ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD syndrome) is an autosomal dominant multisystem disorder with variable expression due to pathogenic constitutional variants in the FLCN gene. Patients with BHD syndrome are predisposed to benign cutaneous fibrofolliculomas/trichodischomas, pulmonary cysts with an associated risk of spontaneous pneumothorax, and renal cell carcinoma. A requirement for updated International consensus recommendations for the diagnosis and management of BHD syndrome was identified. Based on a comprehensive literature review and expert consensus within the fields of respiratory medicine, urology, radiology, dermatology, clinical oncology and clinical genetics, updated recommendations for diagnosis, surveillance and management in BHD syndrome were developed. With the widespread availability of FLCN genetic testing, clinical scenarios in which a diagnosis should be considered and criteria for genetic testing were defined. Following a clinical and/or molecular diagnosis of BHD syndrome, a multidisciplinary approach to disease management is required. Regular renal cancer surveillance is recommended in adulthood and life-long, but the evidence base for additional tumour surveillance is limited and further research warranted. Recommendations for the treatment of cutaneous, pulmonary and renal manifestations are provided. Awareness of BHD syndrome needs to be raised and better knowledge of the clinical settings in which the diagnosis should be considered should enable earlier diagnosis. Further details, including areas for future research topics are available at: https://www.genturis.eu/l=eng/Guidelines-and-pathways/Clinical-practice-guidelines.html .

von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

Childhood pneumothorax in Birt-Hogg-Dubé syndrome: A cohort study and review of the literature.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominantly inherited cancer predisposition syndrome associated with an increased risk of spontaneous pneumothorax (SP) and renal cell carcinoma in the adult population. Recent studies suggest that BHD accounts for up to 10% of all SP in adults and BHD in children with SP have been reported. METHODS: To explore to what extent BHD is the cause of childhood pneumothorax, we studied a Danish BHD cohort consisting of 109 cases from 22 families. Clinical data was gathered by review of medical records. A systematic literature search concerning childhood and adolescence pneumothorax in BHD was performed and identified publications reviewed. RESULTS: In our cohort, three of 109 BHD cases experienced childhood pneumothorax, corresponding to a prevalence of 3%. Reviewing the literature, data regarding more than 800 BHD cases were covered. Only seven previously published cases of childhood pneumothorax in BHD were identified. CONCLUSION: Our findings suggest that BHD is likely the cause of a larger subset of childhood pneumothoraces than hitherto recognized. Awareness of BHD as a cause of childhood pneumothorax needs to be raised to provide patients and relatives with the possibility of specialized management of SP and regular renal cancer surveillance.

Octreotide therapy and restricted fetal growth: pregnancy in familial hyperinsulinemic hypoglycemia.

SUMMARY: Hypoglycemia during pregnancy can have serious health implications for both mother and fetus. Although not generally recommended in pregnancy, synthetic somatostatin analogues are used for the management of blood glucose levels in expectant hyperinsulinemic mothers. Recent reports suggest that octreotide treatment in pregnancy, as well as hypoglycemia in itself, may pose a risk of fetal growth restriction. During pregnancy, management of blood glucose levels in familial hyperinsulinemic hypoglycemia thus forms a medical dilemma. We report on pregnancy outcomes in a woman with symptomatic familial hyperinsulinemic hypoglycemia, type 3. During the patient's first pregnancy with a viable fetus octreotide treatment was instituted in gestational age 23 weeks to prevent severe hypoglycemic incidences. Fetal growth velocity declined, and at 37 weeks of gestation, intrauterine growth retardation was evident. During the second pregnancy with a viable fetus, blood glucose levels were managed through dietary intervention alone. Thus, the patient was advised to take small but frequent meals high in fiber and low in carbohydrates. Throughout pregnancy, no incidences of severe hypoglycemia occurred and fetal growth velocity was normal. We conclude that octreotide treatment during pregnancy may pose a risk of fetal growth restriction and warrants careful consideration. In some cases of familial hyperinsulinemic hypoglycemia, blood glucose levels can be successfully managed through diet only, also during pregnancy. LEARNING POINTS: Gain-of-function mutations in GCK cause familial hyperinsulinemic hypoglycemia.Hypoglycemia during pregnancy may have serious health implications for mother and fetus.Pregnancy with hyperinsulinism represents a medical dilemma as hypoglycemia as well as octreotide treatment may pose a risk of fetal growth restriction.In some cases of familial hyperinsulinemic hypoglycemia, blood glucose levels can be successfully managed through diet only.

Urinary aquaporin-2 excretion before and after transjugular intrahepatic portosystemic shunt insertion for refractory ascites.

OBJECTIVE: The role of renal aquaporin-2 (AQP2) water channel turnover in patients with liver cirrhosis, portal hypertension and water retention remains unclear. Transjugular intrahepatic portosystemic shunt (TIPS) insertion reduces portal hypertension, improves water excretion and lowers plasma vasopressin. The aim of this study was to establish whether TIPS insertion decreases urinary AQP2 excretion (uAQP2) in parallel with improved water excretion. MATERIAL AND METHODS: Fourteen cirrhosis patients with refractory ascites were studied before TIPS insertion and 4 and 12 weeks after insertion. A 24-h urine collection was followed by an oral water load (20 ml/kg body weight) with a 4-h blood and urine sampling. RESULTS: TIPS reduced the portal pressure gradient from a median 18(4) (25-75% InterQuartile-range) to 7(2) mmHg, p < 0.05 and the need for diuretics (p < 0.05). TIPS increased plasma sodium from 136(6) mmol/l to 139(4), (p < 0.05) and diuresis from 1650(1043) ml/24 h to 2230(560) (p < 0.05), although the 24-h urinary sodium excretion did not change. There was no change in the baseline uAQP2 before 274(249) ng/(mmol creatinine/24 h) and 12 weeks after TIPS 242(201). There were no systematic changes in uAQP2, plasma vasopressin or other vasoactive substances during the water loads, before or after TIPS. CONCLUSION: The effective amelioration of portal hypertension improved the patient's water excretion and plasma sodium, but there was no change in renal AQP2 trafficking or vasopressin. These findings do not support a primary role for renal AQP2 water channels in portal hypertensive water retention.