Eva Mildenberger

Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF) - more common than assumed? Report of four cases with transient NIHF and a review of the literature

BackgroundLysosomal storage disorders (LSD) are a rare cause of non immunological hydrops fetalis (NIHF) and congenital ascites. The reported incidence is about 1%. The incidence of idiopathic NIHF is estimated to be about 18%.Patients and methodsWe report four cases with transient hydrops fetalis resulting from LSD and performed a literature review on LSD with NIHF and congenital ascites in combination.ResultsAt present, 12 different LSDs are described to be associated with NIHF or congenital ascites. Most patients had a family history of NIHF, where the preceding sibling had not been examined. A diagnostic approach to the fetus with NIHF due to suspected LSD either in utero or postnatal is suggested. Transient forms of NIHF and/or ascites in association with MPS IVA, MPS VII and NPC are described for the first time in this publication.ConclusionsLSD should be considered in transient hydrops. Enzymatic studies in chorionic villous sample or amniotic cultured cells, once the most common conditions associated with fetal ascites or hydrops have been ruled out, are important. This paper emphasizes the fact that LSD is significantly higher than the estimated 1% in previous studies, which is important for genetic counseling as there is a high risk of recurrence and the availability of enzyme replacement therapy for an increasing number of LSD.

Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C

Objective Congenital sodium diarrhoea (CSD) refers to a form of secretory diarrhoea with intrauterine onset and high faecal losses of sodium without congenital malformations. The molecular basis for CSD remains unknown. We clinically characterised a cohort of infants with CSD and set out to identify disease-causing mutations by genome-wide genetic testing. Design We performed whole-exome sequencing and chromosomal microarray analyses in 4 unrelated patients, followed by confirmatory Sanger sequencing of the likely disease-causing mutations in patients and in their family members, followed by functional studies. Results We identified novel de novo missense mutations in GUCY2C, the gene encoding receptor guanylate cyclase C (GC-C) in 4 patients with CSD. One patient developed severe, early-onset IBD and chronic arthritis at 4u2005years of age. GC-C is an intestinal brush border membrane-bound guanylate cyclase, which functions as receptor for guanylin, uroguanylin and Escherichia coli heat-stable enterotoxin. Mutations in GUCY2C were present in different intracellular domains of GC-C, and were activating mutations that enhanced intracellular cyclic guanosine monophosphate accumulation in a ligand-independent and ligand-stimulated manner, following heterologous expression in HEK293T cells. Conclusions Dominant gain-of-function GUCY2C mutations lead to elevated intracellular cyclic guanosine monophosphate levels and could explain the chronic diarrhoea as a result of decreased intestinal sodium and water absorption and increased chloride secretion. Thus, mutations in GUCY2C indicate a role for this receptor in the pathogenesis of sporadic CSD.

Key features and clinical variability of COG6-CDG.

The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits.

Detection of respiratory viral infections in neonates treated for suspicion of nosocomial bacterial sepsis: a feasibility study.

There is a lack of knowledge concerning the frequency and significance of respiratory viral infections that occur in the neonatal intensive care unit. In the present study, all neonates with suspected nosocomial bacterial sepsis were screened for a panel of respiratory viruses. Respiratory viral infections were detected in 10% of these cases. This was comparable with the frequency of a blood-culture–proven sepsis.

Viral Infections in Neonates with Suspected Late-Onset Bacterial Sepsis-A Prospective Cohort Study.

Objective The aim of our study was to evaluate the occurrence of viral infections in infants with suspected late‐onset bacterial sepsis in a neonatal intensive care unit. Methods In a prospective study, infants with suspected late‐onset bacterial sepsis underwent viral testing alongside routine blood culture sampling. Using a multiplex reverse transcription‐polymerase chain reaction enzyme‐linked immunosorbent assay, nasopharyngeal aspirates were analyzed for adenovirus, respiratory syncytial virus (RSV), influenza virus A and B, H1N1 virus, parainfluenza virus 1 to 4, metapneumovirus, coronavirus, and picornavirus. Stools were examined for adenovirus, rotavirus, norovirus, and enterovirus. Results Between August 2010 and March 2014, data of 88 infants with 137 episodes of suspected late‐onset bacterial sepsis were analyzed. Six infants were diagnosed with a respiratory viral infection (2 × RSV, 4 × picornavirus). Blood culture‐proven bacterial sepsis was detected in 15 infants. Neither viral‐bacterial coinfections nor polymerase chain reaction positive stool samples were found. Conclusion Respiratory viruses can be detected in a considerable number of neonates with suspected late‐onset bacterial sepsis. In contrast, gastrointestinal viral or enterovirus infections appear uncommon in such cases.

Neonatal respiratory insufficiency caused by an (homozygous) ABCA3-stop mutation: a systematic evaluation of therapeutic options.

BACKGROUNDnAutosomal recessive ABCA3 (ATP-binding cassette protein A3) gene mutations have been associated with neonatal respiratory distress and pediatric interstitial lung disease. The clinical course of the disease depends on the underlying mutations. Therefore, knowledge of course, symptoms and treatment of the disease is important.nnnPATIENT AND METHODSnA term newborn suffered from progressive respiratory insufficiency, which led to death at the age of 4.8 months. The girl developed interstitial lung disease. Infections as well as structural and functional disorders of the lung were systematically excluded. A homozygous c.4681C > T (Arg 1561 Stop) mutation of the ABCA3 gene was identified. A literature review of the pathophysiology and treatment options of the disease was done. Therapeutic approaches with corticosteroids, macrolide, and hydroxychloroquine did not improve the clinical course.nnnRESULTSnTherapeutic strategies for chronic interstitial lung disease have been used successfully in cases of a mild clinical course in juvenile patients with ABCA3 gene mutation. In our patient with homozygous ABCA3 gene mutation,they were not effective. Lung transplantation remains as a therapeutic option, but because of donor organ shortage and associated morbidity and mortality it is rarely feasible.nnnCONCLUSIONnMore experience in the treatment of newborns with ABCA3 gene mutations is needed. Randomized, prospective evaluation of the different therapeutic approaches in a specific registry may improve prognosis and treatment of affected individuals.

Identification of novel mutations in the ABCA12 gene, c.1857delA and c.5653–5655delTAT, causing harlequin ichthyosis

Harlequin ichthyosis (HI) is a severe autosomal recessive developmental disorder of the skin that is frequently but not always fatal in the first few days of life. In HI, mutations in both ABCA12 gene alleles must have a severe impact on protein function and most mutations are truncating. The presence of at least one nontruncating mutation (predicting a residual protein function) usually causes a less severe congenital ichthyosis (lamellar ichthyosis or congenital ichthyosiform erythroderma). Here we report on a girl with severe HI diagnosed by prenatal ultrasound at 33 5/7 week gestation. Ultrasound findings included ectropion, eclabium, deformed nose, hands and feet, joint contractures, hyperechogenic amniotic fluid and polyhydramnion. After birth, palliative treatment was provided and she died on her first day of life. Sequence analysis of the ABCA12 gene identified two novel mutations, c.1857delA (predicting p.Lys619) in exon 15 and c.5653-5655delTAT (predicting p.1885delTyr) in exon 37, each in heterozygous state. The c.5653-5655delTAT mutation is not truncating, but the deleted tyrosine at position 1885 is perfectly conserved among vertebrates and molecular studies evaluated the mutation as probably disease causing and damaging.

Ante-, peri- and postnatal factors associated with intraventricular hemorrhage in very premature infants

BACKGROUNDnIntraventricular hemorrhage (IVH) is one of the most serious complications in preterm infants and is associated with neurological sequelae and mortality. Over the past few decades, the rate of IVH has decreased due to improved neonatal intensive care. However, up to 15-25% of very and extremely premature infants (<32 and <28weeks of pregnancy (WOP) respectively) still suffer from IVH.nnnSTUDY PURPOSEnThe aim of this study was to perform an updated, multicenter analysis to identify ante-, peri, and postnatal factors other than gestational age/birth weight associated with IVH of any grade in a large cohort of very and extremely premature infants.nnnMETHODSnWe performed a retrospective analysis in a prospectively conducted multicenter cohort study between 01/01/1998-31/12/2012 at 5 level 3 perinatal centers. All relevant ante-, peri- and neonatal data were collected and univariate as well as multivariate logistic regression analysis was performed.nnnRESULTSn765 inborn infants with a gestational age<32 WOP were enrolled into this study (369 (48.2%) female; 396 (51.8%) male). Birth weight ranged from 315g to 2200g (mean 1149.7g, SD 371.9g); 279 (36.5%) were born ≤27+6 WOP and 486 (63.5%)≥28+0 WOP. IVH was seen in 177 (23.1%) patients. Multivariate analysis revealed that in addition to higher gestational age (OR 0.7, CI [0.6-0.8]), antenatal steroid treatment (OR 0.3, CI [0.2-0.6]) and caesarian section without uterine contraction (OR 0.6, CI [0.4-0.9]) were associated with a lower rate of IVH while RDS (OR 5.6, CI [1.3-24.2]), pneumothorax (OR 2.8, CI [1.4-5.5]) and use of catecholamines (OR 2.7, CI [1.7-4.5]) were associated with an increased risk of IVH. After exclusion of gestational age and birth weight from multivariate analysis, early onset sepsis (OR 1.6, CI [1.01-2.7]) and patent ductus arteriosus (OR 1.9, CI [1.1-3.1]) were associated with a higher rate of IVH. In addition, univariate analysis revealed that Apgar scores at 5min (p<0.001), BDP/ROP/NEC (p<0.001), mechanical ventilation (p<0.001) and inhalative nitric oxide (p<0.001) were significantly associated with IVH.nnnCONCLUSIONSnOur comprehensive analysis demonstrated that the occurrence of IVH in very premature infants is significantly associated with ante-, peri- and postnatal factors being either related to the degree of immaturity or indicating a critical clinical course after birth. The analysis reiterates the necessity for a very close cooperation between obstetricians and neonatologists to reduce the incidence of IVH in this susceptible cohort.

What If the Prenatal Diagnosis of a Lethal Anomaly Turns Out to Be Wrong

Advances in prenatal diagnosis create a unique set of clinical ethics dilemmas. Doctors routinely obtain genetic screening, radiologic images, and biophysical profiling. These allow more accurate diagnosis and prognosis than has ever before been possible. However, they also reveal a wider range of disease manifestations than were apparent when prenatal diagnosis was less sophisticated. Sometimes, the best estimates of prognosis turn out to be wrong. The infant’s symptoms may be less severe or more severe than anticipated based on prenatal assessment. We present a case in which a prenatal diagnosis was made of severe osteogenesis imperfecta, leading to a decision to induce delivery at 31 weeks. On postnatal evaluation, the infant’s disease did not appear to be as bad as had been anticipated. We discuss the ethical implications of such diagnostic and prognostic errors.

Intermittent Dyspnea and Cyanosis in a Newborn Caused by a Hairy Polyp

Hairy polyps were first described by Brown-Kelly in 1918. They are rare benign malformations of the oropharynx and nasopharynx comprising elements of ectodermal and mesodermal origins foreign to the sites in which they are found. Although rare, they have to be considered in children, especially in newborns, with intermittent dyspnea. We herein report a case of a hairy polyp arising from the lateral pharyngeal wall that was diagnosed shortly after birth because of intermittent dyspnea, cyanosis, and a strong urge to gag.