Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome.

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu261 , Leu262 , and Arg265 in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu262 and Arg265 exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu261 , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.

CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases.

Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.

Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype.

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.

Auditory system involvement in late onset Pompe disease: a study of 20 Italian patients.

Glycogen storage disease type II (GSD II), also known as Pompe disease, is an autosomal recessive inherited disorder caused by a reduced activity of acid alpha glucosidase (GAA). Two different clinical entities have been described: rapidly fatal infantile and late onset forms. Hearing loss has been described in classic infantile Pompe patients but rarely in late onset cases. The main purpose of this study was to investigate the involvement of the auditory system in a cohort of Italian patients with late onset GSD II. We have enrolled 20 patients, 12 males and 8 females. The auditory system assessment included speech and pure tone audiometry, impedance audiometry and auditory brainstem responses (ABR). A combined interpretation of those tests allowed us to define the origin of the hearing impairment (sensorineural, conductive or mixed). Clinically, all patients but one denied subjective hearing disturbances. On the other hand, audiological evaluation revealed that 21/40 patient ears (52.5%) had a hearing impairment: 57% had a sensorineural deficit, 33% showed a conductive hearing loss whereas 10% presented with a mixed pattern. Our study revealed that, in this group of GSDII late onset patients, the auditory system impairment was more frequently present than thought with a prominent cochlear involvement. Our results emphasize the importance of a routinely auditory function evaluation in all forms of Pompe disease.

The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin.

Kabuki syndrome and cancer in two patients.

Both hepatoblastoma and neuroblastoma are occasionally associated with congenital syndromes such as Beckwith-Wiedemann syndrome and trisomy 18. There have been no reports of hepatoblastoma in patients with Kabuki syndrome, whereas one patient with neuroblastoma and this syndrome has been reported. In this paper we present two patients with Kabuki syndrome and a neoplasm: a child of 6 years with hepatoblastoma and an infant, of 6 months affected by neuroblastoma.

The theory of the 'mana personality' in Jung's works: a historic-hermeneutic perspective. Part II.

This is the second part of an article that tries to provide a framework of understanding of, and a seminal reflection on, a highly interesting yet little explored psychological construct of Jung's analytical psychology, namely the 'mana personality'. Here I take into consideration some issues around the 'saviour complex', discussed in Jung's seminar on Nietzsche's Zarathustra, concerning both the psychological analysis of the individual and the socio-political level related to the collective horizon of the 1930s. Moreover, I consider the continuity of Jung's analysis of such issues in other works such as 'Psychology and national problems' (1936), Symbols of Transformation (1952), and Aion (1950). I finally make some suggestions concerning Jung's apparent hermeneutic tendency to apply the construct of the mana personality to collective historical phenomena.

Ceci est la deuxième partie d'un article qui cherche à fournir une structure pour la compréhension d'un concept très intéressant et pourtant peu étudié de la psychologie analytique de Jung, à savoir la « personnalité mana ¼, et pour une réflexion fondamentale sur ce concept. Je me penche ici sur des questions concernant le « complexe du sauveur ¼, questions abordées dans le séminaire de Jung sur le Zarathoustra de Nietzsche, et qui concernent à la fois l'analyse psychologique de l'individu et le niveau socio-politique en lien avec l'horizon collectif des années 1930. De plus, je m'intéresse à la continuité de l'analyse de Jung sur ces questions avec d'autres travaux, tels que « Psychologie et problèmes nationaux ¼ (1936), Symboles de la Transformation (1952), et Aïon (1950). Je fais finalement quelques suggestions à propos de la tendance herméneutique manifeste de Jung à appliquer le concept de personnalité mana aux phénomènes historiques collectifs.

Esta es la segunda parte de un artículo que intenta ofrecer un marco de referencia para la compresión de, y una reflexión seminal sobre, un constructo de la psicología analítica de Jung, sumamente interesante y todavía poco explorado, denominado 'personalidad mana'. Aquí tomo en consideración algunos puntos con relación al 'complejo de sabio', desarrollados en el seminario sobre el Zarathustra de Nietzsche, que conciernen tanto al análisis del individuo y al nivel socio-político relativo al horizonte colectivo de 1930. A su vez, considero la continuidad del análisis de Jung sobre dichos temas en otros trabajos como 'Psicología y los problemas nacionales' (1936), Símbolos de Transformación (1952), y Aion (1950). Finalmente, expreso algunas sugerencias con respecto a la tendencia hermenéutica aparente en Jung para aplicar el constructo de la personalidad mana al fenómeno colectivo histórico.

The construct of the 'mana personality' in Jung's works: a historic-hermeneutic perspective. Part I.

According to Jung, the 'mana personality' represents an archetypal phase of the individuation process of remarkable interest in psychological, hermeneutic and theoretical terms. This figure is characterized by a high initiatic potential that fosters the approximation of the consciousness of the Self. At the same time, it entails a risk of psychic inflation or of 'similarity to God'. In this article, divided in two parts, I deal with those aspects through a reconstruction of the development of this notion within Jung's published works, adopting a primarily chronological and, secondarily, thematic approach moving from a textual analysis of relevant passages. In this first part, I consider some passages which deal mainly with the risks of the assimilation of the unconscious in 'La structure de l'inconscient' (1916) that preceded the successive proper treatment of the mana personality's notion presented, and here examined, in 'The relations between the ego and the unconscious' (1928). Successively, I take into consideration some further issues related to it discussed by Jung in 'The structure of the psyche' (1928/1931), 'Archaic man' (1931), and 'Nietzsche's Zarathustra'.

Selon Jung, la « personnalité mana ¼ représente une phase archétypale du processus d'individuation, phase d'un intérêt psychologique, herméneutique et théorique remarquable. Cette figure est caractérisée par un haut potentiel initiatique qui nourrit l'approximation de la conscience du Soi. En même temps, elle comporte le risque d'une inflation psychique, d'une « parenté avec Dieu ¼. Dans cet article, qui est divisé en deux parties, je m'occupe de ces aspects au travers de la reconstruction du développement de cette notion dans les écrits publiés de Jung, adoptant principalement une approche chronologique mais aussi une approche thématique à partir d'une analyse textuelle de passages pertinents. Dans cette première partie, j'examine les passages qui s'occupent surtout des risques d'assimilation de l'inconscient dans « La structure de l'inconscient ¼ (1916) qui a précédé le véritable traitement de la notion de personnalité mana. Celle-ci est ici examinée dans « Dialectique du moi et de l'inconscient ¼ (1928). Je prends ensuite en compte des points qui s'y rapportent et qui sont explorés par Jung dans « La structure de l'âme ¼ (1928/1931), « L'homme archaïque ¼ (1931), et dans «Le Zarathoustra de Nietzsche ¼.

De acuerdo a Jung, la 'personalidad mana' representa una fase arquetipal del proceso de individuación, de un interés remarcable en términos psicológicos, hermenéuticos y teóricos. Esta figura es caracterizada por un alto potencial iniciático que promueve la aproximación de la conciencia del Sí Mismo. Al mismo tiempo, conlleva el riesgo de inflación psíquica o de 'similitud con Dios'. En el presente artículo, dividido en dos partes, trato con dichos aspectos a través de la reconstrucción del desarrollo de esta noción en las obras publicadas de Jung, adoptando un abordaje, inicialmente cronológico y en segunda instancia temático, a través del análisis textual de pasajes relevantes. En esta primera parte, considero algunos pasajes, los cuales dan cuenta de los riesgos de la asimilación del incosnciente en 'La estructura del inconsciente' (1916) que precede el tratamiento sucesivo y correcto de la noción de 'personalidad mana', presentada, y aquí examinada, en 'La relación entre el ego y el inconsciente' (1928). Sucesivamente, tomo en consideración otras cuestiones relacionadas con ésta expresadas por Jung en 'La estructura de la psique' (1928/1931), 'Hombre Arcaico' (1931), y el Zarathustra de Nietzsche.

Mucopolysaccharidosis VI: the Italian experience.

The current paper describes the natural history and management of mucopolysaccharidosis VI (MPS VI) in all patients currently diagnosed with the disease in Italy. Nine patients (5.5-14.4 years) were included in the data review in March 2008. Gestational and perinatal data were normal for all patients. Median age at diagnosis was 1.9 years. During the course of the disease, all patients developed coarsened facial features, short stature, heart valve disease, eye problems, musculoskeletal problems, hepatosplenomegaly and neurological abnormalities. All patients received rhASB enzyme replacement therapy (ERT) and showed improvement or stabilisation in clinical manifestations after onset of therapy. The most frequently reported improvements were increased joint mobility and reduced hepatosplenomegaly. No relevant safety issues of ERT were reported. In conclusion, patients in Italy with MPS VI are diagnosed early in life. All patients have access to ERT and appear to benefit from this therapy.

Clinical phenotype correlates to glycoprotein phenotype in a sib pair with CDG-Ia.

Congenital disorder of glycosylation (CDG) type Ia (PMM2 mutations) is the most common genetic disorder of protein N-glycosylation. The wide clinical spectrum with mild to severe impairment of neurological function and extensive allelic heterogeneity hamper phenotype-genotype comparison. We report on two male adult siblings with the PMM2 mutations c. 385G > A (p.V129M) and c. 422G > A (p.R141H) and partially different clinical phenotype. Patient 2 has a more severe degree of neurological and systemic involvement and a more pronounced decrease in levels of serum glycoproteins. MALDI-TOF mass spectrometry of serum transferrin and alpha-1-antitrypsin shows more pronounced glycosylation defects in the more severely affected patient. Glycoproteomic analysis may reveal differences in CDG-Ia patients with different disease severity and might endorse clinical characterization of CDG-Ia patients.

A double-blind, parallel, multicenter comparison of L-acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys.

Attention deficit hyperactivity disorder (ADHD) is a frequent behavioral problem in young boys with fragile X syndrome (FXS), and its treatment is critical for improving social ability. The short-term efficacy of stimulant medications like methylphenidate (MPH) is well established in children with ADHD. FXS boys treated with MPH have improved attention span and socialization skills; however their mood becomes unstable at higher doses. Therefore, alternative pharmacological treatment of ADHD symptoms is desirable. A recent study showed that carnitine has a beneficial effect on the hyperactive-impulsive behavior in boys with ADHD without side effects. Our previous placebo-controlled trial indicated that L-acetylcarnitine (LAC) reduces hyperactivity in FXS boys. The objective of this study was to determine the efficacy of LAC in a larger sample of FXS boys with ADHD. The study design was randomized, double blind placebo controlled, parallel, and multicenter (with eight centers involved in Italy, France, and Spain). Sixty-three FXS males with ADHD (aged 6-13 years) were enrolled; 7 patients dropped out, 56 completed the one-year treatment, and 51 were included in the statistical analysis. Both groups improved their behavior, showing that psychosocial intervention has a significant therapeutic effect. However, we observed a stronger reduction of hyperactivity and improvement of social behavior in patients treated with LAC, compared with the placebo group, as determined by the Conners' Global Index Parents and the Vineland Adaptive Behavior Scale. Our results show that LAC (20-50 mg/kg/day) represents a safe alternative to the use of stimulant drugs for the treatment of ADHD in FXS children.

Recurrent facial nerve palsy associated with anti-GQ1b IgG antibodies.

Recurrent facial nerve palsy (RFNP) in childhood is usually considered to be a benign disorder. We report a 13-year-old female affected with RFNP in the absence of other neurologic signs, in which elevated serum IgG and IgM anti-GQ1b antibodies were detected. To our knowledge, this is the first example in the literature of RFNP, associated with anti-GQ1b IgG antibodies. The possible role of anti-GQ1b antibodies in isolated cranial neuropathy is discussed.

Subgaleal hematoma in a child with Sturge-Weber syndrome: to prevent stroke-like episodes, is treatment with aspirin advisable?

CASE REPORT: A subgaleal hematoma (SGH) occurred in a young patient with Sturge-Weber syndrome (SWS) who was treated with aspirin after a mild head trauma. MATERIALS AND METHODS: A 4-year-old child with SWS, who was chronically treated with aspirin at an antiplatelet dosage of 3 mg/kg per day, presented with extensive SGH and significant anemia after a mild head trauma. RESULTS AND CONCLUSION: It is conceivable that the minor head trauma and chronic use of aspirin caused the SGH. Based on this event, the chronic use of aspirin in young patients with SWS, as suggested to prevent stroke-like episodes, is disputable.

Expanded Newborn Screening Using Tandem Mass Spectrometry: Seven Years of Experience in Eastern Sicily.

The expanded newborn screening for selected inborn errors of metabolism (IEM) in Sicily was introduced in 2007 by a Regional project entitled "Early detection of congenital metabolic diseases: expanded neonatal screening". It established two newborn screening laboratories, for Western and Eastern Sicily, which started their activity in 2011. Here we present the results of expanded screening (excluding phenylketonuria (PKU)) of the Eastern laboratory from January 2011 to December 2017. Our data highlight the importance of the expanded newborn screening as a basic health program to avoid the underestimation of rare diseases and the need of further investigations even when there are no textbook alterations of the metabolic profiles. We performed our analysis on dried blood spot by tandem mass spectrometry, according to Italian guidelines. A total of 196 samples from 60,408 newborns gave positive screening results (recall rate 0.32%) while 12 babies were true positive, including 2 newborns whose mothers resulted in being affected by a metabolic disease. The overall frequency of IEM found in the screening panel was 1:6041 (mothers excluded) or 1:5034 (mothers included). The introduction of MS/MS technology in Sicily has significantly increased the detection of inherited metabolic disorders, including those not previously covered, with a predictable improved outcome for several disorders.

A single mutation in the GALC gene is responsible for the majority of late onset Krabbe disease patients in the Catania (Sicily, Italy) region.

A high proportion of patients with late onset forms of Krabbe disease is observed in a region north of Catania in Sicily. Molecular analysis in five families from this region shows that this condition is mainly due to a not previously described p.Gly41Ser substitution in the GALC gene that abolishes catalytic activity of the galactocerebrosidase enzyme, as shown by expression studies. Three patients were homozygous for this mutation, the other two were heterozygous, one with a frameshift mutation and one with a missense mutation on the second allele. Therefore, the mutation must be a mild one since it leads to late onset disease in all patients. In addition, it is on a unique haplotype indicating that it represents a founder mutation. This is also supported by the fact that the mutation was not found in three late onset patients from other regions in Sicily, in whom four novel mutations were identified.

Wolf-Hirschhorn syndrome-associated chromosome changes are not mediated by olfactory receptor gene clusters nor by inversion polymorphism on 4p16.

The basic genomic defect in Wolf-Hirschhorn syndrome (WHS), including isolated 4p deletions and various unbalanced de novo 4p;autosomal translocations and above all t(4p;8p), is heterogeneous. Olfactory receptor gene clusters (ORs) on 4p were demonstrated to mediate a group of WHS-associated t(4p;8p)dn translocations. The breakpoint of a 4-Mb isolated deletion was also recently reported to fall within the most distal OR. However, it is still unknown whether ORs mediate all 4p-autosomal translocations, or whether they are involved in the origin of isolated 4p deletions. Another unanswered question is whether a parental inversion polymorphism on 4p16 can act as predisposing factor in the origin of WHS-associated rearrangements. We investigated the involvement of the ORs in the origin of 73 WHS-associated rearrangements. No hotspots for rearrangements were detected. Breakpoints on 4p occurred within the proximal or the distal olfactory receptor gene cluster in 8 of 73 rearrangements (11%). These were five t(4p;8p) translocations, one t(4p;7p) translocation and two isolated terminal deletions. ORs were not involved in one additional t(4p;8p) translocation, in a total of nine different 4p;autosomal translocations and in the majority of isolated deletions. The presence of a parental inversion polymorphism on 4p was investigated in 30 families in which the 4p rearrangements, all de novo, were tested for parental origin (7 were maternal and 23 paternal). It was detected only in the mothers of 3 t(4p;8p) cases. We conclude that WHS-associated chromosome changes are not usually mediated by low copy repeats. The 4p16.3 inversion polymorphism is not a risk factor for their origin.

Cutaneous vasculitis associated with Mycoplasma pneumoniae infection: case report and literature review.

Mycoplasma pneumoniae is an important bacterial agent that causes pneumonia in pediatric patients; it can also affect other organs or systems. Extrapulmonary manifestations include neurological, cardiac, hematologic, renal, gastrointestinal, osteoarticular, cutaneous, and ocular involvement. This report presents a 7-year-old male affected with cutaneous and retinal vasculitis due to M pneumoniae infection without pulmonary detection. The available literature on cutaneous vasculitis and M pneumoniae infection is also reviewed.

Co-infection with Mycoplasma pneumoniae and cytomegalovirus resulting in an acute demyelinating polyneuropathy in a pediatric patient.

A co-infection with Mycoplasma pneumoniae and cytomegalovirus (CMV) resulting in an acute demyelinating polyneuropathy is reported in an immunocompetent girl. Two months following a respiratory infection, the patient showed a symptomatology consisting of weakness in lower limbs, followed by facial asymmetry and arm weakness. Serum M. pneumoniae antibodies were elevated and active CMV infection was diagnosed by polymerase chain reaction (PCR) performed on cerebrospinal fluid. Treatment with oral clarithromycin, intravenous immunoglobulins and ganciclovir was associated with rapid improvement and complete recovery. It is very probable that clinical findings were secondary to the reactivation of CMV caused by persistent M. pneumoniae infection in the respiratory tract. This may be the first report in the pediatric literature of a co-infection of M. pneumoniae and CMV resulting in peripheral nervous system involvement.