In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS).

Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n = 1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n = 1], and MCAP [megalencephaly capillary malformation syndrome; n = 4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients' derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kß1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 µM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.

Primary headaches in children: clinical findings on the association with other conditions.

The aim of the present study is to report on the frequency of some comorbidities in primary headaches in childhood. Two hundred and eighty children (175 males and 105 females; ratio 1.7:1), aged 4 to 14 years, affected by primary headaches were consecutively enrolled in this study. In direct interviews, parents and children gave information about the association of their headaches with different conditions including asthma and allergic disorders, convulsive episodes, sleep disorders and increased body weight, affections some time associated in the literature to headache as comorbidities . In addition, anxiety and depression, attention deficit/hyperactivity disorder, tics, learning disabilities and obsessive-compulsive disorders, using psycho-diagnostic scales were evaluated. Two hundred and eighty children matched for age, sex, race and socio-economic status, were used as controls. No significant association of primary headaches was found with asthma and allergic disorders, convulsive episodes, sleep disorders and increased body weight. Overall behavioral disorders were more common in children who experienced headache than in controls. A significant association of primary headache was found with anxiety and depression (p value < 0.001), but not with the other psychiatric disorders. Primary headaches in children are not associated with most of the psychiatric and systemic conditions herein investigated. On the contrary, there was a significant association with anxiety and depression, as frequently reported in adults.

Acquired peripheral neuropathy: a report on 20 children.

Guillain-Barré syndrome (GBS) is an inflammatory polyneuropathy characterized by acute onset, rapid progression, symmetric muscular weakness, pain, and paresthesias. The incidence of GBS in the pediatric age group is 0.8 cases per 100,000; 50%-70% of the cases are preceded by respiratory or gastrointestinal infectious episodes or vaccination. The etiopathogenesis of GBS has been hypothesized to involve a direct immune-mediated mechanism against the peripheral nerves. A series of 20 patients managed in the Department of Pediatrics of the University of Catania between 2003 and 2011 and evaluated according to epidemiologic, clinical, and therapeutic features is reported.

Ptosis in childhood: A clinical sign of several disorders: Case series reports and literature review.

Blepharoptosis (ptosis) is a common but often overlooked sign that may serve as a sign/manifestation of other conditions, ranging from a mild and purely cosmetic presentation to a severe and occasionally progressive disorder. Ptosis may show an acute onset or may manifest as a chronic disorder. Its presentation may vary: unilateral versus bilateral, progressive versus non-progressive, isolated versus complex which occurs in association with other symptoms, and congenital versus acquired (often concomitant with neuromuscular disorders).Congenital ptosis includes the isolated type-the congenital cranial dysinnervation disorders, which are further, distinguished into different subtypes such as Horner syndrome (HS), and ptosis as a sign/manifestation of various congenital malformation syndromes.In this article, we review the primary causes of ptosis occurring in childhood, and its various clinical presentations, including a short report on selected cases observed in our institution: a classical isolated familial ptosis comprising 14 members over 5 generations, 3 sibling with isolated congenital ptosis who in addition suffered by episodes of febrile seizures, a patient with Duane retraction syndrome who presented congenital skin and hair anomalies, and a girl with HS who showed a history of congenital imperforate hymen. A flowchart outlining the congenital and acquired type of ptosis and the clinical approach to the management and treatment of children with this anomaly is reported.

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies.

Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. 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 (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.

Brain ultrasound features in multiple births due to spontaneous conception compared with assisted reproductive techniques: a cross-sectional, population-based study.

AIM: Multiple pregnancies from spontaneous conception and obtained by assisted reproductive techniques (ART) are associated with a disproportionate share of complications compared with natural singleton pregnancies. The outcome of multiple pregnancies obtained by ART is still the subject of controversial opinions in the medical literature as they are associated with increased rates of perinatal complications, and perinatal mortality, as well as maternal complications. Aim of this study was to determine whether there are differences between these two groups of infants. METHODS: We examined the imaging findings by means of brain ultrasound (performed at birth and sequentially up to their 6th month of age) in a cohort of 296 twins and triplets born following different techniques of assisted fertilization (63 pregnancies; 119 neonates) vs. spontaneous conception (94 pregnancies; 177 neonates). RESULTS: We did record, by means of X square corrected test, statistically significant differences (P=0.002) between the two populations at birth in the number of normal ultrasound scans (ART

Tetralogy of Fallot variant with pulmonary atresia (pseudotruncus arteriosus) in a case of maternal PKU syndrome.

The authors report on a child with a rare variant of the Tetralogy of Fallot with pulmonary atresia also known as Pseudotruncus arteriosus, who was born by a mother affected by classic phenylketonuria (PKU), diet free of phenylalanine until the age of seven years. According to the authors, this is the first example of such rare variant in an offspring of maternal PKU syndrome.

Subacute sclerosing panencephalitis: a case report.

Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of childhood and early adolescence caused by persistent defective measles virus. Clinical manifestations appear many years after the acute measles infection. The incidence of SSPE has substantially declined after the introduction of an effective vaccine. We report a case of a child with SSPE that began with atonia, dysarthria, and intellectual deterioration without the presence of any particular EEG anomalies. We have reported this girl who was affected by this severe affliction in the hope that, because of the rarity of SSPE, it would not go undiagnosed.

HyperCKemia as a biomarker for muscular diseases.

An increased level of serum creatine kinase has been considered as an indirect sign of muscular disorders but it may be an indicator of other diseases (malignant hyperthermia, tumors or endocrinopathy). Some patients present with a stationary clinical condition and absence of muscular symptoms, in whom the unique abnormality is hyperCKemia that is not associated with any biological or genetic diagnosis of MD. In others asymptomatic patients, an increase in CK may be a hematological marker that can predict muscular disease. In this article, we review the causes that can lead to transitory or persistent HC.

Blepharoptosis in children: our experience at the light of literature.

AIMS: We herein report a 5 years experience of management and care of children presenting blepharoptosis at the light of the literature regarding this uncommon pathology. This report aims to display the most common causes of blepharoptosis and its possible treatment. PATIENTS AND METHODS: Clinical and epidemiological data collected from our institution, over a fi ve year period, on 60 patients, 37 males and 23 females with a mean age of 5.4 years (range 0.6 to 15.6 years) affected by blepharoptosis were analyzed. RESULTS: Ptosis was unilateral in 39/60 patients (65%) and bilateral in 21/60 (35%). The causes of ptosis were myogenic (40%), and neurogenic (35%), most commonly congenital. Among the neurogenic ptosis, the most frequent causes were PTOS type 1 and Marcus-Gunn syndrome. All the cases of acquired neurogenic ptosis were associated with paralysis of the oculomotor nerve. Ptosis plus was found in 23.3% of the patients, mechanical origin was present in 1.7% of patients. Family history was positive in the 10% of the patients. CONCLUSIONS: Our series reflect the range of ptosis of the general pediatric population. This study highlights the high degree of heterogeneity in patients with ptosis; only with an accurate analysis of the family and patient history and of the clinical features it is possible to perform an accurate diagnosis, finding the genetic causes and an adequate treatment.

[Accidental ethyl alcohol intoxication in a 30-day-old infant. Clinical findings and neurological follow-up]. / Intossicazione accidentale da alcol etilico in un lattante di 30 giorni. Quadro clinico e follow-up neurologico.

Fetus damages due to alcohol abuse in pregnancy, fetal alcohol syndrome (FAS), are widely documented in the literature, whereas short and long term clinical signs of acute alcohol intoxication in newborn babies are poorly described. In our study we describe the case of a 30-day-old newborn baby erroneously fed with 70 mL of white wine in place of the water for milk dilution. The baby clinical features were torpor, tremors, slight fever without metabolic anomalies typical of classic acute alcohol intoxication such as hypoglycemia, hypothermia, metabolic acidosis and coma. Periodical follow-up a 2, 3, 6 and 12 months were performed in order to evaluate neuromotor development using Bayley Scales of Infant Development II, for children between 1 and 42 months old. The results showed normal psychomotor development in our patient.