SMC1A epilepsy syndrome: clinical data from a large international cohort.

SMC1A epilepsy syndrome or developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85, OMIM #301044) is an X-linked neurologic disorder associated with mutations of the SMC1A gene, which is also responsible for about 5% of patients affected by Cornelia de Lange syndrome spectrum (CdLS). Only described in female patients, SMC1A epilepsy syndrome is characterized by the onset of severe refractory epileptic seizures in the first year of life, global developmental delay, a variable degree of intellectual disability, and dysmorphic facial features not typical of CdLS. This was a descriptive observational study for the largest international cohort with this specific disorder. The main goal of this study was to improve the knowledge of the natural history of this phenotype with particular attention to the psychomotor development and the epilepsy data. The analyzed cohort shows normal prenatal growth with the subsequent development of postnatal microcephaly. The incidence of neonatal problems (seizures and respiratory compromise) is considerable (51.4%). There is a significant prevalence of central nervous system (20%) and cardiovascular malformations (20%). Motor skills are generally delayed. The presence of drug-resistant epilepsy is confirmed; the therapeutic role of a ketogenic diet is still uncertain. The significant regression of previously acquired skills following the onset of seizures has been observed. Facial dysmorphisms are variable and no patient shows a classic CdLS phenotype. To sum up, SMC1A variants caused drug-resistant epilepsy in these patients, more than two-thirds of whom were shown to progress to developmental and epileptic encephalopathy. The SMC1A gene variants are all different from each other (apart from a couple of monozygotic twins), demonstrating the absence of a mutational hotspot in the SMC1A gene. Owing to the absence of phenotypic specificity, whole-exome sequencing is currently the diagnostic gold standard.

Celiac disease prevalence and predisposing-HLA in a cohort of 93 Williams-Beuren syndrome patients.

Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome's patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.

Burden of care in families of patients with rare genetic diseases: analysis of a large Italian cohort.

In the last decade, the number of children and youth with special health care needs (CYSHCN) is increased as a result of the improvement of neonatal and pediatric assistance. The aim of our study was to describe the burden of care of the families caring a CYSHCN in our country, evaluating their living condition in order to explore socio-economic characteristics, health problems, needs and their adaptation processes trying to reach a balance between the needs of the disabled child and those of the other family members. We administered a questionnaire to the parents of CYSHCN during a routine clinical evaluation. From the analyses of questionnaires obtained, parents were the main caregiver of the children and 43,8% of them reported that they were not getting enough support. Burden of care fell on parents and indeed compilers reported an average level of stress of 3,2 (0-5) and more important, the main reported sources of stress were the concern about the future and health of their children. From the analyses of our population emerged unsatisfied needs of these families and their necessity to be effectively supported and integrated into the social fabric of the community. Social supporting is essential to help managing family stress and is evident the needed of these parents for interventions to directly target caregiver needs through the provision of tailored services, such as respite care opportunity, peer support, financial aid and medical home technologies to improve their quality of life.

Pulmonary function in Williams-Beuren syndrome: Spirometric data of 22 Italian patients.

Williams-Beuren syndrome (WBS) is caused by an haploinsufficiency of the 7q11.2 region which involves the elastin gene (ELN). A deficiency of elastin is a known pathophysiological mechanism of emphysema/chronic obstructive pulmonary disease (COPD). A previous study hypothesized a higher risk of COPD in WBS patients. Herein, this phenomenon was further investigated looking for a possible correlation between COPD and WBS. Dynamic lung volumes (forced vital capacity [FVC], FEV1, FEV1/FVC) were measured in 22 patients (age range 18.9 ± 7.4 years) affected with WBS, genetically confirmed, correlating these parameters to respiratory risk factors. Dyspnea, cough and wheezing were detected in 6/22 (27%) patients. Obstructive and restrictive patterns were identified in 6/22 (27%) and 2/22 (9%) cases, respectively with no evidence of irreversible obstruction. CVF, FEV1 and FEV1/CVF mean values were all normal, with values of 91.3% (n.v. > 80%), 84.2% (n.v. > 80%) and 0.82 (n.v. > 0.7), respectively. The severity of the comorbidities did not show a cause-effect relation with the respiratory patterns, nevertheless patients treated with anti-hypertensive drugs had poorer pulmonary function. Our findings are in accordance with previous observations, showing that emphysema/COPD is not a typical finding in young patients with WBS. However, a respiratory function assessment should be included in the follow-up of WBS patients, especially in adolescents/young adults under treatment with anti-hypertensive drugs.

Children with special health care needs attending emergency department in Italy: analysis of 3479 cases.

BACKGROUND: Although children with special health care needs (CSHCN) represent a minority of the population, they go through more hospitalizations, more admissions to the Emergency Department (ED), and receive a major number of medical prescriptions, in comparison to general pediatric population. Objectives of the study were to determine the reasons for admission to the ED in Italian CSHCN, and to describe the association between patient's demographic data, clinical history, and health services requirements. METHODS: Ad hoc web site was created to collect retrospective data of 3479 visits of CSHCN to the ED in 58 Italian Hospitals. RESULTS: Seventy-two percent of patients admitted to ED were affected by a previously defined medical condition. Most of the ED admissions were children with syndromic conditions (54%). 44.2% of the ED admissions were registered during the night-time and/or at the weekends. The hospitalization rate was of 45.6% among patients admitted to the ED. The most common reason for admission to the ED was the presence of respiratory symptoms (26.6%), followed by gastrointestinal problems (21.3%) and neurological disorders (18.2%). 51.4% of the access were classified as 'urgent', with a red/yellow triage code. Considering the type of ED, 61.9% of the visits were conducted at the Pediatric EDs (PedEDs), 33.5% at the Functional EDs (FunEDs) and 4.6% at the Dedicated EDs (DedEDs). Patients with more complex clinical presentation were more likely to be evaluated at the PedEDs. CSHCN underwent to a higher number of medical procedures at the PedEDs, more in comparison to other EDs. Children with medical devices were directed to a PedED quite exclusively when in need for medical attention. Subjects under multiple anti-epileptic drug therapy attended to PedEDs or FunEDs generally. Patients affected by metabolic diseases were more likely to look for medical attention at FunEDs. Syndromic patients mostly required medical attention at the DedEDs. CONCLUSIONS: Access of CSHCN to an ED is not infrequent. For this reason, it is fundamental for pediatricians working in any kind of ED to increase their general knowledge about CHSCN and to gain expertise in the management of such patients and their related medical complexity.

Complex nutritional deficiencies in a large cohort of Italian patients with Cornelia de Lange syndrome spectrum.

Cornelia de Lange syndrome Spectrum (CdLSp) is characterized by intellectual disability, facial dysmorphisms, and growth impairment. Although eating difficulties are a well-known feature of the disease, there is no data regarding the nutritional deficiencies of these patients. The food intake was tracked using a dietary transcription provided by the family/caregivers, biochemical nutritional parameters were measured with laboratory tests and through an accurate clinical evaluation of the incidence of qualitative and quantitative imbalances in a cohort of 73 patients with CdLSp ware determined. Of these 73, 62 (85%) subjects provided a complete and detailed dietary transcription. In the studied population, a quantitative caloric imbalance in 47/62 (76%) subjects was observed. The caloric intake was low in 27/62 (43%) subjects whereas excessive in 20/62 (33%). Only 15/62 (24%) had an optimum caloric intake. Regarding micronutrients, a calcium intake deficiency in 32% of the patients (20/62) was observed. Blood tests revealed a low iron level in 22/73 (30%) of the patients and 25(OH)D deficiency in 49/73 (67%). Serum hypocalcemia was not evidenced. Qualitative and quantitative imbalances resulted in more frequent than expected in CdLSp patients. A qualitative imbalance was more prevalent in younger patients while in older patients prevailed mainly a quantitative disproportion. We found no statistically meaningful correlation between dietary imbalances, genetic, or clinical parameters. Our findings highlight the need for further studies to evaluate the basal metabolic rate of CdLSp patients and find a correlation with their growth impairment.

Williams-Beuren Syndrome and celiac disease: A real association?

Celiac disease (CD) screening in patients with Williams-Beuren Syndrome (WBS) is suggested, although data described in literature are discordant regarding CD prevalence in WBS. We retrospectively collected data from 101 WBS Italian patients [mean age: 13.5 years], to clarify the CD prevalence in a large cohort. All patients underwent a CD biochemical screening: IgA and anti-transglutaminase reflex antibodies (tTGA). CD-specific HLA typing was available for 42 patients. Small intestinal biopsy was performed in patients according to ESPGHAN guidelines. In 7 WBS patients an overt celiac disease was diagnosed. In 3 patients CD was confirmed by symptoms, HLA-DQ heterodimers and CD specific antibodies title, whereas in 4 patients, it was confirmed by a small intestinal biopsy. CD prevalence in our cohort is 6.9% (7/101). In 42/101 patients the CD-specific HLA typing was available, detecting 29/42 (69%) patients genetically predisposed to CD. The CD prevalence and CD-specific HLA prevalence are both higher than in the general population (p < 0.001; p < 0.001). Our cohort is the most numerous described confirming that the CD risk in WBS patients is significantly greater than in general population. Moreover, our HLA typing results, as well as scientific literature, suggest that the higher CD prevalence in WBS patients might not be intrinsically related to the genetic disease itself but with the higher HLA prevalence. However, HLA typing should be performed in bigger WBS cohorts to confirm this hypothesis. Our data confirms that HLA typing is mandatory in WBS patients and that CD screening should be performed only if genetically predisposed.

Nissen fundoplication in Cornelia de Lange syndrome spectrum: Who are the potential candidates?

Cornelia de Lange spectrum (CdLSp) is a rare genetic condition characterized by intellectual disability, facial dysmorphisms, major malformations, growth impairment, and development delay. Approximately 80% of CdLSp patients have gastroesophageal reflux disease (GERD) with a varied clinical presentation. The aim of this study is to define potential clinical/genetic risk factors based on the clinical phenotype description of CdLSp patients with severe GERD who underwent surgical treatment. We retrospectively collected data from 23 CdLSp patients, 13 females and 10 males. Mean age of the patients undergoing surgical treatment was of 4 years. 21/23 (91%) had a molecular characterization, of which 21/21 (100%) had a NIPBL gene mutation, while 2/23 (9%) did not have a genetical characterization, only a clinical diagnosis. Most of our patients presented a moderate-severe severity score (21/23, 91%) with limb malformations evidenced in 10/23 (44%) of our patients and a moderate-severe intellectual disability in 20/23 (87%). Therefore, CdLSp patients harboring NIPBL variants, upper limb malformations and severe psychomotor delay are more likely to suffer from severe GERD, not responsive to proton pump inhibitors treatment. These features should be considered as clinical markers for potentially severe GERD that might require surgical treatment.

Subcutaneous Immunoglobulin in Infantile Chronic Inflammatory Demyelinating Polyneuropathy: A Case Report.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing sensorimotor disorder presumably due to antibody-mediated reactions. It is a rare condition in children, with estimated prevalence as 0.48 per 100,000 among patients younger than 20 years of age. Recommended treatments include immune modulators, intravenous immunoglobulins (IVIgs), steroids, and plasmapheresis. Management of pediatric CIDP is challenging because of the lack of evidence-based efficacy of the current therapies in children. Because of the rarity of this condition, there are no double-blind randomized studies to support the therapeutic choice as well as to identify the optimal first-line therapeutic regimen. IVIgs are widely used but the intravenous administration is usually uncomfortable, especially for children. Subcutaneous immunoglobulins (SCIgs) have proven to be effective in adults with CIDP and in children affected by antibody deficiencies and other different immune and inflammatory disorders. Herein, we described the case of a 7-year-old boy, affected by CIDP who clinically responded to IVIg but was dependent on this therapy. In order to improve his quality of life, we switched to SCIg with excellent result.

Anthropometric characteristics of newborns with Prader-Willi syndrome.

This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader-Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p < .0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS.

Pediatric GIST presenting as anemia.

Gastrointestinal stromal tumors (GIST) are tumors of the gastrointestinal (GI) tract originating from the myenteric ganglion cells (interstitial cells of Cajal), that are very rare in children and adolescents. The most common clinical manifestation is acute or chronic, overt or occult GI bleeding although these tumors are asymptomatic in 10-30% of patients. We report a case of gastric GIST in a 11-year-old girl presenting with an iron deficiency refractory anemia without gastrointestinal symptoms and stool evidence of GI bleeding that caused a slight diagnostic delay.

Acute myeloid leukemia in Baraitser-Winter cerebrofrontofacial syndrome.

Baraitser-Winter malformation syndrome (BWMS), Fryns-Aftimos syndrome (FA), and craniofrontofacial syndromes (CFFs) have all been recently proposed to be part of the same phenotypic spectrum of Baraitser-Winter cerebrofrontofacial syndrome (BWCFF), which is characterized by facial dysmorphism, ocular coloboma, brain malformations, and intellectual disabilities. In addition to that, the recent discovery of missense mutations in one of the two ubiquitously expressed cytoplasmic ß- and γ-acting-encoding genes ACTB (7p22.1) and ACTG1 (17q25.3) in patients carrying a clinical diagnosis of BWSM, FA, or CCF has provided further evidence that these clinical conditions do indeed belong to the same entity at the molecular level. Two cases of BWCFF patients presenting with malignancies (i.e., acute lymphocytic leukemia and cutaneous lymphoma) have been published thus far. Here, we report a 21-year-old female with molecularly confirmed FA, who developed acute myeloid leukemia (AML). The present finding may indicate that actinopathies could be cancer-predisposing syndromes although small numbers and publication bias should be taken into account. © 2016 Wiley Periodicals, Inc.

14q32.3-qter trisomic segment: a case report and literature review.

BACKGROUND: Segmental duplication of the long arm of chromosome 14 (14q) has commonly been reported to affect the proximal segment of 14q, while distal duplication is a rare condition and often associated with segmental monosomy of other chromosomes. CASE PRESENTATION: We report the clinical and genetic characterization of a 4-year-old male patient with 14q32.3-qter trisomy resulting from an adjacent segregation of a paternal reciprocal translocation (14;21)(q32.1;p12). The child shows minor facial anomalies, severe developmental delay, growth retardation, and a history of congenital hypothyroidism and neonatal transitory hyperglycemic crises. CONCLUSIONS: To the best of our knowledge, only 15 other cases of segmental 14q trisomy were documented. We compared molecularly defined cases to identify a minimal common duplicated region and to find genes with a hypothetical role in the phenotype. The presented case supports the previous suggestion of a pure "distal 14q partial duplication" and underlines the clinical variability.

Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability.

BACKGROUND: Nicolaides-Baraitser and Coffin-Siris syndromes are emerging conditions with overlapping clinical features including intellectual disability and typical somatic characteristics, especially sparse hair, low frontal hairline, large mouth with thick and everted lips, and hands and feet anomalies. Since 2012, mutations in genes encoding six proteins of the BAF complex were identified in both conditions. METHODS AND RESULTS: We have clinically evaluated a cohort of 1161 patients with intellectual disability from three different Italian centers. A strong clinical suspicion of either Nicolaides-Baraitser syndrome or Coffin-Siris syndrome was proposed in 11 cases who were then molecularly confirmed: 8 having de novo missense mutations in SMARCA2, two frame-shift mutations in ARID1B and one missense mutation in SMARCB1. Given the high frequency of the condition we set up a one-step deep sequencing test for all 6 genes of the BAF complex. CONCLUSIONS: These results prove that the frequency of these conditions may be as high as the most common syndromes with intellectual deficit (about 1%). Clinical geneticists should be well aware of this group of disorders in the clinical setting when ascertaining patients with intellectual deficit, the specific facial features being the major diagnostic handle. Finally, this work adds information on the clinical differences of the two conditions and presents a fast and sensitive test for the molecular diagnosis.

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.

Hemostatic abnormalities in Noonan syndrome.

BACKGROUND: A bleeding diathesis is a common feature of Noonan syndrome, and various coagulation abnormalities have been reported. Platelet function has never been carefully investigated. METHODS: The degree of bleeding diathesis in a cohort of patients with Noonan syndrome was evaluated by a validated bleeding score and investigated with coagulation and platelet function tests. If ratios of prothrombin time and/or activated partial thromboplastin time were prolonged, the activity of clotting factors was measured. Individuals with no history of bleeding formed the control group. RESULTS: The study population included 39 patients and 28 controls. Bleeding score was ≥2 (ie, suggestive of a moderate bleeding diathesis) in 15 patients (38.5%) and ≥4 (ie, suggestive of a severe bleeding diathesis) in 7 (17.9%). Abnormal coagulation and/or platelet function tests were found in 14 patients with bleeding score ≥2 (93.3%) but also in 21 (87.5%) of those with bleeding score <2. The prothrombin time and activated partial thromboplastin time were prolonged in 18 patients (46%) and partial deficiency of factor VII, alone or in combination with the deficiency of other vitamin K-dependent factors, was the most frequent coagulation abnormality. Moreover, platelet aggregation and secretion were reduced in 29 of 35 patients (82.9%, P < .01 for all aggregating agents). CONCLUSIONS: Nearly 40% of patients with the Noonan syndrome had a bleeding diathesis and >90% of them had platelet function and/or coagulation abnormalities. Results of these tests should be taken into account in the management of bleeding or invasive procedures in these patients.

Cervical spine malformation in cornelia de lange syndrome: a report of three patients.

Cornelia de Lange syndrome (CdLS) is a complex genetic disease with skeletal involvement mostly related to upper limb malformations. We report on three males with clinical and molecular diagnoses of CdLS. Besides typical CdLS features, all showed different cervical spine malformations. To the best of our knowledge, this is an unusual malformation in the CdLS phenotypic spectrum.

Ganglioglioma of the spinal cord in neurofibromatosis type 1.

The oncologic involvement of the spinal cord in neurofibromatosis type 1 (NF1) is not a typical feature of the disease. Here, we present a case of ganglioglioma of the spinal cord in a child with NF1 and try to define if this tumor can be considered coincidental or not. A 4-year-old boy affected by NF1 was diagnosed with a spinal cord-enhancing tumor extending from C4 to D3, with a disappearance in the T2 MRI sequences of the cerebrospinal fluid signal. The patient underwent a subtotal resection. The pathological exam revealed a ganglioglioma. To the best of our knowledge, only 1 other case of spinal cord ganglioglioma has been described in an NF1 patient. We suggest considering ganglioglioma in the differential diagnosis of an NF1 patient with a spinal cord tumor due to its favorable survival rate, especially in relation to the anatomical and surgical issues of this tumor that do not always entail a gross total resection.