Clinician's guide to genes associated with Rett-like phenotypes-Investigation of a Danish cohort and review of the literature.

The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders with data from a Danish cohort of 35 patients with Rett-like phenotypes emphasizing the diagnostic overlap with Pitt-Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett-like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome-related genes described to date, and hence serves as a guide for diagnosing patients with Rett-like phenotypes.

Retrospective study of paracetamol poisoning in children aged zero to six years found no cases of liver injury.

AIM: This study focused on children aged zero to six years with suspected single-dose paracetamol poisoning, which has not been investigated in Denmark. We evaluated the incidence of liver injuries and the use of activated charcoal and N-acetylcysteine treatment. METHODS: Our retrospective study was performed in three paediatric hospital centres from 2001 to 2012. Data on symptoms, time of ingestion, blood biochemistry, treatment and adverse reactions were collected. The results were evaluated against the Rumack-Matthew nomogram. RESULTS: We identified 221 children (58% male), with a mean age of 2.67 ± 1.05 years. Activated charcoal treatment was given in 87% of cases, but only 15% of the children received treatment within one hour of the suspected paracetamol poisoning. Although 80% of the children received N-acetylcysteine treatment, only one case (0.5%) had a toxic plasma paracetamol level according to the treatment nomogram. Abdominal pain or vomiting was associated with higher paracetamol levels in plasma. None of the children developed liver injuries. CONCLUSION: We found a low incidence of significant poisoning and liberal use of N-acetylcysteine and activated charcoal treatment in Danish children aged zero to six years with suspected paracetamol poisoning. Vomiting or abdominal pain was associated with elevated plasma paracetamol levels. No liver injuries were reported.

The neutrophil-to-lymphocyte ratio as disease actvity marker in multiple sclerosis and optic neuritis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). The neutrophil-to-lymphocyte ratio (NLR) has been identified as a disease activity marker in several diseases. We aim to evaluate the significance of the NLR in the different subtypes of MS, optic neuritis (ON) and in relation to disease activity and Expanded Disability Status Scale (EDSS). METHODS: We included 378 patients and 813 healthy controls (HC) from The Nordic Reference Interval Project 2000 (NORIP). Complete blood count, demographic and clinical data from patients were evaluated retrospectively. The NLRs were compared for all participants by Student's t-test. The comparison of NLR between relapse and remission, SPMS and PPMS, and RRMS and progressive MS were all adjusted for age, gender, EDSS and disease duration by using the linear regression model. Pearson correlation analysis was made between NLR and time of blood sampling. Logistic regression models were constructed for EDSS ≥ 4.0 as outcome. RESULTS: The NLR was significantly higher (p < 0.001) in MS and ON compared to HC. Patients in relapse had a higher NLR (p < 0.01) than patients in remission. No difference in NLR was found between RRMS and progressive MS patients and neither between SPMS and PPMS patients. No association was found between NLR and an EDSS score ≥ 4.0. CONCLUSION: NLR was higher in MS and ON patients compared to HC, indicating the occurrence of chronic inflammation. NLR may be an inexpensive and easily accessible supplemental marker of disease activity in RRMS. This needs confirmation in future trials.

A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome - review of the literature.

In a patient with CdLS (IV.16) we identifed a novel single basepair deletion (c.704delG) in RAD21, which encodes a cohesin pathway protein. The variant is predicted to result in a premature stop codon [p.(Ser235Ilefs*19)] and hereby would have a deleterious effect. RAD21 variants have previously been described only in five cases with cohesinopathies (b). Notably, the deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study (a). The index patient can be classified as mild CdLS, but the other family members do not fulfill the diagnostic criteria of CdLS. This study together with previous reports suggests incomplete penetrance associated with RAD21 variants and these individuals may therefore be underdiagnosed.

The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome.

Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.

Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS; MIM #122470, 300590, 610759, 614701, 300882) is a rare and clinically variable disorder that affects multiple organs. It is characterized by intellectual disability (mild to severe), distinctive facial features, prenatal and postnatal growth retardation, and hirsutism. Congenital anomalies include malformations of the upper limbs, gastrointestinal malformation/rotation, pyloric stenosis, diaphragmatic hernia, heart defects and genitourinary malformations. Gastroesophageal reflux disease is present in almost all patients. In addition to classic forms, milder phenotypes have been reported. To date five genes [NIPBL (Nipped-B-like protein), SMC1A (structural maintenance of chromosomes 1A), SMC3 (structural maintenance of chromosomes 3), RAD21 (human homolog of Schizosaccharomyces pombe radiation sensitive mutant 21) and HDAC8 (histone deacetylase 8)] have been associated with CdLS and mutations of these genes comprise the underlying defect in 70% of the patients. Here, we will provide a brief review of the clinical features of CdLS, summarize the known underlying genetic defects, prenatal and postnatal diagnosis possibilities, and genetic counseling.

Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent.

AIM: Prescription of inhaled corticosteroids to children with asthma is recommended at half the nominal dose of adults in order to reduce the risk of systemic side effects. However, there is a lack of pharmacokinetic trials supporting such dose reduction regimens. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed dose combination of beclometasone-dipropionate (BDP) and formoterol after dry powder inhaler (DPI) administration in children, adolescents and adults. METHODS: The pharmacokinetic profiles of formoterol and beclometasone-17-monopropionate (B17MP; active metabolite of BDP) were evaluated over 8 h from two independent studies comprising children (6-11yrs, n = 27), adolescents (12-17 yrs, n = 28) and adults (≥18 yrs, n = 30) receiving a single, fixed dose of BDP/formoterol (children: 200 µg/24 µg, adolescents and adults: 400 µg/24 µg) via DPI. RESULTS: The systemic exposure (AUC) for children versus adults was almost doubled for formoterol and similar for B17MP despite the halved BDP dose administered in children. In adolescents the AUC for formoterol and B17MP were approximately one third higher than in adults for both compounds. Upon normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration (C(max)) correlated inversely with age and body surface area of the patients (r ≤ -0.53; p < 0.0001). CONCLUSION: The systemic exposure to the active ingredients of BDP/formoterol administered as DPI correlates inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children.

Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy.

A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene (ARSA) and succumbed to metachromatic leukodystrophy (MLD). The other patient had a pseudoallele, which does not lead to MLD. The presenting clinical features and low arylsulfatase A activity were explained, in each patients, by a deletion of 22q13 and, thereby, of one allele of ARSA.

4q35 deletion and 10p15 duplication associated with immunodeficiency.

We report a familial cryptic reciprocal translocation between 4q35 and 10p15 leading to deletion of the terminal long arm of chromosome 4 and duplication of the terminal short arm of chromosome 10 in two family members who both have immunological disturbances and a similar facial appearance. The precise location and extent of the deletion and duplication was determined by fluorescence in situ hybridization (FISH). Furthermore, we investigated the deletion breakpoint of a previously reported patient with 4q34.3-qter deletion [Van Buggenhout et al. (2004); Am J Med Genet Part A 131A:186-189].

Changes in body water distribution during treatment with inhaled steroid in pre-school children.

PRIMARY OBJECTIVE: The study aimed to examine the changes in water distribution in the soft tissue during systemic steroid activity. RESEARCH DESIGN: A three-way cross-over, randomized, placebo-controlled, double-blind trial was used, including 4 weeks of fluticasone propionate pMDI 200 microg b.i.d. delivered via Babyhaler, budesonide pressurized metered dose inhaler (pMDI) 200 microg b.i.d. delivered via Nebuchamber and placebo. Spacers were primed before use. In total, 40 children aged 1-3 years, with mild intermittent asthma were included. Twenty-five of the children completed all three treatments. At the end of each treatment period body impedance and skin ultrasonography were measured. METHODS AND PROCEDURES: We measured changes in water content of the soft tissues by two methods. Skin ultrasonography was used to detect small changes in dermal water content, and bioelectrical impedance was used to assess body water content and distribution. MAIN OUTCOMES AND RESULTS: We found an increase in skin density of the shin from fluticasone as measured by ultrasonography (p = 0.01). There was a tendency for a consistent elevation of impedance parameters from active treatments compared to placebo although overall this effect was not statistically significant (0.1 < p < 0.2). However, sub-analyses indicated a significant effect on whole-body and leg impedance from budesonide treatment (p < 0.05). CONCLUSION: Decreased growth during inhaled steroid treatment seems to partly reflect generalized changes in body water.

[Cystic fibrosis and chronic Pseudomonas aeruginosa infection. Possibilities for immunologic prophylaxis and therapy]. / Cystisk fibrose og kronisk Pseudomonas aeruginosa. Muligheder for immunprofylakse og -terapi.

Cystic fibrosis is an autosomal recessive disease, characterised by chronic pulmonary infections, pancreatic insufficiency and increased electrolyte content of sweat. Cystic fibrosis is diagnosed in one out of 4761 children below the age of 15 years. Pulmonary infection was previously caused by Staphylococcus aureus, but after the introduction of penicillin, the mortality was reduced from 61% to 20% within the first five years of life. Today chronic pulmonary infection is primarily caused by Pseudomonas aeruginosa. P. aeruginosa infection produces an immunologically conditioned destruction of the pulmonary tissue, leading to fatal bronchiectasis. P. aeruginosa develops resistance against most antibiotics and chemotherapeutic agents except colistin. Immunological aspects concerning active and passive immunisation are discussed in the article. Until today no useable vaccine has been found, but several candidates are subjects of research.

[Severe systemic infection with Vibrio vulnificus]. / Alvorlig systemisk infektion med Vibrio vulnificus.

Infections with Vibrio vulnificus are not common in Denmark, but in 1994 several cases were identified, probably due to the very hot weather conditions, with seawater temperatures above 20 degrees C. Two cases of infection with V. vulnificus are presented.