Wolf-Hirschhorn Syndrome Research Articles

A large Indian family with rearrangement of chromosome 4p16 and 3p26.3 and divergent clinical presentations

BackgroundThe deletion of the chromosome 4p16.3 Wolf-Hirschhorn syndrome critical region (WHSCR-2) typically results in a characteristic facial appearance, varying intellectual disability, stereotypies and prenatal onset of growth retardation, while gains of the same chromosomal region result in a more variable degree of intellectual deficit and dysmorphism. Similarly the phenotype of individuals with terminal deletions of distal chromosome 3p (3p deletion syndrome) varies from mild to severe intellectual deficit, micro- and trigonocephaly, and a distinct facial appearance.Methods and resultsWe investigated a large Indian five-generation pedigree with ten affected family members in which chromosomal microarray and fluorescence in situ hybridization analyses disclosed a complex rearrangement involving chromosomal subregions 4p16.1 and 3p26.3 resulting in a 4p16.1 deletion and 3p26.3 microduplication in three individuals, and a 4p16.1 duplication and 3p26.3 microdeletion in seven individuals. A typical clinical presentation of WHS was observed in all three cases with 4p16.1 deletion and 3p26.3 microduplication. Individuals with a 4p16.1 duplication and 3p26.3 microdeletion demonstrated a range of clinical features including typical 3p microdeletion or 4p partial trisomy syndrome to more severe neurodevelopmental delay with distinct dysmorphic features.ConclusionWe present the largest pedigree with complex t(4p;3p) chromosomal rearrangements and diverse clinical outcomes including Wolf Hirschorn-, 3p deletion-, and 4p duplication syndrome amongst affected individuals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0251-5) contains supplementary material, which is available to authorized users.

Prenatal molecular cytogenetic analysis of a mild dysmorphic fetus with a huge unbalance karyotype involving partial 9p deletion and partial 18q duplication

Partial 9p deletion syndrome and partial 18q duplication syndrome each have distinct clinical features. We describe the prenatal molecular cytogenetic analysis of a de novo unbalanced karyotype with deletion of 9p23-pter and duplication of 18q12.2-qter in a mild dysmorphic female fetus. Fetal ultrasonography was performed and detailed karyotype analyses were conducted using a combination of G-banding, SKY analysis and FISH with chromosome arm specific sub-telomeric DNA probes and chromosomal region specific BAC clone probes. The fetal sonography and fetal echocardiography at 17 weeks’ gestation did not reveal any anomaly while the fetus had a large unbalance karyotype of 46,XX,der(9)t(9;18) (p23;q12.2) de novo. Its external phenotype at 21 weeks appeared to have some mild dysmorphic features including hypertelorism, low-set ears, micrognathia/retrognathia, clenched hands and rocker bottom feet. These dysmorphic features are seen in the Edward syndrome but with milder degrees.

Cri du Chat Syndrome: a Case Report with Recurrent Pneumonia and Chronic Stridor

Introduction Cri du chat syndrome is a rare genetic disorder due to deletion of variable length of short arm of chromosome 5(5p). It mainly presents with typical cat like cry, facial dysmorphism, poor growth with feeding problems and severe cognitive, speech, and motor delays. Case Report We present here a one year old child who did not presented with typical features but presented with recurrent pneumonia with chronic stridor since early infancy. On evaluation we found short flabby epiglottis and we did karyotyping which showed 5P deletion syndrome. Conclusion Cri du chat syndrome can be presented with atypical features like chronic stridor and recurrent pneumonia without having typical cat like cry. Early diagnosis is necessary for proper counselling of parents and treatment of the patient.

Follicular Bronchiolitis in a Child With 1p36 Deletion Syndrome

SESSION TITLE: Lung Pathology Student/Resident Case Report Posters SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 27, 2015 at 01:30 PM - 02:30 PM INTRODUCTION: The rarity of pulmonary manifestations in children with chromosome 1p36 deletion syndrome makes a diagnosis of follicular bronchiolitis (FB) a unique challenge. CASE PRESENTATION: A one year old female was diagnosed with a chromosome 1p36 deletion after birth. She has hypotonia, developmental delay, visual abnormalities, growth and feeding related problems, which are common features of this disorder. She presented with tachypnea, several months of productive cough and wheezing that were unresponsive to antibiotics, albuterol, and corticosteroids. On exam, she was dysmorphic, hypotonic, with increased respiratory distress, and mild splenomegaly. A chest CT showed compression of the right upper lobe (RUL) bronchus and an ill-defined soft tissue fullness in right hilum. She was admitted with concern for neuroblastoma and immunodeficiency. An extensive autoimmune, infectious, and immunodeficiency work-up was negative, except for a low CD4/CD8 ratio. She was found to have elevated metanephrines; however, her MIBG did not show evidence of an avid lesion. Flexible bronchoscopy disclosed compression of the RUL bronchus. Lung biopsy revealed findings consistent with follicular bronchiolitis, whereas lymph node biopsy showed reactive follicular and interfollicular hyperplasia. She was treated with IV steroids and did not have any recurrence. DISCUSSION: Notably, our patient has a complex chromosomal anomaly that does not typically present with pulmonary problems; however, deletions in chromosome 1p36 have been linked to reactive lymphoid hyperplasia and follicular lymphoma. FB is a rare disease in children. In adults, most cases are associated with collagen vascular diseases, immunodeficiency, or hypersensitivity reaction.1 This disease is characterized by bronchiolar narrowing by external compression due to lymphoid hyperplasia, which is seen in our patient.2 Affected children may present with tachypnea, respiratory distress and failure to thrive. Lung biopsy is necessary for confirmation of diagnosis. There are no well-established guidelines for the treatment of this condition, but macrolides and steroids have been suggested to have a benefit.3 Immunosuppressive agents are generally reserved for refractory cases. CONCLUSIONS: To our knowledge, this is the first case of FB reported on a child with chromosome 1p36 deletion. The etiology of this disease in children is unknown; however, diagnosis should be considered in a child with chronic bronchial obstruction. Reference #1: Yousem S.A., et al. Follicular bronchitis/bronchiolitis. Hum Pathol. 1985 Jul;16(7):700-706. Reference #2: Kinane B.T., et al. FB in the Pediatric Population. Chest. 1993; 104:1183-1186. Reference #3: Dias A., et al. FB: A Rare Cause of Persistent Atelectasis in Children. Respiratory Medicine Case Reports. 2013; 10:7-9. DISCLOSURE: The following authors have nothing to disclose: Marissa Love, Jane Taylor, Wendy Estrellado No Product/Research Disclosure Information

Children with rare diseases: do they really have an increased risk of developing epilepsy?

Symptoms involving the central nervous system (CNS) are frequently part of the variable clinical picture of genetic-dysmorphic syndromes. Intellectual disability represent the most common associated finding, but epilepsy is very frequently reported, for example in chromosomal abnormalities [1-3]. Seizure risk has been pointed out to be significantly higher in those with chromosomal abnormalities with respect to general population [4-6], and represent an important element to recognize and define for both diagnostic and therapeutic purposes. Seizures' semeiology, severity and frequency can be highly variable in different syndromes, depending on the type of genetic defect, but even amongst subjects with the same genotype there can be a great variability in clinical manifestations, even intrafamiliarly. Therefore, within the association between genetic syndromes and epilepsy, we should consider two possible situations: 1) Syndromes in which epilepsy could represent a “specific marker”. In certain conditions the recognition of a peculiar electroclinical phenotype could give a significant contribution to diagnostic definition of the syndrome. The best known example is Angelman syndrome [7,8], in which the electroencephalographic (EEG) pattern could suggest the suspected diagnosis even in infants and toddlers, i.e. before the “classical” clinical and behavioral phenotype becomes evident. But epilepsy can represent a significant clinical marker in other conditions as well, such as Rett syndrome [9], Wolf-Hirschhorn syndrome [10], and other recently defined deletion or duplication syndromes. 2) Syndromes in which epilepsy is reported occasionally. In these conditions the diagnostic value of the electroclinical phenotype is limited, but the correct identification and treatment of the symptom still has an important effect on individual and familial health and quality of life. Finally in genetic syndromes some special considerations should be made regarding the role of interictal EEG abnormalities and discussing clinical indications of antiepileptic treatment.

Children with rare diseases, is it true that they have an enhanced anesthesiological risk?

The anesthesiological approach to rare diseases (RD) is particularly challenging for providers. The high number of pathologies and the scarcity of clinical reports impedes to arrange a pool of dedicated anaesthesiologists. When facing RD, the risk linked to unaware malpractice is often due to lack of experience, mostly of urgent/emergent procedures [1]. It is probably impossible to know all relevant aspects in more than 8000 pathologies that affect approximately 6-8% of the population [2]. In order to reduce anesthesiological risk, it is mandatory to develop a systematic approach. 1. First and foremost, let’s take advantage of previous experiences. There are specific search engines available online [http://www.orphananesthesia.eu; http://www. orpha.net; http://www.omim.org ], which briefly summarize the knowledge about RDs. Furthermore, for major pathologies there are national and international main centres providing medical counselling. As a whole, we can attribute the anesthesiological risk to four cohorts. Careful evaluation should be dedicated to current systemic impairments [3]. Children affected by cystic fibrosis need special care, due to specific organ failure. In some types of porphyrias it is mandatory to achieve a good control on pain, anxiety and nausea, because stressful events could trigger a severe crisis. In some cases, pathological processes can affect pharmacodynamics causing abnormal responses to drugs, such as the enhancement of curarization in myasthenic patients, or a real adverse event like the risk of Malignant Hyperthermia associated with Wolf-Hirschhorn Syndrome [4] or Arthrogryposis. A third item to investigate is whether anesthetic drugs can interact with specific concurrent therapies. There are some suggestions that the previous therapy with eculizumab, a new monoclonal antibody for the treatment of paroxysmal nocturnal haemoglobinuria, predisposes to haemolytic crisis in occurrence of general anesthesia. The last cohort, but the most frequent, concerns the difficult management of airways. Craniofacial malformations can represent a very big deal due to mandible hypoplasia such as Pierre Robin syndrome or Treacher-Collins syndrome; hemifacial microsomia such as Goldenhar syndrome; midface hypoplasia as Apert syndrome [5], Crouzon syndrome, Pfeiffer syndrome and macroglossia such as Hurler’s syndrome, Hunter’s syndrome, or weakness of atlanto-occipital joint such as Downs syndrome, EhlersDanlos syndrome type IV or osteogenesis imperfecta. Tracheal intubation should indeed be avoided in syndromes as epidermolysis bullosa to prevent severe tracheal lesions. In conclusion, besides patients with a clear diagnosis, sometimes a simple pathology can hide unknown RDs [6]. For this reason the pre-anesthesiological evaluation is crucial, more than ever in syndromic children, to assess the risk before undergoing general anesthesia or sedation. This allows the best strategy to work safely to be put in place and to improve outcome.

Eating epilepsy characterised by late-onset epileptic spasms in a case of Cri du chat syndrome

Monica Lodi *, Erika Rebessi , Eliana Parente , Elisa Micalizzi , Maurizio Viri , Donatella Milani , Antonino Romeo a a Pediatric Neurology Unit and Epilepsy Center, Department of Neuroscience, ‘‘Fatebenefratelli e Oftalmico’’ Hospital, Milano, Italy b Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, University of Milan Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milano, Italy

AB097. Clinical and molecular characterization of patients with 6p25 deletion syndrome

Objective Chromosomal imbalances and rearrangements have been implicated in the etiology of intellectual disability and congenital anomalies. Many of these imbalances are caused by submicroscopic deletions or duplications not detected through conventional cytogenetic analysis. The advances in technology for detecting copy number changes, most notably chromosomal microarray analysis (CMA) has allowed the detection of these submicroscopic deletions or duplications. Submicroscopic 6p25 deletion is now recognized as a clinically identifiable syndrome. Clinical features in this syndrome include intellectual disability, developmental delay, hypotonia, sensorineural hearing loss, midface hypoplasia, ocular anomalies, cardiac defects and varying central nervous system anomalies. The aim of this report is to describe the phenotypic range of individuals with 6p25 deletion syndrome in the South East Asian population.

AB024. Chromosome microarray analysis (CMA) for the diagnosis of children with developmental delay and multiple congenital anomalies in Singapore.

Chromosome microarray analysis (CMA) is a sensitive method to identify submicroscopic changes too small to be detected by conventional karyotyping. Due to its high-sensitivity in identifying regions with structural variation and hence the genes involved, it is recommended to be the first-tier genetic test for children with intellectual disabilities, development delay or multiple congenital anomalies, and is routinely available in USA and many countries in Europe. Our lab has started offering this as a clinical test based on the research experience on screening >400 children with developmental delay and multiple congenital anomalies since February 2014. To date, 271 patients have been screened using the Agilent 4×180K CGH + SNP array. Copy number variants (CNVs) ranging in size from 10 kb to 154 Mb were found in 109 patients (40%). Pathogenic and likely pathogenic CNVs were found in 55 (20%). These included 45 with deletions, 8 with duplications and 2 patients with both deletion and duplication. Recurrent microdeletion and microduplication syndromes including the Angelman/Prader-Willi syndrome [5], 1p36 microdeletion [3], Williams syndrome [2], 22q11.2 distal deletion syndrome [2], 16p13.3 microdeletion syndrome [2], Cat Eye syndrome, Cri du Chat syndrome, Miller Decker syndrome, 3q29 microdeletion, 15q24 microdeletion, and 1q43q44 syndrome were among the variants detected in our patients. CNVs of uncertain clinical significance were detected in 54 (20%) individuals: 32 were duplications, 18 were deletions and one with both deletion and duplication. However, due to the high cost of the test, parental testing was not performed and hence, significance of these variants could not be established conclusively. In conclusion, CMA is a powerful tool in identifying pathogenic chromosomal copy number alternations. However, due to the high cost of the test, parental testing for the cases where variants of uncertain significant are found is often not possible. CMA is useful in identifying pathogenic structural rearrangement. More data are necessary to be collected to enhance interpretation of the results.

Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function.

Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the CaM KMT gene.

Wolf-Hirschhorn syndrome: A review and update.

Since 4p- was first described in 1961, significant progress has been made in our understanding of this classic deletion disorder. We have been able to establish a more complete picture of the WHS phenotype associated with distal 4p monosomy, and we are working to delineate the phenotypic effects when each gene on distal 4p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families of individuals with a diagnosis of WHS. In addition, establishing the molecular underpinnings of the disorder will potentially suggest targets for molecular treatments. Thus, the next step is to determine the precise effects of specific gene deletions. As we look forward to deepening our understanding of distal 4p deletion, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our WHS cohort closely as they age to determine the presence or absence of some of these comorbidities, including hepatic neoplasms, hematopoietic dysfunction, and recurrence of seizures. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. New animal models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development.

1p36 deletion syndrome: an update.

Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes.

Abstract 4357: Key differences revealed in NSD2 kinetics using truncated versus full-length protein

Abstract Histone lysine methyltransferases (HKMTs) are a class of enzymes that transfer a methyl group from S-adenosyl-L-methionine (SAM) to lysine residues on histone tails. The nuclear receptor SET domain-containing (NSD) family of proteins is known to methylate lysine 36 of histone H3 (H3K36). Abnormal methylation at H3K36 has been widely implicated in a variety of cancers and diseases, therefore, the enzymes responsible for this posttranslational modification are of interest from a drug-discovery standpoint. NSD2 (MMSET/WHSC1), a representative of this family, was found to be highly expressed in a multitude of human tumors and has been directly linked to multiple myeloma and Wolf-Hirschhorn syndrome. The chromosomal translocation t(4:14)(p16;q32) that occurs in 15% of myeloma patients is associated with both increased production of NSD2 and poor prognosis while loss of the NSD2 gene at the 4p16.3 region results in Wolf-Hirschhorn syndrome. In order to better understand the multi-dimensional nature of NSD2, full-length and truncated versions of the protein were generated to evaluate NSD2 kinetics. The biochemical activity of each NSD2 construct was assessed using (1) a radioactive assay measuring 3H transfer from SAM to the histone substrate or (2) LC-MS/MS analysis of the NSD2-dependent product. Full-length NSD2 prefers a nucleosomal substrate; whereas, C-terminal truncation of a highly charged region (AA 12-14-1240) resulted in a loss of nucleosomal activity and a gain of activity using a peptide derived from Histone H3. Additionally, LC-MS/MS mapping revealed a shift in the methylation site from H3K36 to H3K18 when using the truncated system. More detailed kinetic analysis revealed that the FL/nucleosome reaction catalyzes processive methylation while truncated NSD2 methylates the peptide distributively. Lastly, key changes in inhibitor specificity were observed. An alternative C terminal region, residues 1341-1365, was required to maintain potency of the product inhibitor SAH but not the close analog sinefungin. This may be indicative of the ping-pong kinetics proposed for FL NSD2 implying that SAH targets the NSD2-nucleosome bound form of the enzyme (UC vs. nucleosome) while sinefungin does not (NC vs. nucleosome). While a truncated NSD2/peptide system would be much easier to screen, profile and characterize in the search for inhibitors, the results found herein indicate that screening a full-length NSD2/nucleosome system may be more physiologically relevant. Citation Format: Melissa B. Pappalardi, Jessica L. Schneck, Rosalie Matico, Michael Huddleston, Wangfang Hou, Patrick McDevitt, Roland Annan, Robert Kirkpatrick, Ryan Kruger. Key differences revealed in NSD2 kinetics using truncated versus full-length protein. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4357. doi:10.1158/1538-7445.AM2015-4357

Prenatal diagnosis of a case with combined Wolf-Hirschhorn syndrome and Jacobsen syndrome

To detect chromosomal imbalance in a fetus with complex congenital heart disease, and to correlate the genotype with the phenotype. Routine G-banding was carried out to analyze the karyotypes of the fetus and its parents, and single nucleotide polymorphisms array (SNP-array) was used for delineating fine genomic aberrations. The detected aberrations were confirmed with multiplex ligation-dependent probe amplification (MLPA). The fetus and its parents all showed a normal karyotype, while array-SNP has detected a 13.87 Mb duplication at 4p16.3-p15.33 and a 15.65 Mb deletion at 11q23.3-q25 in the fetus. The results were confirmed by the MLPA assay. The partial trisomy 4p (Wolf-Hirschhorn syndrome) and partial monosomy 11q (Jacobsen syndrome) probably underlie the complex heart defects detected in the fetus. Analysis of the karyotypes of its parents offered no help for the determination of the aberrant type and recurrent risk. Compared with routine karyotype analysis, aberrant regions can be identified with array-SNP with greater resolution and accuracy. This has provided useful information for prenatal diagnosis and genetic counseling.

Hereditary neuropathies with self-mutilation

Although self-mutilation (SM) is not rare in the general population, the most common causes for this mode of destructive behavior are mental retardation and psychiatric ailments. There are 2 types of neuropathies with mutilation, those with spontaneous mutilation of tissues and the others in which the patients mutilate themselves. A number of hereditary disorders are associated with SM. Among the eight MIM (Mendelian Inheritance in Man) entries associated with SM, there are four conditions, which are associated with peripheral neuropathy (choreoacanthocytosis,.acanthocytosis with neurological impairment, congenital insensitivity to pain with anhydrosis and the paroxysmal neuropathy of type I tyrosinemia). The other four (Tourette syndrome, Lesch-Nyhan syndrome, LeschNyhan phenotype with normal hypoxanthine guanine phosphoribosyle transferase and Cridu-chat syndrome) are not associated with peripheral neuropathy. It is quite surprising that in the latest editions of the classical textbooks of pediatrics, pediatric neurology and adult neurology SM is mentioned only with regard to Lesch-Nyhan syndrome. In this paper, we describe our experience with a number of hereditary mutilating neuropathies and review some of the recent advances in the neurobiology of SM. The recognition and awareness of this outstanding clinical sign may be helpful in reaching a correct diagnosis and offering symptomatic treatment, to avoid potential tissue damage at an earlier stage of the disease. (J Pediatr Neurol 2004; 2(4): 205-211).

Growth profiles of 34 patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) encompasses multiple congenital anomalies and mental retardation and is caused by partial deletions in the short arm of chromosome 4. Prenatal-onset growth deficiency is one of the WHS characteristics. Assessing and recording growth profiles of patients with WHS were the aims of this study. Anonymous questionnaire surveys were conducted with cooperation of a WHS peer-support group in Japan, and data from 34 WHS patients (12 males and 22 females; age, 1-23 years) were retrospectively collected. Height, weight, and head circumference (occipitofrontal head circumference) were measured and plotted on the standard growth charts of healthy Japanese children. Results indicated that most WHS patients showed growth retardation under the 3rd percentile since the first year of life and extremely poor body-weight gain after pubertal age. These findings are characteristic of WHS patients. The assessed growth patterns in this study could help monitoring and documentation of growth of WHS patients.

A case of 9p deletion syndrome with Duane retraction syndrome.

The chromosome 9p deletion syndrome is a rare but specific clinical event. The clinical manifestations include dysmorphic facial features (trigonocephaly, midface hypoplasia, upward slanting palpebral fissures, and a long philtrum) and psychomotor retardation. Here we report a child with chromosome 9p deletion with Duane retraction syndrome, which has never been reported in the literature before.

Tigroid pattern of cerebral white matter involvement in chromosome 6p25 deletion syndrome with concomitant 5p15 duplication.

Sub-telomeric deletions of the short arm of chromosome 6 are a well-described clinical entity characterized by developmental impairment, hypotonia, eye abnormalities and defects in the heart and kidneys. Chromosome 5p terminal duplication is a rarer entity, associated with developmental impairment and facial dysmorphism. We report a 3-year-old patient with a chromosome 6p25.1pter deletion and chromosome 5p15.1pter duplication who had global developmental impairment and unusual cerebral white matter changes, with hypoplastic corpus callosum and cerebellar vermis on magnetic resonance imaging -brain scan. We discuss the differential diagnosis to consider in patients with this appearance on magnetic resonance imaging -brain scan and reiterate the need for chromosome analysis in patients with this pattern of developmental anomaly. Tigroid pattern of cerebral white matter involvement has not been reported in chromosomal deletion/duplication syndromes. With the increasing use of molecular karyotyping for patients with multiple congenital anomalies and developmental delay, it is important to consider the exact size and nature of chromosomal deletion/duplication, in order to provide families with prognostic information and recurrence risk. This in turn, will help provide valuable information regarding the natural history of rare chromosomal imbalances.

Epilepsy in 1p36 Deletion Syndrome Is Not Associated with Deletion Size

1p36 deletion syndrome is the most common subtelomeric deletion syndrome. The main clinical features are intellectual disability, characteristic craniofacial features, and epilepsy. Recent analysis revealed that a minimum deletion of 2.2 Mb from the telomere is essential for full manifestations of 1p36 deletion syndrome. Generally, severity of neurological symptoms in patients with 1p36 deletion syndrome correlates with the size of the deletion; however, the incidence of epilepsy does not correlate with deletion size. Some patients with minimum deletions never show symptoms of epilepsy, but there are patients who manifest intractable epilepsy, especially epileptic spasms. This evidence indicates that the responsible region for epilepsy is in the minimum deletion region, but the penetrance of epilepsy is not complete. Prognosis of brain development in patients with 1p36 deletions is related to the outcome of epilepsy treatment. Careful follow-up for infantile patients with 1p36 deletion syndrome would be recommended for early diagnosis and intervention for epilepsy.

Wolf–Hirschhorn Syndrome and Epilepsy: An Overview

The Wolf–Hirschhorn syndrome (WHS, OMIM194190) is a contiguous gene deletion syndrome of the distal part of the short arm of chromosome 4 (4p16 region) characterized by a distinctive facial appearance, intrauterine and postnatal growth delay, intellectual disability, and seizures. The WHS clinical spectrum is complex and variable. Typically, more than 90% of WHS-related patients begin seizures in the first 3 years of life. In these cases, most of the epilepsy is well controlled, and over half of the patients stopped having seizures after adolescence. Etiology and/or genetics of their seizures were unclear. The clinical data on the association between epilepsy and chromosomal abnormalities is likely to improve our understanding of the functions and mechanisms of genes related to epilepsy. Future studies would be needed for a deeper understanding of WHS.