Endocrine Abstracts

Introduction: Immune mediated cases of severe insulin resistant diabetes are very rare. We report responses to immunosuppression with rituximab in two patients.Case 1: A 31 year old black African female, BMI 22.84 kg/m², was referred with new onset diabetes, diagnosed shortly following a miscarriage. She had weight loss, acanthosis nigricans, nocturnal hypoglycaemia and severe hyperandrogenism . She was on an insulin pump and required >1000 units in...

Objectives: Noonan Syndrome (NS) is an autosomal dominant multi-system disorder characterised by short stature (SS), distinctive facial features and cardiovascular abnormalities. Mutations in multiple genes regulating the RAS-MAPK pathway have been identified in NS including 5 recently described novel LZTR1 variants. We identified 2 novel LZTR1 variants in patients with features of growth hormone insensitivity and NS. The molecular function of LZTR1 ...

Objective: To evaluate the real-world experience of patients with generalized (GL) and partial (PL) lipodystrophy initiating treatment with metreleptin as part of an early access program (EAP).Methods: A retrospective data collection was conducted from four countries for patients enrolled in the EAP. A descriptive analysis was performed on selected patient characteristics, baseline organ impairments and complications, and response to metreleptin therapy,...

The study of humans carrying dominant negative mutations in PPAR gamma has contributed significantly to our understanding of its role in human physiology. To date, comparable studies of PPAR alpha have not been reported. Using a pooled approach, we undertook exon sequencing of PPARA in 11,848 adult participants of the Fenland study, a population-based cohort study with detailed metabolic phenotyping. Twenty-nine PPARA missense variants were detected (allelic ...

Introduction: Familial partial lipodystrophy (FPL) is a rare genetic disorder characterised by a selective lack of subcutaneous fat that is associated with insulin resistance and diabetes. FPL has been reported to be caused by mutations in the peroxisome proliferator activator receptor-γ (PPARG) gene, which encodes a key transcription factor that regulates adipocyte differentiation and insulin sensitivity.Material and methods: The objective of this ...

Background: The low dose dexamethasone suppression test (LDDST) is an important investigation for suspected Cushing’s syndrome (CS). The traditional definition of normal suppression of serum cortisol to ≤50 nmol/l (0.5 mg 6 hrly × 48 hrs) comes from a time when biochemical auto analysers did not routinely detect very low values. Previous studies reported 5.1–8.3% of patients with Cushing’s disease (CD) suppressed to <50 nmol/l at 48 hrs. Many clin...

Objectives: The homozygous GHR pseudoexon (6Ψ) mutation leads to aberrant splicing of the GHR gene with clinical and biochemical heterogeneity. We investigated whether the phenotypic variability could be explained by transcript heterogeneity i.e. ratio of abnormal (6Ψ GHR) to normal (WT GHR) transcripts and/or the presence of concurrent defects in other short stature (SS) genes.Methods: 6 Ψ GHR ...

Background: Novel pathogenic mechanisms involving replicative and oxidative stress have recently been described in familial glucocorticoid deficiency (FGD); including mutations in NNT. NNT supplies high concentrations of NADPH needed by the glutathione and thioredoxin anti-oxidant systems to detoxify mitochondrial H2O2.Six patients, from a consanguineous Kashmiri family, were diagnosed with glucocorticoid deficiency between...

Cushing’s disease (CD) is very rare in prepubertal children, and remains a challenge to diagnose and manage. We review the diagnostic features and therapeutic outcome of prepubertal (defined as testicular volume <4 ml (M) and breast stage <2 (F)) CD patients treated in a single centre. Fifteen prepubertal patients (median age 9.4 years; range 5.8–13.7) fulfilled standard diagnostic criteria for CD and there was male preponderance (12 M (80%), median age 9.1 y...

Peroxisome proliferator activated receptor gamma (PPARγ), a ligand-inducible transcription factor, is essential for adipocyte differentiation and lipogenesis. We previously described a kindred in which some individuals were heterozygous for a frameshift/premature stop mutation, (A553ΔAAAiT)fs.185(stop186) in PPARγ, with the truncated protein being non-functional and lacking dominant negative activity1. PPARγ null heterozygotes had norm...