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Peroxisome biogenesis disorders (PBDs) represent a spectrum of human genetic disorders that are characterized by damaged peroxisome assembly. In the newborn period, the characteristics of affected patients include dysmorphic facial features, neonatal hypotonia, seizures, ocular abnormalities, poor feeding, liver cysts with hepatic dysfunction and skeletal defects. These can be caused by a defect in at least 14 different PEX genes. In this study, whole-exome sequencing (WES) was performed on samples from two Chinese newborns with clinical features of Zellweger syndrome. WES identified two novel mutations (c.2416+1G>T and c.2489delT) in patient 1 and another two novel mutations (c.1483+1G>A and c.1727dupG) in patient 2 in the PEX1 gene. All four mutations have a serious influence on the protein function, which also highlights the power of WES, particularly in clinically challenging cases.

Maternal nutrition is an important public health problem in low-income countries around the world and mothers from this setting are considered as a nutritionally vulnerable group. Due to the nursing process, mothers are subjected to nutritional stresses. Frequent pregnancies followed by lactation and poor feeding habits result in poor birth outcomes and increase morbidity and mortality risk of mothers and their children. The objective of this review is to identify systematically, appraise and synthesize the best available evidence on the maternal feeding practice and its outcome in developing countries. Electronic search of Medline, Pub Med, Health Inter-network access to Research Initiative (HINARI), and Google Scholar databases were conducted. Results of interest were maternal feeding practice and its outcome. Many studies concluded that the most frequent proximate causes of maternal malnutrition include inadequate food intake, poor nutritional quality of diets, frequent infections and short inter-pregnancy intervals. Majority of the reviewed articles also reported that in developing world women are more likely to suffer from nutritional deficiency than men. The feeding practices, dietary intakes and nutritional status of women in most developing countries were short of the national and international recommendations. The diets of women and mothers are often overlooked socioeconomic conditions, cultural beliefs, taboos and misconceptions are the major determinant factors for poor maternal feeding practice, which increase not only women’s chance of being malnourished but increases the chance of intrauterine growth retardation and childhood malnutrition. The effect of poor dietary habits and feeding practices of mothers do not end with poor birth outcomes and nutritional status of the newborn but may extend on influencing children eating behavior, which results with poor health and nutritional status of children. Dietary counseling in order to achieve optimal nutritional situation of women through behavioral change programs, when appropriate and a need for more comprehensive applied research studies as a means to find scientific solution are recommended.

Background Adequate nutrition in early life is a prerequisite for human capital formation and economic development. Although poor feeding practices is a problem predominantly thought to exist in low-income and middle income countries, malnutrition is rapidly rising among developed nations as well. In this context, and in light of scarcity of protein sources, utilization of crops-such as chickpea-as a source of micro and macro nutrients is mandatory in the long route to nutritional improvement. Scope and approach In this review, we outline interesting features of the chickpea crop, in terms of its nutritional value and agronomic potential that may help combat several health issues in both Western countries as well as in many low income sectors in developing countries. Key Findings and Conclusions: On the global scale, chickpea consumption is steadily increasing in recent years. In developing countries, chickpea brings a variety of taste and texture to the cereal-based diet, as well as high-quality protein , fiber, carbohydrates and minerals, thereby ensuring a balanced diet and improving the nutritional status of the population. In developed countries, chickpea may be an ultimate source of protein for the increasing vegetarian/vegan populations. On top of that, allergenicity issues, content of phytoestrogens and more, are negligible in chickpea. For all these reasons, this crop should be considered as an outstanding source of protein, the ultimate alternative to soybeans, as well as the next health-food for human consumption.

Purpose To describe the clinical presentation and implications of mitochondrial DNA depletion disorder of two siblings with early fatal encephalomyopathy and a novel mutation in the RRM2B gene. The relevant literature is reviewed. Methods We describe two brothers aged 2.5 months and 1 month, respectively, who were hospitalized in a tertiary pediatric medical center for evaluation of focal seizures, hypotonia, poor feeding, failure to thrive, lactic acidosis, and developmental delay. The older brother also had seizures, and the younger had severe bilateral neurosensory deafness. Results Genetic sequencing of the RRM2B gene revealed the same novel mutation in both the siblings. Both children died due to respiratory failure at ages 3 and 2.5 months, respectively. Conclusion The combination of neonatal hypotonia, developmental delay, and lactic acidosis should raise a clinician's suspicion of a mitochondrial depletion disorder and prompt further genetic studies.

About bout 30% of children under five years old were stunted as a consequence of poor feeding practices and repeated infections. The study determined the feeding practice of mothers of under-five children in Naga City, Cebu, Philippines. The study utilized the descriptive method involving 330 respondents in five districts of the City of Naga, Cebu. Questionnaire was used in data collection and it was translated to Cebuano to extract the necessary data from the respondents. The findings showed the majority of the children under-five year-old were breastfed by their mothers immediately after birth. Furthermore, nearly all respondents did not practice exclusive breastfeeding, however, a considerable number of respondents continue to breastfeed after six months. Plain water, vitamins or medicines and clear broth topped the list of liquids introduced by the respondents, while vitamin A-rich vegetables, foods rich in carbohydrates and iodine-rich foods ranked first, second and third respectively in the list of solid foods for complementary feeding. Most of the respondents did not introduce products that are fortified with iron. Breastfeeding practices in urban areas lack knowledge of the importance of iron-fortified complementary feeding as well as exclusive breastfeeding.

Obesity is the most common cause of metabolic complications and poor quality of life in Prader-Willi syndrome (PWS). Hyperphagia and obesity develop after an initial phase of poor feeding and failure to thrive. Several mechanisms for the aetiology of obesity in PWS are proposed, which include disruption in hypothalamic pathways of satiety control resulting in hyperphagia, aberration in hormones regulating food intake, reduced energy expenditure because of hypotonia and altered behaviour with features of autism spectrum disorder. Profound muscular hypotonia prevents PWS patients from becoming physically active, causing reduced muscle movements and hence reduced energy expenditure. In a quest for the aetiology of obesity, recent evidence has focused on several appetite-regulating hormones, growth hormone, thyroid hormones and plasma adipocytokines. However, despite advancement in understanding of the genetic basis of PWS, there are contradictory data on the role of satiety hormones in hyperphagia and data regarding dietary intake are limited. Mechanistic studies on the aetiology of obesity and its relationship with disease pathogenesis in PWS are required. . In this review, we focused on the available evidence regarding mechanisms of obesity and potential new areas that could be explored to help unravel obesity pathogenesis in PWS.

Background: Carbonic anhydrase 12 (CA12) deficiency, a newly recognized rare disorder, has been described among Israeli Bedouin kindred as an autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration, visible salt precipitation after sweating, poor feeding and slow weight gain in infancy. Case presentation: We present two adolescents diagnosed with CA12 deficiency who developed severe rhabdomyolysis as a result of physical activity in a hot climate. Conclusions: This presentation highlights a previously unreported but significant clinical complication of this disorder and emphasizes the persistent risk of excessive salt loss via sweat and a need for certain precautions, such as increased salt intake and avoidance of prolonged and/or strenuous exercise.

A full-term (40+2/7 weeks) male baby, weighing 2.8 kg, was born to non-consanguineous parents by normal vaginal delivery. He was referred at 9 hours of age with lethargy, poor feeding, feeble cry and generalised hypotonia. On admission, he had normal vitals, and general examination showed bilateral undescended testes (not palpable in the scrotal sac or inguinal canal) with well-developed scrotum, adequate phallus size, and normal urethral and anal opening. Systemic examination revealed mild to moderate stupor, weak and feeble cry, generalised hypotonia but preserved deep tendon reflexes, and his facial features were notable for retrognathia, high-arched palate and bilateral low-set ears (figures 1 and 2). While evaluating for floppy neonate, features of central hypotonia (very poor sensorium, feeding difficulty and brisk DTRs) were found. After initial stabilisation, Ryle’s tube feeding was started. Figure 1 Truncal and axial hypotonia. Figure 2 Facial profile. In central hypotonia, which clinical feature is absent? 1. Low tone without weakness. 2. Normal or brisk deep tendon reflexes. 3. Preserved neonatal reflexes. 4. Fasciculations. …

3-Hydroxyisobutyryl-CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome-like phenotype, mitochondrial dysfunction, and increased C4-OH. We report the most severe case to date in a full-term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow-up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.

BackgroundEarly diagnosis of neonatal sepsis is essential to prevent severe complications and avoid unnecessary use of antibiotics. The mortality of neonatal sepsis is over 18%in many countries. This study aimed to develop a predictive model for the diagnosis of bacterial late-onset neonatal sepsis.MethodsA case-control study was conducted at Queen Sirikit National Institute of Child Health, Bangkok, Thailand. Data were derived from the medical records of 52 sepsis cases and 156 non-sepsis controls. Only proven bacterial neonatal sepsis cases were included in the sepsis group. The non-sepsis group consisted of neonates without any infection. Potential predictors consisted of risk factors, clinical conditions, laboratory data, and treatment modalities. The model was developed based on multiple logistic regression analysis.ResultsThe incidence of late proven neonatal sepsis was 1.46%. The model had 6 significant variables: poor feeding, abnormal heart rate (outside the range 100–180 x/min), abnormal temperature (outside the range 36o-37.9 °C), abnormal oxygen saturation, abnormal leucocytes (according to Manroe’s criteria by age), and abnormal pH (outside the range 7.27–7.45). The area below the Receiver Operating Characteristics (ROC) curve was 95.5%. The score had a sensitivity of 88.5% and specificity of 90.4%.ConclusionA predictive model and a scoring system were developed for proven bacterial late-onset neonatal sepsis. This simpler tool is expected to somewhat replace microbiological culture, especially in resource-limited settings.

Background: With births generated with assisted reproductive techniques (ARTs) increasingly, the effect of ARTs on infant feeding behaviors is an essential topic to explore. However, limited literature focused on this topic. The objective of this study is to examine the effect of ARTs on infant feeding behaviors. Materials and Methods: Participants, including 41 mothers who conceived with ARTs and 935 conceived spontaneously, were drawn from a prospective birth cohort between January 2015 and December 2015. The participants were followed up at 1, 3, 6, 8, and 12 months postpartum at their residences through a face-to-face interview. Feeding behaviors, including breastfeeding initiation, partial/exclusive breastfeeding duration and formula introduction were assessed using World Health Organization-recommended definitions. Cox and logistic regression models were applied to examine the association of assisted conception with feeding behaviors. Results: Breastfeeding initiation rates were comparable between women who conceived with and without ARTs (70.7% versus 76.0%). Breastfeeding duration and formula introduction were significantly shorter and earlier in assisted conceptions in univariate analyses at 6 months postpartum [crude hazard ratios (HRs), 95% confidence intervals (CIs) 2.02 (1.03-3.84), and 1.63 (1.09-2.44)]. However, after controlling for covariates, assisted conception was only associated with shorter breastfeeding duration at 6 months postpartum [adjusted HR 1.99, 95% CI 1.05-3.80], no significant differences were found in infant feeding outcomes at 12 months postpartum among women with ART conception versus general conception. Mothers who conceived through ARTs with cesarean deliveries were at the highest risks of shorter breastfeeding duration and earlier formula introduction than mothers who conceived spontaneously with vaginal deliveries. Conclusions: Mothers who conceive through ARTs are associated with shorter breastfeeding durations for the first 6 months, compare to mothers who conceive spontaneously. Furthermore, cesarean delivery has a joint effect with the treatment of ARTs on promoting the development of poor feeding behaviors.

Improper feeding practice in children is one of the causes of nutritional problems in developing countries. This case causes 1.5 million children to die. Feeding practice is a behavior to control the types and the amount of food for children. This study aimed to identify the mother feeding practice to children in the provision of nutrition in a PAUD at Jatinangor sub-district. This study used a descriptive quantitative approach. The population in this study were mothers who had children aged 3-6 years, respondents were chosen using total sampling technique. There were 55 respondents in this study. Data collection used a CFPQ questionnaire (Comprehensive Feeding Practice Questionnaire) to identify the mother's feeding practice. Data were analyzed using the 75 percentile value of the total score of the questionnaire. Data is presented using frequency distribution. The result showed that 39 (70.9%) mothers had poor feeding practice and 16 (29.1%) mother had good feeding practice. These results illustrate that mother feeding practice is still not appropriate in fulfilling nutrition for children. Nurses as a health worker are expected to improve mothers’ knowledge regarding how to apply good and balanced food that appropriate with children's need.Keywords: Children, feeding practice, nutritional status of children.

Background 6 month old baby, known case of Trisomy 21 with poor feeding. Case report A 6 month old baby girl was brought to emergency department by the mother as she was not feeding well for last few hours.Baby was born at term with an antenatal diagnosis of trisomy 21.She was exclusively breast fed since birth.Mom noticed an unusual appearance of a hard palate that she had not observed before.Her first impression was probably a cleft palate. On examination in emergency department baby was well looking ,alert with features of trisomy 21.Local examination of the palate revealed a piece of hazelnut that was stuck inside the hard palate.It was removed with the help of a spatulaunder direct visualisation in left lateral position.Baby was then discharged home as she was taking her feeds well. Discussion Foreign bodies of hard palate are rare.Most cases occur in infants.It can present in a variety of ways and most common is usual appearance mimicking oral pathology with poor feeding.Sometimes the diagnosis is challenging and there is always a choking hazard if there is delay in diagnosis.

Introduction Metabolic crisis in the neonatal period is an infrequently encountered, but potentially devastating presentation of an inborn error of metabolism. Due to the rarity of these disorders, diagnosis may be delayed. Furthermore, presentation may closely mimic neonatal sepsis, a much more frequently encountered condition. We describe the case of a neonate who presented at day nine with non-specific symptoms and signs. Careful evaluation of biochemical abnormalities led to a timely diagnosis of a rare, potentially life threatening metabolic disorder – Argininosuccinic Aciduria. Clinical Case A nine day old female infant presented with three days of poor feeding, lethargy and reduced urine output. Examination identified hypothermia (34.5C), tachypnoea, and a decreased level of consciousness. She was the first child of non-consanguineous Irish parents, with no family history of metabolic disorders. She was delivered at term by spontaneous vaginal delivery to non-consanguinous Irish parents, following an uncomplicated pregnancy. There were no septic risk factors or concerns at discharge on day 3. Blood glucose and inflammatory markers were normal. She was fluid resuscitated and commenced on broad-spectrum antibiotics. Despite treatment, she deteriorated. Venous blood gas showed respiratory alkalosis (pH 7.458, pCO2 3.92, HCO3 20.8, BE -2.4, lactate 1.0) prompting further investigation. Serum ammonia was 562. Retrospective review of investigations identified an unrecordable urea ( Conclusion Argininosuccinic aciduria is a rare, autosomal recessive disorder of urea cycle metabolism caused by deficiency of argininosuccinic lyase. Clinical and biochemical manifestations depend on the severity of enzyme deficiency. In the neonatal variant, it typically presents with hyperammonaemia, encephalopathy and respiratory alkalosis. This case highlights the importance of considering inborn errors of metabolism in the assessment of a sick neonate.

Background There is a national strategy ATAIN aimed at reducing term admissions to the neonatal unit. Whilst this is aimed at looking at potentially preventable term admissions to the neonatal unit, it does not address the issue of re-admission following discharge from the postnatal ward or neonatal unit. Given the limited midwifery resources in the community, we believe some of the re-admissions are potentially preventable if there were adequate resources to support the mother and baby at home. Aims To review the reasons for readmissions from home and identify potentially avoidable causes. Methods We retrospectively reviewed the BadgerNet neonatal electronic patient record to identify readmissions over the last financial year between 01/04/2017 and 31/03/2018. A standard excel profoma was used to collect and analyse the data. The reason for admission, interventions carried out and outcome was reviewed including the length of stay. Results In the last financial year there were 142 babies resulting in 143 readmissions to the postnatal or transitional care ward. Of these 120 babies were re-admitted for jaundice as a primary cause of admission. Of these jaundiced babies, 31 also had associated weight loss noted on admission. One baby had two episodes of re-admission for jaundice. Five of these babies had an infection screen, which were negative and antibiotics were discontinued by 48hrs. The median length of stay was 4 days and the range was between 3 and 11 days. Only one had admission to the neonatal unit with bronchiolitis. The total length of stay for the 120 babies was 446 days. Another 22 babies were readmitted because of weight loss. The median length of stay was 3 days and the range was between 1–4 days. The total length of stay for the 22 babies was 70 days. Of all the re-admission, 99 were breastfeeding on re-admission, 24 were mixed feeds and 19 bottle fed. Conclusions The two main reasons for readmissions were jaundice and weight loss. There was an overlap of this because a proportion of jaundiced babies were noted to have weight loss or poor feeding on readmission. We believe that these are potentially avoidable readmissions if there was sufficient feeding support for the mother and babies in the community. It would alleviate the additional emotional stress imposed on the mother and family by the readmission. It would also reduce the impact on the bed occupancy on an already stretched maternity and transitional care wards.

Pathogenic DNM1L mutations cause a mitochondrial disorder with a highly variable clinical phenotype characterized by developmental delay, hypotonia, seizures, microcephaly, poor feeding, ocular abnormalities, and dysarthria. We report the case of an 8-month-old female with autosomal dominant, de novo DNM1L c. 1228G>A (p. E410K) mutation and mitochondrial disorder, septo-optic dysplasia, hypotonia, developmental delay, elevated blood lactate, and severe mitochondrial cardiomyopathy leading to nonischemic congestive heart failure and cardiogenic shock resulting in death. This case suggests that cardiac involvement, previously undescribed, can be a clinically important feature of this syndrome and should be screened for at diagnosis.

Aims To share our use of four-way communication between paediatric intensive care (PIC), tertiary neurology, parents and a district general hospital in an unusual situation. Method A male baby was born at 37 weeks weighing 2410 and had symmetrical IUGR. Initial tests did not reveal a cause. The baby was admitted to hospital twice because of poor feeding and poor weight gain. Aged 2 months he had marked hypotonia and was admitted for the second time. Echocardiogram showed left ventricular hypertrophy, serum lactate was elevated at 4.5 mmol/L (n 7.7 mmol/L, serum lactate had increased to 8.4 mmol/L. Leigh’s syndrome was strongly suspected but not definite. This is an inherited, usually mitochondrial, untreatable and terminal disorder. Due to impending respiratory failure a transfer to PICU was requested. A conference call initially involving the Consultant Paediatrician, Paediatric Neurologist and Paediatric Intensivist concluded that initiation of intensive care would inevitably lead to palliation in this case. We then invited parents to join the conference call who were able to ask the specialist questions directly and finally agree that intensive care was not in the best interests of their child. Results The baby was palliated in the DGH and died 24 hours later. 15 months later genetic tests confirmed novel heterozygous recessive mutations in a complex 1 gene as the cause of the Leigh syndrome. Conclusions We believe that use of technology to ensure clear communication in a complex situation was vital in achieving the appropriate outcome for our patient. This approach could easily be adopted wherever call conferencing is available.

Aim To discuss the case of a baby presenting with reversible progressive paralysis due to infantile botulism. Case This is the first case of infantile botulism in the UK since 2013 which presented after long haul travel to USA. A five month old girl with no history of illness presents with a rapidly progressing descending symmetrical paralysis. She had no significant past medical or familial history. Her initial complaint was difficulty in breast feeding followed by a rapid deterioration with hypotonia and respiratory failure. As a result, she was intubated and ventilated for 11 days whilst she was investigated extensively in paediatric intensive care. She was clinically thought to have infantile botulism and after a positive culture she was successfully treated with Baby BIG (immunoglobulin) for infantile botulism. She is back to her normal baseline. Investigations Initial blood tests and cerebrospinal fluid analysis including cell counts, protein and glucose were normal. Echocardiogram, electro-encephalogram and nerve conduction study were normal. Needle electromyography (EMG) found small, short and polyphasic motor unit action potentials. A PCR for detection of Clostridium botulinum type B neurotoxin genes in faecal specimens was negative. The mouse assay test was only partly positive and diagnosis was eventually confirmed by stool culture. Discussion Infantile botulism is an orphan disease that specifically affects infant less than 12 months of age. It is most commonly acquired in the United States with between 70–100 cases reported annually. In the UK it is a rare disease; there are now fourteen reported cases of infantile botulism in the UK. It is due to absorption of botulin toxin produced within the intestinal tract by temporary colonising clostridia. Infantile botulism typically presents with constipation and poor feeding. However, the clinical presentation may vary from mild hypotonia to severe bulbar paralysis and sudden infant death. It is a rare but important differential diagnosis in progressive hypotonia or paralysis in an infant in the UK. It has a completely reversible cause and effective treatment. As a result, this case highlights the importance of taking an accurate travel and diet history.

Neonatal abstinence syndrome (NAS) refers to a constellation of signs occurring in newborn infants who were exposed to opioids or opiates in utero. These manifestations include poor feeding, gastrointestinal disorders, abnormal sleep patterns, and neurological signs such as jitteriness, tremors, and seizures (1, 2). Myoclonus, jitteriness, and tremors often may be interpreted as seizures and therefore treated as epileptic seizures. Objective: To determine whether seizure like activity observed in infants with NAS correlate with electroencephalogram (EEG) findings. Design/ Method: We reviewed the standard EEG or video electroencephalogram (VEEG) of infants with NAS who were admitted because of seizure-like clinical activity. The exclusion criteria were major neurological anomalies, hypoxic ischemic encephalopathy, metabolic disorders, or with clinical diagnosis other than NAS. Results: Forty neonates met study criteria; 28 had standard EEG recordings and 18 had VEEG. Mean gestational age was 38.5 weeks. The onset of seizure-like clinical activity was as early as day 1 and as late as day 16 of life. The clinical seizure-like activity described at the referring hospital were jerking, rhythmic movement of the extremities, or tremors. Only three (7.5%) neonates had epileptic seizures. There were increased sharp transients in frontal, central, temporal, and or occipital regions. VEEG showed disturbed non-rapid eye movement (REM) sleep with frequent arousal, jittery movements, or sleep myoclonus. Conclusion: Clinical seizure-like activity correlates poorly with epileptic seizures in infants with NAS. In neonates with NAS, a VEEG would be useful to determine if the clinical seizure-like activity is of epileptic origin or not, prior to initiation of anti-seizure medications.

The aim of this chapter is to highlight a rare endocrine condition (Congenital Hyperinsulinism, CHI), which can cause low blood glucose levels leading to permanent brain injury. Many Paediatric Nurses are unfamiliar with this condition. CHI is caused by unregulated insulin secretion from the pancreas and typically presents in the newborn period, but it can also present later in life. It is imperative for Paediatric Nurses to be knowledgeable on the subject of CHI as they are usually the first to identify the infant’s low blood glucose levels, often accompanied by non-specific symptoms such as floppiness, jitteriness, fitting, lethargy, or poor feeding. It is always important to consider CHI if an infant or child presents with unexplained recurrent and persistent hypoglycaemia.

Nowadays severe illness in neonates is fortunately rare in Norway. However, newborns present with non-specific symptoms, making diagnostics in this age group challenging, and neonatologists need to think broadly in order not to overlook serious illness. We present the case of a nine-day-old who was severely ill when she arrived at hospital. She was born in gestational week 37 after a normal pregnancy. The birth was complicated by shoulder dystocia, rupture of the umbilical cord and fracture of the clavicle. Thereafter she had a normal stay in the maternity ward for three days. At home she appeared healthy and gained weight until she returned to hospital after thirteen hours of poor feeding, irritability and fever. The symptoms turned out to be caused by bacterial meningitis. During the first week of hospitalisation she developed ventriculitis, brain abscesses and sinus vein thrombosis. It was later discovered that she had severely impaired hearing, and thereafter she developed hydrocephalus requiring surgical drainage. The mortality from neonatal bacterial meningitis has dropped from almost 50 % in the 1970s to less than 10 % today, but the morbidity has remained unchanged. It is crucial that clinicians are alert to this diagnosis, as delayed treatment can worsen the prognosis.

Galactosemia type I is caused by a deficiency of the galactose-1-phosphate uridylyltransferase enzyme, encoding by the GALT gene. This pathology is inherited in an autosomal recessive pattern. Following galactose intake by galactosemic neonates, a toxic buildup of galactose metabolism intermediates is produced. Promptly, various signs appeared such as lethargy, poor feeding, jaundice, and hepatomegaly. Treatment is relatively easy to achieve to prevent acute symptoms and save the baby's life. However, even when patients undergo lifelong galactose dietary restrictions, some subjects develop mild to severe long-term complications. The mutational spectrum is characterized by allele heterogeneity, where few alleles have high frequency and a clear ethnic distribution. Missense mutations are the most common variants and are distributed along the whole GALT gene, altering functional and structural features of the enzyme. Dietary treatments consist of eliminating lactose- and galactose-rich foods and supplying formulas of soy milk. This diet should be maintained through the whole life of the patient. In contrast, the diet should be absolutely normal in the Duarte form of galactosemia. Experts reached a consensus and recommended the consumption of fruits, vegetables, legumes, unfermented soy products, and hard chesses.

Hereditary fructose intolerance is an autosomal recessive disorder of fructose metabolism caused by catalytic deficiency of aldolase B enzyme [ 1 ]. The disease is typically expressed when fructose- and sucrose-containing foods are first introduced in the diet; acute manifestations include nausea, vomiting, abdominal distress, and symptomatic hypoglycemia [ 1 , 2 ]. Chronic fructose ingestion eventually leads to poor feeding, growth retardation and gradual liver and/or renal failure [ 3 , 4 ]. Some patients may remain undiagnosed until adulthood because of a self-protective avoidance of sweet tasting food that prevents the development of acute toxicity from fructose containing food; however, these subjects may suffer intermittent symptoms throughout life, leading to potentially serious misdiagnosis [ 4 ]. We report the case of a patient with unrecognized hereditary fructose intolerance in which chronic gastrointestinal complaints, low body weight, and unexplained food avoidance were addressed as manifestations of an eating disorder during adolescence.

Infants and children with congenital heart disease are contended with growth challenges. The causes are multifactorial and contributed by hypermetabolism, poor feeding, limited tolerance to feeding, and iatrogenic caloric deficits from procedural interruptions and fluid volume restriction that are inherent in the intensive care unit. Providing enteral and parenteral nutrition support, with attentive surveillance to nutrition delivery, can mitigate growth faltering in this population.

Background Infants with neonatal abstinence syndrome (NAS) initially experience neurologic excitability, poor feeding, and/or hyperphagia in the setting of increased metabolic demand. Because the longitudinal effects of these early symptoms and behaviors on weight trends are unknown, we sought to contrast weight gain patterns through age 1 year for infants diagnosed with NAS with matched controls. Methods Retrospective cohort of 70 singletons with a gestational age of ≥37 weeks and an ICD-9 or ICD-10 diagnosis of NAS made ≤7 days after birth with institutional follow-up matched to patients without NAS. Infants were matched on gestational age (±2 weeks), birth weight (±20 g), sex (exact), and insurance type (exact). Quantile regression methods were used to estimate 10th, 25th, 50th, 75th and 90th percentiles of weight over time. Results The mean gestational age for an infant with NAS was 38.8 weeks (standard deviation [SD], 1.3). The mean birth weight was 3.141 kg (SD, 0.510). NAS patients had a median of 24 weights recorded between birth and 400 days (inter-quartile range [IQR], 16–32 weights). Patients without NAS had a median of 12 weights recorded (IQR, 10–16). Growth curves were similar over the first 400 days of life. Patients with NAS had non-significantly higher and lower estimated weights for the 90th and 10th percentiles, respectively. Conclusion Infants with a diagnosis of NAS grew similarly to controls during their first year. Given the frequently-encountered NAS symptoms of hyperphagia and irritability, future studies may evaluate whether early differences in caregiver feeding exist and whether they have longer-term impacts on growth.

Poor breastfeeding and complementary feeding practices predict child stunting and wasting in South Asia, suggesting that initiatives to end undernutrition in the region should focus on improving the diets of young children. This review of the literature finds that South Asia has made relatively good progress in improving breastfeeding practices compared with other regions, but the lack of diversity in complementary foods and low frequency of feeding continue to be problems. Children who are most at risk of experiencing poor feeding include those who are born small, have younger mothers, and live in poorer households or in communities with less access to, or lower uptake of, primary health services. Initiatives to improve feeding practices have not produced substantial improvement, particularly in complementary feeding, because such efforts have lacked the coverage, intensity, comprehensiveness, and continuity needed. Policy, legal, and program actions to protect, promote, and support recommended feeding practices should be informed by situation analyses and formative research on context-specific drivers of poor practices. The actions should involve multiple sectors and stakeholders, including governments, the private sector, communities, and households.

Background Poor diet and high infection rates inflicted by low socio-economic status and poor environments among infants and young children appear to be major causes of severe malnutrition. Objective To determine the practical and likely effectiveness in rehabilitation of severe malnutrition. Methods A descriptive observational study was conducted on 27 children at three different sites: (1) Five inpatients at the Inpatient Ward, Cipto Mangunkusumo Hospital, Jakarta (IP-CM); (2) 8 out- patients at the Metabolic and Nutrition Clinic, Cipto Mangunkusumo Hospital (OP-CM); (3) 14 outpatients at the Nutrition Clinic, Bogor (NC). All the patients followed were aged

ObjectiveTo characterize the epidemiology of wasting and identify the main predictors of wasting, severe wasting and poor weight-for-height in children.DesignWe analysed a nationally representative sample of 2028 children (Multiple Indicator Survey, 2010).SettingRoyal Kingdom of Bhutan.SubjectsChildren aged 0–23 months.ResultsWasting prevalence was significantly higher among infants aged 0–11 months than among children aged 12–23 months (12·0 v. 6·7 %; P=0·004) and among boys than girls (11·0 v. 7·5 %; P=0·04). Children from the Western region had 63 % higher odds of being wasted than children from the Central/Eastern regions (adjusted OR (AOR)=1·63; 95 % CI 1·14, 2·34). Poor feeding practices were among the most significant predictors of wasting and severe wasting. Children who were given prelacteal feeds in the first days of life had 2·5 times higher odds of being severely wasted than those who were not (AOR=2·49; 95 % CI 1·19, 5·19); inadequate complementary feeding in children aged 0–23 months was associated with 58 % higher odds of being wasted (AOR=1·58; 95 % CI 1·02, 2·47) and 2·3 times higher odds of being severely wasted (AOR=2·28; 95 % CI 1·13, 4·58). The association of poor infant feeding practices with wasting and severe wasting was particularly significant in infants (0–11 months).ConclusionsProgrammes for the detection and treatment of severely wasted children need to prioritize very young children (0–11 months), particularly in the Western region. Programmes for the prevention of wasting need to prioritize the improvement of complementary foods and feeding practices in children aged 6–23 months.

A wide variety of prey animals possess damage-released chemical alarm cues that evoke antipredator responses in both conspecifics and some heterospecifics. Several studies have indicated that food availability may influence body condition and in doing so, affect the production of alarm cues. We examined whether food availability (high and low) and temperature (27, 30 and 32 °C) interacted to affect the production of chemical alarm cues by juveniles of a marine tropical prey fish, Pomacentrus moluccensis. Results indicate that poorly-fed fish had depleted energy reserves with rising temperatures compared to well-fed fish. Fish with a poor feeding history also showed depressed growth rate across all temperature treatments. The alarm cues produced by experimental fish triggered stronger antipredator responses as temperature increased up to 30 °C, regardless of the feeding history or body condition of the donor. However, at 32 °C, alarm cues from poorly-fed fish did not elicit as effectively an antipredator response in conspecifics compared to those produced by well-fed fish. The results highlight that warming oceans, in isolation but also in conjunction with changes in food supply, may have a drastic impact on chemically-mediated predator-prey interactions.

Mothers of hyperbilirubinemic newborns frequently report to us that their infant is feeding poorly. As poor feeding in an extremely hyperbilirubinemic newborn may be an early sign of bilirubin encephalopathy, we hypothesized that neonatal hyperbilirubinemia would suppress the volume of feed ingested and diminish sucking parameters in comparison with minimally jaundiced neonates.To determine whether hyperbilirubinemia does diminish feeding and sucking in neonates.Neonates in a well-baby nursery with serum total bilirubin (STB) ≥15.0mg/dL were compared with those with transcutaneous bilirubin ≤10mg/dL. Neonur, a modification of Krohn's Nutritive Sucking Apparatus, was used to quantify sucking parameters. Measurements during a 5min feeding period included volume ingested (measured manually), number of sucks, average maximum sucking pressure, number of bursts, average burst duration, pause between bursts duration, number of sucks per burst, and average intersuck interval. Outcome measures were volume ingested and, presuming decreased volume, sucking parameter analysis would determine the component affected by hyperbilirubinemia.17 hyperbilirubinemic newborns (STB 17.8±1.6mg/dL) were compared with 24 controls, all with transcutaneous bilirubin10.0mg/dL. The volume of feed ingested was similar between the hyperbilirubinemic newborns and controls (30.00 [20.00-42.50] ml vs. 25.00 [15.00-30.00] ml, p=0.2) (median [95% confidence interval]). No significant differences were noted in any of the other sucking parameters measured.At concentrations of STB in the range of 15-20mg/dL, hyperbilirubinemia did not diminish feed volume or sucking parameters in term newborns. Poor feeding in moderately hyperbilirubinemic newborns cannot be attributed to the level of bilirubin per se.

Neurometabolic disorders are a group of inborn errors of metabolism where neurological symptoms predominate especially convulsions which are usually resistant to antiepileptic drugs. Other symptoms include poor feeding, vomiting, lethargy, seizures, and loss of consciousness. Because of the nonspecific overlapping symptoms, confirming the diagnosis depends mainly on the specific investigation that is done in highly specialized laboratories. The clinical picture can be more complicated in the presence of two diseases in the same family and more difficult if present in the same patient. This is not extremely rare in countries with high prevalence of consanguineous marriage like Egypt. The situation is more complicated when we add the lack of specific investigations, metabolic specialized labs and the deficiency of documentation. In this case report, we present the challenges that we met in diagnosis and counseling of a family with both Tay–Sachs and maple syrup urine disease depending mainly on history, clinical data and a few diagnostic investigations.

BACKGROUND An understanding of the dynamics that affect the nutrient content of forages with advancing growth stages is critical for designing equally dynamic feeding programmes. This study compared the agronomic characteristic and feeding values of forages from barley, rye, wheat, oats and triticale weekly from tillering (Z 24-25) to dough stages of maturity (Z 83-87). RESULT Digestible dry matter yield of cereal species increased rapidly (P 0.05) until the dough stage when it increased to 10.4 t ha(-1) . The nutritive quality of cereal species decreased with advancing growth stages, and this was more pronounced in barley and rye with rapid reductions in their energy and digestibility values. Changes in the nutritive value of cereal forages indicated a strong relationship (P < 0.05) with the leaf-stem ratio of the plants. The animal response reflected the changes in feeding value of cereal species with advancing growth stages. The average live weight gain of lambs decreased (P < 0.05) from an average of 203 g d(-1) on 2 May to 142 g d(-1) on the 13 June. CONCLUSION Wheat and oats, and to a lesser extent triticale, provided higher quality forages than barley and rye. All cereal species had poor feeding qualities between ear emergence and milk stages (Z 71-75). © 2016 Society of Chemical Industry.

Objective Obstetrical and medical complications in pregnancy may necessitate delivery between 34 and 37 weeks' gestation. To assist decision making and patient counseling, we sought to determine the prevalence of neonatal morbidities between 34 and 37 weeks' gestation. Study design Retrospective cohort study of live births was conducted at our institution over a seven year period. Multiple gestations and congenital anomalies were excluded. The prevalence of neonatal morbidities between 34 and 37 were calculated. Results 1060 births between weeks 34–36 and 975 births occurred during week 37. Gestational age was inversely related to NICU admission, days in NICU, intubation, poor feeding, hyperbilirubinemia, and respiratory distress (p Conclusion There is decreased neonatal morbidity for each week gained between 34 and 37 weeks' gestation.

Background: The burden of neonatal septicaemia has remained high worldwide and even more severe in the developing countries like ours. Clinical manifestation is variable and non-specific thereby resulting in delay in diagnosis. Blood culture which is the gold standard for diagnosis of neonatal septicaemia (NNS) has many drawbacks due to long waiting time for culture process, low yield, improper inoculation adding to the problem of late diagnosis. Haematological parameters have been utilized in rapid and early diagnosis of NNS and prompt treatment thus circumventing problems associated with drawbacks in blood culture. Objective: The study was to identify the common clinical features of neonatal septicaemia and haematological indices that were commonly utilized in rapid diagnosis of NNS, and also to determine their sensitivity, specificity, positive predictive and negative predictive value. Materials and Methods: The study was prospective and neonates that had clinical features suggestive of neonatal septicaemia were enrolled consecutively into the study. The patients were appropriately investigated including blood cultures, CSF cultures and urine among others, also blood sample for packed cell volume (PCV), total white cell count (TWBC), absolute neutrophil count (ANC), absolute platelet count (APC). Immature to mature neutrophil ratio (I/MNR), immature to total neutrophil ratio (I/TNR) and micro-ESR (erythrocyte sedimentation rate) was also done and analyzed. Results: The common clinical symptoms were fever 39.5%, poor feeding 33.6%, excessive cry 38.7%, difficulty in breathing 50.0%, yellowish skin 26.9%, while the common physical signs were hyper/hypothermia 41.1%, tachypnoea 41.2%, septic umbilical stump 64.0%, hepatomegally 37.3% and convulsions 42.0%. Blood culture yield was positive in 41.82% and mortality was as high as 28.00%, the incidence of NNS was 5.9/1000 live births. The haematological parameters as marker of NNS PCV, TWBC, ANC, APC, I/MNR, I/TNR and micro-ESR individually were statistically significant (P < 0.05), also their individual sensitivity, specificity, positive and negative predictive values were highly associated with neonatal septicaemia. However, when they were tested in combinations these markers of neonatal septicaemia had low sensitivity, specificity and their predictive values were weak in excluding NNS. Conclusions: The need for early and rapid diagnosis of NNS is pertinent, culturing of the appropriate specimens remains the only way to identify the aetiological organisms, but is associated with delay. Haematological indices are excellent markers of NNS and analysis is rapid and can easily be done in our laboratory settings, and when utilized efficiently, it would circumvent the delay associated with blood culture for long waiting period for the result, thereby reducing morbidity and mortality.

Poor feeding practices result in inadequate nutrient intakes in young children in developing countries. To improve practices, local food-based complementary feeding recommendations (CFR) are needed. This cross-sectional survey aimed to describe current food consumption patterns of 12–23-month-old Myanmar children (n106) from Ayeyarwady region in order to identify nutrient requirements that are difficult to achieve using local foods and to formulate affordable and realistic CFR to improve dietary adequacy. Weekly food consumption patterns were assessed using a 12-h weighed dietary record, single 24-h recall and a 5-d food record. Food costs were estimated by market surveys. CFR were formulated by linear programming analysis using WHO Optifood software and evaluated among mothers (n20) using trial of improved practices (TIP). Findings showed that Ca, Zn, niacin, folate and Fe were ‘problem nutrients’: nutrients that did not achieve 100 % recommended nutrient intake even when the diet was optimised. Chicken liver, anchovy and roselle leaves were locally available nutrient-dense foods that would fill these nutrient gaps. The final set of six CFR would ensure dietary adequacy for five of twelve nutrients at a minimal cost of 271 kyats/d (based on the exchange rate of 900 kyats/USD at the time of data collection: 3rd quarter of 2012), but inadequacies remained for niacin, folate, thiamin, Fe, Zn, Ca and vitamin B6. TIP showed that mothers believed liver and vegetables would cause worms and diarrhoea, but these beliefs could be overcome to successfully promote liver consumption. Therefore, an acceptable set of CFR were developed to improve the dietary practices of 12–23-month-old Myanmar children using locally available foods. Alternative interventions such as fortification, however, are still needed to ensure dietary adequacy of all nutrients.

KEY POINTS An eight-day-old full-term baby girl presented to our centre with a one-day history of fever, poor feeding and fussiness. There was no history of respiratory symptoms, drowsiness, seizures, vomiting or rash. Her prenatal history was unremarkable. Rupture of membranes had preceded vaginal

A 48-hour-old male infant born at 38+3/7 weeks’ gestation is transported from home via ambulance to the emergency department (ED) for poor feeding, lethargy, duskiness, and rhythmic twitching of lower extremities. The mother received prenatal care from a midwife. The pregnancy was complicated by a maternal genital herpes outbreak in the first trimester. The mother was given valacyclovir for viral suppression and no herpetic lesions are noted at delivery. Clear artificial rupture of membranes is performed by the midwife 5 hours before delivery and the infant is born via vaginal delivery into a water birthing tub with a disposable liner. Apgar scores are 7, 8, and 9 at 1, 5, and 10 minutes. The umbilical cord is not cut based on the parents’ request for umbilical nonseverance. The placenta is washed and dried, wrapped in muslin, and left attached to the infant until the midwife cuts the cord with sterilized scissors before transfer to the ED. Postnatal history is remarkable for poor feeding. The infant has difficulty latching on and receives supplemental formula as well as donor unpasteurized breast milk from a lactation consultant. On the morning of admission, the infant has perioral cyanosis and is unresponsive. In the ED, he is cyanotic with shallow respirations and is found to be hypothermic (rectal temperature of 95.3°F [35.2°C]), and hypoglycemic (peripheral blood glucose level of 15 mg/dL [0.83 mmol/L]) with multifocal clonic seizures. He is tachycardic, with a …

A thriving, previously healthy 3-month-old girl presented with a 4-day history of fever, irritability and poor feeding. On admission, she was tachycardic, had cool peripheries with normal central perfusion, pulse volume and blood pressure. There was no obvious source of infection from clinical

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A 27 days old neonate presented with poor feeding, severe respiratory distress and septic shock without any palpable abdominal mass. On evaluation found to have features of overt late onset neonatal sepsis and right sided pneumonia. The initial working diagnosis was poorly resolving pneumonia however upon further evaluation found to have blood gas and ultrasonographic evidence of infantile hypertrophic pyloric stenosis (IHPS). Good perioperative care is required to prevent complications.

Macrophagic myofasciitis is a rare inflammatory myopathy characterized by peri-fascicular macrophage infiltration without muscle necrosis. Here we report two children presented in the early infancy. Case 1: a 5-month-old girl presented with lack of neck control and floppiness. On examination, generalized hypotonia, absent deep tendon reflexes, and motor power of 2/5 (Medical Research Council grade) were observed. Case 2: a 17-day-old boy presented with poor feeding, tachypnea, and floppiness. On examination, decreased tone in all limbs and power of

Prader-Willi syndrome (PWS) is a complex multisystem disorder due to the absent expression of the paternally active genes in the PWS critical region on chromosome 15 (15q11.2-q13). The syndrome is considered the most common genetic cause of obesity, occurring in 1:10,000-1:30,000 live births. Its main characteristics include neonatal hypotonia, poor feeding, and lack of appetite in infancy, followed by weight gain, lack of satiety, and uncontrolled appetite, frequently after the age of 2-3 years. The clinical picture includes short stature, multiple endocrine abnormalities (hypogonadism, growth hormone/insulin-like growth factor-I axis dysfunction, hypothyroidism, central adrenal insufficiency), dysmorphic features, scoliosis, osteoporosis, mental retardation, and behavioral and psychiatric problems. Subjects with PWS will become severely obese unless their food intake is strictly controlled. Constant and obsessive food seeking behavior can make life very difficult for both the family and caretakers. Prevention of obesity is mandatory in these patients from the first years of life, because once obesity develops it is difficult to maintain the control of food intake. In fact, PWS subjects die prematurely from complications conventionally related to obesity, including diabetes mellitus, metabolic syndrome, sleep apnea, respiratory insufficiency, and cardiovascular disease. The mechanisms underlying hyperphagia in PWS are not completely known, and to date no drugs have proven their efficacy in controlling appetite. Consequently, dietary restriction, physical activity, and behavior management are fundamental in the prevention and management of obesity in PWS. In spite of all available therapeutic tools, however, successful weight loss and maintenance are hardly accomplished. In this context, clinical trials with new drugs have been initiated in order to find new possibilities of a therapy for obesity in these patients. The preliminary results of these studies seem to be encouraging. On the other hand, until well-proven medical treatments are available, bariatric surgery can be taken into consideration, especially in PWS patients with life-threatening comorbidities.

The significance of anaerobic bacteria as a pathogen in urinary tract infection (UTI) in children is unclear. A two-month-old infant presenting with poor feeding received a diagnosis of polymicrobial anaerobic UTI by next-generation sequencing and was found to have obstructive uropathy. Anaerobic bacteria may be a cause of UTI in children with urinary tract obstruction.

A poorly feeding neonate presents the clinician with a diagnostic challenge. Feeding difficulties and irritability may be due to sepsis, congenital heart disease, inborn errors of metabolism, non-accidental head trauma, as well as a vast variety of other pathologies. Teratomas are rare pediatric tumors that can occasionally present in the immediate neonatal period and can manifest in the infant's central nervous system (CNS) with non-specific symptoms of poor feeding, lethargy, and somnolence. Operative resection remains the cornerstone of treatment; however, there is no well-defined role for adjuvant chemotherapy or radiation in these treatments. We report a case of a four-week-old female presenting with progressive feeding intolerance secondary to a near holocord thoracic spinal teratoma. Her tumor was surgically resected and she was treated with adjuvant chemotherapy and radiation for 13 months and is now in clinical remission. While rare, intramedullary spinal cord lesions should be considered in the differential diagnosis of infants presenting with poor feeding and hypotonia.

Tokgoz Y, Erdem AO, Ozbey BC, Terlemez S. A rare reason in a child with feeding intolerance: Intravaginal struvite stone. Turk J Pediatr 2018; 60: 86-88. Vaginal stones are rarely seen in childhood; they are categorized as primary and secondary whether they are a foreign object focus (nidus) or not. Urethrovaginal fistula is the most common etiological cause; other etiologies are considerably rarely reported. Primary vaginal stones are formed as a result of urinary salt accumulate. A 14-year-old girl, suffering from an unidentified neurodegenerative disease, was admitted with complaints of cough, poor feeding and vomiting. Abdominal X-ray showed a large calcific mass; further evaluation revealed a vaginal struvite stone, and it was removed surgically. No anatomical reason was determined for the formation of stone and it was accepted as primary vaginal stone.

Central adrenal insufficiency (CAI) is a life-threatening condition caused by either pituitary disease (secondary adrenal insufficiency) or impaired hypothalamic function with inadequate CRH production (tertiary adrenal insufficiency). ACTH deficiency may be isolated or, more frequently, occur in conjunction with other pituitary hormone deficiencies and midline defects. Genetic mutations of the TBX19 causing isolated CAI are rare but a number of genes encoding transcription factors involved in hypothalamic-pituitary gland development, as well as other genes including POMC and PC1, are associated with ACTH deficiency. CAI is frequently identified in congenital, malformative, genetic, and epigenetic syndromes as well as in several acquired conditions of different etiologies. The signs and symptoms vary considerably and depend on the age of onset and the number and severity of associated pituitary defects. They may include hypoglycemia, lethargy, apnea, poor feeding, prolonged cholestatic jaundice, jitteriness, seizures, and sepsis in the neonate, or nonspecific signs such as fatigue, hypotension, vomiting and hyponatremia without hyperkalemia in children. The diagnosis of CAI relies on the measurement of morning cortisol concentrations along with dynamic test for cortisol release with different stimulating agents. Early recognition of CAI and its correct management are mandatory in order to avoid both morbidity and mortality in affected neonates, children and adolescents.

Background Congenital cysts and fistulas of the neck are common in children, often located in the head and neck area. Belonging to the group of tumor-like conditions, dermoid and epidermoid cysts are dysontogenetic lesions with seldom multiple co-occurrences in infants. Case report We report on a nine-month-old female with a persisting congenital fistula of the tongue. The patient was admitted with acute poor feeding and hypersalivation, which started within the last 24 h. Magnetic resonance imaging detected a fistula of the tongue connected to sublingual cystic lesions. Intraoral surgical removal of three cystic lesions and the fistula was performed under general anesthesia. Histopathological analysis confirmed the coexistence of an epidermoid cyst and two dermoid cysts. Conclusion Sudden feeding difficulties in combination with dysphagia and tongue displacement in pediatric patients pose an emergency situation that requires prompt diagnostic clarification. A persisting congenital fistula of the tongue is a clear indication of dysontogenetic lesions, including malformations, tumors, and tumor-like lesions. Congenital sublingual cysts are rare in infants, but can be life threatening when present. Surgical excision with histopathological analysis is essential to exclude any form of malignancy and malignant transformation.