ABSTRACT: Since the early 1990s the management of children with cystic fibrosis (CF) has come a long way and advances in both nutritional and medical care have resulted in a median age of survival of 30-35 years, as compared with a life expectancy of <1 year in the 1950s. The first definitive reports of glucose intolerance or diabetes in CF are from 1955. The combination of CF and related diabetes (CFRD) has a negative impact on survival. CFRD is now the most common complication of CF (50% of the CF patients will develop diabetes by the age of 30 years), and is associated with a 6-fold increase in morbidity and mortality. CFRD is usually asymptomatic and can remain undetected for up to 4 years prior to diagnosis. The objective of this report was to review the current literature (Medline and Pubmed searches) on CFRD in children and adolescents and provide a comprehensive report of incidence, prevalence and pathophysiology of insulin deficiency and insulin insensitivity. Along with survival and prognosis in CFRD the current management strategies in the diagnosis, monitoring and treatment of CFRD will also be addressed.
Hormone Research in Paediatrics 01/2010; 73(1):15-24.
Pediatric Diabetes 09/2009; 10 Suppl 12:43-50. · 2.16 Impact Factor
ABSTRACT: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification.
Clinical review of patients with nonsense MC2R mutations.
Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations.
Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement.
Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.
Clinical Endocrinology 01/2009; 71(2):171-5. · 3.17 Impact Factor
Pediatric Diabetes 08/2008; 9(4 Pt 1):338-44. · 2.16 Impact Factor
ABSTRACT: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by distinct clinical, biochemical, and genetic abnormalities. The prevalence of FGD is unknown, with the likelihood that cases remain undiagnosed. We noted a significant proportion of our FGD cases are Irish Travelers. Irish Travelers are an endogamous nomadic group ethnically and genetically distinct from Roma gypsies.
The objective of the study was to describe the clinical features and assess the prevalence of FGD amongst Irish Travelers in the Republic of Ireland and describe their phenotype.
Diagnosis of FGD was based on clinical features, high ACTH, and low cortisol concentrations with normal renin and aldosterone concentrations and exclusion of other causes of adrenal failure. Data from the Republic of Ireland Census 2006 were used.
We identified 21 cases of FGD, generating an overall prevalence of one in 201,898. We report nine Irish Travelers (five females) with FGD related to a new gene negative for melanocortin-2 receptor and melanocortin-2 receptor accessory protein mutations. Of a total population of 22,557 Travelers, this yields a disease prevalence of one in 2506 with a carrier frequency of one in 25 in this group and represents a prevalence of one in 665 and a carrier frequency of one in 13 in the 4- to 15-yr Traveler age group. All nine children had a later onset of FGD due to the fact that their initial investigations revealed normal cortisol (422-575 nmol/liter) and ACTH (<34 ng/liter) concentrations.
We report a high prevalence of FGD among Irish Travelers. Their subtle phenotype and initial normal biochemistry may delay the early diagnosis of FGD.
Journal of Clinical Endocrinology & Metabolism 07/2008; 93(7):2896-9. · 6.50 Impact Factor