Graph theory in paediatric epilepsy: A systematic review.

Graph theoretical studies have been designed to investigate network topologies during life. Network science and graph theory methods may contribute to a better understanding of brain function, both normal and abnormal, throughout developmental stages. The degree to which childhood epilepsies exert a significant effect on brain network organisation and cognition remains unclear. The hypothesis suggests that the formation of abnormal networks associated with epileptogenesis early in life causes a disruption in normal brain network development and cognition, reflecting abnormalities in later life. Neurological diseases with onset during critical stages of brain maturation, including childhood epilepsy, may threaten this orderly neurodevelopmental process. According to the hypothesis that the formation of abnormal networks associated with epileptogenesis in early life causes a disruption in normal brain network development, it is then mandatory to perform a proper examination of children with new-onset epilepsy early in the disease course and a deep study of their brain network organisation over time. In regards, graph theoretical analysis could add more information. In order to facilitate further development of graph theory in childhood, we performed a systematic review to describe its application in functional dynamic connectivity using electroencephalographic (EEG) analysis, focussing on paediatric epilepsy.

Primary Microcephaly with Novel Variant of MCPH1 Gene in Twins: Both Manifesting in Childhood at the Same Time with Hashimoto's Thyroiditis.

This study is a clinical report on twin females affected by primary microcephaly who displayed at molecular analysis of heterozygous novel MCPH1 variant. The twins at the age of 10 years developed, in coincidental time, a diagnosis of autoimmune juvenile thyroiditis. The main clinical features presented by the twins consisted of primary microcephaly with occipitofrontal circumference measuring -2 or -3 standard deviation, facial dysmorphism, typical nonsyndromic microcephaly, and mild intellectual disability. Molecular analysis of the major genes involved in primary microcephaly was performed and the following result was found in the twins: MCPH1 ; chr8.6357416; c.2180 C > T (rs 199861426), p.Pro727. Leu; heterozygous; missense; variant of uncertain significance (class 3). At the age of 10 years, the twins started to have, in coincidental time, marked asthenia and episodes of emotiveness, and laboratory exams disclosed a high level of antithyroid peroxidase leading to the diagnosis of autoimmune juvenile thyroiditis with normal thyroid function. The novel heterozygous MCPH1 variant found in the twins may be directly or indirectly involved in the onset of the primary microcephaly. The thyroid disorder in the twins and its onset, in a coincidental time, confirmed the effect of genetic predisposition on the pathogenesis of the immune thyroiditis.

Genotype-phenotype variable correlation in Wilson disease: clinical history of two sisters with the similar genotype.

BACKGROUND: Wilson disease (WD) is an Autosomal-Recessive disorder due to mutations of ATP7B gene on chromosome 13q14.3. Inadequate protein function leads to low ceruloplasmin blood levels and copper accumulation in liver, basal ganglia and chornea. Main clinical manifestations are hypertransaminasemia, tremors, dysarthria, dystonia and psychiatric symptoms. The phenotypic variability in WD is considerable and its onset can be heterogeneous: the most common type in childhood is the hepatic involvement, followed by the neurological one or others. The presence of a genotype-phenotype correlation has not yet been fully demonstrated. The phenotypic variability may be explained by the intervention of other modifier genes regulating copper metabolism in the presence of mutations ATP7B. CASE PRESENTATION: A streaking phenotypic variability was observed in two Sicilian sisters carrying the same genotype for ATB7B gene [c.3207C > A / c.3904-2A > G]. Although both started to present signs at age 10 years, onset was characterized by neurological signs in the first (tremors, motor incoordination, language and cognitive impairment), while liver involvement has been the only sign in the other. They started the same chelation therapy. After a 20-year follow-up the former is severely affected (MRI evidence of basal ganglia copper deposits and hyperchogenic liver, thrombocytopenia), while the latter presents only a moderate liver enlargement. In literature, the splice mutation c.3904-2A > G is also reported in Egypt population, associated with acute liver failure or chronic hepatic disease, and it could be typical of Mediterranean area, not being reported in other geographical zones. CONCLUSION: Based on our clinical experience in Eastern Sicily, there is a considerable phenotypic variability in WD, even in the presence of an identical genotype. The mutation c.3904-2A > G could be associated with this phenotypic variability in Mediterranean population, but further studies should be conducted. This condition could be explained by the intervention of modifier genes regulating copper metabolism in the presence of defective ATP7B protein function. Further investigations on their role by Next Generation Sequencing or Whole Exome Analysis might have a profound impact on patients' management and in particular on therapy.

Chromosome 15q BP3 to BP5 deletion is a likely locus for speech delay and language impairment: Report on a four-member family and an unrelated boy.

BACKGROUND: Deletions in chromosome 15q13 have been reported both in healthy people and individuals with a wide range of behavioral and neuropsychiatric disturbances. Six main breakpoint (BP) subregions (BP1-BP6) are mapped to the 15q13 region and three further embedded BP regions (BP3-BP5). The deletion at BP4-BP5 is the rearrangement most frequently observed compared to other known deletions in BP3-BP5 and BP3-BP4 regions. Deletions of each of these three regions have previously been implicated in a variable range of clinical phenotypes, including minor dysmorphism, developmental delay/intellectual disability, epilepsy, autism spectrum disorders, behavioral disturbances, and speech disorders. Of note, no overt clinical difference among each group of BP region deletions has been recorded so far. METHODS: We report on a four-member family plus an additional unrelated boy affected by a BP3-BP5 deletion that presented with typical clinical signs including speech delay and language impairment. A review of the clinical features associated with the three main groups of BP regions (BP4-BP5, BP3-BP5, and BP3-BP4) deletions is reported. RESULTS: Array-CGH analysis revealed in the mother (case 1) and in her three children (cases 2, 3, and 4), as well as in the unrelated boy (case 5), the following rearrangement: arr (hg19) 15q13.1-q13.3 (29.213.402-32.510.863) x1. CONCLUSION: This report, along with other recent observations, suggests the hypothesis that the BP region comprised between BP3 and BP5 in chromosome 15q13 is involved in several brain human dysfunctions, including impairment of the language development and, its deletion, may be directly or indirectly responsible for the speech delay and language deficit in the affected individuals.

A New Patient with Potocki-Lupski Syndrome: A Literature Review.

Speech delay, intellectual disability, and behavioral disturbances are the main clinical manifestations of Potocki-Lupski syndrome. Other features include infantile hypotonia, the absence of major dysmorphism, sleep disorders, and congenital anomalies, particularly of the cardiovascular system. A male patient with Potocki-Lupski syndrome is reported herein. He showed speech and borderline cognitive delay, behavioral troubles with no signs suggestive of autism, in the absence of major dysmorphism. A de novo 17p12-p11.2 duplication spanning 3.6 Mb was detected, with boundaries from 15,284,052 to 18,647,233 (hg19 assembly). At the age of 5 years, the child showed a noticeable improvement of speech skills and a moderate scholastic performance was reached. Upon analysis of the clinical manifestations of the present patient and those reported in existing literature, we found that the syndrome may present in various degrees of clinical expressivity. Affected patients may manifest symptoms ranging from mild behavioral disturbances to severe degrees of autism.

Hypoglossal nerve paralysis in a child after a dental procedure.

Unilateral palsy of the hypoglossal nerve is a rare complication of orthodontic procedures. The main reported causes of HNP are: orthopedic and otorhinolaryngology surgical interventions, and in particular maneuvers involving compression or overstretching of the hypoglossal nerve, dental procedures and traumas, and also infections, motoneuron disorders, tumors, vascular diseases. Diagnosis is usually performed by electrophysiology studies (EMG-VCN), and brain magnetic resonance imaging (MRI) is useful to exclude other causes. The prognosis depends on the location and extension of the damage. Currently there is not a standardized treatment approach except the speech therapy, although, in some cases, the high-dose steroid treatment could be useful. We describe the case of a ten-year-old female, who was admitted in our Unit after a deviation of the tongue associated with dysarthria and dysphagia, occurred after the application of a mobile orthodontic device.

A Probable Topiramate-Induced Limbs Paraesthesia and Rigid Fingers Flexion.

INTRODUCTION: Topiramate is a well-known anticonvulsant drug with a broad spectrum of actions. It has been proposed in the treatment of several types of epileptic seizures both in monotherapy and in add-on. Its usage has been extended to other disorders including migraine, essential tremor, obesity, alcohol and drug addiction. The most frequent side-effects of topiramate include dizziness, somnolence, insomnia, and ataxia. Paraesthesia, metabolic acidosis, kidney stones, hypohidrosis, cognitive impairment and eye symptoms have also been reported. CASE REPORT: We report on a girl affected by epileptic seizures treated with levetiracetam for five years. Due to worsening of the seizures, the dosage of this drug was increased and afterwards lowdosage topiramate was initiated. After 12 days from the introduction of topiramate, the girl began to present neurologic signs including limbs rigidity, pain, incoordination and flexed fingers. Gradual withdrawn of the topiramate resulted in progressive resolution of the symptomatology. This clinical episode could represent a probable topiramate-related side effect (Naranjo score 5), never reported before in this form.

A clinical review on megalencephaly: A large brain as a possible sign of cerebral impairment.

Megalencephaly and macrocephaly present with a head circumference measurement 2 standard deviations above the age-related mean. However, even if pathologic events resulting in both megalencephaly and macrocephaly may coexist, a distinction between these two entities is appropriate, as they represent clinical expression of different disorders with a different approach in clinical work-up, overall prognosis, and treatment. Megalencephaly defines an increased growth of cerebral structures related to dysfunctional anomalies during the various steps of brain development in the neuronal proliferation and/or migration phases or as a consequence of postnatal abnormal events. The disorders associated with megalencephaly are classically defined into 3 groups: idiopathic or benign, metabolic, and anatomic. In this article, we seek to underline the clinical aspect of megalencephaly, emphasizing the main disorders that manifest with this anomaly in an attempt to properly categorize these disorders within the megalencephaly group.

A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas.

BACKGROUND: The INI1/SMARCB1 gene protein product has been implicated in the direct pathogenesis of schwannomas from patients with one form of schwannomatosis [SWNTS1; MIM # 162091] showing a mosaic pattern of loss of protein expression by immunohistochemistry [93% in familial vs. 55% in sporadic cases]. AIM OF STUDY: To verify whether such INI1/SMARCB1 mosaic pattern could be extended to all schwannomas arising in the sporadic and familial schwannomatoses [i.e. to SMARCB1-related (SWNTS1) or LZTR1-related (SWNTS2) schwannomatosis or to SMARCB1/LZTR1-negative schwannomatosis] and whether it could be involved in classical NF2 or solitary peripheral schwannomas METHODS: We blindly analysed schwannoma samples obtained from a total of 22 patients including (a) 2 patients (2 males; aged 38 and 55 years) affected by non-familial SMARCB1-associated schwannomatosis (SWTNS1); (b) 1 patient (1 female; aged 33 years) affected by familial schwannomatosis (SWTNS1/ SMARCB1 germ line mutations); (c) 5 patients (3 males, 2 females; aged 33 to 35 years) affected by non-familial (sporadic) LZTR1-associated schwannomatosis (SWNTS2); (d) 3 patients (3 males; aged 35 to 47 years) affected by familial schwannomatosis (SWTNS2/ LZTR1 germ line mutations); (e) 2 patients (1 male, 1 female; aged 63 and 49 years, respectively) affected by non-familial schwannomatosis (SWTNS, negative for SMARCB1, LZTR1 and NF2 gene mutations); (f) 4 patients (3 males, 1 females; aged 15 to 24 years) affected by classical NF2 (NF2: harbouring NF2 germ line mutations; and (g) 5 patients (3 males, 2 females; aged 33 to 68 years) who had solitary schwannomas. [follow-up = 15-30 years; negative for constitutional/somatic mutation analysis for the SMARCB1, LZTR1 and NF2 genes] were (blindly) analyzed. The INI1/SMARCB1 immunostaining pattern was regarded as (1) diffuse positive nuclear staining [= retained expression] or (2) mosaic pattern [mixed positive/negative nuclei = loss of expression in a subset of tumour cells]. RESULTS: All solitary peripheral schwannomas and NF2-associated vestibular schwannomas showed diffuse nuclear INI1/SMARCB1 staining in 97-100% of neoplastic cells; schwannomas obtained from all cases of non-familial and familial schwannomatosis and NF2-associated non-vestibular schwannomas showed a mosaic pattern ranging from 10 to 70% of INI1/SMARCB1-positive expression. We did not record a complete lack of nuclear staining. CONCLUSIONS: The present data suggests that (a) mosaic loss of immunohistochemical INI1/SMARCB1 expression, despite the interlesional variability, is a reliable marker of schwannomatosis regardless of the involved gene and it might help in the differential diagnosis of schwannomatosis vs. solitary schwannomas and (b) INI1/SMARCB1 expression is not useful in the differential with mosaic NF2, since NF2-associated peripheral schwannomas show the same immunohistochemical pattern.

A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features.

Neurocutaneous disorders represent a heterogeneous group of conditions affecting the skin (with pigmentary/vascular abnormalities, hamartomas or tumors) and the central and peripheral nervous systems. In recent years, besides the well-known neurocutaneous diseases (e.g., the different forms of neurofibromatosis, tuberous sclerosis complex, Sturge-Weber syndrome and mosaic pigmentary/hamartomatous disorders), new distinctive syndromes have been characterized, extending our knowledge on the spectrum of these conditions. The concurrent presence of pigmentary abnormalities (both of the hypo- and hyperpigmented type), and primary microcephaly has not been commonly reported. We report on a 4.5-year-old girl with primary microcephaly, who had in addition moderate to severe developmental delay, behavioral and stereotypic abnormalities and a cutaneous pattern of paired hypo- and hyperpigmented lesions variously distributed over the body, particularly on the trunk. Failure to thrive and mild facial dysmorphic features were also present. To our knowledge, this complex malformation (neurocutaneous) phenotype has not been previously reported.

Total Hemi-overgrowth in Pigmentary Mosaicism of the (Hypomelanosis of) Ito Type: Eight Case Reports.

Pigmentary mosaicism of the (hypomelanosis of) Ito type is an umbrella term, which includes phenotypes characterized by mosaic hypopigmentation in the form of streaks, whorls, patchy, or more bizarre skin configurations (running along the lines of Blaschko): these cutaneous patterns can manifest as an isolated skin disorder (pigmentary mosaicism of the Ito type) or as a complex malformation syndrome in association with extracutaneous anomalies (most often of the musculoskeletal and/or nervous systems) (hypomelanosis of Ito). Affected individuals are anecdotally reported to have also partial or total body hemi-overgrowth (HOG), which often causes moderate to severe complications.We studied the occurrence and features of HOG in the 114 children and adults with mosaic pigmentary disorders of the Ito type diagnosed and followed up (from 2 to 22 years; average follow-up 16 years) at our Institutions.Eight patients (5 M, 3 F; aged 4 to 25 years; median age 16 years) out of the 114 analyzed (7%) fulfilled the criteria for unilateral HOG, with differences in diameter ranging from 0.4 to 4.0 cm (upper limbs) and 1.0 to 9.0 cm (lower limbs). Moreover, among these 8 patients, 5/8 filled in the 75th to 90th percentile for height; 6/8 had associated kyphoscoliosis; and 5/8 showed cognitive delays. No tumour complications were recorded. Overall, 6/8 HOG patients presented with additional (extracutaneous) syndromic manifestations, apart from the HOG (ie, with a clinical phenotype of hypomelanosis of Ito).The present study, which includes children and adults with the longest follow-up so far recorded, confirms the association between pigmentary mosaicism of the Ito type and HOG lowering previous estimates (7% vs 16%) for HOG in the context of mosaic hypopigmentation. A careful examination, looking at subtle to moderate asymmetries and associated complications within the spectrum of these mosaic pigmentary disorders, is recommended.

Unilateral Eye Blinking Arising From the Ictal Ipsilateral Occipital Area.

We report on an 18-month-old boy with unilateral left eye blinking as a single ictal manifestation without facial twitching. The clinical onset of this phenomenon was first recorded (as an occasional event) at age 3 months, and it was overlooked. By age 6 months, the child's blinking increased to almost daily occurrence in clusters: during blinking the infant showed intact awareness and occasional jerks in the upper limbs and right leg. A video-electroencephalography (video-EEG) documented clinical correlation with a focal pattern arising from the left occipital region, and brain magnetic resonance imaging (MRI) revealed severe brain damage, consisting in poroencephalic hollows and increased spaces in the convexities involving a large area of the left cerebral hemisphere. The boy was prescribed sodium valproate (30 mg/kg/d), resulting in drastic reduction of his clinical seizures. Follow-up to his current age documented good general status, with persistent partial right hemilateral seizures. The blinking progressively disappeared, and is no longer recorded. The pathogenic hypotheses of the unilateral ictal blinking include involvement of the ipsilateral cerebral hemisphere and/or the cerebellar pathways. Review of previous reports of unilateral eye blinking, arising from the ictal ipsilateral brain, revealed that different damaged regions may give rise to blinking ictal phenomena, likely via the trigeminal fibres innervating the subdural intracranial structures and the pial vessels in the ipsilateral affected brain. The eye blinking in the present child represents a further example of an ictal phenomenon, which is predictive of the damaged brain region.

Diagnosis, Management, and New Therapeutic Options in Childhood Neurofibromatosis Type 2 and Related Forms.

Neurofibromatosis type 2 (NF2; MIM # 101000) is an autosomal dominant disorder characterized by the development of vestibular schwannomas (VSs); schwannomas of other cranial, spinal, and cutaneous nerves; cranial and spinal meningiomas or other central nervous system tumors (eg, ependymomas and astrocytomas) or both. Additional features include eye (eg, early onset cataracts, optic nerve sheath meningiomas, retinal or pigment epithelial hamartomas or both, and epithelial retinal membranes) and skin abnormalities (eg, flat dermal [NF2 plaques] or spherical subcutaneous nodular schwannomas or both, and few, atypical café-au-lait spots). Clinically, children with NF2 fall into 2 main groups: (1) congenital NF2 with bilateral VSs detected as early as the first days to months of life, which can be stable or asymptomatic for 1-2 decades and suddenly progress; and (2) severe prepubertal (Wishart type) NF2 with multiple (and rapidly progressive) central nervous system tumors other-than-VS, which usually presents first, years before VSs, both associated with more marked skin and eye involvement (vs the classical mild adult [Gardner type] NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature). Individuals manifesting unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localized to a part of the peripheral nervous system have mosaic or segmental NF2; individuals developing multiple nonVS, nonintradermal cranial, spinal, and peripheral schwannomas (histologically proven) have schwannomatosis (SWNTS). NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin proteins; mosaic or segmental NF2 is because of mosaic phenomena for the NF2 gene, whereas SWNTS is caused by germline and possibly mosaic mutations either in the SMARCB1 gene (SWNTS1; MIM # 162091) or the LZTR1 gene (SWNTS2; MIM # 615670), both falling within the 22q region. Data driven from in vitro and animal studies on the merlin pathway allowed biologically targeted treatment strategies (employing Lapatinib, Erlotinib, Everolimus, Picropodophyllin, OSU.03012, Imatinib, Sorafenib, and Bevacizumab) aimed at multiple tumor shrinkage or regression or both and tumor arrest of progression with functional improvement.

Hypomelanosis of Ito: a round on the frequency and type of epileptic complications.

There is an ample evidence that hypopigmentation of the skin along the Blaschko's lines is frequently associated with neurological disorders. Nowadays, the term "Hypomelanosis of Ito" (HI) is applied when, together with the cutaneous lesions, various and multisystem organs are involved. Among these, the most frequent are cerebral manifestations, such as cognitive delay and epileptic seizures. For this reason, hypomelanosis of Ito has been included in the group of neurocutaneous syndromes, neurologic manifestations being one of the most frequent. Epileptic seizures have been reported in patients with this disorder, but in a very few particular attention has been focused on the type and frequency of epilepsy and on the response to the treatment. Herein, we report on five patients with HI who showed episodes of epileptic seizures with onset in childhood, in absence of malformative anomalies except for the skin lesions. A survey on the frequency and types of epileptic seizures in HI children and in the literature is reported.

Propranolol: Effectiveness and Failure in Infantile Cutaneous Hemangiomas.

Infantile hemangiomas (IHs) occur in early infancy and are considered to be one of the most frequent childhood tumors. Poor responsiveness to the treatment and complications are reported in about 10 % of patients. For years, the most common treatments for cutaneous and complicated IHs were corticosteroids, interferon-α, vincristine, laser therapy, or surgical intervention. More recently, treatment with propranolol has been reported with high success rates, both in the cutaneous and complicated form of IHs, and it is now considered to be the first-line treatment for IHs. Herein we report five cases of cutaneous IHs who presented at our unit between January 2011 and June 2012: in three of five patients, the lesion improved soon after the beginning of propranolol treatment; one case presented slow but complete resolution; and in one patient the treatment was unsuccessful. Patients who do not respond to propranolol have been seldom reported in the literature. However, the failure of propranolol treatment in childhood hemangiomas has been more frequent in our experience than that reported in previous case series. More attention should be given to the cases that poorly or negatively respond to treatment, and to the mechanisms underlying the failure to respond to treatment with propranolol.

Type II Autoimmune Hepatitis and Small Duct Sclerosing Cholangitis in a Seven Years Old Child: An Overlap Syndrome?

INTRODUCTION: Autoimmune hepatitis is an inflammatory disease with multifactorial ethiopatogenesis, characterized by lympho-monocytic infiltration of liver, presence of serum autoantibodies (ANA, SMA, LKM-1) and high levels of immunoglobulins. Overlap syndromes are defined as the association of autoimmune hepatitis with cholestatic diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. The boundaries of these syndromes as distinct pathological entities are still matter of debate and they could be part of a major liver autoimmune disease. Furthermore, cholestatic diseases may present even with atypical features (AMA-negative primary cirrohosis, primary sclerosing cholangitis with normal cholangiography). CASE PRESENTATION: We herein describe a case of a 7 year-old child affected by an overlap syndrome between type 2 autoimmune hepatitis and small duct primary sclerosing cholangitis. Although characterized by a severe onset, the disease showed a good response to treatment with prednisone and azathioprine. CONCLUSIONS: The association of type 2 autoimmune hepatitis and small duct primary cholangitis has been rarely reported in literature and this report adds new data on this still unclear entity.

Early acute pancreatitis in a child with compound heterozygosis ∆F508/R1438W/Y1032C cystic fibrosis: a case report.

INTRODUCTION: Recent studies suggest an important role of the cystic fibrosis transmembrane conductance regulator gene in the development of pancreatitis. It occurs approximately in 20% of patients with cystic fibrosis and almost exclusively in pancreatic sufficient people. Newborn screening and improved panels of deoxyribonucleic acid mutation analysis techniques are revealing more rare and nonclassical pictures of the disease, generally associated with pancreatic sufficiency and with an increased risk of developing pancreatitis. Mutations R1438 and Y1032 are considered rare mutations, and, when singularly associated with ∆F508, lead to a mild phenotype with pancreatic sufficiency and no detectable respiratory involvement. CASE PRESENTATION: We present the case of a Caucasian girl, aged six years, whose genotype was characterized by three different mutations ∆F508, R1438W and Y1032C, never reported, together, in the same patient. She presented with a positive immunoreactive trypsinogen screening, a borderline sweat test, and, in the first years, a favorable pulmonary course, and pancreatic sufficiency. At the age of six years, she presented with a sudden episode of acute abdominal pain, anorexia and fever. A diagnosis of pancreatitis was made after clinical and laboratory examinations. Venous rehydration, bowel rest and therapy with ursodeoxycholic acid resulted in complete remission.The treatment was successful, with normalization of her symptoms and laboratory parameters within four weeks. CONCLUSION: There has been a vast expansion in the understanding of the wide range of phenotypes associated with cystic fibrosis transmembrane conductance regulator dysfunction since the discovery of the cystic fibrosis transmembrane conductance regulator gene. The genotype-phenotype correlation in pancreatitis is rare compared to other organ manifestations, since this is seen almost exclusively among pancreatic sufficient patients with cystic fibrosis. Our study supports that compound heterozygosis ∆F508-R1438W/Y1032C is a 'cystic fibrosis-causing genotype' characterized by an immunoreactive trypsinogen positive screening, abnormal sweat chloride testing, and pancreatic sufficiency, with an increased risk of acute pancreatitis at an early age.

Hepatitis B vaccine in celiac disease: yesterday, today and tomorrow.

Some studies showed that in celiac patients the immunological response to vaccination is similar to that one found in general population except for vaccine against hepatitis B virus (HBV). The non-responsiveness to HBV vaccine has also been described in healthy people, nevertheless the number of non-responders has been demonstrated to be higher in celiac disease (CD) patients than in healthy controls. Several hypothesis explaining this higher rate of unresponsiveness to HBV vaccine in CD patients have been described, such as the genetic hypothesis, according with CD patients carrying the disease-specific haplotype HLA-B8, DR3, and DQ2, show a lower response to HBV vaccine both in clinical expressed CD patients and in healthy people carrying the same haplotype. On the other hand, it has been demonstrated that the gluten intake during the vaccination seems to influence the response to the same vaccine. Moreover, it has been demonstrated a possible genetic predisposition to hepatitis B vaccine non-responsiveness likely due to the presence of specific human leukocyte antigen haplotypes and specific single nucleotide polymorphism in genes of cytokine/cytokine receptors and toll like receptors, but the pathogenic mechanism responsible for this low responsiveness still remains unclear. The aim of this review is to focus on the possible pathogenic causes of unresponsiveness to HBV vaccine in CD patients and to propose an alternative vaccination schedule in order to improve the responsiveness to HBV vaccine in this at-risk patients.

Congenital familial myasthenic syndromes: disease and course in an affected dizygotic twin pair.

The present report describes clinical variability in an affected dizygotic twin pair. Twin 1 showed classical features of the congenital myasthenic syndromes (CMS), that is, ptosis, dysphonia, asthenia and hypotonia. In twin 2, these clinical signs were less pronounced, but subtle resulting in severe lumbar hyperlordosis. Molecular analysis, performed for both twins, revealed the presence of three polymorphisms in the heterozygous form in RAPSN gene. The present report highlights the clinical variability of the CMS.