Case report: severe hypertrophic cardiomyopathy in a female neonate caused by de novo variant in NDUFB11.

Background: Hypertrophic cardiomyopathy in the neonate has a diverse genetic background, and non-sarcomeric variants may not be identified on commercial genetic testing panels. NDUFB11 is an X-linked mitochondrial Complex I protein and is known to cause histiocytoid cardiomyopathy but has not been described in female infants with hypertrophic cardiomyopathy. We present this first reported case of obstructive hypertrophic cardiomyopathy in a female neonate secondary to a pathogenic variant in NDUFB11. Case summary: A term female neonate presented following a prenatal diagnosis of biventricular hypertrophy and growth restriction. She developed lactic acidosis after birth and whole-genome sequencing identified a de novo variant in the mitochondrial Complex I gene, NDUFB11 (c.391G>A, p.Glu131Lys). There was progression of left ventricular hypertrophy and obstruction, with rapid development of heart failure symptoms. She was unresponsive to beta-blocker medical therapy and was not suitable for advanced mechanical support. There was subsequent clinical deterioration resulting in death by 3 months of age. Discussion: Hemizygous variants in NDUFB11 have been associated with hypertrophic cardiomyopathy in male infants previously, and skewed X-linked inactivation likely resulted in the presentation described here in a female infant. This variant was not identifiable by commercial cardiomyopathy panels. We highlight the importance of rapid whole-genome sequencing in cases of infantile hypertrophic cardiomyopathy and the importance of genetic diagnosis in guiding prognosis and care for these individuals.

Exploring the neurological features of individuals with germline PTEN variants: A multicenter study.

OBJECTIVE: PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. METHODS: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. RESULTS: One hundred and seven patients with PHTS (median age 8.7 years; range 3-21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. INTERPRETATION: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

Registry-derived stage (RD-Stage) for capturing stage at diagnosis for pancreatic carcinoma in Australia.

INTRODUCTION: Stage of pancreatic carcinoma at diagnosis is a strong prognostic indicator of morbidity and mortality, yet is poorly notified to population-based cancer registries ("cancer registries"). Registry-derived stage (RD-Stage) provides a method for cancer registries to use available data sources to compile and record stage in a consistent way. This project describes the development and validation of rules to capture RD-Stage (pancreatic carcinoma) and applies the rules to data currently captured in each Australian cancer registry. MATERIALS AND METHODS: Rules for deriving RD-stage (pancreatic carcinoma) were developed using the American Joint Commission on Cancer (AJCC) Staging Manual 8th edition and endorsed by an Expert Working Group comprising specialists responsible for delivering care to patients diagnosed with pancreatic carcinoma, cancer registry epidemiologists and medical coders. Completeness of data fields required to calculate RD-Stage (pancreatic carcinoma) and an overall proportion of cases for whom RD stage could be assigned was assessed using data collected by each Australian cancer registry, for period 2018-2019. A validation study compared RD-Stage (pancreatic carcinoma) calculated by the Victorian Cancer Registry with clinical stage captured by the Upper Gastro-intestinal Cancer Registry (UGICR). RESULTS: RD-Stage (pancreatic carcinoma) could not be calculated in 4/8 (50%) of cancer registries; one did not collect the required data elements while three used a staging system not compatible with RD-Stage requirements. Of the four cancer registries able to calculate RD-Stage, baseline completeness ranged from 9% to 76%. Validation of RD-Stage (pancreatic carcinoma) with UGICR data indicated that there was insufficient data available in VCR to stage 174/457 (38%) cases and that stage was unknown in 189/457 (41%) cases in the UGICR. Yet, where it could be derived, there was very good concordance at stage level (I, II, III, IV) between the two datasets. (95.2% concordance], Kendall's coefficient = 0.92). CONCLUSION: There is a lack of standardisation of data elements and data sources available to cancer registries at a national level, resulting in poor capacity to currently capture RD-Stage (pancreatic carcinoma). RD-Stage provides an excellent tool to cancer registries to capture stage when data elements required to calculate it are available to cancer registries.