Progressive Depletion of B and T Lymphocytes in Patients with Ataxia Telangiectasia: Results of the Italian Primary Immunodeficiency Network.

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.

Neurocutaneous syndromes in art and antiquities.

Neurocutaneous syndromes are a group of genetic disorders affecting the skin, the central and peripheral nervous system, and the eye with congenital abnormalities and/or tumors. Manifestations may also involve the heart, vessels, lungs, kidneys, endocrine glands and bones. When people with these disorders are portrayed in works of art, physicians have speculated on possible diagnoses. In particular, many figures have been labeled as possibly having a neurocutaneous disorder, sometimes distorting the popular conception of these diseases. We review numerous documents, drawings, prints, lithographs, xylographs, and portraits which span the ages from antiquity to the era of the pioneers behind the eponyms, depicting a large spectrum of neurocutaneous disorders.

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity.

Medical advances have dramatically improved the long-term prognosis of children and adolescents with inborn errors of immunity (IEIs). Transfer of the medical care of individuals with pediatric IEIs to adult facilities is also a complex task because of the large number of distinct disorders, which requires involvement of patients and both pediatric and adult care providers. To date, there is no consensus on the optimal pathway of the transitional care process and no specific data are available in the literature regarding patients with IEIs. We aimed to develop a consensus statement on the transition process to adult health care services for patients with IEIs. Physicians from major Italian Primary Immunodeficiency Network centers formulated and answered questions after examining the currently published literature on the transition from childhood to adulthood. The authors voted on each recommendation. The most frequent IEIs sharing common main clinical problems requiring full attention during the transitional phase were categorized into different groups of clinically related disorders. For each group of clinically related disorders, physicians from major Italian Primary Immunodeficiency Network institutions focused on selected clinical issues representing the clinical hallmark during early adulthood.

Design and Validation of a Custom NGS Panel Targeting a Set of Lysosomal Storage Diseases Candidate for NBS Applications.

Lysosomal storage diseases (LSDs) are a heterogeneous group of approximately 70 monogenic metabolic disorders whose diagnosis represents an arduous challenge for clinicians due to their variability in phenotype penetrance, clinical manifestations, and high allelic heterogeneity. In recent years, the approval of disease-specific therapies and the rapid emergence of novel rapid diagnostic methods has opened, for a set of selected LSDs, the possibility for inclusion in extensive national newborn screening (NBS) programs. Herein, we evaluated the clinical utility and diagnostic validity of a targeted next-generation sequencing (tNGS) panel (called NBS_LSDs), designed ad hoc to scan the coding regions of six genes (GBA, GAA, SMPD1, IDUA1, GLA, GALC) relevant for a group of LSDs candidate for inclusion in national NBS programs (MPSI, Pompe, Fabry, Krabbe, Niemann Pick A-B and Gaucher diseases). A standard group of 15 samples with previously known genetic mutations was used to test and validate the entire flowchart. Analytical accuracy, sensitivity, and specificity, as well as turnaround time and costs, were assessed. Results showed that the Ion AmpliSeq and Ion Chef System-based high-throughput NBS_LSDs tNGS panel is a fast, accurate, and cost-effective process. The introduction of this technology into routine NBS procedures as a second-tier test along with primary biochemical assays will allow facilitating the identification and management of selected LSDs and reducing diagnostic delay.

West syndrome: a comprehensive review.

Since its first clinical description (on his son) by William James West (1793-1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2) hypsarrhythmia, and (3) developmental arrest or regression as "West syndrome", new and relevant advances have been recorded in this uncommon disorder. New approaches include terminology of clinical spasms (e.g., infantile (IS) vs. epileptic spasms (ES)), variety of clinical and electroencephalographic (EEG) features (e.g., typical ictal phenomena without EEG abnormalities), burden of developmental delay, spectrum of associated genetic abnormalities, pathogenesis, treatment options, and related outcome and prognosis. Aside the classical manifestations, IS or ES may present with atypical electroclinical phenotypes (e.g., subtle spasms; modified hypsarrhythmia) and may have their onset outside infancy. An increasing number of genes, proteins, and signaling pathways play crucial roles in the pathogenesis. This condition is currently regarded as a spectrum of disorders: the so-called infantile spasm syndrome (ISs), in association with other causal factors, including structural, infectious, metabolic, syndromic, and immunologic events, all acting on a genetic predisposing background. Hormonal therapy and ketogenic diet are widely used also in combination with (classical and recent) pharmacological drugs. Biologically targeted and gene therapies are increasingly studied. The present narrative review searched in seven electronic databases (primary MeSH terms/keywords included West syndrome, infantile spasms and infantile spasms syndrome and were coupled to 25 secondary clinical, EEG, therapeutic, outcomes, and associated conditions terms) including MEDLINE, Embase, Cochrane Central, Web of Sciences, Pubmed, Scopus, and OMIM to highlight the past knowledge and more recent advances.

Introduction to phacomatoses (neurocutaneous disorders) in childhood.

The Dutch ophthalmologist, Jan van der Hoeve, first introduced the terms phakoma/phakomata (from the old Greek word "ϕαχοσ" = lentil, spot, lens-shaped) to define similar retinal lesions recorded in tuberous sclerosis (1920) and in neurofibromatosis (1923). He later applied this concept: (a) to similar lesions in other organs (e.g. brain, heart and kidneys) (1932) and (b) to other disorders (i.e. von Hippel-Lindau disease and Sturge-Weber syndrome) (1933), and coined the term phakomatoses. At the same time, the American neurologist Paul Ivan Yakovlev and psychiatrist Riley H. Guthrie (1931) established the key role of nervous systems and skin manifestations in these conditions and proposed to name them neurocutaneous syndromes (or ectodermoses, to explain the pathogenesis). The Belgian pathologist, Ludo van Bogaert, came to similar conclusions (1935), but used the term neuro-ectodermal dysplasias. In the 1980s, the American paediatric neurologist Manuel R. Gomez introduced the concept of "hamartia/hamartoma" instead of phakoma/phakomata. "Genodermatoses" and "neurocristopathies" were alternative terms still used to define these conditions. Nowadays, however, the most acclaimed terms are "phacomatoses" and "neurocutaneous disorders", which are used interchangeably. Phacomatoses are a heterogeneous group of conditions (mainly) affecting the skin (with congenital pigmentary/vascular abnormalities and/or tumours), the central and peripheral nervous system (with congenital abnormalities and/or tumours) and the eye (with variable abnormalities). Manifestations may involve many other organs or systems including the heart, vessels, lungs, kidneys and bones. Pathogenically, they are explained by interplays between intra- and extra-neuronal signalling pathways encompassing receptor-to-protein and protein-to-protein cascades involving RAS, MAPK/MEK, ERK, mTOR, RHOA, PI3K/AKT, PTEN, GNAQ and GNA11 pathways, which shed light also to phenotypic variability and overlapping. We hereby review the history, classification, genomics, clinical manifestations, diagnostic criteria, surveillance protocols and therapies, in phacomatoses: (1) predisposing to development of tumours (i.e. the neurofibromatoses and allelic/similar disorders and schwannomatosis; tuberous sclerosis complex; Gorlin-Goltz and Lhermitte-Duclos-Cowden syndromes); (2) with vascular malformations (i.e. Sturge-Weber and Klippel-Trenaunay syndromes; megalencephaly/microcephaly-capillary malformation syndromes; CLOVES, Wyburn-Mason and mixed vascular nevus syndromes; blue rubber bleb nevus syndrome; hereditary haemorrhagic telangiectasia); (3) with vascular tumours (von Hippel-Lindau disease; PHACE(S)); (4) with pigmentary/connective tissue mosaicism (incontinentia pigmenti; pigmentary/Ito mosaicism; mTOR-related megalencephaly/focal cortical dysplasia/pigmentary mosaicism; RHOA-related ectodermal dysplasia; neurocutaneous melanocytosis; epidermal/papular spilus/Becker nevi syndromes; PENS and LEOPARD syndromes; encephalocraniocutaneous lipomatosis; lipoid proteinosis); (5) with dermal dysplasia (cerebellotrigeminal dermal dysplasia); and (6) with twin spotting or similar phenomena (phacomatosis pigmentovascularis and pigmentokeratotica; and cutis tricolor).

Neurocutaneous melanocytosis (melanosis).

Neurocutaneous melanosis (NCM; MIM # 249400; ORPHA: 2481], first reported by the Bohemian pathologist Rokitansky in 1861, and now more precisely defined as neurocutaneous melanocytosis, is a rare, congenital syndrome characterised by the association of (1) congenital melanocytic nevi (CMN) of the skin with overlying hypertrichosis, presenting as (a) large (LCMN) or giant and/or multiple (MCMN) melanocytic lesions (or both; sometimes associated with smaller "satellite" nevi) or (b) as proliferative melanocytic nodules; and (2) melanocytosis (with infiltration) of the brain parenchyma and/or leptomeninges. CMN of the skin and leptomeningeal/nervous system infiltration are usually benign, more rarely may progress to melanoma or non-malignant melanosis of the brain. Approximately 12% of individuals with LCMN will develop NCM: wide extension and/or dorsal axial distribution of LCMN increases the risk of NCM. The CMN are recognised at birth and are distributed over the skin according to 6 or more patterns (6B patterns) in line with the archetypical patterns of distribution of mosaic skin disorders. Neurological manifestations can appear acutely in infancy, or more frequently later in childhood or adult life, and include signs/symptoms of intracranial hypertension, seizures/epilepsy, cranial nerve palsies, motor/sensory deficits, cognitive/behavioural abnormalities, sleep cycle anomalies, and eventually neurological deterioration. NMC patients may be symptomatic or asymptomatic, with or without evidence of the typical nervous system changes at MRI. Associated brain and spinal cord malformations include the Dandy-Walker malformation (DWM) complex, hemimegalencephaly, cortical dysplasia, arachnoid cysts, Chiari I and II malformations, syringomyelia, meningoceles, occult spinal dysraphism, and CNS lipoma/lipomatosis. There is no systemic involvement, or only rarely. Pathogenically, single postzygotic mutations in the NRAS (neuroblastoma RAS viral oncogene homologue; MIM # 164790; at 1p13.2) proto-oncogene explain the occurrence of single/multiple CMNs and melanocytic and non-melanocytic nervous system lesions in NCM: these disrupt the RAS/ERK/mTOR/PI3K/akt pathways. Diagnostic/surveillance work-ups require physical examination, ophthalmoscopy, brain/spinal cord magnetic resonance imaging (MRI) and angiography (MRA), positron emission tomography (PET), and video-EEG and IQ testing. Treatment strategies include laser therapy, chemical peeling, dermabrasion, and surgical removal/grafting for CMNs and shunt surgery and surgical removal/chemo/radiotherapy for CNS lesions. Biologically targeted therapies tailored (a) BRAF/MEK in NCM mice (MEK162) and GCMN (trametinib); (b) PI3K/mTOR (omipalisib/GSK2126458) in NMC cells; (c) RAS/MEK (vemurafenib and trametinib) in LCMNs cells; or created experimental NMC cells (YP-MEL).

Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: First descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes.

The earliest examples of neurofibromatosis (in this case type 1, NF1) can be traced in the Ebers Papyrus (Ancient Egypt, 1.500 B.C.), in a Hellenistic statuette (Smyrna, 323 B.C.), in the coinage of the Parthians kings (247 B.C.) and in some 13th century monks' drawings. These earlier examples are somewhat less well defined as compared to the most recent better defined reports credited as having NF1 including an Inca child mummy (1480-1650 AD), Ulisse Aldrovandi's homuncio ("Monstrorum Historia", 1592 A.D.) with mosaic NF1 or the illustrations seen in the 18th century "Buffon's Histoire Naturelle" and "Cruveilhier's Anatomie Pathologique du Corps Human". The first English language report on NF1 was made by Akenside in 1768 and the first systematic review by Robert William Smith in 1849, while Virchow's pupil, Friedrich Daniel von Recklinghausen, in 1882, was the first to understand the origin of skin tumors and to name them neurofibromas. The touching story of Joseph C. Merrick (the "Elephant man," (who had Proteus syndrome and not NF1), in 1884, played an important role in the later misconception of NF1, as did the novel by Vicotr Hugo on the hunchback Quasimodo. The studies by van der Hoeve (1921), Yakovlev and Guthrie (1931), and Van Bogaert (1935), categorized "von Recklinghausen's" neurofibromatosis among the phakomatoses and the neurocutaneous syndromes. The first known mention of an acoustic neuroma (at autopsy) is attributed to Eduard Sandifort (1777 AD) while John H. Wishart made the earliest autoptic description of neurofibromatosis type 2 (NF2), in 1822, in a 21-year-old man with bilateral acoustic neuromas, who manifested signs since his infancy (Wishart subtype NF2). Smith likely described the first case of schwannomatosis in 1849. Older, Virchow, von Recklinghausen, and Verocay first classified "neuromas" and Masson and Penfield first used the word "schwannoma" taking it from Theodore Schwann's works. In 1903 Henneberg and Koch described NF2 in detail. Young, Eldridge, and Gardner, in the late '70, established NF2 as a distinct familial entity (Gardner subtype NF2). Schwannomatosis, the late entry of the different forms of neurofibromatosis, was credited in the middle '90.

Rediagnosing one of Smith's patients (John McCann) with "neuromas tumours" (1849).

In 1849, the Irish Professor of Surgery, Sir Robert William Smith, by publishing his "Treatise on the Pathology, Diagnosis and Treatment of Neuroma", collected six previous examples of "general development of neuromatous tumours" and reported three further cases (two personal and one referred) of what is nowadays known as neurofibromatosis. Among these latter cases, there was a 35-year-old cattle-driver, John McCann, who was first admitted at hospital in 1840 because of a large tumour on the right side of his neck thought to be malignant (and a second tumour sublingually) but not operated. McCann was readmitted in 1843 ("in an emaciated state"), because of an immense tumour in his thigh dying few months later "with hepatic symptoms". Smith's post-mortem examination revealed dozens of smaller additional tumours. Based on application of modern diagnostic criteria (to McCann's portrait at second referral) and on pathological grounds (reconsideration of the histopathological report of McCann's neuroma of the thigh), we tentatively hypothesise that this patient could be the earliest (illustrated) example of either: (1) a malignant peripheral nerve sheath tumour (MPNST); (2) neurofibromatosis type 2 (NF2); or (3) schwannomatosis (SWNTS). The progressively enlarging masses, the emaciated state and the later death are in favour of a MPNST (against is the lack of malignant appearance at histopathology); the clinical (and gross pathological) appearance of the tumours as large, rounded, encapsulated, eccentric lesions deflecting the parent nerve over the surface of the tumour is typical of schwannomas (thus, in favour of NF2 or SWTNS). Whatever diagnosis we could consider these tumours could be secondary to a (local) mosaic loss of heterozygosity and ultimately represent type 2 segmental manifestations superimposed on an ordinary autosomal dominant trait (i.e., NF1, NF2 or SWTNS).

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 de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity.

Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

Klippel-Trenaunay syndrome in a boy with concomitant ipsilateral overgrowth and undergrowth.

Klippel-Trenaunay syndrome comprises congenital vascular malformations of the capillary (nevus flammeus), venous (varicosities) or lymphatic systems and disturbed (usually over-) growth of one or more extremities and adjacent parts of the trunk. In some individuals the affected body area may show reduced rather than increased growth. Such patients have been described inverse Klippel-Trenaunay syndrome and included within the spectrum of the syndrome. We report on a 3-year-old boy with vascular malformation of the nevus flammeus type extending from the right buttock to the sole of the right foot with clinical and radiological evidence of leg varicosities and underlying deficiency of the soft tissues and bone. In addition, he had macrodactyly of the first, second, and third toes with small nails, and cutaneous syndactyly of the second and third toes of the ipsilateral foot. Cranial magnetic resonance imaging showed high signal lesions in the peritrigonal areas with normal spinal images. This mosaic phenotype demonstrates that decreased and increased growth can coexist in the same body area of an individual with Klippel-Trenaunay syndrome.

Pediatric Hashimoto's encephalopathy with peripheral nervous system involvement.

Hashimoto encephalopathy is a syndrome of encephalopathy associated with elevated concentration of circulating serum anti-thyroid antibodies usually responsive to steroid therapy. We report a 13-year-old girl with Hashimoto encephalopathy and peripheral nervous system involvement. The child had experienced high-grade pyrexia, global headache and sleeplessness. After admission she had an ileus with a distended urinary bladder, hallucinations and cognitive impairment. She had reduced deep tendon reflexes and distal sensory deficiency. Anti-thyroglobulin antibodies were raised at 2121 IU/mL (normal, 0-40) and the anti-thyroperoxidase was high at 886 IU/mL (normal, 0-50). Progressive neurological and psychiatric remission was noted after i.v. methylprednisolone. Follow-up magnetic resonance imaging showed complete resolution of the foci of signal abnormality previously yielded. This case report is the first, to the best of our knowledge, to describe peripheral nervous system involvement in a child with a diagnosis of Hashimoto's encephalopathy.

Motor imagery for paediatric neurorehabilitation: how much do we know? Perspectives from a systematic review.

Background: Motor Imagery (MI) is a cognitive process consisting in mental simulation of body movements without executing physical actions: its clinical use has been investigated prevalently in adults with neurological disorders. Objectives: Review of the best-available evidence on the use and efficacy of MI interventions for neurorehabilitation purposes in common and rare childhood neurological disorders. Methods: systematic literature search conducted according to PRISMA by using the Scopus, PsycArticles, Cinahl, PUBMED, Web of Science (Clarivate), EMBASE, PsychINFO, and COCHRANE databases, with levels of evidence scored by OCEBM and PEDro Scales. Results: Twenty-two original studies were retrieved and included for the analysis; MI was the unique or complementary rehabilitative treatment in 476 individuals (aged 5 to 18 years) with 10 different neurological conditions including, cerebral palsies, stroke, coordination disorders, intellectual disabilities, brain and/or spinal cord injuries, autism, pain syndromes, and hyperactivity. The sample size ranged from single case reports to cohorts and control groups. Treatment lasted 2 days to 6 months with 1 to 24 sessions. MI tasks were conventional, graded or ad-hoc. MI measurement tools included movement assessment batteries, mental chronometry tests, scales, and questionnaires, EEG, and EMG. Overall, the use of MI was stated as effective in 19/22, and uncertain in the remnant studies. Conclusion: MI could be a reliable supportive/add-on (home-based) rehabilitative tool for pediatric neurorehabilitation; its clinical use, in children, is highly dependent on the complexity of MI mechanisms, which are related to the underlying neurodevelopmental disorder.

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.

Spinal neurofibromatosis with central nervous system involvement in a set of twin girls and a boy: further expansion of the phenotype.

BACKGROUND: Familial spinal neurofibromatosis is a form of neurofibromatosis 1 (NF1), consisting of extensive, symmetrical, histologically proven, multiple neurofibromas of the spinal roots at every level and of all major peripheral nerves sometimes associated with typical NF1 stigmata; most cases underlie NF1 gene mutations. OBJECTIVES: The objectives of this study are (1) to report the findings in a set of 16-year-old monozygotic twin girls and a 14-year-old boy and (2) to review the existing literature. METHODS AND RESULTS: In this article, we report the cases of three children who (1) had manifested mildly different symptomatic neuropathy (twins, aged 4 years; and a boy, aged 9 years) associated with massive, symmetrical neurofibromas; (2) had few café-au-lait spots with irregular margins and pale brown pigmentation; (3) were presented with, at brain magnetic resonance imaging (MRI), bilateral, NF1-like high-signal abnormalities in the basal ganglia; (4) yielded missense NF1 gene mutations in exon 39; and (5) had unaffected parents with negative NF1 genetic testing as well as discuss 12 families and 20 sporadic and 5 additional cases that presented spinal neurofibromatosis within classical NF1 families (53 cases) that were reported in the literature. CONCLUSIONS: This article presents the first report on (1) spinal neurofibromatosis in a set of affected monozygotic twins; (2) the earliest onset of the disease; and (3) the occurrence of high signal lesions in the brain at MRI.

Case report: A gain-of-function of hamartin may lead to a distinct "inverse TSC1-hamartin" phenotype characterized by reduced cell growth.

Mutations of TSC1 and TSC2 genes cause classical Tuberous Sclerosis Complex (TSC), a neurocutaneous disorder characterized by a tendency to develop hamartias, hamartomas, and other tumors. We herein report on a girl, now aged 5 years, who presented a previously unreported, distinct clinical phenotype consisting of primary microcephaly (head circumference = 40 cm, -5.6 standard deviations), brain anomalies including hypoplasia of the corpus callosum (with a residual draft of the genu), simplified parieto-temporal gyral pattern, colpocephaly with ectasia of the temporal ventricular horns, intellectual disability, and a general pattern of reduced growth (with weight and height < 3rd centiles). No classical features of TSC were recorded; the girl harbored a novel missense variant in TSC1 (c.611G > A). We hypothesize that her clinical phenotype could be related to a "gain-of-function" of the TSC1 protein product hamartin, causing an increase in the effects of the protein on inhibition of its intracellular targets (i.e., mTORC or RAC1 pathways), resulting in a distinct "inverse TSC1-hamartin" phenotype characterized by reduced growth of cells instead of the more classical predisposition to increased cell growth.

Efficacy of videogames and exergames in pediatric neurorehabilitation: a systematic review.

INTRODUCTION: In recent years, the rehabilitation of children with neurological disorders has taken into account the possibility of using videogaming consoles and virtual reality systems to make children's therapy more enjoyable, motivating, participated and effective. This study aims at conducting a systematic review about the use and the efficacy of digital games in pediatric neurorehabilitation. EVIDENCE ACQUISITION: In accordance with the PRISMA approach, a rather wide-ranging search was conducted on PubMed, Scopus, and Web of Science databases by using different combinations of keywords based on MeSH terms. EVIDENCE SYNTHESIS: Fifty-five papers have been included into this review, namely, 38 original studies and 17 reviews. The total number of children and adolescents is 573, with 58% of them being affected by cerebral palsy. Despite a wide variability in the adopted protocols, devices, assessment tools, and a more frequent focus on motor aspects than on cognitive ones, the results of the majority of the analyzed studies support the safety (i.e., absence of severe adverse effects) and efficacy of the videogame-based therapy. CONCLUSIONS: Videogames, when administered by means of commercial consoles or ad-hoc digital systems, seem to be a valid support for physical therapy. Further researchers are needed to deeply investigate the role of this approach in cognitive therapy and cognitive outcomes.