Deirdre E. Donnelly

Outcomes in children treated for persistent bacterial bronchitis.

Background: Persistent bacterial bronchitis (PBB) seems to be under-recognised and often misdiagnosed as asthma. In the absence of published data relating to the management and outcomes in this patient group, a review of the outcomes of patients with PBB attending a paediatric respiratory clinic was undertaken. Methods: A retrospective chart review was undertaken of 81 patients in whom a diagnosis of PBB had been made. Diagnosis was based on the standard criterion of a persistent, wet cough for >1 month that resolves with appropriate antibiotic treatment. Results: The most common reason for referral was a persistent cough or difficult asthma. In most of the patients, symptoms started before the age of 2 years, and had been present for >1 year in 59% of patients. At referral, 59% of patients were receiving asthma treatment and 11% antibiotics. Haemophilus influenzae and Streptococcus pneumoniae were the most commonly isolated organisms. Over half of the patients were completely symptom free after two courses of antibiotics. Only 13% of patients required ⩾6 courses of antibiotics. Conclusion: PBB is often misdiagnosed as asthma, although the two conditions may coexist. In addition to eliminating a persistent cough, treatment may also prevent progression to bronchiectasis. Further research relating to both diagnosis and treatment is urgently required.

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

Background Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. Methods We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Results Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. Conclusions Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

The clinical spectrum of the m.10191T>C mutation in complex I-deficient Leigh syndrome

Mitochondrial respiratory chain diseases represent one of the most common inherited neurometabolic disorders of childhood, affecting a minimum of 1 in 7500 live births. The marked clinical, biochemical, and genetic heterogeneity means that accurate genetic counselling relies heavily upon the identification of the underlying causative mutation in the individual and determination of carrier status in the parents. Isolated complex I deficiency is the most common respiratory chain defect observed in children, resulting in organ‐specific or multisystem disease, but most often presenting as Leigh syndrome, for which mitochondrial DNA mutations are important causes. Several recurrent, pathogenic point mutations in the MTND3 gene – including m.10191T>C (p.Ser45Pro) – have been previously identified. In this short clinical review we evaluate the case reports of the m.10191T>C mutation causing complex I‐deficient Leigh syndrome described in the literature, in addition to two new ones diagnosed in our laboratory. Both of these appear to have arisen de novo without transmission of the mutation from mother to offspring, illustrating the importance not only of fully characterizing the mitochondrial genome as part of the investigation of children with complex I‐deficient Leigh syndrome but also of assessing maternal samples to provide crucial genetic advice for families.

Advances in the Genetics of Familial Renal Cancer

We discuss recent advances in the diagnosis and management of renal cell cancer (RCC) given the enhanced molecular genetics knowledge in this area. A number of hereditary renal cancer syndromes have been described, including von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary leiomyomatosis/RCC syndrome, and hereditary papillary renal cancer. Early molecular diagnosis now facilitates the management and prevention of RCC in families. Recommendations for screening in families are discussed.

Familial Pediatric Endocrine Tumors

Pediatric endocrine tumors are rare but have fairly characteristic presentations. We describe an approach to diagnosis and management of five of the most common presentations including gonadoblastoma, paraganglioma, medullary thyroid cancer, adrenal cancer, and pituitary adenoma. Genetic testing can aid in the early detection and prevention and management of tumors in patients and in other family members.

Epidemiology, clinical features, and genetics of multiple endocrine neoplasia type 2B in a complete population.

This paper reports the first published prevalence of Multiple endocrine neoplasia type 2B (MEN 2B). Estimates of the epidemiology of MEN 2B were based on a single population with one centralized genetic clinic. MEN 2B remains a relatively rare condition and can be easily missed if the diagnosis has not been considered.

Phenotypic variability in a three-generation Northern Irish family with Sotos syndrome.

Sotos syndrome is an overgrowth disorder with autosomal dominant inheritance caused by mutations and deletions in the nuclear receptor Set domain-containing protein 1 gene. In general, affected individuals have an advanced bone age, macrocephaly, characteristic facial gestalt and learning difficulties. Genotype–phenotype correlations are unclear. Full penetrance is seen and 95% of cases are de novo. Here, we report a three-generation pedigree, with at least eight affected individuals, shown to harbour the nuclear receptor Set domain-containing protein 1 missense mutation c. 6115C>T. To our knowledge, this is the largest Sotos family reported. The observed phenotype is extremely variable, thus highlighting the clinical heterogeneity that may occur.

Constellation of Five Facial Features of Tuberous Sclerosis in a Child with a TSC2 1808A>G Mutation

This article presents the case of an 8-year-old boy with a TSC2 1801A>G mutation who has five facial features of tuberous sclerosis complex.

Novel PEX11B Mutations Extend the Peroxisome Biogenesis Disorder 14B Phenotypic Spectrum and Underscore Congenital Cataract as an Early Feature

Purpose Peroxisomes perform complex metabolic and catabolic functions essential for normal growth and development. Mutations in 14 genes cause a spectrum of peroxisomal disease in humans. Most recently, PEX11B was associated with an atypical peroxisome biogenesis disorder (PBD) in a single individual. In this study, we identify further PEX11B cases and delineate associated phenotypes. Methods Probands from three families underwent next generation sequencing (NGS) for diagnosis of a multisystem developmental disorder. Autozygosity mapping was conducted in one affected sibling pair. ExomeDepth was used to identify copy number variants from NGS data and confirmed by dosage analysis. Biochemical profiling was used to investigate the metabolic signature of the condition. Results All patients presented with bilateral cataract at birth but the systemic phenotype was variable, including short stature, skeletal abnormalities, and dysmorphism—features not described in the original case. Next generation sequencing identified biallelic loss-of-function mutations in PEX11B as the underlying cause of disease in each case (PEX11B c.235C>T p.(Arg79Ter) homozygous; PEX11B c.136C>T p.(Arg46Ter) homozygous; PEX11B c.595C>T p.(Arg199Ter) heterozygous, PEX11B ex1-3 del heterozygous). Biochemical studies identified very low plasmalogens in one patient, whilst a mildly deranged very long chain fatty acid profile was found in another. Conclusions Our findings expand the phenotypic spectrum of the condition and underscore congenital cataract as the consistent primary presenting feature. We also find that biochemical measurements of peroxisome function may be disturbed in some cases. Furthermore, diagnosis by NGS is proficient and may circumvent the requirement for an invasive skin biopsy for disease identification from fibroblast cells.

Leydig Cell Tumor of the Testis in Tuberous Sclerosis: Lack of Second Hit Events

This article presents the case of an adult patient with tuberous sclerosis complex who presented with large right benign and left malignant Leydig cell tumors. The tumors were examined to determine if they showed the classic hallmarks of TSC1/TSC2 involvement.