASC) have experienced multiple traumas and are a high-risk group for posttraumatic stress disorder (PTSD). The effects of trauma are known to be associated with sleep problems; indeed sleeping problems are core features of PTSD. However, there has been no systematic research examining the sleep of this high risk group of children. This study presents the first evidence on the sleeping patterns of Afghan UASC living in the UK. A total of 222 male Afghan children, aged 13–18, were interviewed using validated self-report questionnaires measuring sleeping patterns and PTSD. Overall, UASC patterns for bed time and rise time appear acculturated to the country of asylum. Mean UASC sleep onset latency scores were approximately 20 minutes greater compared with normative scores, which may be a reflection of UASC pre-migration and post-migration experiences. As expected, UASC who screened above the clinical cut-off for PTSD reported significantly greater sleep onset latency, increased nightmares, and less total sleep time compared to the non-PTSD group. The results may be of particular interest to clinicians given that, compared to screening for PTSD, screening for sleep problems may be a less culturally disputed form of initial assessment indicating distress in UASC. Similarly, the field of UASC and refugee child interventions is largely focused on trauma, yet sleep may provide a novel avenue for equally or more effective treatment.     

On the deletion 4p16 Wolf-Hirschhorn syndrome.

Two girls (aged 46 and 5 months) and one boy aged 5 months) were studied and found to have the Wolf-Hirschhorn syndrome. Chromosomal complement in all three cases implicated the deletion of the 4p16 band ; in two of them an extra segment of autosomal material was found to be translocated to 4p. Parents' karyotypes were normal. It is concluded that the expression of the 4p16 monosomy is stronger than that of some simultaneous partial trisomies.