Diagnosis and therapy of pediatric tumors have a very long and productive history, and we feel indebted toward those pioneers who first opened the way to the understanding of the pathways that underlie the basic mechanisms of these special tumor types. The diagnosis of pediatric malignant tumors is often challenging.1–3 Accordingly, over the last two decades, there has been an increasing interest worldwide about the identification of tumor markers useful for both diagnostic and therapeutic purposes in pediatric oncology.4–14 Apart from neuroblastoma, hepatoblastoma, and germ cell tumors, the majority of solid pediatric tumors have no tumor-specific markers detectable in the serum of patients. In the present special issue, our aim is to provide original and review articles dealing with some pediatric tumors, emphasizing clinical, biochemical, and pathological features, which can be exploited by pediatricians, regardless of their subspecialties, in their daily practice. The need for a multidisciplinary approach, particularly with the joint effort of clinical and laboratory counterparts, is evident throughout the articles presented herein. This special issue begins with an overview on adrenocortical tumors in childhood. These neoplasms are relatively rare in pediatric age and their diagnosis (benign vs. malignant) is still challenging.15 In this regard, the article by Salvatorelli et al discusses the clinical, laboratory, and pathologic features useful in daily practice for achieving an accurate diagnosis. The article by Tumino et al summarizes the current understanding on bonemarrow transplantation for both malignant and nonmalignant hemopathies. They report some new interesting acquisitions about the allogeneic transplant with a haploidentical, semi-compatible, donor.16 The article by Ruggeri et al focuses on the pathophysiology of merlin structure and function, on its posttranslational and upstream/downstream regulation in the different forms of NF2 in the pediatric age.17 Neuroblastoma is one of the most frequent solid tumors in children. About half of the cases are metastatic, and its prognosis today still remains unfavorable despitemany new therapeutical approaches. The articles by Marino et al and Balaguer et al deal with typical biomarkers of neuroblastoma: the former focuses mainly on vanillylmandelic and homovanillic acids,18whereas the latter on metaiodobenzylguanidine (MIBG), a molecule that can be marked with radioactive 123or 131-iodine; due to the ability of neuroblastoma to uptake MIBG, this marker turns out to be extremely useful for diagnosis, follow-up, and treatment.19 Acute lymphoblastic leukemia is the most frequent childhood neoplasm, and its prognosis in the last two decades has become very good for most patients. Bonaccorso and colleagues discuss about the pathways involved in the leukemogenic process, and the prospective of a tailored treatment according to single specific profile, to further increase the efficacy with less toxicity.20 Extracranial malignant germ cell tumors have a favorable prognosis in children, with more than 80% survival rate. Yolk sac tumor is the histotype producing alfa-fetoprotein. Moscheo et al, in their article, discuss the role of thismarker at diagnosis and in the follow-up, as well as a prognostic factor.21 La Spina et al review the state of art of tumoral lysis syndrome by providing a comprehensive overviewof a complication that can occur in all pediatric neoplasms. The early recognition and, preferably, the prevention of tumoral lysis syndrome may have a huge impact on clinical practice.22 Bone sarcomas in childhood, if treatedwith a multidisciplinary approach including orthopedics and oncologists, present good results in terms of outcome for localized cases, while patients with metastatic disease are
Abstract Metabolic stone disease is the leading etiology in children with urolithiasis. Ten percent of these cases are caused by cystinuria. In the last decades the genetic origin of cystinuria was clearly defined with two major gene defects in the SALC3A1 gene on chromosome 2 and in the SLC7A9 gene on chromosome 19. As a consequence the reabsorption of dibasic amino acid cystine in the proximal renal tubules is disturbed. Renal colics caused by urolithiasis in the adolescent patient represent the classical clinical picture. Diagnosis is made by quantitative determination of amino acids in 24 h urine sampling with elevated excretion of the cystine. Treatment includes dilution and alkalinization of urine in mild cases and pharmacotherapy with D-penicillinamine and Alpha-mercaptopropionylglycine in severe cases. In the future, new approaches such as the antisense technology will open a new therapeutic gate.
Sleep disorders are common in children and include both respiratory and non-respiratory causes. An awareness of these conditions is important due to the recognized complications of untreated sleep disorders in childhood. This review provides an overview of common sleep disorders in childhood including an overview of treatment options.
Effective metaphylactic treatment is available for the different types of stone. A high urine volume achieved by sufficient intake of appropriate beverages is the most important goal in the treatment of the pediatric stone patient. Specific dietary and, if required, pharmacological measures tailored to the individual requirements can prevent or reduce recurrences and decrease the burden of invasive procedures in patients with recurrent stone disease.
During fetal life, a right balance between oxidants and antioxidants is required for survival and growth of the fetus. At birth, an overproduction of free radicals (FRs) together with poor antioxidant defenses may be detrimental for developing organs and tissues. Protecting the newborn infant against perinatal oxidative stress (OS) is a health care priority, and therefore the search for new, safe, and efficacious antioxidants has been a major quest during the last decade. Due to its antioxidant and anti-inflammatory properties, lutein, a compound belonging to the xanthophyll family of carotenoids, is one of the most promising molecules with clinical application during neonatal age. Lutein is not synthesized by humans, hence the intake primarily depends on diet. In the neonatal period, fresh human milk is the main source of lutein, though lutein-enriched infant formulas are now available. Oral supplementation represents an alternative source of lutein, and it has been demonstrated to decrease plasma biomarkers of OS and increase antioxidant capacity in the first days of life.
Abstract Hyperphenylalaninemia (HPA) is a biochemical condition characterized by mildly or strongly elevated concentrations of the amino acid phenylalanine (Phe) in the blood. HPA is commonly diagnosed by newborn screening. The primary cause of HPA is phenylketonuria (PKU), an inborn error of metabolism characterized by persistently elevated plasma concentrations of Phe secondary to a total or partial deficiency of the liver enzyme phenylalanine hydroxylase. The treatment of babies affected with PKU is based on a Phe-restricted diet, aiming to maintain blood Phe concentrations within a range of 120 to 360 μmol/L to prevent the spectrum of neurological disorders associated with PKU, that is, microcephaly, learning disability, epilepsy, pyramidal and extrapyramidal signs, and behavioral changes. This metabolic disorder mainly affects the white matter (e.g., dysmyelination, demyelination, and hypomyelination) and the cortical-subcortical structures. A delay in starting the dietary treatment, or an inadequate Phe-restricted diet, may relentlessly lead to brain damage.
The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of inherited, progressive neurodegenerative diseases. Manifestations may begin between the neonatal period and young adulthood, depending on the various subtypes. The different phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in the remaining neurons. Neurons appear to die because of increased rates of apoptosis and altered autophagy as occurs in lysosomal storage diseases. A total of 13 neuronal ceroid lipofuscinoses (CLN) genetic forms have been identified so far (CLN type 1-14). In the present review, we propose a classification scheme of themajor forms and report the case of a familial recurrence of NCL type 10, with a mutation in the CLN10 gene coding for the cathepsin D protein.
Dendritic cells (DCs) are the sentinel innate immune cells that initiate antigen-specific adaptive immune responses. On the one hand, DCs have been extensively analyzed because of their roles in immune response against pathogens, and on the other hand, there are numerous other studies that have investigated their role in immune tolerance of autoimmune disorders such as type 1 diabetes, systemic lupus erythematosus, multiple sclerosis (MS), and psoriasis. The presence, recruitment, and activation of DCs in the cerebral spinal fluids of experimental allergic encephalomyelitis and MP models, initiated the long array of studies of pathogenic and the potential therapeutic role of DCs in MS. Many classic disease-modifying therapies that are employed have used strategies to alter the maturation and function of DCs; several other novel therapeutic strategies are currently under investigations, which we aim to briefly review in this article. We have focused on reviewing the role of DCs in the central nervous system (CNS), underlying their pathogenesis involvement, and proposing targeting therapies for autoimmune CNS disorders.
Narcolepsy is a lifelong central hypersomnia characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Behavioral and psychiatric comorbidities are often associated clinical features. It is divided into two subtypes, narcolepsy type-1, and narcolepsy type-2, depending on the presence of cataplexy and the cerebrospinal fluid hypocretin-1 levels. An autoimmune process, along with environmental factors, has been hypothesized to cause the disease. Among children and adolescents, incidence in Europe falls between 0.14 and 0.3 in 100,000, with a reported increase in the incidence after the 2009 H1N1 pandemic influence and vaccination. Currently, specific pediatric diagnostic criteria and cut-off instrumental values are lacking. Clinical presentation of the disease may differ between children and adults, and misdiagnoses or diagnostic delays are still an issue. The treatment is based on behavioral and pharmacological therapy, but drugs in children are prescribed off-label. Overall, pathogenic mechanism of narcolepsy and data on drug efficacy in children are still limited: more research is needed to develop new drugs and to reach approval of current treatments in the pediatric population.
The aim was to analyze the factors that are associated with growth delay (GD) and malnutrition in preterm infants during the first year of life. The trial included 150 preterm children. The data of life history and anthropometry were studied. The trial showed statistically significant correlation of GD in preterm babies with intrauterine growth restriction, prolonged respiratory care and tube feeding, formula feeding, anemia of prematurity, and severe asphyxia at birth. To optimize health care in preterm infants, it is necessary to consider the factors that correlate with GD and give the recommendations how to prevent or treat pathological and deficit conditions.
Free radicals (FRs) are continuously produced during aerobic metabolism and are characterized by high reactivity. They participate in many important physiological processes, but if produced in high concentrations, they lead to oxidative stress (OS) development and disturb pro-oxidative/antioxidative balance toward the oxidation of lipids, proteins, carbohydrates, or nucleic acids.[1] Each of these reactions may have deleterious consequences and differential effects on the distinct cell populations of the body, with certain specific cell types being particularly vulnerable in perinatal period.[2] Pathologies resulting from oxidative damage are grouped together and categorized as “free radical disease in the neonate” (FRD). Such pathologies include retinopathy of prematurity (which in severe cases may lead to blindness), bronchopulmonary dysplasia (a particularly debilitating pulmonary lesion in the preterm infant), periventricular leukomalacia (an important cause of severe neurodisability in premature infants), and necrotizing enterocolitis.
Hyperphenylalaninemia (HPA) is a biochemical condition characterized by mildly or strongly elevated concentrations of the amino acid phenylalanine (Phe) in the blood. HPA is commonly diagnosed by newborn screening. The primary cause of HPA is phenylketonuria (PKU), an inborn error of metabolism characterized by persistently elevated plasma concentrations of Phe secondary to a total or partial deficiency of the liver enzyme phenylalanine hydroxylase. The treatment of babies affected with PKU is based on a Phe-restricted diet, aiming to maintain blood Phe concentrations within a range of 120 to 360 mu mol/L to prevent the spectrum of neurological disorders associated with PKU, that is, microcephaly, learning disability, epilepsy, pyramidal and extrapyramidal signs, and behavioral changes. This metabolic disorder mainly affects the white matter (e.g., dysmyelination, demyelination, and hypomyelination) and the cortical-subcortical structures. A delay in starting the dietary treatment, or an inadequate Phe-restricted diet, may relentlessly lead to brain damage.
Tetrahydrobiopterin (BH4) is a natural and essential cofactor for the enzymatic hydroxylation of phenylalanine (Phe) and tyrosine (Tyr), and for two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ethermonooxygenase. Five separate genetic conditions affecting BH4 synthesis or recycling have been identified so far, including deficiency in (1) 6pyruvoyltetrahydropterin synthase; (2) dihydropteridine reductase; (3) GTP cyclohydrolase I; (4) sepiapterin reductase; and (5) pterin-4a-carbinolamine dehydratase. These disorders cause hyperphenylalaninemia and impaired synthesis of serotonin and dopamine since tyrosine hydroxylase and neuronal tryptophan hydroxylase require BH4 and serotonin/dopamine products (5-hydroxytryptophan and L-dopa). All these five genetic conditions can be identified by newborn screening procedures due to elevated blood levels of Phe (with the sole exception of sepiapterin reductase deficiency). BH4 loading tests and measurement of neurotransmitter metabolites, pterins, and folates in cerebrospinal fluid can add further important information on disease severity. Untreated patients develop a complex neurological phenotype, which includes Parkinson-like features, brain degeneration, and early death. The gold standard treatment of severe disorders of BH4 metabolism is based on replacement therapy with BH4, 5-hydroxytryptophan, L-dopa, and carbidopa, with the addition, in certain cases, of folinic acid supplements and pramipexole. Dopamine agonists can improve L-dopa therapy, making treatment easier, relieving symptoms, stabilizing clinical course, and possibly ameliorating long-term outcomes. The outcome of patients with disorders of biopterin synthesis can be favorable, with either normal or near-normal cognition, and with some residual neurological symptoms usually manifesting diurnal variation, that is, worst when patients become tired or when the dosage or interval for medications is inadequate.
Cobalamin C (Cbl-C) defects are inherited autosomal recessive disorders of vitamin B-12 (or cyanocobalamin [CNCbl]) metabolism. These defects are caused bymutations in the methylmalonic aciduria and homocystinuria Cbl-C type (MMACHC; MIM # 609831) gene located on chromosome 1p34.1, which catalyzes the reductive decyanation of CNCbl, thus impairing the biosynthesis of 5'-deoxyadenosylcobalamin, adenosylcobalamin, and methylcobalamin. This impairment results in methylmalonic acidemia [MMA; MIM # 277400] combined with hyperhomocysteinemia and hypomethioninemia. Clinically, Cbl-C defects are characterized by a constellation of systemic signs and symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy, are common in the early-onset form of the disease, but are rare in its adult-onset counterpart. Administration of hydroxocobalamin (OHCbl), betaine, and folinic acid represents main therapeutic approaches. No proven efficacy has been demonstrated for carnitine and dietary protein restrictions. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adjustment exist. Despite these measures, the long-term outcome is unsatisfactory especially in patients with early onset, who experience frequent progression of their neurological and ocular impairment. The unfavorable outcome suggests that a better understanding of the pathophysiology of the disease is needed to improve treatment protocols and to develop new therapeutic approaches.
Abstract Lysosomal storage disorders (LSDs) are a heterogeneous group of inborn errors of metabolism caused by inherited deficiencies of any of the lysosomal functions, leading to the accumulation of undegraded substrates in multiple tissues and organs. Two-third of LSDs involves the central nervous system, thus representing the most common cause of pediatric neurodegenerative diseases. Substantial progress has been made in our understanding of the pathophysiology of LSDs, leading to newly targeted therapeutic options. Enzyme replacement therapy (ERT) is currently available for seven LSDs including Gaucher disease, Fabry disease, Pompe disease, and mucopolysaccharidosis (MPS) I (Hurler disease), II (Hunter disease), IV A (Morquio A), and VI (Maroteaux–Lamy disease). ERT reduces lysosomal storage, thus slowing or sometimes avoiding progressive visceral damage altogether. However, ERT is unable to cross the blood–brain barrier (BBB), thus lacking efficacy on neurological manifestations. In patients with MPS I (Hurler disease) under 2 years of age and in selected patients with other LSD, hematopoietic stem cell transplantation is indicated. To bypass the BBB, other approaches, using small molecules are currently being tested and include substrate reduction therapy, which decreases the amount of substrate (currently available for type 1 Gaucher disease and for Niemann–Pick type C disease) and pharmacological chaperones, which enhance the residual activity of the mutant enzyme.
Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations in the a-galactosidase A gene on chromosome Xq22, resulting in a-galactosidase A enzyme deficiency. It is characterized by progressive accumulation of lipids (e.g., globotriaosylceramide) in the lysosomes of a variety of cell types, including neural cells. Neurological manifestations, other than cerebrovascular accidents, include small fiber neuropathy and dysautonomic disorders. Small fiber peripheral neuropathy often is clinically manifested at young ages. Peripheral pain can be chronic and/or can occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with AFD often remain undiagnosed until the emergence of amore typical clinical manifestation, characterized by chronic renal and cardiac failure. Early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level, which can substantially improve the quality of these patients. Thus, it is important that physicians consider AFD in the differential diagnosis of neurological manifestations to provide an appropriate diagnostic and therapeutic workup.
Neurological involvement is a typical feature of several inherited metabolic diseases. The onset of signs and/or symptoms may appear as early as the first days of life or after an interval of normal or near-normal growth and development. Metabolic decomposition usually presents with a severe clinical phenotype, which include poor feeding, vomiting, lethargy, seizures, and loss of consciousness. This spectrum ofmanifestations is often fatal; however, severe neurological sequelae and/or regression of neurodevelopmental milestones can be the prominent signs in those who survive. Overall, treatable inborn errors ofmetabolism can be divided in three groups, namely: (Group 1) inborn errors of intermediary metabolism giving rise to acute or chronic intoxication; (Group 2) inborn errors of intermediary metabolism affect in genergetic processes; and (Group 3) inborn errors involving cellular organelles, including lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. The spectrum of neurological manifestations includes developmental delay, seizures and epilepsy, pyramidal and extrapyramidal signs, movement disorders, vision and hearing impairment, peripheral neuropathy, and psychiatric abnormalities. The main anatomical/imaging patterns reflects selective vulnerability of nervous system substance and include atrophy, (predominantly) symmetrical abnormalities, and dysmyelination, As several patients with neurometabolic diseases responds favorably to therapeutic trials, early detection and early intervention is of utmost importance to prevent catabolic-related damage and to revert to normal or near-normal parameters neurodevelopmental milestones.
The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders caused by deficiency of enzymes catalyzing the stepwise degradation of glycosaminoglycans dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate, and hyaluronic acid. There are seven groups of MPS, which are MPS-I (MPS-I-H or Hurler syndrome; MPS-I-S or Scheie syndrome; and MPS-I-HS or Hurler-Scheie syndrome), MPSII (Hunter syndrome), MPS-III (Sanfilippo syndrome types A to D), MPS-IV (Morquio syndrome types A and B), MPS-VI (Maroteaux-Lamy syndrome), MPS-VII (Sly syndrome), andMPS-IX (Natowicz syndrome). All are inherited as autosomal recessive diseases, with the exception of Hunter syndrome, which follows an X-linked recessive inheritance pattern. The MPSs affect multiple organ systems (including bone, heart, and visceral organs), leading to organ failure. Involvement of central nervous system occurs only in the forms with heparan sulfate accumulation, that is, MPS-I, MPS-II, MPS-III, andMPS-VII. Therapy is available for MPS-I, MPS-II, MPS-IV, and MPS-VI. This review provides a casebased overview of the different forms of MPS with neurological involvement.
Obesity is a condition of excessive body fat or adipose tissue. In children, obesity is defined as a weight ≥ 95th percentile BMI for age while overweight or at risk for obesity is defined as a weight ≥ 85th but < 95th percentile BMI for age. Pediatric obesity has become a worldwide public health concern as children, leading to series health consequences. In this review, the etiology, consequences, assessment and treatment of childhood obesity are discussed.
