Domhnall O'Halloran

Relationships between insulin‐like growth factor‐1 levels and growth hormone concentrations during diurnal profiles and following oral glucose in acromegaly

OBJECTIVE The aim of this study was to refine the biochemical definition of disease activity in acromegaly by comparing serum growth hormone (GH) measurements during a 10‐hour day profile with serum GH values during an oral glucose tolerance test.

Type 1 diabetes mellitus, coeliac disease, and lymphoma: a report of four cases

Introduction Patients with Type 1 diabetes mellitus have a high prevalence of coeliac disease, symptoms of which are often mild, atypical, or absent. Untreated coeliac disease is associated with an increased risk of malignancy, particularly of lymphoma. We describe four patients with Type 1 diabetes mellitus and coeliac disease who developed lymphoma.

Novel DAX1 mutations in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.

Mutations of the DAX1 gene (Dosage‐sensitive sex reversal‐Adrenal hypoplasia congenita critical region on the X chromosome gene 1), which encodes a novel orphan nuclear receptor, have been identified in patients with X‐linked adrenal hypoplasia congenita (AHC) and hypogonadotrophic hypogonadism (HHG). We have investigated two kindreds with AHC and HHG for DAX1 mutations.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype–phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca2+o) homeostasis. To elucidate the role of AP2σ2 in Ca2+o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype–phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype–phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

The effects of CV205-502 in patients with hyperprolactinaemia intolerant and/or resistant to bromocriptine.

CV205-502 is a new non-ergot dopamine agonist currently being studied for the treatment of hyperprolactinaemia. We have assessed the effects of CV205-502 on prolactin secretion and the clinical consequences of hyperprolactinaemia in 16 patients with hyperprolactinaemia who had previously been unsuccessfully treated with bromocriptine. These patients had been either intolerant of and/or resistant to the effects of bromocriptine. Sixteen patients, all women in an age range between 20 and 49 years (mean 31.5 years), were treated for periods of between 8 and 52 weeks with doses of CV205-502 ranging from 0.075 to 0.3 mg taken once daily at night. Seven out of 10 of the patients, who were intolerant of bromocriptine, tolerated CV205-502 better with fewer side effects although the nature of the side effects was similar to that associated with bromocriptine. Only 1 patient from this group stopped taking CV205-502 due to side effects. Six of 11 patients exhibiting bromocriptine resistance showed a significant reduction in the degree of hyperprolactinaemia but normoprolactinaemia was achieved in only 1. Galactorrhoea ceased in 2 of 6 patients, menstruation resumed in 6 of 11 patients presenting with amenorrhoea, and 2 patients conceived. In patients with bromocriptine intolerance and/or resistance, CV205-502 is useful as a second line treatment.

Insulin as a substance of misuse in a patient with insulin dependent diabetes mellitus

Doctors should be alert to the possibility of insulin misuse, and should consider psychological evaluation, in an insulin dependent diabetic patient with poor control

Quantitative Whole-Body MRI in Familial Partial Lipodystrophy Type 2: Changes in Adipose Tissue Distribution Coincide With Biochemical Improvement

OBJECTIVE Familial partial lipodystrophy type 2 (Online Mendelian Inheritance in Man no. 151660) is a systemic disorder characterized by regional lipoatrophy and lipohypertrophy, severe insulin resistance, and early cardiovascular death. At initial presentation, whole-body MRI allows the radiologist to accurately characterize patients with familial partial lipodystrophy and helps differentiate familial partial lipodystrophy from many other subtypes of lipodystophy. We present the findings of serial quantitative MRI analysis in two patients with familial partial lipodystrophy type 2 and outline the objective imaging changes that occur during medical therapy with oral rosiglitazone. CONCLUSION Cervical adipose volume and visceral adipose area increased by 105% and 60% in the two patients and hepatic fat fraction decreased by 55% during a 21-month period of medical therapy. These changes coincided with a decrease in biochemical indexes of insulin resistance. Whole body quantitative MRI may therefore help to demonstrate the subclinical changes in fat deposition that occur as a result of novel treatment of familial partial lipodystrophy and with continued research may play a role in guiding the choice, duration, and intensity of novel medical therapy.

Clinical features and autoimmune associations in patients presenting with Idiopathic Isolated ACTH deficiency

Idiopathic Isolated ATCH deficiency (IIAD) is a rare cause of secondary adrenal insufficiency. As the condition is rare, and the diagnostic criteria ill‐defined, there are few good clinical descriptions in the literature. We have described presenting features, autoimmune associations, natural history and responses to CRF, in a large case series of patients presenting with IIAD.

SDHB gene positive metastatic paraganglioma associated with lesions which demonstrate both positive and negative uptake of 18FDG PET and 131MIBG

### Learning Points for Clinicians Paragangliomas are rare caetacholamine secreting neuroendocrine tumours. The diagnosis and management of these tumours is often difficult, particularly as a diagnosis of metastases is often made retrospectively when disease recurrence occurs. In recent years, the role of genotyping has allowed us to better predict which tumours are more likely to be metastatic. Mutations in the SDHB gene have been associated with higher rates of metastatic disease.1 Unfortunately, mutations in this gene can also lower the sensitivity of radiolabeled metaiodobenzylguanidine (MIBG). MIBG scanning is considered the gold standard imaging modality for the diagnosis of recurrent disease but this case illustrates the potential diagnostic pitfalls associated with this imaging modality in cases of SDHB gene mutations. The case demonstrates the importance of genotyping as a diagnostic and predictive tool and the importance of clinical acumen in the face of negative test results. This gentleman underwent a MRI of pelvis in February 2011 for investigation of possible sacroiliitis on a background of known inflammatory bowel disease. This MRI demonstrated a 2.3 × 2.3 cm nodule posterior to the pubic …