Congenital hyperinsulinism. / Medfødt hyperinsulinisme.

This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common cause of persistent neonatal hypoglycaemia. The condition is a rare monogenic disorder characterised by elevated insulin secretion and is a result of mutations in genes that regulate insulin secretion from pancreatic beta cells. The anabolic effect of insulin induces systemic glucose uptake and inhibits gluconeogenesis, glycogenolysis, ketogenesis and lipolysis. Low levels of glucose and ketone bodies in the blood are harmful to the central nervous system and can lead to brain damage or death. Early diagnosis and treatment of congenital hyperinsulinism are therefore crucial for a good prognosis.

Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes.

PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype-genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.

Yellow skin without jaundice. / Gul hud uten gulsott.

In cases of infants with yellow colouration, both the sclerae and the skin should be examined. The top priority is to rule out conjugated hyperbilirubinaemia, which may be a symptom of biliary atresia. Children with this condition will first develop yellow sclerae, and will have jaundice that continues beyond the first two weeks of life. Although discoloured stools are a classic sign of biliary atresia, they are not always present. Children over two weeks of age with yellow skin should therefore be assessed immediately, regardless of the colour of the stool.

Serum concentrations of C-reactive protein in healthy term-born Norwegian infants 48-72 hours after birth.

AIM: To determine serum C-reactive protein (CRP) concentrations in healthy term-born infants shortly after birth. METHODS: We sampled blood from 182 infants along with the routine neonatal screening programme at 48-72 hours of age from consecutively recruited healthy infants without signs of infection and a gestational age (GA) of at least 37 weeks. The blood was stored at minus 20°C until analysis in one assay after the end of the study. RESULTS: The CRP levels were positively skewed. The median concentration was 5.0 mg/L, 48.9% of the neonates had values <5.0 mg/L, 19.8% ≥10.0 mg/L, 7.1% ≥20.0 mg/L and 1.1% (2 neonates) >30 mg/L. The CRP level was positively related to GA and duration of labour, slightly higher in boys than girls and after vaginal compared to Caesarean delivery. CONCLUSION: In healthy neonates born at term, the CRP concentrations did not vary substantially with various common perinatal clinical conditions, and levels above 30 mg/L were uncommon at two to three days of age.

Selective ultrasound screening for developmental hip dysplasia: effect on management and late detected cases. A prospective survey during 1991-2006.

BACKGROUND: Early treatment is considered essential for developmental dysplasia of the hip (DDH), but the choice of screening strategy is debated. OBJECTIVE: We evaluated the effect of a selective ultrasound (US) screening programme. MATERIALS AND METHODS: All infants born in a defined region during 1991-2006 with increased risk of developmental dysplasia of the hip, i.e. clinical hip instability, breech presentation, congenital foot deformities or a family history of DDH, underwent US screening at age 1-3 days. Severe sonographic dysplasia and dislocatable/dislocated hips were treated with abduction splints. Mild dysplasia and pathological instability, i.e. not dislocatable/dislocated hips were followed clinically and sonographically until spontaneous resolution, or until treatment became necessary. The minimum observation period was 5.5 years. RESULTS: Of 81,564 newborns, 11,539 (14.1%) were identified as at-risk, of whom 11,190 (58% girls) were included for further analyses. Of the 81,564 infants, 2,433 (3.0%) received early treatment; 1,882 (2.3%) from birth and 551 (0.7%) after 6 weeks or more of clinical and sonographic surveillance. An additional 2,700 (3.3%) normalised spontaneously after watchful waiting from birth. Twenty-six infants (0.32 per 1,000, 92% girls, two from the risk group) presented with late subluxated/dislocated hips (after 1 month of age). An additional 126 (1.5 per 1,000, 83% girls, one from the risk group) were treated after isolated late residual dysplasia. Thirty-one children (0.38 per 1,000) had surgical treatment before age 5 years. Avascular necrosis was diagnosed in seven of all children treated (0.27%), four after early and three after late treatment. CONCLUSION: The first 16 years of a standardised selective US screening programme for developmental dysplasia of the hip resulted in acceptable rates of early treatment and US follow-ups and low rates of late subluxated/dislocated hips compared to similar studies.

Early surfactant and non-invasive ventilation versus intubation and surfactant: a propensity score-matched national study.

OBJECTIVE: To compare outcome after less invasive surfactant administration (LISA) and primary endotracheal intubation (non-LISA) in infants born before gestational age (GA) 28 weeks. SETTING: All neonatal intensive care units (NICUs) in Norway during 2012-2018. METHODS: Defined population-based data were prospectively entered into a national registry. We compared LISA infants with all non-LISA infants and with non-LISA infants who received surfactant following intubation. We used propensity score (PS) matching to identify non-LISA infants who were similar regarding potential confounders. MAIN OUTCOME VARIABLES: Rate and duration of mechanical ventilation (MV), survival, neurological and gastrointestinal morbidity, and need of supplemental oxygen or positive pressure respiratory support at postmenstrual age (PMA) 36 and 40 weeks. RESULTS: We restricted analyses to GA 25-27 weeks (n=843, 26% LISA) because LISA was rarely used at lower GAs. There was no significant association between NICUs regarding proportions treated with LISA and proportions receiving MV. In the PS-matched datasets, fewer LISA infants received MV (61% vs 78%, p<0.001), and they had fewer days on MV (mean difference 4.1, 95% CI 0.0 to 8.2 days) and lower mortality at PMA 40 weeks (absolute difference 6%, p=0.06) compared with all the non-LISA infants, but only a lower rate of MV (64% vs 97%, p<0.001) and fewer days on MV (mean difference 5.8, 95% CI 0.6 to 10.9 days) compared with non-LISA infants who received surfactant after intubation. CONCLUSION: LISA reduced the rate and duration of MV but had no other clear benefits.

Extremely Preterm Infant Admissions Within the SafeBoosC-III Consortium During the COVID-19 Lockdown.

Objective: To evaluate if the number of admitted extremely preterm (EP) infants (born before 28 weeks of gestational age) differed in the neonatal intensive care units (NICUs) of the SafeBoosC-III consortium during the global lockdown when compared to the corresponding time period in 2019. Design: This is a retrospective, observational study. Forty-six out of 79 NICUs (58%) from 17 countries participated. Principal investigators were asked to report the following information: (1) Total number of EP infant admissions to their NICU in the 3 months where the lockdown restrictions were most rigorous during the first phase of the COVID-19 pandemic, (2) Similar EP infant admissions in the corresponding 3 months of 2019, (3) the level of local restrictions during the lockdown period, and (4) the local impact of the COVID-19 lockdown on the everyday life of a pregnant woman. Results: The number of EP infant admissions during the first wave of the COVID-19 pandemic was 428 compared to 457 in the corresponding 3 months in 2019 (-6.6%, 95% CI -18.2 to +7.1%, p = 0.33). There were no statistically significant differences within individual geographic regions and no significant association between the level of lockdown restrictions and difference in the number of EP infant admissions. A post-hoc analysis based on data from the 46 NICUs found a decrease of 10.3%in the total number of NICU admissions (n = 7,499 in 2020 vs. n = 8,362 in 2019). Conclusion: This ad hoc study did not confirm previous reports of a major reduction in the number of extremely pretermbirths during the first phase of the COVID-19 pandemic. Clinical Trial Registration: ClinicalTrial.gov, identifier: NCT04527601 (registered August 26, 2020), https://clinicaltrials.gov/ct2/show/NCT04527601.

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. OBJECTIVE: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

[A 6-day-old girl with weight loss]. / En seks dager gammel pike med vektnedgang.

Newborn children normally lose up to 10% of their birth weight during the first week of life. With greater weight loss one must consider low intake and pathological losses. We describe a 6-day-old girl with nearly 19% weight loss and hypertonic dehydration caused by hypogalactia. Principles for treatment of hypertonic dehydration and strategies for finding these children are discussed.

[Substitution treatment of drug addicts during pregnancy: consequences for the children?]. / Har legemiddelassistert rehabilitering i svangerskapet konsekvenser for barna?

BACKGROUND: Substitution treatment of opioid-dependent addicts was introduced in Norway in 1998. During the last 10 years, approximately 150 infants have been born to mothers taking part in this programme. MATERIAL AND METHODS: 10 mothers, who took part in the substitution treatment programme, gave birth to 15 infants at Haukeland University Hospital in the period 1999-2005. The infants were observed and monitored at the Department of Pediatrics, Haukeland University Hospital. RESULTS: During pregnancy, six of the infants were only exposed to opiates, i.e methadone or buprenorphine. Eight infants were also exposed to heroine, benzodiazepines or cannabis. As a group, these infants had lower birth weight than the national average. 14 of the 15 children developed neonatal abstinence syndrome (NAS), 10 needed treatment and two children died from sudden infant death syndrome (SIDS). Long-term follow-up showed that six of 13 children had normal psychomotor development, five had various degrees of delayed psychomotor development and two children had symptoms indicating a hyperkinetic disorder. Five children were in foster care. INTERPRETATION: Infants of women included in substitution treatment programmes for drug addicts are at high risk compared to infants of women without such addiction. For the newborn, NAS was a frequent complication. The study also showed that symptoms of hyperkinetic disorder and delayed psychomotor development were common. Children who had been exposed to opiates in combination with additional drugs seemed to have a high risk of delayed development and behaviour disorders. As they get older many were placed in foster care, despite well-coordinated, multidisciplinary treatment for the mother.

Normal Neurological Development During Infancy Despite Massive Hyperammonemia in Early Treated NAGS Deficiency.

A girl born at term was admitted to the neonatal intensive care unit because of mild respiratory distress after a complicated delivery. She recovered, but was readmitted at 58 h of life with mild respiratory distress and increased muscle tone. Neonatal abstinence syndrome because of maternal use of lithium, clomipramine, and quetiapine during pregnancy was suspected, but at 115 h of life she became unresponsive, and an immediate work-up for coma was initiated. An ammonia of 2,235 µmol/l was found, and treatment with sodium benzoate, sodium phenylacetate, arginine, glucose, and N-carbamylglutamate (NCG, Carbaglu®) was started. This treatment normalized plasma ammonia levels within 16 h.Biochemical results suggested a mitochondrial urea cycle defect, either of N-acetyl glutamate synthase (NAGS) or carbamoyl phosphate synthetase 1. DNA analysis later confirmed a diagnosis of NAGS deficiency. Under long-term treatment with NCG, the patient developed normally at last follow-up at 7 months of age.In conclusion, the standard neonatal situation of a neurologically compromised newborn turned out as a treatable rare inborn error of metabolism. In all neonates with somnolence and coma and hence the suspicion of a bacterial sepsis, plasma ammonia should be included in the work-up. NCG was immediately beneficial for the patient described and should be considered for the emergency treatment of neonatal hyperammonemia. Even a very high ammonia may allow for a normal neurological development in infancy (and possibly beyond).

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

[Fetal injury and alcohol drinking during pregnancy]. / Fosterskade ved alkoholbruk i svangerskap.

BACKGROUND: There is still an ongoing discussion whether moderate alcohol consumption during pregnancy is harmful to the fetus. In most western countries, however, total abstinence is recommended. MATERIAL AND METHODS: Over the last five years we have seen 64 infants and children with alcohol-related disorders. We present the clinical records of one alcohol-damaged child, and present the latest recommended categorisation of alcohol-related disorders in infants and children. RESULTS: In our experience, some women with heavy alcohol consumption are allowed to continue their abuse without interference from health professionals. Children of women with moderate alcohol consumption may be seriously damaged. Updated research on pregnancy and alcohol that we have reviewed provide clear evidence that brain structure as well as brain function are affected by heavy prenatal alcohol exposure. INTERPRETATION: Use of alcohol in pregnancy, also in moderate amounts, is a serious risk factor for fetal damage. Therefore complete abstinence from alcohol during pregnancy should be recommended. For the alcohol-damaged children, early recognition and appropriate treatment will give the child a better opportunity for future optimal development.

Immediate treatment versus sonographic surveillance for mild hip dysplasia in newborns.

OBJECTIVE: We conducted a blinded, randomized, controlled trial to examine whether mildly dysplastic but stable or instable hips would benefit from early treatment, as compared with watchful waiting. PATIENTS AND METHODS: A total of 128 newborns with mild hip dysplasia (sonographic inclination angle [alpha angle] of 43 degrees -49 degrees ) and stable or instable but not dislocatable hips were randomly assigned to receive either 6 weeks of abduction treatment (immediate-treatment group) or follow-up alone (active-sonographic-surveillance group). The main outcome measurement was the acetabular inclination angle, measured by radiograph, at 1 year of age. RESULTS: Both groups included 64 newborns, and there was no loss to follow-up. With the exception of a small but statistically significant excess of girls in the active-sonographic-surveillance group, there were no statistically significant differences in baseline characteristics between the 2 groups. The mean inclination angle at 12 months was 24.2 degrees for both groups (difference: 0.1 [95% confidence interval (CI): -0.8 to 0.9]), and all children had improved and were without treatment. The mean alpha angle was 59.7 degrees in the treatment group and 57.1 degrees in the active-surveillance group for a difference of 2.6 degrees evaluated after 1.5 and 3 months (95% CI: 1.8 to 3.4; P < .001). At 1.5 months of age, the hips had improved in all treated children but not in 5 children under active surveillance (P = .06). Among the sonographic-surveillance group, 47% received treatment after the initial surveillance period of 1.5 months. CONCLUSIONS: Active-sonographic-surveillance halved the number of children requiring treatment, did not increase the duration of treatment, and yielded similar results at 1-year follow-up. Given a reported prevalence of 1.3% for mildly dysplastic but stable hips, a strategy of active surveillance would reduce the overall treatment rate by 0.6%. Our results may have important implications for families as well as for health care costs.