Isabella Vasta

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome–associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

Germline missense mutations affecting KRAS isoform B are associated with a severe noonan syndrome phenotype

Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart disease, and multiple skeletal and hematologic defects. NS is an autosomal dominant trait and is genetically heterogeneous. Gain of function of SHP-2, a protein tyrosine phosphatase that positively modulates RAS signaling, is observed in nearly 50% of affected individuals. Here, we report the identification of heterozygous KRAS gene mutations in two subjects exhibiting a severe NS phenotype with features overlapping those of cardiofaciocutaneous and Costello syndromes. Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions (Val152Gly and Asp153Val) perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor.

Feeding problems and malnutrition in spinal muscular atrophy type II

The aim of the study was to conduct a survey using a dedicated questionnaire to assess feeding difficulties and weight gain in a population of 122 Spinal Muscular Atrophy (SMA) type II patients, aged between 1 and 47 years. All the answers were entered in a database and were analysed subdividing the cohort into age groups (1-5, 6-10, 11-14, 15-19, 20-29, and 30-50 years). Six out of our 122 patients (5%), all younger than 11 years, had weights more than 2SD above the median for age matched controls, whilst 45 (37%) had weights less than 2SD below the median. Chewing difficulties were reported in 34 of the 122 patients (28%) and limitation in the ability to open the mouth in 36 (30%) and both were increasingly more frequent with age. Swallowing difficulties were reported in 30 patients (25%). The results of our survey suggest that a number of patients with SMA type II have limited jaw opening, and chewing and swallowing difficulties. Our findings raise a few issues concerning standards of care that should be implemented in the monitoring and management of feeding difficulties and weight gain.

Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade

Mutations in genes coding for transducers participating in the RAS/MAPK pathway have been identified as the molecular cause underlying a group of clinically related developmental disorders with cognitive deficits of variable severity. To determine the spectrum of cognitive defects associated with dysregulation of this signal cascade, we studied the profile of cognitive abilities in patients with mutations affecting the PTPN11, SOS1, HRAS, KRAS, BRAF, RAF1, and MEK1 genes and phenotype–genotype correlations. Our findings support the observation that heterogeneity in cognitive abilities can be at least partially ascribed to the individual affected genes and type of mutation involved. While mutations affecting transducers upstream of RAS were less frequently associated with mental retardation, mutations in downstream components of the pathway were generally associated with a more severe cognitive impairment. Among patients with a heterozygous PTPN11 mutation, the T468M substitution was associated with a mean IQ significantly higher compared to that of individuals carrying the N308D change. Our study provides insights on the range of cognitive abilities in patients with gene mutations causing dysregulation of RAS signaling suggesting that the presence and severity of cognitive involvement can be predicted in part by the gene involved.

Electroclinical Patterns and Evolution of Epilepsy in the 4p– Syndrome

Summary:  Background: Wolf–Hirschhorn syndrome (WHS) is a well‐known clinical entity caused by partial deletion of the short arm of one chromosome 4 (4p– syndrome). Seizures occur in almost all the cases, but studies on the electroclinical disorder and its evolution are still scarce. We present a longitudinal study of the electroclinical features in 10 children with WHS.

Visual Function in Noonan and LEOPARD Syndrome

The aim of the study was to assess various aspects of visual and visuoperceptual function in patients with Noonan syndrome (NS) or LEOPARD syndrome (LS) with mutations affecting the PTPN11, SOS1 and RAF1 genes. Twenty-four patients were assessed with a battery of tests assessing visual function including ophthalmological and orthoptic evaluation and age appropriate behavioural visual tests, including measures of crowding acuity (Cambridge crowding cards), and stereopsis (TNO test). Twenty-one subjects were also assessed with the visuo-motor integration (VMI) test. Twenty of the 24 patients (83%) had abnormalities of visual function on at least one of the tests used to assess visual function or on ophthalmological examination, and 7 of 21 (33%) also had abnormalities on VMI. Ocular movements and stereopsis were most frequently abnormal (50% and 79%, respectively). Our results suggest that visual and visuoperceptual abilities are commonly impaired in patients with Noonan and LEOPARD syndrome and they are probably related to a multifactorial etiology.

Obstructive Sleep Apnea in Costello Syndrome

Costello syndrome (CS) was initially described by Costello in 1971; it is caused by a germline mutation in HRAS proto‐oncogene. The aim of the present study was to evaluate the respiratory activity during sleep in a group of subjects with CS. We studied 10 consecutive patients, 4 males and 6 females, aged 3–29 years, affected by CS. All patients underwent clinical, neurological, otholaryngologic and radiologic evaluation, and a full‐night polysomnography in the sleep laboratory. Polysomnography showed that seven patients presented a relevant number of respiratory events of obstructive type during sleep. The apnea‐hypopnea index (AHI) ranged from 0 to 19.2 events per hour (mean index = 7.5 ± 6.9 events/hr). In one patient AHI was not evaluable because of tracheostomy. Apnea induced mild or moderate hemoglobin desaturations (mean of lowest SpO2 values = 85.4 ± 5.5%). Only sporadic respiratory pauses of central type were observed (mean number of central apnea per study: 7.2 ± 6.8 events/hr). Sleep structure was fragmented, with a high number of awakenings (mean number of awakenings was 13.2 ± 8.1; of these, 4.8 ± 2.5 lasted longer than 2 min). In all patients, otolaryngologic and radiologic observations revealed one or more sites of narrowing in the upper airways. Our results suggest that Costello patients have a high prevalence of obstructive sleep‐related respiratory disorders, which need to be assessed by means of polysomnography.

Isolated myocardial non-compaction in an infant with distal 4q trisomy and distal 1q monosomy

We report on a female infant with a partial 4q trisomy and 1q monosomy who presented from birth an isolated non-compaction of the left ventricular myocardium (ILVNC). The baby was born at 37 weeks with a birth weight of 2120 g. At the last clinical examination (age 24 months), she presented a senile-like appearance, narrow palpebral fissures, telecanthus, epicanthus, a broad nasal bridge, low set and posterior angulated ears, a long philtrum, and a mouth with a thin vermilion border and dimple below the lower lip (Fig. 1). She also had an anteriorly displaced anus and rocker-bottom feet. Neurological examination disclosed hypotonia and severe mental retardation. Cerebral MRI showed moderate ventricular dilatation and a hypoplastic corpus callosum. 2D-echocardiography revealed multiple, prominent myocardial trabeculations and numerous recesses at the left ventricular apical and mid-ventricular level, perfused by the main left ventricular cavity (Fig. 2). Systolic and diastolic functions were normal. An ECG showed sinus rhythm with non-specific intraventricular conduction delay. No arrhythmias or embolic events occurred. Chromosomes were scored by R (RBG) banding and fluorescence in-situ hybridisation with chromosomes 1 and 4 specific painting probes. The proband’s karyotype (46,XX der (1)(1pter fi 1q43:: 4q31 fi 4qter) revealed an unbalanced segregation of a balanced t(1;4)(q43;q31) translocation detected in the normal father. The patient was trisomic for the 4q31 fi qter region and monosomic for the 1q43 fi 1qter segment.

Ocular manifestations in Wolf-Hirschhorn syndrome

INTRODUCTION Wolf-Hirschhorn syndrome (WHS) multiple congenital anomalies/mental retardation is caused by partial deletion of the short arm of chromosome 4 and can be considered a contiguous gene syndrome, characterized by typical facial appearance, mental retardation, growth delay, and seizures. METHODS We investigated the ocular defects in a population of 10 patients with WHS and analyzed the relationship between ocular findings and the extent of deletion on chromosome 4. RESULTS The ocular abnormalities found included hypertelorism, strabismus, refractive errors, epicanthal folds, proptosis, downslanting palpebral fissures, microphthalmos, microcornea, iris coloboma, optic nerve coloboma, ocular cyst, ptosis, glaucoma, and nystagmus. Different breakpoints of the chromosomal rearrangement were observed in individual patients, ranging from 4p15.1 to 4p16.3, and the size of chromosomal deletion ranged from 2.6 to 26 million base pairs. CONCLUSIONS Congenital glaucoma and colobomatous ocular cysts have rarely been described in WHS patients that were previously reported. In all cases exhibiting strabismus, an exodeviation was present. Comparing genotype with ocular phenotype, a relationship between the size of deletion and the severity of the ocular involvement was observed in all cases but one.

Rhythmic tongue movements during sleep: a peculiar parasomnia in Costello syndrome.

We describe a peculiar parasomnia observed in four Costello infants, characterized by periodic rhythmic movements of the tongue. Ten Costello patients (4 male; age range 9 months to 29 years) underwent 1 full‐night laboratory‐based video polysomnography. The four youngest patients (2 male and 2 female; age range 9–31 months) presented during sleep repeated stereotyped movements of the tongue, producing a sucking‐like or licking‐like movement, mostly during non‐rapid eye movement (NREM) sleep. Rhythmic tongue movements in Costello syndrome show the features of an NREM sleep parasomnia. Tongue movements during sleep probably originate from brainstem structures and could be facilitated by an impaired control of the oropharyngeal and tongue muscles.