Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

Epidemiology and outcomes of tibial plateau fractures in adults aged 60 and over treated in the United Kingdom.

BACKGROUND: Tibial plateau fractures are common in older adults, often resulting from low-energy falls. Although lower limb fragility fracture care has evolved, the management of tibial plateau fractures in older patients remains poorly researched. This study aimed to define the epidemiology, treatment and outcomes of tibial plateau fractures in patients aged over 60 years. METHODOLOGY: Patients aged 60 years or older with a tibial plateau fracture who presented to a single trauma center between January 2008 and December 2018 were identified. Incomplete records were excluded. Epidemiological data, fracture classification, injury management, radiological outcomes, complications, and mortality were assessed via retrospective case note and radiograph review. Local ethics approval was obtained. RESULTS: Two-hundred and twenty patients with a mean age of 74 years (range 60-100) were included. 73% were female and 71% of injuries were sustained following low-energy falls. Median follow up was three months. 50% of fractures involved the lateral plateau. 60% of injuries were treated non-operatively. 76% of patients had their weight-bearing restricted for the first six weeks, with little difference between operatively and non-operatively managed patients. 8% of all patients required subsequent knee replacement. All-cause mortality at 30-days and one-year were 2% and 5% respectively. CONCLUSION: The majority of tibial plateau fractures in the over 60s are sustained from low-energy trauma. Management is relatively conservative when compared with younger cohorts. The data reported brings up questions of whether surgical treatment is beneficial to this patient group, or whether restricted weight bearing is either possible or beneficial. Prospective, multi-center comparative trials are needed to determine whether increased operative intervention or different rehabilitation strategies purveys any patient benefit.