Objective: Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the incidence and risk factors of diazoxide-induced PH in a large HH cohort to provide recommendations for anticipating and preventing PH in diazoxide-treated patients with HH. Design and Patients:Retrospective cohort study involving four UK regional HH centres; review of case notes of HH patients on diazoxide. Measurements:The diagnosis of PH was based on clinical and echocardiography evidence. Patient and treatment-related risk factors were analysed for association.Results: Thirteen (6 men) of 177 HH diazoxide-treated patients developed PH, an incidence of 7%. In the PH group, HH was diagnosed at median (range) of 9 (1,180) days, with diazoxide commenced 4 (0,76) days from diagnosis and reaching a maximum dose of 7 (2.5,20) mg/kg/d. The majority (8 of 13 patients) developed PH within 2 weeks of diazoxide. Complete diazoxide withdrawal, but not dose reduction, led to PH resolution at 41 (3,959) days. In three patients, PH continued beyond 12 months.Risk factors for the development of PH included the presence of congenital heart disease (CHD) (P = .008), and total fluid volume exceeding 130 mL/kg/d in the immediate 24 hours preceding diazoxide (P = .019). Conclusion:Pulmonary hypertension can occur in 7% of diazoxide-treated HH patients. Risk factors include the presence of congenital heart disease and fluid overload.Recommendations include echocardiography and fluid restriction to 130 mL/kg/d prior to diazoxide treatment and immediate discontinuation of diazoxide if PH develops. K E Y W O R D Sdiazoxide, echocardiography, hyperinsulinism, hypoglycaemia, pulmonary hypertension | 771 CHEN Et al.
IntroductionConstitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive disorder that results from homozygous germline mutations in one of the mismatch repair genes MLH1, MSH2, MSH6 and PMS. CMMRD syndrome results in a predisposition to childhood malignancy, with an increased risk of developing central nervous system (CNS), haematological and gastro-intestinal (GI) tract cancers. Colorectal polyps and cutaneous manifestations resembling neurofibromatosis type 1 are common. We present the case of a patient with CMMRD syndrome and bronchiectasis, an association not previously documented in the literature.Case reportA 13-year-old boy of Pakistani origin born to consanguineous parents was referred to the paediatric outpatient clinic with anaemia. Both parents had a diagnosis of Lynch syndrome and elder brother a diagnosis of CMMRD syndrome with a previous history of CNS primary neuro-ectodermal tumour and basal cell carcinoma. Consultation revealed a history of chronic productive cough and recurrent lower respiratory tract infections with evidence of finger clubbing on examination. Cutaneous manifestations included a large scalp congenital melanocytic naevus, multiple CALMs, hypopigmented lesions and axillary and inguinal freckling.Persistent left lower lobe changes were noted on chest X-ray. Bronchoscopy demonstrated normal airway anatomy with increased secretions noted from left lower lobe bronchus. CT chest confirmed a diagnosis of bronchiectasis. Sweat test and ciliary biopsy were normal. Immunoglobulin A was low at <0.7 g/L while lymphocyte subset analysis was unremarkable. Baseline pulmonary function testing demonstrated a moderate restrictive defect with no evidence of obstruction. Genetic screening was performed in light of family history which identified a familial homozygous MSH6 sequence variant, c.3175del p.(Val1059fs), consistent with a diagnosis of CMMRD syndrome.Bowel screening was undertaken and colonoscopy identified a large colorectal villous adenoma with focal high-grade dysplasia. The patient subsequently developed focal seizures and was diagnosed with a right fronto-parietal brain tumour with three metastatic lesions. Biopsy, although not conclusive, was felt to be representative of a high-grade glial or embryonal tumour.ConclusionCMMRD syndrome is associated with a complex array of clinical manifestations and a wide tumour spectrum. Bronchiectasis has not been previously documented in the literature and should be considered where a history of chronic respiratory symptoms exists.
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