West Suffolk Hospital,West Suffolk NHS Foundation Trust

Spontaneous pneumothorax is a common respiratory presentation that may signal underlying genetic disease. Familial pneumothorax occurs in ~10% of primary cases, yet 75% remain genetically unclassified. We report identical twin brothers presenting with spontaneous pneumothoraces in adulthood, leading to a diagnosis of Tatton-Brown-Rahman syndrome (TBRS), a DNMT3A-related overgrowth disorder not previously associated with pneumothorax. Both individuals exhibited tall stature, mild intellectual disability, hypermobility, and cardiac abnormalities. Whole genome sequencing identified a rare de novo DNMT3A missense variant (c.1585 G > A, p.D529N) absent from population databases and predicted to be damaging. Methylation profiling confirmed genome-wide hypomethylation consistent with impaired DNMT3A function, supporting pathogenicity. No variants were found in known familial pneumothorax genes. Apical blebs observed at surgery and connective tissue features suggest a mechanistic link between TBRS and pneumothorax, analogous to other monogenic connective tissue disorders. This case expands the phenotypic spectrum of TBRS and highlights the importance of genetic evaluation in familial pneumothorax. Diagnosis enables personalised care, including surveillance for extrapulmonary complications such as aortic root dilatation and haematological malignancy. Our findings suggest that TBRS should be considered in patients presenting with pneumothorax, tall stature, and neurodevelopmental features. Further cases are needed to confirm this association and refine clinical management strategies.

e20684 Background: Single-agent ICIs are approved for the first-line treatment of aNSCLC and PDL1 ≥50%. Early cross-over of survival curves raise concerns about early mortality in this group. Current controversies exist about upfront intensification with ICI-chemotherapy and the increasing use of ICIs in patients near the end-of-life. To our knowledge, this is one of the largest study to explore early mortality in patients with aNSCLC receiving single-agent ICI. Methods: 1571 patients treated between 2017-2023 from 18 UK centres were included into this retrospective real-world study. Multiple imputations were used to handle data missing at random and pooled estimates were combined. Multivariate logistic regression was used for 30- and 60-day mortality. Variables were selected through a combination of domain knowledge and LASSO regression. Results: 5.6% and 12.4% of patients experienced 30- and 60-day mortality respectively. Baseline demographics within total cohort were median age 70-years, 52% male, 76% non-squamous histology, 14% brain metastases, 11% liver metastases, 76% de-novo stage 4 disease, and 93% pembrolizumab as ICI of choice. Performance status (PS) of ≥2 (OR 2.36; p <0.001), neutrophil-lymphocyte ratio (NLR) (OR 1.21; p =0.008), neutrophil-eosinophil ratio (NER) (OR 1.33; p <0.001), and albumin (OR 0.88; p <0.001) were associated with 30-day mortality [Table 1]. PS ≥2 (OR 1.77; p <0.001), NLR (OR 1.39; p <0.001), NER (OR 1.29; p <0.001), albumin (OR 0.89; p <0.001), brain metastasis (OR 1.99; p =0.002), and liver metastasis (OR 1.88; p =0.007) were associated with 60-day mortality. Age, sex, BMI, smoking status, histology, and deprivation indices were not associated with 30- or 60-day mortality. Most common cause of 30-day death was NSCLC (79.6%) followed by non-cancer causes (11.4%). Conclusions: Poor PS and elevated inflammatory indices (NLR, NER, albumin) were associated with 30-day mortality, reflecting systemic effects of disease and/or patient frailty. The latter emergence of brain and liver metastases as 60-day prognostic markers may indicate the need for ICI-chemotherapy combination in fit patients. Multivariate logistic regression for 30-day and 60-day mortality. 30-day mortality[OR (95%CI); p -value] 60-day mortality[OR (95%CI); p -value] Age 0.98 (0.96-1.00) 0.086 1 (0.98-1.02) 0.907 Performance status ≥2 2.36 (1.63-3.42) <0.001 1.77 (1.31-2.39) <0.001 Haemoglobin 1.02 (1.00-1.03) 0.023 1.01 (1.00-1.02) 0.064 Albumin 0.88 (0.84-0.91) <0.001 0.89 (0.86-0.91) <0.001 NLR 1.21 (1.05-1.39) 0.008 1.39 (1.18-1.65) <0.001 NER 1.33 (1.14-1.54) <0.001 1.29 (1.12-1.48) <0.001 Brain metastasis – – 1.99 (1.29-3.06) 0.002 Liver metastasis – – 1.88 (1.19-2.98) 0.007 Index of Multiple Deprivation – – 1.06 (1.00-1.12) 0.062

Abstract Abdominal aortic aneurysm (AAA) is a major health concern with curative surgery requiring open or endovascular aortic repair (EVAR). Transient secondary (hypogonadotrophic) hypogonadism post-operatively is relatively common due to surgical stress or opioid analgesia. Primary (hypergonadotropic) hypogonadism is rare and usually permanent. Mechanisms include compromised gonadal blood supply through cross-clamping (open repair), inadvertent vessel ligation, thrombosis or microembolisation. We describe a case of de novo primary hypogonadism following open AAA repair. A 67-year-old man underwent elective open repair of a 5.5 cm infrarenal AAA in December 2024. His peri-operative course was uncomplicated. He had no prior history of orchitis, testicular trauma, chemotherapy or radiotherapy. He had fathered two children and reported normal sexual function and secondary sexual characteristics prior to surgery. A few months post-operatively, he developed episodic sweating and hot flushes. His body hair, shaved pre-operatively, had failed to regrow over the axillae, torso, and pubic region and facial shaving was reduced to alternate days from daily. He had gained a stone in weight, attributed to smoking cessation pre-operatively. He also reported loss of spontaneous erections and reduced libido. There had not been any testicular pain. On examination, he appeared hypogonadal, with loss of secondary sexual characteristics and small, soft, non-tender testes. Testing in primary care in April 2025 had demonstrated undetectable 09:00 hrs testosterone (<0.09 nmol/L), mildly elevated prolactin (824 mIU/L), normal TSH (1.03 mIU/L) and low cortisol (115 nmol/L). Endocrine evaluation in May 2025 confirmed severe primary hypogonadism with low 09:00 hrs testosterone (1.82 nmol/L) and elevated gonadotropins (FSH 22.4 IU/L, LH 12 IU/L). Prolactin (290 mIU/L), thyroid function and cortisol (449 nmol/L) were normal. Testicular ultrasound doppler in December 2025 confirmed testicular atrophy, with bilateral small testes measuring 2.5 cm, showing uniform echotexture and preserved, albeit reduced, vascular flow. Following testosterone replacement, his sweats settled, spontaneous erections returned and body hair regrowth resumed. The temporal relationship of the presentation of primary hypogonadism to AAA repair strongly suggests a link and the ultrasound findings suggest it is permanent. This is theoretically more likely after open repair due to the increased and prolonged insult, including aortic cross-clamping. However, while there are reported cases of primary hypogonadism occuring after EVAR, we believe this is the first reported case occuring after open repair. Clinicians may need to consider androgen deficiency in men presenting with persistent non-specific symptoms post-AAA repair, including weight gain, loss of energy and libido.