Cognitive-Behavioral Profile in Pediatric Patients with Syndrome 5p-; Genotype-Phenotype Correlationships.

(1) Background: 5p minus Syndrome (S5p-) is a neurodevelopmental disorder caused by a deletion in the short arm of chromosome 5. Among the phenotypic characteristics of S5p-, the most characteristic and representative element is a monochromatic cry with a high-pitched tone reminiscent of a cat's meow. Individuals may also show great phenotypic heterogeneity and great genetic variability. Regarding cognitive-behavioral aspects of the syndrome, the studies are scarce and do not establish a general profile of the main cognitive-behavioral particularities that this syndrome presents. The main objective of this work was to describe the development profile of a cohort of 45 children with 5p minus Syndrome, concerning the biomedical, genetic, cognitive, and behavioral aspects. Establishing putative genotype-phenotype (cognitive-behavioral profiles) relationships in our cohort, from an interdisciplinary approach. (2) Methods: A selection of instruments of measures was selected for neuropsychological assessment (3) Results: In general, children with S5p- have a higher cognitive level than a communicative and motor level. Language difficulties, especially expressive ones, influence the frequency and severity of the most frequent behavioral problems in S5p. The most significant problem behavior of children with S5p-, especially girls, is self-harm. Compulsive behavior, limited preferences, and interest in monotony are significantly more frequent in subjects with better cognitive levels. We also find a significant correlation between the size of the loss of genetic material on 5p and the cognitive level of the subjects. (4) Conclusions: We described for the first time, the cognitive-behavioral profile of a cohort of minors with S5p-. Remarkably, it was found that language, especially of an expressive nature, modulates the most frequent behavioral aspects in subjects with lower cognitive levels, so it is essential to develop verbal or alternative communication strategies adjusted to these individuals.

[Prenatal diagnosis for a fetus with 5p deletion syndrome].

OBJECTIVE: To explore the genetic basis for a fetus with club foot detected upon mid-pregnancy ultrasonography. METHODS: Amniotic fluid of the fetus and peripheral blood samples of its parents were collected and subjected to G-banding karyotype analysis and copy number variation sequencing (CNV-seq). The result was verified by fluorescence in situ hybridization (FISH). RESULTS: The fetus and its parents all had a normal karyotype. CNV-seq analysis revealed that the fetus has harbored a 23.12 Mb on chromosome 5 and a 21.46 Mb duplication on chromosome 7. FISH assay has verified that its mother has carried a cryptic t(5;7)(p14.3;q33) translocation. CONCLUSION: CNV-seq combined with FISH can effectively detect cryptic chromosome aberrations, and can help to reduce severe birth defects and provide a basis for prenatal genetic counseling.

Prenatal diagnosis for a fetus with 5p deletion syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with club foot detected upon mid-pregnancy ultrasonography.@*METHODS@#Amniotic fluid of the fetus and peripheral blood samples of its parents were collected and subjected to G-banding karyotype analysis and copy number variation sequencing (CNV-seq). The result was verified by fluorescence in situ hybridization (FISH).@*RESULTS@#The fetus and its parents all had a normal karyotype. CNV-seq analysis revealed that the fetus has harbored a 23.12 Mb on chromosome 5 and a 21.46 Mb duplication on chromosome 7. FISH assay has verified that its mother has carried a cryptic t(5;7)(p14.3;q33) translocation.@*CONCLUSION@#CNV-seq combined with FISH can effectively detect cryptic chromosome aberrations, and can help to reduce severe birth defects and provide a basis for prenatal genetic counseling.

[Neonatal cri-du-chat syndrome revelead by facial dysmorphism and weak suction: a case report]. / Syndrome de cri du chat révélé par une dysmorphie cranio-faciale et faible succion chez un nouveau-né: à propos d'un cas.

Cri-du-chat syndrome is a rare genetic disorder, due to a deletion of the short arm of chromosome 5 (5p-). Its incidence is ranging from 1/15000 to 1/50000 live births. This was a one-day-old male newborn from a non-consanguineous marriage, the first pregnancy uncomplicated and carried to term with a birth weight of 2295g. Clinical examination revealed: craniofacial dysmorphism with hypertelorism and microcephaly, hypotonia, poor suction and clubfoot more marked on the right, the rest of the examination was unremarkable. During hospitalization, a high-pitched monochromatic cry mimicking a cat's meow was observed. The clinical diagnosis was confirmed by fluorescence in situ hybridization, showing a deletion of the short arm of chromosome 5 (5p15.2). The basic malformative work-up came back without any other abnormalities. The association of a high-pitched monochromatic cry with craniofacial dysmorphism in a newborn should indicate the need for cytogenetic study, in particular fluorescence in siti hybridization.

Long-Term Follow-Up on Bilateral Posterior Hypothalamic Deep Brain Stimulation for Treating Refractory Aggressive Behavior in a Patient with Cri du Chat Syndrome: Analysis of Clinical Data, Intraoperative Microdialysis, and Imaging Connectomics.

Posterior hypothalamic-deep brain stimulation (pHyp-DBS) has been reported as a successful treatment for reducing refractory aggressive behaviors in patients with distinct primary diagnoses. Here, we report on a patient with cri du chat syndrome presenting severe self-injury and aggressive behaviors toward others, who was treated with pHyp-DBS. Positive results were observed at long-term follow-up in aggressive behavior and quality of life. Intraoperative microdialysis and imaging connectomics analysis were performed to investigate possible mechanisms of action. Our results suggest the involvement of limbic and motor areas and alterations in main neurotransmitter levels in the targeted area that are associated with positive results following treatment.

Cri du chat syndrome patients have DNA methylation changes in genes linked to symptoms of the disease.

BACKGROUND: Cri du chat (also called 5p deletion, or monosomy 5p) syndrome is a genetic disease caused by deletions of various lengths in the short (p) arm of chromosome 5. Genetic analysis and phenotyping have been used to suggest dose-sensitive genes in this region that may cause symptoms when a gene copy is lost, but the heterogeneity of symptoms for patients with similar deletions complicates the picture. The epigenetics of the syndrome has only recently been looked at with DNA methylation measurements of blood from a single patient, suggesting epigenetic changes in these patients. Here, we conduct the deepest epigenetic analysis of the syndrome to date with DNA methylation analysis of eight Cri du chat patients with sibling- and age-matched controls. RESULTS: The genome-wide patterns of DNA methylation in the blood of Cri du chat patients reveal distinct changes compared to controls. In the p-arm of chromosome 5 where patients are hemizygous, we find stronger changes in methylation of CpG sites than what is seen in the rest of the genome, but this effect is less pronounced in gene regulatory sequences. Gene set enrichment analysis using patient DNA methylation changes in gene promoters revealed enrichment of genes controlling embryonic development and genes linked to symptoms which are among the most common symptoms of Cri du chat syndrome: developmental delay and microcephaly. Importantly, this relative enrichment is not driven by changes in the methylation of genes on chromosome 5. CpG sites linked to these symptoms where Cri du chat patients have strong DNA methylation changes are enriched for binding of the polycomb EZH2 complex, H3K27me3, and H3K4me2, indicating changes to bivalent promoters, known to be central to embryonic developmental processes. CONCLUSIONS: Finding DNA methylation changes in the blood of Cri du chat patients linked to the most common symptoms of the syndrome is suggestive of epigenetic changes early in embryonic development that may be contributing to the development of symptoms. However, with the present data we cannot conclude about the sequence of events between DNA methylation changes and other cellular functions-the observed differences could be directly driving epigenetic changes, a result of other epigenetic changes, or they could be a reflection of other gene regulatory changes such as changed gene expression levels. We do not know which gene(s) on the p-arm of chromosome 5 that causes epigenetic changes when hemizygous, but an important contribution from this work is making the pool of possible causative genes smaller.

Quantitative evaluation of treatment response to lenalidomide by applying fluorescence in situ hybridization for peripheral blood granulocytes in a patient with 5q- syndrome.

The introduction of lenalidomide has significantly improved clinical outcomes in myelodysplastic syndrome (MDS) with isolated interstitial deletion of the long arm of chromosome 5 (del(5q)) (5q- syndrome). These days, MDS with isolated del(5q) includes cases with one additional chromosome abnormality other than monosomy 7 or del(7q), and so we need a better way to monitor tumor cells in each patient than the clinical parameters used to date. An 82-year-old woman with MDS with isolated del(5q) was treated with lenalidomide daily for 21 days in a 4-week cycle. Fluorescence in situ hybridization with CSF1R located at 5q was applied to the peripheral blood samples. Because mature lymphocytes are not involved in the MDS clone, based on the nuclear morphology, polymorphonuclear cells (PMNs) and round-shaped nuclear cells (RSNs) were separately evaluated during treatment. After a single course of treatment, the number of PMNs with del(5q) decreased; by the end of the second course of treatment, both PMNs and RSNs with del(5q) had disappeared. The dynamics of 5q- PMNs is a simple but rapid and reliable indicator to confirm the effect of lenalidomide in MDS with del(5q).

Novel rearrangements between different chromosomes with direct impact on the diagnosis of 5p- syndrome.

OBJECTIVES: Copy Number Variations (CNVs) in the human genome account for common populational variations but can also be responsible for genetic syndromes depending on the affected region. Although a deletion in 5p is responsible for a syndrome with highly recognizable phenotypical features, other chromosomal abnormalities might overlap phenotypes, especially considering that most studies in 5p use traditional cytogenetic techniques and not molecular techniques. METHODS: The authors have investigated 29 patients with clinical suspicion of 5p- syndrome using Chromosomal Microarray (CMA), and have gathered information on previous tests, clinical signs, symptoms, and development of the patients. RESULTS: The results showed 23 pure terminal deletions, one interstitial deletion, one deletion followed by a 3 Mb duplication in 5p, three cases of 5p deletion concomitant to duplications larger than 20 Mb in chromosomes 2, 9, and 18, and one 5p deletion with a chromosome Y deletion. CMA showed relevant CNVs not typically associated with 5p- that may have contributed to the final phenotype in these patients. CONCLUSIONS: The authors have identified three novel rearrangements between chromosomes 5 and 2 (Patient 27), 5 and 18 (Patient 11), and 5 and Y (Patient 22), with breakpoints and overlapped phenotypes that were not previously described. The authors also highlight the need for further molecular investigation using CMA, in different chromosomes beyond chromosome 5 (since those cases did not show only the typical deletion expected for the 5p- syndrome) to explain discordant chromosomal features and overlapped phenotypes to unravel the cause of the syndrome in atypical cases.

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.

Tubo-ovarian abscess in a patient with cri du chat syndrome: A case report.

A tubo-ovarian abscess is an infection that occurs as a sequela of pelvic inflammatory disease. There is no reported association between a tubo-ovarian abscess and cri du chat syndrome in the medical literature. Herein, we report the case of a 44-year-old woman with cri du chat syndrome who was subsequently diagnosed with a tubo-ovarian abscess. After emergent laparotomy, simple total hysterectomy, and bilateral adnexectomy, the patient was discharged 13 days postoperatively without complications.

Is 5q deletion in de novo Acute Myelogenous Leukemia (AML) with excess blasts a surrogate marker for the cryptic t(7;21)(p22;q22)? A case report and review of literature.

Although the 5q- syndrome is common in both de novo and treatment related myelodysplastic syndrome (MDS) and the World Health Organization defined 5q- syndrome as a specific type of MDS, it is less common in acute myelogenous leukemia (AML). Recently, it was suggested that AML with diploidy/tetraploidy and/or 5q alterations may be associated with the cryptic translocation, t(7;21)(p22;q22) resulting in RUNX1-USP42 gene fusion and this association may have been underestimated. Here, we report another case of de novo AML with cryptic t(7;21)(p22;q22) associated with a 5q deletion.

Prenatal Diagnosis of Fetal Trisomy 5 Mosaicism with Congenital Pulmonary Airway Malformation Type 3: A Case Report.

Background: Trisomy mosaicism of chromosome 5 is uncommon with few cases described. Case report: A 41-year-old woman underwent ultrasound (US) at 16 weeks, which showed oligohydramnios and intrauterine growth restriction (IUGR). Amniocentesis discovered a karyotype of 47,XX,+5/46,XX. US at 19 weeks disclosed IUGR, enlargement of right side of heart, main pulmonary artery dilatation, and a suspected congenital pulmonary airway malformation (CPAM) in the inferior lobe of the left lung. Due to poor fetal prognosis, the parents opted for legal termination of pregnancy. At postmortem, a wide ventricular septal defect and CPAM type 3 were found. Cytogenetic analyses on fetal tissues detected mosaic trisomy 5 in skin, thymus, kidneys and CPAM. Placenta and fetal peripheral blood revealed normal female karyotype. Discussion/conclusion: These results suggest that if a fetus presents normal phenotypic features, mosaicism may be confined to extraembryonic structures, otherwise, in case of malformations, it may be carried by affected organs.

18F-FDG PET brain findings in disease-discordant monozygotic mosaic twins with Cri du Chat (5p-) syndrome.

We describe the first report on the genotype-phenotype patterns and [18F] fluoro-deoxygluycose (18F-FDG) Positron Emission Tomography (PET) findings in two disease-discordant monozygotic twins with Cri du Chat syndrome (CdcS) presenting deletion of 5p, 46, XY, del(5)(p14)/46, XY. One twin showed a severe phenotype; significant 18F-FDG PET hypometabolism (p=0.001) was revealed in the left and right hemispheres, thalamus, cerebellum, and midbrain, whereas hypermetabolism was detected in the left premotor cortex. The other twin presented a mild phenotype; significant hypometabolism was detected only in the right side (parahippoccampal gyrus and cerebellum). Further studies should investigate the causes of phenotypic discordance in twins with CdcS.

A pediatric BAL case with double Ph chromosomes and trisomy 5.

Biphenotypic acute leukemias (BAL) are known as a type of leukemia involving cells with myeloid and along with lymphoid origin, in which genomic changes are detected. It has been stated that the most common genomic changes in BAL are t(9;22) and the translocations of the 11q23 region, these anomalies cause poor prognostic effects. We detected trisomy 5 (+5) in addition to the double Ph chromosome in a case where we investigated the genomic changes using molecular and conventional cytogenetic methods. Bone marrow transplantation was planned due to the poor response to prednisone. According to the information we have obtained, our report will be the first article to discuss the aberrations found in addition to the Ph chromosome in BAL and the effect of these aberrations on prognosis. However, the double observation of the Ph chromosome, which has a poor prognostic effect, is expected to affect the prognosis more negatively, this case will contribute to the literature in terms of trisomy 5. We think that more case reports are needed to reveal the anomalies and their prognostic significance in BAL.

Prenatal diagnosis of Cri-du-Chat syndrome with concomitant distal trisomy 10q syndrome in one fetus with ultrasound anomalies.

OBJECTIVE: The aim of this work was to characterize the genetic abnormalities and prenatal diagnosis indications in one fetus with Cri-du-Chat syndrome with codependent 10q24.2-q26.3 duplication in prenatal screening. MATERIALS AND METHODS: A 31-year-old woman had a second trimester serum screening that indicated the fetus was at low risk. During this pregnancy, the woman underwent amniocentesis at 18+4 weeks' gestation because of adverse fertility history and nuchal fold thickening. Cytogenetic analysis and next-generation sequencing analysis were simultaneously performed to provide genetic analysis of fetal amniotic fluid. According to abnormal results, parental chromosome karyotype of peripheral blood was performed to analysis. RESULTS: CNV-seq detected a 14.00 Mb deletion at 5p15.33-p15.2 and a 34.06 Mb duplication at 10q24.2-q26.3 in the fetus. Cytogenetic analysis of the fetus revealed a karyotype of 46, XY, der(5) t(5;10) (p15.2;q26.3). The karyotype of pregnant women was 46,XX,t(5;10) (p15.2;q24.2). The pregnancy was subsequently terminated after sufficient informed consent. CONCLUSION: This is the first study that reports prenatal diagnosis of a Cri-du-Chat syndrome with concomitant 10 q24.2-q26.3 duplication. Adverse pregnancy history has to be as an important indicator for prenatal diagnosis, and the genetic factors of abnormal pregnancy should be identified before next pregnancy. Nuchal fold thickening is closely related to fetal abnormalities. Combined with ultrasonography, the use of CNV-seq will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies.

The general movements assessment and effects of an early intervention in an infant with Cri du chat syndrome: a case report.

BACKGROUND: Cri du chat syndrome (CdCS) is a rare orphan genetic disorder. Infants with CdCS have a neurodevelopmental dysfunction, but there are limited studies on their spontaneous movements or effect of the early interventions in children with CdCS. This study aimed to describe early spontaneous movements and investigate the effects of an early intervention in an infant with the CdCS. CASE: We analyzed the detailed general movements assessment (GMA) of an infant with CdCS at 14 weeks, and the Bayley Scales of Infant and Toddler Development-third edition (Bayley-III) were used for the determining and the follow-up of developmental functioning at 14 weeks, 6 months and 12 months. The infant was included in an early intervention beginning from 14 weeks. Fidgety movements were absent. The motor repertoire appeared significantly reduced, and the movement character was monotonous at 14 weeks. Although the infant achieved some developmental milestones with the early intervention program, the improvements were not reflected in the Bayley-III composite score. CONCLUSIONS: As a consequence, abnormal GMA results, including fidgety movements and concurrent movement patterns, seen in CdCS can be associated with early signs of neurodevelopmental dysfunction. Early intervention programs in infants with genetic disorders could help enable the early achievement of motor milestones.

Retinopathy in a Full-Term Infant with Cri-du-Chat Syndrome.

Cri-du-chat (CdC) is a 5p chromosomal deletion syndrome. CdC has numerous systemic associations but only a few ocular manifestations have been documented. In this report we present novel ocular findings of peripheral avascular retina and retinal hemorrhages in a full-term female infant, born to non-consanguineous parents, who had clinical features of cri-du-chat syndrome and genetic confirmation. The retinal hemorrhages resolved. However, the temporal avascular retina in our full-term patient remained. Further analysis of the 5p locus showed 3 genes: CTNND2, SEMA5A and SLC6A18 that not only fit our patient's external phenotype and ophthalmoscopic findings of retinal hemorrhages, but were also key in proper ocular development and neurogenesis, suggesting a genetic contribution by the short-arm of chromosome 5 to proper retinal maturation. Given these findings and their association with cri-du-chat, special attention on screening examinations should include a thorough evaluation of retinal vascularization in CdC patients, even in full-term neonates.