Branding of subjects affected with genetic syndromes of severe short stature in developing countries.

In Ecuador, a developing South American country, subjects affected with genetic syndromes of severe short stature are commonly referred to as dwarfs or midgets. Furthermore, and because in earlier studies some patients had evidenced mental retardation, such abnormality is assumed to exist in all affected subjects. Herein, we present two discrete instances in which this type of branding occurs. The first is that of individuals with Laron syndrome who are still called 'dwarfs' and considered as having a degree of mental retardation despite evidence showing otherwise. A similar problem, that of a girl affected with a genetic syndrome of short stature, which might include mental retardation, is also discussed. Considering that stigmatising is a form of discrimination, it concerns us all. Hence, the use of derogatory terms such as midget, dwarf or cretin, that might unintentionally occur even when delivering the best and most devoted medical care, must be eliminated.

Tratamiento farmacológico de las alteraciones de conducta en el Síndrome de Cornelia de Lange, a propósito de un caso / Pharmacological treatment of behavioral disorders in Cornelia de Lange Syndrome. A case report

El síndrome de Cornelia de Lange (SCL) es un trastorno genético caracterizado por presentar distintos trastornos somáticos y retraso del desarrollo psicomotor con problemas conductuales. Presentamos el caso de un varón de 8 años que acude a la consulta por alteraciones de conducta. Destaca retraso cognitivo y motor importante: no emite lenguaje. Muy rígido ante cambios y nuevos entornos. Muestra alteraciones conductuales en esas circunstancias: heteroagresividad contra objetos y autolesiones. Ensayamos con risperidona en base a la similitud de esta clínica con la del trastorno del espectro autista. Muestra mejoría significativa, disminuyendo hasta 3 puntos en la Escala de Impresión Clínica Global. Las pruebas científicas acerca del tratamiento de esta clínica provienen en su mayor parte de estudios de caso único. Aunque el tratamiento con risperidona podría ser eficaz y bien tolerado, se requieren más estudios que permitan avanzar en el conocimiento del tratamiento farmacológico de las alteraciones conductuales en SCL

Cornelia de Lange Syndrome (CdLS) is a genetic disorder characterized by different somatic impairments and retarded psychomotor development. 8-year-old male diagnosed with CdLS comes to Children' Psychiatry assesment presenting behavioural disorder as well as delayed motor and cognitive development. He cannot talk and only pictograms are used for communication. Severe cognitive rigidity, specially to manage changes and new contexts. In these cases, he shows aggressiveness against objects and self-injurious behaviour. A trial test of risperidone is started based on similarities betweeen these behavioral disorders and those present in autism spectrum. He shows a remarkable improvement, decreasing three points in the Clinical Global Impression. Scientific evidence mostly derives from case reports studies. That implies the quality of scientific evidence is low. Though the treatment with risperidone may be effective and well tolerated, more studies are required to move forward on the pharmacological treatment of behavioral disorders in CdLS

Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo.

Cornelia de Lange syndrome (CdLS) is a rare disease characterized by cognitive impairment, multisystemic alterations and premature aging. Furthermore, CdLS cells display gene expression dysregulation and genomic instability. Here, we demonstrated that treatment with antioxidant drugs, such as ascorbic acid and riboceine, reduced the level of genomic instability and extended the in vitro lifespan of CdLS cell lines. We also found that antioxidant treatment partially rescued the phenotype of a zebrafish model of CdLS. Gene expression profiling showed that antioxidant drugs caused dysregulation of gene transcription; notably, a number of genes coding for the zinc finger (ZNF)-containing Krueppel-associated box (KRAB) protein domain (KRAB-ZNF) were found to be downregulated. Taken together, these data suggest that antioxidant drugs have the potential to ameliorate the developmental phenotype of CdLS.

Successful Growth Hormone Therapy in Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is a both clinically and genetically heterogeneous syndrome. In its classical form, it is characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay, and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the cohesin pathway, have been identified to cause CdLS. Growth hormone (GH) secretion has been reported as normal, and to our knowledge, there are no reports on the effect of recombinant human GH treatment in CdLS patients. We present a patient born small for gestational age with persistent severe growth retardation [height -3.4 standard deviation score (SDS)] and mild dysmorphic features, who was treated with GH from 4.3 years of age onward and was diagnosed 6 years later with CdLS using whole-exome sequencing. Treatment led to a height gain of 1.6 SDS over 8 years. Treatment was interrupted shortly due to high serum insulin-like growth factor-1 serum values. In conclusion, GH therapy may be effective and safe for short children with CdLS.

Sedation and general anesthesia for patients with Cornelia De Lange syndrome: A case series.

Cornelia De Lange syndrome (CdLS) is a rare congenital disease characterized by typical facial dysmorphism, developmental disability, and limb deficiency defects. Various congenital malformations and medical complications have been described with gastroesophageal reflux as the major one. CdLS patients often require multiple high-risk anesthetic procedures. At San Gerardo Hospital (Monza, Italy) the management of CdLS patients is routinely organized through a standard protocol and a dedicated pediatric anesthesia team has been implemented. We report on a retrospective descriptive analysis of the anesthetic records of the CdLS patients admitted to San Gerardo Hospital from January 2010 to December 2015. We retrieved: demographics, genetic profiles, type of procedures, anesthetic approaches, anesthetics usage and complications. Data are reported as median (interquartile range) values. Twenty-seven patients (11 female), with age 12 (7-15) years old, weight 24 (14-35) kg, and severity score of 25 (18-32) were included. NIBPL mutations were the most frequently represented. We analyzed 58 procedures (30 esophagogastroduodenoscopies, 8 evoked auditory potential tests, 5 radiodiagnostics, 5 catheters positioning, 4 bronchoscopies) managed by sedation (36) and general anesthesia (6). Each patient underwent one (1-2) anesthetic procedure. Propofol (59%), sevoflurane (31%), fentanyl (24%), and ketamine (10%) were used. Three out of six endotracheal intubations were difficult. The only documented intraoperative complications were three episodes of desaturation (oxygen saturation <90%) occurring during sedations and were managed without the need for an invasive control of the airways. Implementation of a specific management protocol and a dedicated allowed to provide anesthesia to CdLS patients without the occurrence of major complications. © 2016 Wiley Periodicals, Inc.

A 6-year-old boy with Cornelia de Lange syndrome and Coats disease: case report and review of the literature.

Cornelia de Lange syndrome (CdLS) can result in multiple congenital abnormalities and numerous ocular findings. We report the case of a 6-year-old boy with history of CdLS who presented with Coats disease. The findings in this case are compared to those found in the two previously reported cases of concomitant CdLS and Coats disease. The low incidence of these two disorders makes it highly unlikely that the connection is random in these 3 cases. The number of patients with both Cornelia de Lange syndrome and Coats disease is likely underestimated due to the difficulty in examining the peripheral retina in this patient population.

HDAC8: a multifaceted target for therapeutic interventions.

Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors critical to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.

L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.

Cohesinopathies are human genetic disorders that include Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS.

Epilepsy in patients with Cornelia de Lange syndrome: a clinical series.

PURPOSE: Cornelia de Lange (CdLS) syndrome is characterized by multiple congenital anomalies and mental retardation. Epilepsy is a clinical feature found in about 20% of cases, but there are no data about its electroclinical features and long-term outcome. METHODS: we describe a clinical series of fourteen Caucasian CdLS paediatric patients who developed epilepsy, with special reference to the long term prognosis. RESULTS: Epilepsy manifested between age 0.6 and 16.3 years. The majority of patients (64.3%) presented with partial seizures and interictal EEGs mainly revealed focal epileptic paroxysms involving temporal and parietal areas. Thirteen of 14 children became seizure-free with treatment. Valproate monotherapy was used in eight patients (57.1%), controlling seizures in seven. Otherwise monotherapy with topiramate, levetiracetam, carbamazepine and oxcarbazepine appeared to be effective in controlling seizures in four cases. At the end of the follow-up (age range, 7.3-24.2 years; follow-up, 8.2±3.9 years), thirteen patients were seizure free (three still in therapy), while in one patient seizures were not controlled. CONCLUSIONS: Partial epilepsy is the most common type of epilepsy in CdLS patients. In the majority of cases the prognosis of this epilepsy is favourable and therapy can be withdrawn after few years of complete seizure control.

Anestesia general combinada con analgesia epidural para ureteroneocistostomía en un paciente con síndrome de Cornelia de Lange / General anaesthesia combined with epidural analgesia for ureteroneocystostomy in a patient with Cornelia de Lange syndrome

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Embolia gaseosa durante cirugía laparoscópica en lactante con síndrome de Cornelia de Lange / Air embolism during laparoscopic surgery in an infant girl with Cornelia de Lange syndrome

El síndrome de Cornelia de Lange es un cuadro polimalfomativopoco frecuente, con características fenotípicasparticulares (alteraciones craneofaciales comomicrocefalia o hipertricosis con sinofridia; alteracionescutáneas como hirsutismo; anomalías de las extremidades),asociado en un alto porcentaje a retraso mental yotro tipo de anomalías (digestivas, cardiacas, endocrinas).Presentamos el caso de una paciente de 2 meses deedad en la que se realizó por vía laparoscópica, una plastiaantirreflujo, cierre de defecto diafragmático y gastrostomía.Como antecedentes a destacar neumoníasaspirativas de repetición e hipertensión arterial. Duranteel inicio de la intervención quirúrgica, hubo dos episodiosde desaturación brusca, hipotensión y bradicardia,con diagnóstico probable de embolia aérea, que seresolvieron aplicando tratamiento específico. El manejoanestésico en estos pacientes para cirugía laparoscópicaes realmente complejo, por lo que hay que conocer demanera profunda la patología y complicaciones que puedansurgir(AU)

Cornelia de Lange syndrome involves multiplemalformations with particular phenotypic features(craniofacial abnormalities such as microcephaly orhypertrichosis with synophrys; cutaneous abnormalitiessuch as hirsutism, and limb anomalies) and it isassociated with a high percentage of mental retardationand complications such as digestive tract abnormalities,cardiac defects, and endocrine disorders. We report thecase of a 2-month-old infant girl who underwent alaparoscopic antireflux procedure, with closure of adiaphragmatic hernia and a gastric stoma. The medicalhistory included repeated episodes of aspirationpneumonia and hypertension. Early in the procedure, 2episodes of sudden desaturation, hypotension, andbradycardia with a probable diagnosis of air embolism.The complications resolved with specific treatment.Anesthetic management for laparoscopic surgery in thesepatients is truly complex and must be informed by athorough understanding of the disease and complicationsthat may develop(AU)

Pharmacological treatment of aggressive behavior and emesis in the Cornelia de Lange Syndrome.

Chlorpromazine and fluphenazine decanoate were employed to treat aggressive behavior and emesis in a 22-year-old patient with Cornelia de Lange syndrome. Institution of the above neuroleptics, following an unsuccessful trial of diazepam, produced reductions of 95.1 per cent and 37.9 per cent for aggressive behavior and emesis, respectively. Four follow-up observations, occurring at 3-week intervals, revealed maintenance of low rates of aggressive behavior and continued reductions in emesis (mean reduction of 81.5 per cent). These findings are important for their a) inclusion of direct behavioral observation as the data base, and b) initial promising effects of neuroleptics for a rare mental retardation syndrome.