Natural history of neurofibromatosis type 2 with onset before the age of 1 year.

Neurofibromatosis type 2 (NF2) with onset before the first year of life has been anecdotally reported in the literature. We (a) prospectively (years 1997-2012) followed up three unrelated NF2 children, all harbouring NF2 gene mutations whose onset of disease was before age 1 year, and (b) systematically reviewed published reports on NF2 in the youngest age group (i.e. onset <1 year). The present three children had (1) small (<1 cm), bilateral vestibular schwannomas (VSs) detected (as an incidental finding) at magnetic resonance imaging (MRI) by the age of 4 to 5 months that were asymptomatic for 10 to 14 years, with sudden and rapid (<12 months) progression in two cases at the age of 11 and 15 years, respectively; (2) development of large numbers of skin NF2 plaques mainly in atypical locations (i.e. face, hands, legs and knees), which reverted to normal skin appearance at the time of VSs progression; (3) lens opacities (n = 1) and NF2 retinal changes (n = 2) detected as early as age of 3-4 months; (4) diffuse (asymptomatic) high signal lesions at brain MRI in the periventricular regions (alike cortical dysplasia); and (5) unaffected first-degree relatives who did not harbour NF2 gene abnormalities. This represents the youngest NF2 group with the longest prospective follow-up so far reported. NF2 may present as a congenital form with bilateral VSs presenting as early as the first months of life and with natural history different to that which occurs in classical NF2.

Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection.

Gelastic epilepsy are focal seizures manifesting as recurrent brief seizures starting as laughter or grimaces. They are most commonly associated with other types of seizures and can be secondary to infectious, malformative, metabolic, or neoplastic processes involving the central nervous system. We report on an 18-month-old girl who presented since the age of 2 months with multiple, recurrent, unprovoked episodes of stereotypical laughter. Brain magnetic resonance study revealed an hypothalamic hamartoma. Endoscopic tumor disconnection of the hamartoma resulted in rapid resolution of neurological symptomatology.

Denosumab and Zoledronic Acid Differently Affect Circulating Immune Subsets: A Possible Role in the Onset of MRONJ.

This work investigated whether the anti-resorptive drugs (ARDs) zoledronic acid (Zol) and denosumab (Dmab) affect differently the levels of circulating immune cell subsets, possibly predicting the risk of developing medication-related ONJ (MRONJ) during the first 18 months of treatment. Blood samples were collected from 10 bone metastatic breast cancer patients receiving cyclin inhibitors at 0, 6, 12, and 18 months from the beginning of Dmab or Zol treatment. Eight breast cancer patients already diagnosed with MRONJ and treated with cyclin inhibitors and ARDs were in the control group. PBMCs were isolated; the trend of circulating immune subsets during the ARD treatment was monitored, and 12 pro-inflammatory cytokines were analyzed in sera using flow cytometry. In Dmab-treated patients, activated T cells were stable or increased, as were the levels of IL-12, TNF-α, GM-CSF, IL-5, and IL-10, sustaining them. In Zol-treated patients, CD8+T cells decreased, and the level of IFN-γ was undetectable. γδT cells were not altered in Dmab-treated patients, while they dramatically decreased in Zol-treated patients. In the MRONJ control group, Zol-ONJ patients showed a reduction in activated T cells and γδT cells compared to Dmab-ONJ patients. Dmab was less immunosuppressive than Zol, not affecting γδT cells and increasing activated T cells.

Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients.

The term twin spotting refers to phenotypes characterized by the spatial and temporal co-occurrence of two (or more) different nevi arranged in variable cutaneous patterns, and can be associated with extra-cutaneous anomalies. Several examples of twin spotting have been described in humans including nevus vascularis mixtus, cutis tricolor, lesions of overgrowth, and deficient growth in Proteus and Elattoproteus syndromes, epidermolytic hyperkeratosis of Brocq, and the so-called phacomatoses pigmentovascularis and pigmentokeratotica. We report on a 28-year-old man and a 15-year-old girl, who presented with a previously unrecognized association of paired cutaneous vascular nevi of the telangiectaticus and anemicus types (naevus vascularis mixtus) distributed in a mosaic pattern on the face (in both patients) and over the entire body (in the man) and a complex brain malformation (in both patients) consisting of cerebral hemiatrophy, hypoplasia of the cerebral vessels and homolateral hypertrophy of the skull and sinuses (known as Dyke-Davidoff-Masson malformation). Both patients had facial asymmetry and the young man had facial dysmorphism, seizures with EEG anomalies, hemiplegia, insulin-dependent diabetes mellitus (IDDM), autoimmune thyroiditis, a large hepatic cavernous vascular malformation, and left Legg-Calvé-Perthes disease (LCPD) [LCPD-like presentation]. Array-CGH analysis and mutation analysis of the RASA1 gene were normal in both patients.

Generalised epilepsy with febrile seizures plus (GEFS(+)): molecular analysis in a restricted area.

PURPOSE: Mutation analysis of the SCN1B, SCN1A and GABRG2 genes in children affected by Genetic (Generalised) Epilepsy with Febrile Seizures plus (GEFS(+)) and their affected and some unaffected family members, coming from a restricted geographic area, was performed. METHODS: Eight GEFS(+) families (58 members) diagnosed according to current GEFS(+) criteria were studied. RESULTS: A heterozygous point mutation A2336G was detected in exon 13 of the SCNA1 gene in three affected members of one family but not in their unaffected relatives; a novel Ile1944Thr mutation was located within the intracellular C-terminal region of the SCNA1 gene in the proband and his healthy father in a second family. In the former family, the proband had dysmorphic features including large forehead, large nasal bridge, pointed nasal tip, triangular nostrils, deep nasolabial folds, thin upper lips with large mouth, congenital gingival hyperplasia with wide gingiva and mental retardation, abnormalities not previously listed in the clinical spectrum of GEFS(+). CONCLUSIONS: Our study confirms that just a few GEFS(+) families have mutations in the five genes classically known and reinforces the genetic and also the phenotypic variability of GEFS(+) featuring clinical manifestations. Question rises whether the cognitive problems seen in two siblings and dysmorphic features in one of them may be related to the channelopathy as it occurs in other well-known ion channel disorders.

Primary headache: role of investigations in a cohort of young children and adolescents.

BACKGROUND: We report a study conducted in children and adolescents who are affected by primary headaches. The aim was to establish the most useful investigations for diagnosing headaches. METHODS: The current study involved 300 consecutively hospitalized children and adolescents selected according to the criteria of the second edition of the International Classification of Headache Disorders. The following examinations were performed in all patients: full ophthalmologic; brain magnetic resonance imaging (MRI); electroencephalography; echocardiogram; and electrocardiogram. Dental, otorhinolaryngology, echocardiography of the supra-aortic trunks, abdominal ultrasound, and visual- and auditory-evoked potentials were carried out in patients according to the clinical signs associated with headache. RESULTS: In a large number of cases routine laboratory analysis and neurophysiologic investigations were within the normal value when neurologic examination was normal. Electroencephalography, ophthalmologic studies and cerebral MRI are advisable as they can reveal precocious pathologic events, even in the absence of evident or alarming clinical signs. CONCLUSION: As widely reported in the literature, most of these investigations may be of little clinical value, but the authors reasoned that electroencephalography, ophthalmologic investigations and a cerebral MRI may be noteworthy because such studies may reveal a precocious pathologic event which can change the prognostic value of the headache. In addition, negative results on cerebral MRI may relieve the anxiety of parents and in turn may positively influence the clinical course of headache in children and adolescents.

Alu-element insertion in an OPA1 intron sequence associated with autosomal dominant optic atrophy.

PURPOSE: Autosomal dominant optic atrophy (ADOA) is the most common form of hereditary optic neuropathy caused by mutations in the optic atrophy 1 (OPA1) gene. It is characterized by insidious onset with a selective degeneration of retinal ganglion cells, variable loss of visual acuity, temporal optic nerve pallor, tritanopia, and development of central, paracentral, or cecocentral scotomas. Here we describe the clinical and molecular findings in a large Italian family with ADOA. METHODS: Routine ophthalmologic examination and direct sequencing of all coding regions of the OPA1 gene were performed. Further characterization of a new OPA1 gene insertion was performed by reverse transcription-PCR (RT-PCR) of RNA from patients and control subjects. RESULTS: We identified an Alu-element insertion located in intron 7 of OPA1 causing an in-frame deletion of exon 8 in 18 family members. CONCLUSIONS: The predicted consequence of this mutation is the loss of the guanosine triphosphatase (GTPase) activity of OPA1. Alu insertions have been reported in the literature as causing human genetic disease. However, this is the first report of a pathogenic OPA1 gene mutation resulting from an Alu insertion.

Role of probiotics in pediatric patients with Helicobacter pylori infection: a comprehensive review of the literature.

BACKGROUND: The current guidelines suggest the use of triple therapy as first choice treatment of Helicobacter pylori infection, although the eradication failure rate is more than 30%. Current interest in probiotics as therapeutic agents against H. pylori is stimulated not only by the clinical data showing efficacy of some probiotics in different gastrointestinal diseases but also by the increasing resistance of pathogenic bacteria to antibiotics, thus the interest for alternative therapies is a real actual topic. AIM: To review in vitro and in vivo studies on the role of probiotics in H. pylori infection focusing on the paediatric literature. MATERIALS AND METHODS: Pre-clinical and clinical paediatric studies in English assessing the role of probiotics in H. pylori infection identified by MEDLINE search (1950-2009) were reviewed. RESULTS: In vitro studies demonstrated an inhibitory activity of probiotics on H. pylori growth and that this effect is extremely strain specific. Available data in children indicate that probiotics seems to be efficacious for the prevention of antibiotic associated side-effects, and might be of help for the prevention of H. pylori complications by decreasing H. pylori density and gastritis, and for the prevention of H. pylori colonization or re-infection by inhibiting adhesion to gastric epithelial cells. There is no clear evidence that probiotics may increase the H. pylori eradication rate. CONCLUSION: Both in vitro and in vivo studies provide evidence that probiotics may represent a novel approach to the management of H. pylori infection.

The neurology of coeliac disease in childhood: what is the evidence? A systematic review and meta-analysis.

AIM: The aim of this article was to review and conduct a meta-analysis of the paediatric literature on the neurology of coeliac disease. METHOD: We conducted a review of paediatric studies published in English assessing neurological illness in coeliac disease identified through a MEDLINE search (1950-2009). Calculation of computed relative risk, odds ratio, and risk difference was performed using the fixed effect method if applicable. RESULTS: Fifteen studies were analysed (11 772 participants). The meta-analysis showed that (1) the relative risk of epilepsy in individuals with coeliac disease, and of coeliac disease in individuals with epilepsy, compared with the general population, was 2.1 and 1.7, respectively, and the risk difference was close to zero, indicating that it was probably a chance association; and (2) the relative risk of headache in individuals with the disease compared with comparison groups was 3.2. In two studies, cerebellar ataxia was documented in 2.7 to 5.4% of participants; in two further studies, the risk of cerebellar dysfunction was zero. Two studies found an association between coeliac disease and peripheral neuropathy. Brain white matter lesions were recorded in two other studies. An association between autism and coeliac disease is disputed. Interpretation Children with coeliac disease are at risk of developing neurological complications, but the risk is lower than in adulthood. The discrepancy might be due to short disease duration, early elimination of gluten from the diet, stricter adherence to diet, or different susceptibility to immune-mediated disorders.

Microcephaly, sensorineural deafness and Currarino triad with duplication-deletion of distal 7q.

Currarino syndrome (CS) is a peculiar form of caudal regression syndrome [also known as autosomal dominant sacral agenesis (OMIM no. 176450)] characterised by (1) partial absence of the sacrum with intact first sacral vertebra, (2) a pre-sacral mass and (3) anorectal anomalies (Currarino triad). We studied a 3-year-old girl with Currarino triad who had additional systemic features and performed array comparative genomic hybridisation to look for chromosomal abnormalities. This girl had the typical spectrum of anomalies of the CS including (a) partial sacral agenesis (hemisacrum with remnants of only sacral S1-S2 vertebrae and a residual S3 vertebral body) associated with complete coccygeal agenesis, (b) pre-intrasacral dermoid, (c) intra-dural lipoma, (d) ectopic anus and (e) tethered cord. She had, in addition, pre- and post-natal growth impairment (<3rd percentile), severe microcephaly (<-3 SD) with normal gyration pattern and lack of cortical thickening associated with a hypoplastic inferior vermis, facial dysmorphism, sensorineural deafness and decreased serum levels of IGF-1. A de novo 10.3-Mb duplication of 7q34-q35 and an 8.8-Mb deletion on 7q36 were identified in this patient. The Homeobox HLXB9 (CS) gene is contained within the deletion accounting for the CS phenotype including microcephaly. The spectrums of associated abnormalities in the IGF-1 deficiency growth retardation with sensorineural deafness and mental retardation syndrome (OMIM no. 608747) are discussed. To the best of our knowledge, this is the first reported case of a patient with distal 7q chromosomal imbalance and features of CS triad (including microcephaly) and the first documented case of a patient with normal gyration pattern microcephaly. The spectrum of associated anomalies in this newly recognised phenotype complex consists of growth failure, typical facial anomalies with additional (previously unreported) nervous system abnormalities (e.g. sensorineural deafness) and somatomedin C deficiency.

A boy born with multiple lesions of atrophoderma.

AIMS: The Atrophodermas include a large group of disorders appearing as localized or widespread depressed skin areas and characterized by underlying dermal atrophy. The present study aims to report a peculiar form of previously unreported focal dermal atrophy. METHODS: We studied over a period of 5 years a boy who manifested, since birth, multiple hypopigmented cutaneous atrophic lesions of the atrophoderma type in a mosaic distribution over the body and the legs. RESULTS: This boy did no develop other cutaneous or systemic stigmata except for an idiopathic thrombocytopenic purpura (ITP) manifested at age 2 years. Full serum, metabolic and infective analyses; full ophthalmological examination; ultrasound examination of the heart and internal organs; skeletal x-rays; brain magnetic resonance imaging; and DNA analysis of the PORCN (Focal Dermal Hypoplasia - FDH) gene in this boy yielded normal results. Pathological analysis of multiple skin specimens from an affected area revealed slightly reduced dermal thickness; hyperpigmentation of the basal layer; homogenized and disarrayed collagen bundles; perivascular chronic infiltrates of lymphocytes and histiocytes; and normal skin appendages. Currently, the child is healthy; he has mildly improved skin status with less-evident skin depression throughout the lesion areas and no further complication has been recorded. The histological and clinical appearance of the skin lesions and the course were against any known disorder in the group of the atrophodermas. CONCLUSIONS: The cutaneous lesions seen in this boy represent a possibly new congenital skin disorder characterized by multiple, benign areas of focal dermal atrophy in a mosaic distribution.

Recurrent obstructive hydrocephalus in a 4-month-old infant.

INTRODUCTION: Transient, recurrent or permanent causes of hydrocephalus in children are usually due to tumours, cerebral bleeding or colloid cysts and complications of infectious meningitis or secondary to poisoning. Recurrent, obstructive hydrocephalus is very rare. CASE REPORT: We report a 4-month-old boy who suffered at least three different episodes of obstructive hydrocephalus presumably caused by intermittent valvular blockage of the normal aqueduct cerebrospinal flow as indirectly demonstrated by serial standard and dynamic brain imaging studies. In addition, he had congenital left hydronephrosis secondary to congenital ureteropelvic junction stenosis. The child underwent an endoscopic third ventriculostomy with only transient post-surgical complications (i.e. central diabetes insipidus). DISCUSSION: The neurological symptoms rapidly improved after surgery, and the child is currently doing well with normal psychomotor development.

Neonatal autoimmune hypothyroidism: a patient report.

BACKGROUND: Acquired primary hypothyroidism in neonates and infants under 3 years of age is very rare. Herein we report the case of an infant female affected by acquired autoimmune hypothyroidism. PATIENT REPORT: The infant was transferred to the Pediatric Clinic, University of Catania, Italy for evaluation of dysmorphic features, growth and motor retardation, and hypothyroidism on laboratory testing. Neonatal screening test for TSH and PKU was negative. An ultrasound scan showed a non-homogeneous thyroid gland which was increased in volume. Based on the laboratory results, the diagnosis of autoimmune hypothyroidism was made and L-thyroxine treatment was initiated at 50 microg/day. CONCLUSIONS: Autoimmune hypothyroidism in infancy is rare, but early recognition and therapy are essential to prevent neurologic damage and growth deficits. In this patient we would like to underline the early age of appearance of autoimmune thyroid disease and the possible onset of pathologic events before birth.

Italian consensus conference on epilepsy and pregnancy, labor and puerperium.

To facilitate an integrated and rational approach to the care of women with epilepsy of childbearing potential, a group of experts appointed by Italian scientific societies in the fields of epileptology, neonatology, pediatrics, neuropediatrics, child neuropsychiatry, obstetrics, and gynecology held a joint meeting in Santa Trada di Cannitello, Reggio Calabria, Italy, on October 15-16, 2004, with the aim of reaching consensus on the optimal management of these women. An ad hoc system for the classification of available published evidence and the opinions of experts was developed and used to grade recommendations on different aspects related to counseling, diagnostic, and treatment issues. The present document summarizes available evidence on the reciprocal interactions between epilepsy, antiepileptic drugs, fertility, contraception, pregnancy, delivery, breastfeeding, and the offspring. Recommendations are made concerning the information and counseling that should be provided to women with epilepsy with respect to issues related to contraception, conception, pregnancy, labour, and puerperium. More detailed recommendations on the same issues are provided to physicians and other healthcare professionals involved in the care of these women, with special reference to choice of effective contraception, optimization of antiepileptic drug therapy, use of prenatal diagnostic tests and other monitoring procedures, and appropriate management practices in relation to childbirth, puerperium, and the care of the child.

Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue.

OBJECTIVES: To establish the prevalence of headache in children with celiac disease (CD), the response to a gluten-free diet, and the prevalence of CD in children affected by headache. METHODS: This hospital-based study included 2 steps. In the retrospective part, 354 children with CD answered a questionnaire investigating the presence of headache before and after the gluten-free diet. The same questionnaire was administered to 200 healthy children matched for sex and age. In the prospective part, 79 children affected by headache were screened for CD by antitransglutaminase IgA. Diagnosis of CD was confirmed by duodenal biopsy; before starting a gluten-free diet patients underwent a brain positron emission tomography study. After 6 months of follow-up children were reevaluated for the presence of headache. RESULTS: Overall, 88 patients with CD complained of headaches before the diagnosis of CD as compared with 16 in the control group (24.8% vs 8%, P < 0.001). After the institution of a gluten-free diet, the headaches significantly improved in 68 children (77.3%), of whom 24 (27.3%) were headache-free during the study period. Four of 79 (5%) headache patients were found to have CD compared with 0.6% of the general population (P = 0.005). The brain positron emission tomography studies did not show any anomalies. During the follow-up, headaches improved in all 4 children with CD. CONCLUSIONS: We recorded -- in our geographical area -- a high frequency of headaches in patients with CD and vice versa with a beneficial effect of a gluten-free diet. Screening for CD could be advised in the diagnostic work-up of patients with headache.

Infantile spasms in the setting of Sturge-Weber syndrome.

INTRODUCTION: The prevalence and outcome of the most frequent type of epilepsy in infancy-infantile spasms (IS)-are well characterized in the setting of most neurocutaneous disorders. By contrast, still there is no study describing the natural history of IS in the setting of Sturge-Weber syndrome (SWS). MATERIALS AND METHODS: Two patients with SWS and IS were identified in our series and five in the literature. The aim of study is to evaluate the clinical, electroencephalographic (EEG) and imaging features of our cases and to compare our cases with those described in the literature. IS in the setting of SWS is an uncommon but possible event (2/19 patients seen over 13 years in our institutions). RESULTS: We confirmed the correlation between IS and severity of SWS cutaneous and neural (extension of leptomeningeal capillary malformation) phenotype. IS in SWS seems to be atypical both from a clinical viewpoint (they are asymmetric) and from a laboratory viewpoint (EEG is not classically hypsarrhythmic).

Neurofibromatosis type 1 and infantile spasms.

BACKGROUND: There is no agreement on the prevalence, natural history and outcome of infantile spasms (IS) in neurofibromatosis type 1 (NF1). By contrast, its prevalence and outcome are well characterised in the setting of other neurocutaneous disorders (e.g. tuberous sclerosis). MATERIALS AND METHODS: The aim of the present study was to try to establish a genotype-phenotype correlation in IS in the setting of NF1. A retrospective (years 1990-2000) and prospective (years 2000-2006) study in three paediatric centres in Italy were taken as referral populations for: (1) children with NF1 and (2) neurological problems in childhood. RESULTS: Ten NF1 patients have had IS. The calculated population-based: (1) prevalence of IS in NF1 (0.76%) was higher than the reported frequency of IS in the general population (0.02-0.05%) and (2) frequency of NF1 in the IS series in two out of three centres (0.62-0.90%) was lower than the estimated frequencies in the literature (1.5-3.0%). Patients had psychomotor delay preceding the spasms (50%), symmetrical spasms (50%), typical (80%) and modified (20%) hypsarrhythmia and foci of spikes and waves and a good response to corticosteroid treatment (50%). Outcome was good in 30%. Imaging revealed high-signal foci in atypical locations (sub-cortical and central brain regions). Deoxyribonucleic acid analysis revealed three novel NF1 gene mutations without genotype-phenotype correlation. CONCLUSION: Even though the combination of IS and NF1 does not seem to be coincidental, it is certainly an unusual event in NF1--rarer than in other neurocutaneous disorders. Spasms in NF1 are not associated with specific genetic defects.

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.

The power of stories in Pediatrics and Genetics.

On the occasion of the opening ceremony of the 43rd Sicilian Congress of Pediatrics, linked with Italian Society of Pediatrics SIP, SIN, SIMEUP, SIAIP and SINP, held in Catania in November 2015, the Organizing Committee dedicated a tribute to Professor John Opitz and invited him to give a Masters Lecture for the attendees at the Congress. The theme expounded was "Storytelling in Pediatrics and Genetics: Lessons from Aesop and from Mendel". The contribution of John Opitz to the understanding of pediatric clinical disorders and genetic anomalies has been extremely relevant. The interests of Professor John Opitz are linked not only to genetic disorders but also extend to historical medicine, history of the literature and to human evolution. Due to his exceptional talent, combined with his specific interest and basal knowledge in the genetic and pediatric fields, he is widely credited to be one of the best pediatricians in the world.

Clinical heterogeneity in familial congenital ptosis: analysis of fourteen cases in one family over five generations.

This report describes a proband and his family consisting of 14 patients affected with simple congenital ptosis. Pedigree suggests an autosomal dominant pattern with 70-90% penetrance. The family includes patients with both unilateral and bilateral involvement, and cases with and/or without complex synkinesia. Left unilateral preponderance is striking, and pedigree analysis suggests the possibility of a modifier gene determining laterality. This study represents the first report of a large family with congenital autosomal dominant simple ptosis which demonstrates the full clinical spectrum of this condition.