Wolf-Hirschhorn Syndrome Research Articles

Lexical and gestural development in 5p deletion syndrome—A case report

PurposeIndividuals with 5p deletion syndrome (also known as cri du chat syndrome) have various speech and language problems. The aim of this work was to examine early gestural and lexical development in a boy with this syndrome and to see to what extent his skills in these areas were delayed and/or deviant when compared to typically developing children. MethodThe participant’s parents completed the Norwegian adaptation of the MacArthur-Bates Communicative Development inventories (CDI) ten times over a period of five years. His scores were compared to those of typically developing infants aged eight to 20 months. ResultsIt was found that the subject followed a considerably delayed, but not deviant, developmental trajectory in three areas, receptive vocabulary, productive vocabulary and communicative gestures, compared to typically developing infants and toddlers. ConclusionThe speech and language problems of individuals with 5p deletion syndrome, which have been documented in the domains of phonetics and phonology and grammar, also extend to gestural and lexical development. The findings of this study will have clinical implications for assessment, in that a broad assessment of gestural and lexical skills should be carried out as early as possible as a basis for interventions to improve communicative skills.

Reply to: The Spectrum of Movement Disorders in 18p Deletion Syndrome.

Reply to: The Spectrum of Movement Disorders in 18p Deletion Syndrome.

Refinement of the critical genomic region for hypoglycaemia in the Chromosome 9p deletion syndrome

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

Open traumatic distal femoral physeal fracture in a pediatric patient with tetrasomy 18p syndrome

Background. Because they are associated with a high energy mechanism, open distal femoral physeal fractures are rare injuries. Appropriate management of these injuries is critical in the pediatric population due to the increased risk of damage to the physis and subsequent growth disturbance and deformity after injury. Pediatric fractures may also represent the sequelae of genetic syndromes (particularly connective tissue disorders), nutritional abnormalities, or conditions that predispose to abnormal bone mineral density.
 Clinical case. In this case report, we present the case of a 9-year-old girl with tetrasomy 18p who presented with a grossly displaced right open distal femoral physeal fracture in the setting of isolated, lower extremity trauma. The patient underwent an irrigation and debridement, followed by an open reduction and cross-pinning through the distal femoral epiphysis. After the operation, the patient was made non-weight-bearing in a cast for 4 weeks, and at 6 weeks, the pins were removed. The patient had full range of motion at the 6-month follow-up and then resumed her preinjury level of play at school.
 Discussion. Tetrasomy 18p results in inherent muscle weakness that may interfere in the normal soft tissue sleeve of muscles stabilizing long bones. This may result in greater displacement of fractures sustained during trauma, which may lead to a greater rate of vascular injury, physeal injury, and poor overall prognosis. It is imperative for clinicians to be familiar with tetrasomy 18p and its associated orthopedic manifestations.
 Conclusion. There is scarce literature on the management of physeal fractures in patients with tetrasomy 18p. In the case described here, we report a good outcome with the standard of care using preoperative and postoperative antibiotics, irrigation and debridement, open fracture fixation, and immobilization in a cast postoperatively. The duration of non-weight-bearing was also increased by 1 week and the pins were removed 1 week later than we would have for patients without any bone or connective tissue disorders.

Breakpoint delineation in 5p- patients leads to new insights about microcephaly and the typical high-pitched cry.

BackgroundCri du chat syndrome (CdCS) is a rare syndrome caused by a partial or complete deletion of the short arm of chromosome 5 (5p‐). The main clinical features include a high‐pitched cry, facial asymmetry, microcephaly, round face at birth, epicanthal folds, hypotonia, delayed growth and development.MethodsWe studied 14 Brazilian patients with CdCS using genomic array in order to better define the 5p breakpoints and recognize copy number variations (CNVs) that contribute to clinical manifestations associated with the syndrome.ResultsArray confirmed terminal deletions in 13 patients and an interstitial deletion in one patient. It was also possible to map the breakpoints and associate a genomic region of 4.7 Mb to the development of head circumference and cat‐like cry. We also found other CNVs concomitant to the 5p deletion including a 9p duplication, a 17q deletion, and a 22q deletion in three different patients.ConclusionWith advancements of molecular cytogenomic methods in the last two decades, it was possible to evidence cryptic alterations and improve the genotype–phenotype correlation. In this work, we describe a new genomic region associated with microcephaly and cat‐like cry and highlight the importance of precise delineation of 5p deletion breakpoints and detection of other CNVs in CdCS patients to improve genotype–phenotype correlation to perform a complete clinical and molecular diagnosis.

High yield recombinant expression and purification of oncogenic NSD1, NSD2, and NSD3 with human influenza hemagglutinin tag

The nuclear receptor-binding SET Domain (NSD) family consists of NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 histone methyltransferases that are crucial for chromatin remodeling. NSDs are implicated in developmental disorders such as Wolf-Hirschhorn and Sotos syndromes as well as various cancers including t(4; 14)(p16; q32) myeloma, an incurable cancer in plasma cells. NSDs have been the target of intensive study to understand their biological functions more fully and inform anti-cancer drug design. Recombinant protein expression and purification of human NSDs using an E. coli expression system are notoriously challenging, but the production of pure, stable, and active NSDs is essential for further studies. To overcome production challenges, we propose a cost-efficient approach optimized to produce a high yield of NSDs using a modified E. coli expression system. We found that tagging the NSDs with a human influenza hemagglutinin (HA) tag greatly improved the quality of the recombinant NSDs, resulting in more than 95% pure, stable, and active NSD-HAs, with an increase in production yield up to 22.4-fold and up to 6.25 mg/L from LB E. coli culture, and without further purification such as ion-exchange or size-exclusion chromatography.

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 18months of follow-up.

Prenatal detection of 1p36 deletion syndrome: ultrasound findings and microarray testing results

Objective Only a small number of reports have been made on the prenatal ultrasound findings observed in 1p36 deletion syndrome. We explored prenatal diagnosis of 1p36 deletion by ultrasound as well as chromosomal microarray (CMA), and delineated the fetal presentation of this syndrome. Study design This was a retrospective analysis of 10 new prenatal cases of 1p36 deletion identified by CMA at a single Chinese medical center. Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, sonographic findings, CMA results and pregnancy outcomes. Results One case was diagnosed because of a positive cell-free DNA (cfDNA) testing result for terminal 1p deletion, and the remaining nine cases were identified because of an abnormal ultrasound findings, including early miscarriage, structural abnormalities and fetal growth restriction. CMA revealed 1p36 deletions to be terminal in six cases, and interstitial in four cases. Deletion sizes ranged from 1.7 to 42.7 Mb. Conclusions Prenatal findings such as cardiac malformations, especially Ebstein anomaly, and fetal growth retardation should warrant the diagnosis of 1p36 deletion and invasive genetic testing using CMA.

Clinical utility of noninvasive prenatal screening for expanded chromosome disease syndromes

PurposeTo assess the clinical performance of an expanded noninvasive prenatal screening (NIPS) test (“NIPS-Plus”) for detection of both aneuploidy and genome-wide microdeletion/microduplication syndromes (MMS). MethodsA total of 94,085 women with a singleton pregnancy were prospectively enrolled in the study. The cell-free plasma DNA was directly sequenced without intermediate amplification and fetal abnormalities identified using an improved copy-number variation (CNV) calling algorithm. ResultsA total of 1128 pregnancies (1.2%) were scored positive for clinically significant fetal chromosome abnormalities. This comprised 965 aneuploidies (1.026%) and 163 (0.174%) MMS. From follow-up tests, the positive predictive values (PPVs) for T21, T18, T13, rare trisomies, and sex chromosome aneuploidies were calculated as 95%, 82%, 46%, 29%, and 47%, respectively. For known MMS (n=32), PPVs were 93% (DiGeorge), 68% (22q11.22 microduplication), 75% (Prader–Willi/Angleman), and 50% (Cri du Chat). For the remaining genome-wide MMS (n=88), combined PPVs were 32% (CNVs ≥10Mb) and 19% (CNVs <10Mb). ConclusionNIPS-Plus yielded high PPVs for common aneuploidies and DiGeorge syndrome, and moderate PPVs for other MMS. Our results present compelling evidence that NIPS-Plus can be used as a first-tier pregnancy screening method to improve detection rates of clinically significant fetal chromosome abnormalities.

De novo truncating variant in NSD2gene leading to atypical Wolf-Hirschhorn syndrome phenotype

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.

Wolf-Hirschhorn syndrome. Description of five cases characterized by means of single nucleotide polymorphism microarrays

Wolf-Hirschhorn syndrome is a polymalformative entity due to the microdeletion in the distal region of the short arm of chromosome 4 (4p16.3), which produces a series of clinical manifestations that can vary depending on the type and size of the genetic defect in this contiguous gene syndrome. Five patients are presented, three of them female, all with the primary clinical findings, characterized by "Greek warrior helmet appearance" facial feature, growth retardation and psychomotor development delay. In addition to the partial deletion in the distal region of the short arm of chromosome 4, two additional genetic alterations were found in two patients, through the use of single nucleotide polymorphism arrays. The clinical characteristics of Wolf-Hirschhorn syndrome are highlighted in order to guide the diagnosis, provide interdisciplinary medical care and, through its confirmation, provide adequate family genetic counseling.

Partial Monosomy 4p and Trisomy 12q due to a t(4;12)(p16.3;q24.31) Familial Translocation in Two Cousins

Wolf-Hirschhorn syndrome (WHS) is caused by a distal 4p monosomy usually involving the region of the WHSC1 and WHSC2 genes. About 40-45% of WHS patients show an unbalanced translocation leading to both 4p monosomy and partial trisomy of another chromosome arm. In this case report, we describe 2 female cousins (P1 and P2) with a derivative chromosome leading to a 4p16.3pter deletion and 12q24.31qter duplication. Conventional karyotyping and genomic analyses showed that they both had the same rearrangement derived from a balanced parental translocation involving chromosomes 4 and 12, t(4;12)(p16.3;q24.31). The rearrangements occurred between 4p16.3pter and 12q24.31qter detected by array-CGH analysis, with a 2.7-Mb loss at 4p and a large 12.4-Mb gain at 12q. Both affected patients shared global developmental delay and craniofacial dysmorphisms with some distinct phenotypic findings associated with both WHS and 12qter trisomy. P2 was more severely impaired than P1, and she showed severe intellectual disability, seizures, midface hypoplasia, unilateral microtia, and deafness which were absent in P1. Previous studies of distal 4p monosomies have found phenotypic variability in WHS which does not correlate with haploinsufficiency of specific genes. Features of 12q trisomies are diverse with developmental and growth delay, intellectual disability, behavioral problems, and facial abnormalities. Collectively, our analysis of the literature of 3 similar translocations involving 4p and 12q, together with the clinical features of the affected cousins in this familial translocation, permits an evaluation of genes closely linked to WHSC1 and WHSC2 in the context of WHS and the genes involved in 12q trisomy.

A Scalable Platform for Producing Recombinant Nucleosomes with Codified Histone Methyltransferase Substrate Preferences

Wolf-Hirschhorn Syndrome Candidate 1 (WHSC1; also known as NSD2) is a SET domain-containing histone lysine methyltransferase. A chromosomal translocation occurs in 15–20% of multiple myeloma patients and is associated with increased production of WHSC1 and poor clinical prognosis. To define the substrate requirements of NSD2, we established a platform for the large-scale production of recombinant polynucleosomes, based on authentic human histone proteins, expressed in E. coli, and complexed with linearized DNA. A brief survey of methyltransferases whose substrate requirements are recorded in the literature yielded expected results, lending credence to the fitness of our approach. This platform was readily ‘codified’ with respect to both position and extent of methylation at histone 3 lysines 18 and 36 and led to the conclusion that the most readily discernible activity of NSD2 in contact with a nucleosome substrate is dimethylation of histone 3 lysine 36. We further explored reaction mechanism, and conclude a processive, rather than distributive mechanism best describes the interaction of NSD2 with intact nucleosome substrates. The methods developed feature scale and flexibility and are suited to thorough pharmaceutical-scale drug discovery campaigns.

Prenatal diagnosis for a pedigree affected with Wolf-Hirschhorn syndrome due to a subtle chromosomal translocation

To make molecular diagnosis of an infant affected with severe developmental delay and multiple birth defects, assisting prenatal diagnosis for the second pregnancy. Standard G-banded karyotyping was performed for the fetus and his parents. Single nucleotide polymorphism array (SNP array) was used to detect submicroscopic chromosomal aberration. Fluorescence in situ hybridization (FISH) was employed to determine the parental origin of the aberration. Both the proband and the fetus harbored a 5.4 Mb distal 4p deletion and a 6.9 Mb distal 6q duplication. FISH confirmed that the mother has carried a balanced translocation involving 4p and 6q. The unbalanced chromosomal aberration in the proband and the fetus were both derived from the mother. Both patients showed a Wolf-Hirschhorn syndrom phenotype and partial phenotype of 6q trisomy. SNP array combined with FISH are essential for the detection of cryptic chromosomal aberrations which may be missed by coventional karyotyping analysis.

Prenatal findings in 1p36 deletion syndrome: New cases and a literature review.

1p36 deletion syndrome is considered to be the most common deletion after 22q11.2 deletion. It is characterized by specific facial features, developmental delay, and organ defects. The primary objective of the present multicenter study was to survey all the cases of 1p36 deletion diagnosed prenatally by French cytogenetics laboratories using a chromosomal microarray. We then compared these new cases with the literature data. Ten new cases were reported. On average, the 1p36 deletion was diagnosed at 19weeks of gestation. The size of the deletion ranged from 1.6 to 16Mb. The 1p36 deletion was the only chromosomal abnormality in eight cases and was associated with a complex chromosome 1 rearrangement in the two remaining cases. The invasive diagnostic procedure had always been prompted by abnormal ultrasound findings: elevated nuchal translucency, structural brain abnormality, retrognathia, or a cardiac defect. Multiple anomalies were present in all cases. We conclude that 1p36 deletion is not associated with any specific prenatal signs. We suggest that a prenatal observation of ventriculomegaly, congenital heart defect, or facial dysmorphism should prompt the clinician to consider a diagnosis of 1p36 deletion syndrome.

ABORDAGEM FISIOTERAPÊUTICA PELO CONCEITO NEUROEVOLUTIVO BOBATH NA SÍNDROME CRI DU CHAT: ESTUDO DE CASO

Cri du Chat Syndrome (CDCS) is a genetic disease that results from an extremely small deletion (5p15.2) or a deletion of the entire short arm of the chromosome (5p). It is a rare disease, with an incidence of 1/15000 to 1/50000 live births, with a higher prevalence in females. The clinical manifestations are characterized by typical crying, known as meowing of cat, inferior deviation of the extremities of the lips, rounded face, height and weight below the standards, wide nasal bridge, epicanthic folds, ears with low implantation, hypotonia, hypertelorism, microretrognatism and delayed psycho-motor development. The treatment is based on early rehabilitation, in which physiotherapy works to prevent complications and to correct deformities. Thus, the objective of this study was to verify the efficacy of the Bobath Concept contribution in the treatment of patients with CDCS. The case study was done with a 4-year-old female child with a confirmed diagnosis by genetic screening. The patient was submitted to the evaluation through the Denver Test and Pediatric Disability Assessment (PEDI) protocols. The intervention was performed in 20 sessions at the physical therapy clinic of ANPR in Maringá-PR, for 30 minutes, with repetitions of 2 times a week, totaling 2 months of treatment, through the Bobath Concept. Motor stimulation was performed in the patient according to their needs. The results show that the treatment through the physiotherapeutic approach, using the Bobath Concept can improve the child's motor development, promoting her independence.

The Many Faces of Xenopus: Xenopus laevis as a Model System to Study Wolf-Hirschhorn Syndrome.

Wolf–Hirschhorn syndrome (WHS) is a rare developmental disorder characterized by intellectual disability and various physical malformations including craniofacial, skeletal, and cardiac defects. These phenotypes, as they involve structures that are derived from the cranial neural crest, suggest that WHS may be associated with abnormalities in neural crest cell (NCC) migration. This syndrome is linked with assorted mutations on the short arm of chromosome 4, most notably the microdeletion of a critical genomic region containing several candidate genes. However, the function of these genes during embryonic development, as well as the cellular and molecular mechanisms underlying the disorder, are still unknown. The model organism Xenopus laevis offers a number of advantages for studying WHS. With the Xenopus genome sequenced, genetic manipulation strategies can be readily designed in order to alter the dosage of the WHS candidate genes. Moreover, a variety of assays are available for use in Xenopus to examine how manipulation of WHS genes leads to changes in the development of tissue and organ systems affected in WHS. In this review article, we highlight the benefits of using X. laevis as a model system for studying human genetic disorders of development, with a focus on WHS.

Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy.

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

Skin picking disorder in 97 Italian and Spanish Cri du chat patients.

Skin picking (SP) disorder is characterized by recurrent SP resulting in skin lesions. Several studies estimated its prevalence as approximately 2-4 % of the general population. It is also present in a high percentage of patients with intellectual and developmental disabilities, such as Cri du chat (CdC) syndrome, a rare genetic disorder caused by variable size deletions of the short arm of chromosome 5. The aim of this study was to evaluate, in 97 patients with CdC syndrome, the following data: frequency of SP, patient's age at onset, type, and topographic-anatomic distribution of the lesions presented. The results show that 85% of patients confirm a SP disorder, usually concentrated on the hands, fingers, and the face, with onset between 6 and 10 years of age, regardless of patient's sex. Evidence for early appearance of SP behavior, high prevalence in stressful circumstances, and efficacy of distracting actions immediately suggest the possibility that proper parental information about SP behavior and parental education concerning the methods to deal with this problem may result in its efficient reduction already in childhood.

Beyond the Phenotype: A Pediatric Case Series of Seizure and EEG Characteristics in Wolf-Hirschhorn Syndrome

AbstractWolf-Hirschhorn syndrome (WHS) is a rare genetic syndrome caused by deletion of a portion of the short arm of chromosome 4 (del 4p16.3). Aside from the many phenotypic abnormalities common in WHS, seizures are seen in the vast majority of the patients and are a potentially treatable cause of significant morbidity especially in the younger age group. Currently, however, little information is available regarding the associated seizure phenotypes, electroencephalographic (EEG) features, and seizure/epilepsy outcomes. This case series highlights the seizure phenotypes and EEG findings in three patients with WHS.