Suresh Chandran

Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia

The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors (such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase (GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism.

Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism

Summary Background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia. Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation. Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease. Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI. Learning points HH is a cause of severe hypoglycaemia in the newborn period. Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease. 18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions. Gallium-68 tetra-aza-cyclododecane-N N′N″N-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions. The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear. Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.

Medications That Increase Osmolality and Compromise the Safety of Enteral Feeding in Preterm Infants

Background: Medications added to preterm milk feeds have the potential to raise osmolality, causing feed intolerance and necrotizing enterocolitis. Objective: The aim of this study was to evaluate changes in the osmolality of milk feeds and water with 14 medications and the diluent amounts required to keep the osmolality below the safety threshold of ≤450 mOsm/kg. Changes in the osmolality of milk with medications while on continuous infusion over 2 and 4 h were determined. Methods: This study was designed to measure the osmolality of 14 commonly used medications in preterm infants both neat and when supplemented with expressed breast milk (EBM), EBM with fortifier (EBMF), preterm formula (PTF), and water. Dose-effect curves were plotted, and the volume of each diluent was calculated to keep the osmolality ≤450 mOsm/kg. Time-effect curves were plotted at 2 and 4 h for each medication for both EBM and EBMF. Results: Neat osmolality of all except 5 medications were above 2,000 mOsm/kg. The osmolality rose with decreasing proportions of diluents used, depicting an indirect curvilinear relationship between the increasing dilution and osmolality for all except 2 medications. As a diluent, EBM was required in lower dilutions than EBMF. Dilutions needed for additives with PTF were very similar to those of EBM. The change in osmolality over time with additives was statistically significant for EBMF. Conclusions: EBM and PTF were found to be safer diluents than EBMF for enteral additives. The practice of keeping milk feeds with medications for continuous feeding is safe for a period of 4 h in EBM.

Meconium Peritonitis: Correlation of Antenatal Diagnosis and Postnatal Outcome - An Institutional Experience over 10 Years.

Objective: To identify the fetal and neonatal imaging characteristics of meconium peritonitis (MP) and their clinical outcome. We also studied the role of prenatal ultrasound (US) in antenatal diagnosis and its use in predicting the need for surgical intervention postnatally. Material and Methods: We conducted a retrospective analysis of a cohort of 18 infants with MP from April 2004 to March 2014. Results: Prenatal US detected MP-related abnormalities in 15/18 (83.3%) fetuses. The median gestational age at initial diagnosis of MP was 24 weeks (range 19-31). Fetal ascites (93.3%) was the most common prenatal US finding. Of the 18 infants, 12 (66.7%) required surgical intervention. The overall survival rate was 94.4%. All infants with a prenatal US scan showing meconium pseudocyst or bowel dilatation required surgical intervention postnatally. Discussion: A combination of ascites, intraperitoneal calcification, and echogenic bowel on fetal US raises a high suspicion of MP. Surgical intervention is indicated in the presence of meconium pseudocyst on fetal or postnatal US scan. Antenatal US has high specificity (100%) but low sensitivity (22.2%) in detecting meconium pseudocyst. A favorable outcome can be expected with early antenatal diagnosis and timely surgical intervention in a tertiary hospital.

Current perspectives on neonatal hypoglycemia, its management, and cerebral injury risk

Glucose is an essential substrate for mammalian cells; in particular, the brain needs glucose continuously as a primary source of energy. Hypoglycemia is the most common biochemical finding in the neonatal period. However, despite the common occurrence, there is still controversy on the definition of hypoglycemia in the newborn period. This has led to the development of guidelines designed to identify infants at-risk and the implementation of an operational threshold for physicians to consider intervention. In healthy term infants, the optimal hormonal and metabolic adaptations during the immediate neonatal period ensure an adequate energy substrate for the vital organs, whereas the abnormal glucose homeostasis observed in preterm and growth-retarded infants is multifactorial in origin. For these high-risk infants, it is important to identify, screen, and prevent significant hypoglycemia. Detailed investigations are warranted in infants with severe and persistent hypoglycemia. Neonatal hypo- glycemia is a major cause of brain injury. The speculated mechanisms of cellular injury include excitatory neurotoxins active at N-methyl-D-aspartate receptors, increased mitochondrial free radical generation with initiation of apoptosis and altered cerebral energetic characteristics. This hypoglycemic brain injury predominantly affects parieto-occipital regions causing cognitive, sensory, psychomotor, and behavioral deficits in children. This state of the art review article covers the fetal-neonatal metabolic adaptation, glucose homeostasis in normal and abnormal conditions, management strategies, and late neurological sequelae of hypoglycemia.

Cyclopia: isolated and with agnathia–otocephaly complex

Cyclopia is a rare form of lethal holoprosencephaly (HPE) due to incomplete cleavage of prosencephalon during embryogenesis, leading to failure of the orbits of the eye to divide into two cavities. We report two cases, one with cyclopia and another case of cyclopia with agnathia–otocephaly complex (AOC). AOC (also known as agnathia–microstomia–synotia syndrome) is a rare lethal congenital malformation of the first branchial arch characterised by the association of agnathia (agenesis of mandible) or mandibular hypoplasia, melotia (anteromedial malposition of ears), microstomia (small mouth), aglossia or microglossia (absent or rudimentary tongue). These two reported cases had in common a single eye and alobar HPE. The first case was live born and the second stillborn. Both mothers did not have antenatal care.

Umbilical cord anomalies: antenatal ultrasound findings and postnatal correlation

Umbilical cord anomalies are rare. The differential diagnosis for a cystic structure around the umbilical cord and its insertion include pseudocyst, omphalomesenteric duct cyst, haemangioma, omphalocele or anterior abdominal wall defects. Although cord anomalies can be detected through antenatal ultrasound scans (US), very often a definitive diagnosis cannot be made. This may affect the management of the infant at birth. In cases where antenatal US was not diagnostic, current evidence supports the use of MRI to help in making an accurate diagnosis. We report two cases of umbilical cord anomalies. The first case was diagnosed in antenatal US as an omphalocele, but was found to be an allantoic cyst with hamartoma on postnatal diagnosis. The second case was not detected on antenatal US, and was diagnosed postnatally as a small omphalocele with vitellointestinal duct remnants.

Pneumatosis intestinalis in a preterm infant: should we treat all intestinal pneumatosis as necrotising enterocolitis?

Gastric pneumatosisis a very rare site of pneumatosis intestinalis (PI), and we report this finding in a preterm female infant with cyanotic congenital heart disease. The infant was stable initially on nasal intermittent mandatory ventilation; however, torrential pulmonary flow through a large patent ductus arteriosus prompted closure using oral ibuprofen. After an episode of haematochezia, she developed PI, affecting mainly the gastric wall and small intestine with portal venous gas. Her bowel movements were regular, with no abdominal distension or significant gastric aspirates. She was haemodynamically stable with negative infective markers. Management consisted of endotracheal intubation and ventilation, gastric decompression and broad-spectrum antibiotics. Both the gastric and intestinal pneumatosis resolved within 24u2009hours and she made an uneventful recovery. If PI is not due to necrotising enterocolitis, enteral nutrition can be initiated early and prolonged course of broad-spectrum antibiotics could have been avoided.

Cutis marmorata telangiectatica congenita with skin ulceration: a rare benign skin vascular malformation

Cutis marmorata telangiectatica congenita (CMTC) is a sporadic congenital disorder characterised by localised or generalised cutaneous vascular anomaly. CMTC was first described in 1922 by Van Lohuizen as a pattern of reticulate erythema and telangiectasia infrequently associated with skin atrophy and/or ulceration.1 It is a rare benign skin lesion that is often apparent at birth with more than 50% of patients with CMTC having variations of associated defects. Body asymmetry is the most common (33%) associated anomaly reported.1nnA 5-day-old female baby was born at term following an uneventful pregnancy. At birth, she weighed 2800u2009g, and her growth profile was appropriate for her age. Her general physical examination was unremarkable except for the appearance of a 3×4u2009cm bluish-purple skin lesion over the right knee. The skin lesion had erythematous reticulated appearance at the periphery and ulceration at the centre with subcutaneous atrophy (figure 1). There was no limb asymmetry, other vascular lesions, bony defects …

Neonatal airway: challenging endotracheal intubation in infants with tracheal malformations at birth

Intubating newborn infants can be exacting. We describe two cases of endotracheal intubations in infants born with tracheal malformations. A male infant aged 30 weeks required intubation at birth for respiratory distress. Repeated attempts at intubation failed to achieve an optimal endotracheal tube position as the tube could not advance beyond the vocal cords. Hence ventilation continued with suboptimal air entry in the lungs. Bronchoscopy and CT scan confirmed tracheal stenosis. Slide tracheoplasty was successfully executed on day 78 of life. A female infant aged 33u2009weeks was intubated at birth for perinatal depression. Attempts at intubation were unsuccessful due to non-visualisation of the laryngeal inlet. Oesophagus was intubated and attempts to inflate showed air entry in the lungs, suggesting a fistulous communication between oesophagus and airway. A contrast oesophagogram showed a fistula connecting oesophagus and carina. With airway patency in question and associated major anomalies, parents were counselled and support was withdrawn.