Features of the Wolf-Hirschhorn Syndrome (WHS) from Infant to Young Teenager.
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ABSTRACT:
SUBMITTER: Popescu DE
PROVIDER: S-EPMC10413881 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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Features of the Wolf-Hirschhorn Syndrome (WHS) from Infant to Young Teenager.
Popescu D E DE Marian D D Zeleniuc M M Samoila Ch C Belengeanu V V
Balkan journal of medical genetics : BJMG 20230731 1
Wolf-Hirschhorn syndrome is a rare condition caused by terminal deletions, of variable size, in the short arm of chromosome 4. The syndrome displays the combination of typical morphological facial variations, intellectual disability, language delay, and various malformations. This report describes the clinical aspect and developmental evolution of a male patient with Wolf-Hirschhorn syndrome, from infancy to adolescence. The patient was first examined and diagnosed at 11 months, with follow-up a ...[more]
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Project description:In an attempt to define the distinctive Wolf-Hirschhorn syndrome (WHS) phenotype, and to map its specific clinical manifestations, a total of eight patients carrying a 4p16.3 microdeletion were analyzed for their clinical phenotype and their respective genotypes. The extent of each individual deletion was established by fluorescence in situ hybridization, with a cosmid contig spanning the genomic region from MSX1 (distal half of 4p16.1) to the subtelomeric locus D4S3359. The deletions were 1.9-3.5 Mb, and all were terminal. All the patients presented with a mild phenotype, in which major malformations were usually absent. It is worth noting that head circumference was normal for height in two patients (those with the smallest deletions [1.9 and 2.2 Mb]). The currently accepted WHS critical region (WHSCR) was fully preserved in the patient with the 1.9-Mb deletion, in spite of a typical WHS phenotype. The deletion in this patient spanned the chromosome region from D4S3327 (190 b4 cosmid clone included) to the telomere. From a clinical point of view, the distinctive WHS phenotype is defined by the presence of typical facial appearance, mental retardation, growth delay, congenital hypotonia, and seizures. These signs represent the minimal diagnostic criteria for WHS. This basic phenotype maps distal to the currently accepted WHSCR. Here, we propose a new critical region for WHS, and we refer to this region as "WHSCR-2." It falls within a 300-600-kb interval in 4p16.3, between the loci D4S3327 and D4S98-D4S168. Among the candidate genes already described for WHS, LETM1 (leucine zipper/EF-hand-containing transmembrane) is likely to be pathogenetically involved in seizures. On the basis of genotype-phenotype correlation analysis, dividing the WHS phenotype into two distinct clinical entities, a "classical" and a "mild" form, is recommended for the purpose of proper genetic counseling.
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Project description:BackgroundWolf-Hirschhorn Syndrome (WHS) is a rare, congenital disease characterized by a distinctive facial phenotype, seizures, intellectual disability and developmental delay, and pre and postnatal growth requiring lifelong care. The psychosocial status of the family caregivers of children diagnosed with WHS is unknown. This study aims to characterize the sociodemographic and psychosocial profile of WHS caregivers and analyze how these variables impact their quality of life (QoL) and well-being.ResultsThe sociodemographic and clinical profile of 22 Spanish caregivers of children with WHS and the characteristics of those affected have been described. Significant relationships were found between sociodemographic and psychosocial characteristics among caregivers. The impact on the parents' QoL and negative relationship with the symptomatology were assessed. The use of engagement strategies such as problem focused coping was associated with improved psychological QoL and social support.ConclusionsWHS caregivers share similarities in their profile and needs with caregivers of children with other rare diseases. Pychosocial support groups involving parents caring for children with the same disease could improve caregivers' well-being and QoL by strengthening their social support network and using positive coping styles.
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Project description:Complex, and sometimes intractable, seizures affect the quality of life and cognitive development of over 90% of individuals with Wolf-Hirschhorn syndrome (WHS). Fine resolution genotype-phenotype mapping of the WHS locus recently identified a candidate gene whose probable function has led to insights into a mechanism connecting WHS seizures with those of Dravet syndrome, a distinct condition caused by mutations in SCN1A and SCN1B. In addition to this possible molecular mechanistic connection, these disorders' seizures share a strikingly similar constellation of features, including clinical presentation, seizure types, early age of onset, EEG pattern, and responses to specific anti-epileptic drugs. Based in part on these similarities, we suggest that a highly successful Phase III clinical trial of a formulation of cannabidiol for Dravet syndrome seizures may be directly translatable into possible benefits for WHS individuals with challenging seizure patterns. © 2016 Wiley Periodicals, Inc.
| S-EPMC6585685 | biostudies-literature
Project description:Wolf-Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf-Hirschhorn syndrome facial phenotype.
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Project description:BackgroundWolf-Hirschhorn syndrome (WHS) is a common genetic condition and prenatal diagnosis is difficult due to heterogeneous expression of this syndrome and rather non-specific ultrasound findings. Objective of this study was to examine the prenatal ultrasound findings in fetuses with Wolf-Hirschhorn syndrome (WHS).MethodsRetrospective assessment of 18 pregnancies that were seen at three tertiary referral centers (Universities of Bonn, Tuebingen and Nuernberg / Germany). Findings of prenatal ultrasound examinations, genetic results and outcome were compared. Additionally, findings of our study were compared to previous small case series from the literature and then compared to data on postnatal frequencies and abnormalities in affected patients.ResultsMedian gestational age at the time of examination was 23 + 1 weeks' (range: 13 + 4 to 29 + 1 weeks') with female-to-male ratio of > 2.5:1. Most frequent ultrasound findings were facial abnormalities, symmetric IUGR and microcephaly that presented in 94.4, 83.3 and 72.2% of cases, respectively. The combination of microcephaly and hypoplastic nasal bone was a particularly characteristic finding. Growth retardation presented in all fetuses > 20 weeks, but not below. Other frequent abnormalities included cardiac anomalies in 50 and single umbilical artery (SUA) in 44.4% of fetuses.ConclusionWHS should be considered in the presence of symmetric IUGR together with microcephaly, hypoplastic nasal bone and facial abnormalities on prenatal ultrasound. Genetic testing by chromosomal microarray analysis (CMA) is strongly recommended in this context.
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Project description:Wolf-Hirschhorn syndrome (WHS) is a rare disease caused by deletion in the distal moiety of the short arm of chromosome 4. The objectives of this study were to report the most representative oral findings of WHS, relate them with other clinical characteristics of the disease, and establish possible phenotype-genotype correlation. The study was conducted at 6 reference centers distributed throughout Spain during 2018-2019. The study group consisted of 31 patients with WHS who underwent a standardized oral examination. Due to behavioral reasons, imaging studies were performed on only 11 of the children 6 years of age or older. All participants had previously undergone a specific medical examination for WHS, during which anatomical, functional, epilepsy-related, and genetic variables were recorded. The most prevalent oral manifestations were delayed tooth eruption (74.1%), bruxism (64.5%), dental agenesis (63.6%), micrognathia (60.0%), oligodontia (45.5%), and downturned corners of the mouth (32.3%). We detected strong correlation between psychomotor delay and oligodontia (p = 0.008; Cramér's V coefficient, 0.75). The size of the deletion was correlated in a statistically significant manner with the presence of oligodontia (p = 0.009; point-biserial correlation coefficient, 0.75). Certain oral manifestations prevalent in WHS can form part of the syndrome's phenotypic variability. A number of the characteristics of WHS, such as psychomotor delay and epilepsy, are correlated with oral findings such as oligodontia and bruxism. Although most genotype-phenotype correlations are currently unknown, most of them seem to be associated with larger deletions, suggesting that some oral-facial candidate genes might be outside the critical WHS region, indicating that WHS is a contiguous gene syndrome.
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Project description:Wolf-Hirschhorn syndrome is characterized by severe growth and mental retardation, microcephaly, seizures and 'Greek helmet' facies, caused by partial deletion of the short arm of chromosome 4. Growth charts are given from 0-4 years of age, based on the study of 101 individuals. Use of these specific growth charts is recommended, because standard growth charts are inapplicable for patients with WHS.
| S-EPMC2413080 | biostudies-other
Project description:ObjectiveWolf-Hirschhorn syndrome (WHS) is a congenital malformation syndrome with poor prognosis. It is associated with a heterozygous deletion of chromosome 4p16.3. Adequate knowledge of prenatal phenotypes and proper prenatal counseling are essential for intrauterine diagnosis.MethodWe retrospectively analyzed 11 prenatal cases of WHS diagnosed using low-depth whole-genome sequencing (copy number variation sequencing) performed at our hospital from May 2017 to September 2022 and reviewed their prenatal ultrasound reports in detail. We also analyzed WHS cases (including prenatal and postnatal) with abnormal prenatal ultrasound findings in the published literature over the past 20 years.ResultsAmong the 11 fetuses with a prenatal diagnosis of WHS in our hospital, four cases showed abnormal prenatal ultrasound findings, including shrunken kidneys, ventricular septal defect, a small stomach, fetal growth restriction (FGR), enlarged posterior fossa, and soft ultrasonic markers. Our four cases were combined with 114 published WHS cases with prenatal ultrasound abnormalities from other medical institutions. Of the 118 cases, 59.3% (70 of 118) were multiple malformations. The most frequent ultrasound features observed in all 118 cases were FGR (76.3%, 90 of 118), followed by facial anomalies (28.8%, 34 of 118), central nervous system anomalies (27.1%, 32 of 118), and soft ultrasound markers (23.7%, 28 of 118). Other less common phenotypes included cardiac anomalies (19.5%, 23 of 118), genitourinary anomalies (19.5%, 23 of 118), increased NT/NF (12.7%, 15 of 118), skeletal anomalies (11.9%, 14 of 118), a single umbilical artery (10.2%, 12 of 118), gastrointestinal anomalies (9.3%, 11 of 118), oligohydramnios (8.5%, 10 of 118), cystic hygroma (5.1%, six of 118), hydrops/pleural effusion/ascites (2.5%, three of 118), and polyhydramnios (2.5%, three of 118).ConclusionThis study improved our understanding of the prenatal presentation of WHS by analyzing prenatal ultrasound abnormalities. The timely identification of prenatal ultrasound abnormalities can provide accurate consultation for pregnant women, improve the prenatal detection of WHS, and enable early prenatal management and intervention of WHS.
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Project description:BackgroundWolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome caused by partial 4p deletion highly variable in size in individual patients. The core WHS phenotype is defined by the association of growth delay, typical facial characteristics, intellectual disability and seizures. The WHS critical region (WHSCR) has been narrowed down and NSD2 falls within this 200 kb region. Only four patients with NSD2 variants have been documented with phenotypic features in detail.Case presentationHerein, we report the case of a 12-year-old boy with developmental delay. He had dysmorphic facial features including wide-spaced eyes, prominent nasal bridge continuing to forehead, abnormal teething and micrognathia. He also had mild clinodactyly of both hands. Using whole-exome sequencing, we identified a pathogenic mutation in NSD2 [c.4029_4030insAA, p.Glu1344Lysfs*49] isolated from peripheral blood DNA. Sanger confirmation of this variant revealed it as a de novo truncating variant in the family.ConclusionHere, we reported a boy with de novo truncating variant in NSD2 with atypical clinical features comparing with 4p16.3 deletion related WHS. Our finding further supported the pathogenesis of truncating variants in NSD2 and delineated the possible symptom spectrum caused by these variants.
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Project description:Deletions in the 4p16.3 region are associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome involving variable size deletions. In this study, we perform a cytogenomic integrative analysis combining classical cytogenetic methods, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and systems biology strategies, to establish the cytogenomic profile involving the 4p16.3 critical region and suggest WHS-related intracellular cell signaling cascades. The cytogenetic and clinical patient profiles were evaluated. We characterized 12 terminal deletions, one interstitial deletion, two ring chromosomes, and one classical translocation 4;8. CMA allowed delineation of the deletions, which ranged from 3.7 to 25.6 Mb with breakpoints from 4p16.3 to 4p15.33. Furthermore, the smallest region of overlapping (SRO) encompassed seven genes in a terminal region of 330 kb in the 4p16.3 region, suggesting a region of susceptibility to convulsions and microcephaly. Therefore, molecular interaction networks and topological analysis were performed to understand these WHS-related symptoms. Our results suggest that specific cell signaling pathways including dopamine receptor, NAD+ nucleosidase activity, and fibroblast growth factor-activated receptor activity are associated with the diverse pathological WHS phenotypes and their symptoms. Additionally, we identified 29 hub-bottlenecks (H-B) nodes with a major role in WHS.
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