A Family with Co-existing SDHB and SDHD Mutations Causing Hereditary Paraganglioma Syndrome

Introduction: We report the co-occurrence of a SDHD and a SDHB mutation in a family with hereditary paraganglioma syndrome.  We compare this finding to simultaneous haploinsufficiency of BRCA1 and BRCA2.Presentation of Case: The 28 year old proband presented as an isolated case in the family with a malignant phaeochromocytoma.  Sequencing and MLPA of SDHD and SDHB were performed.  A SDHD splice site mutation, c.169+5GA, was identified in the proband, his sister and their father.  In addition, a SDHB exon 1 deletion was identified by MLPA in the proband, his sister and their mother.  Both mutations have been described previously and considered to be pathogenic. An appropriate screening programme was instituted for carrier relatives. Conclusions: To our knowledge, this is the first report of two SDH subunit mutations in a single family.  Though there was no family history to suggest inherited disorder, the simultaneous testing of both genes was diagnostic.  The family history is consistent with suggestions that the penetrance of SDHB/SDHD mutations is lower than initially thought

Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers

Repetitive behaviours in typically developing 2-year-olds

Background:  Repetitive behaviours are an essential part of the diagnosis of autism but are also commonly seen in typically developing children. The current study investigated the frequency and factor structure of repetitive behaviours in a large community sample of 2-year-olds. Methods:  A new measure, the Repetitive Behaviour Questionnaire (RBQ-2) was completed by 679 parents. Results:  The RBQ-2 had good psychometric properties. A four-factor model provided the best fit for the data, accounting for 51% of the variance, and suggested 4 sub-scales: unusual sensory interests, repetitive motor movements, rigidity/adherence to routine and preoccupations with restricted patterns of interest. These sub-scales closely resembled repetitive behaviour subtypes within the ICD-10 criteria for autism. Repetitive behaviours of every type were frequently reported. Higher scores were found for all children, and especially boys, on the subscale relating to preoccupations with restricted patterns of interests. Conclusion:  The results support the proposal that repetitive behaviours represent a continuum of functioning that extends to the typically developing child population