Stephen M. P. O'Riordan

Management of cystic fibrosis-related diabetes in children and adolescents

TheDepartment of Pediatrics, University of Minnesota Children’sHospital, Minneapolis, USACorresponding author:Dr. Stephen MP O’Riordan MRCPI, MDThe Developmental Endocrinology and Research GroupThe Department of Clinical and Molecular GeneticsThe Institute of Child Health, University College London30 Guliford StreetLondon WC1N 1EH.Tel: +44-020-7242-9789, ext. 0732;fax: +44-020-7404-6191;e-mail: s.oriordan@ich.ucl.ac.ukAcknowledgments:PeterHindmarsh,MehulDattani,HilaryHoeyand Nicola Bridges.Conflicts of interest: The authors have declared no conflictsof interest.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency

Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.

VALIDATION OF CONTINUOUS GLUCOSE MONITORING IN CHILDREN AND ADOLESCENTS WITH CYSTIC FIBROSIS - A PROSPECTIVE COHORT STUDY

OBJECTIVE To validate continuous glucose monitoring (CGM) in children and adolescents with cystic fibrosis. RESEARCH DESIGN AND METHODS Paired oral glucose tolerance tests (OGTTs) and CGM monitoring was undertaken in 102 children and adolescents with cystic fibrosis (age 9.5–19.0 years) at baseline (CGM1) and after 12 months (CGM2). CGM validity was assessed by reliability, reproducibility, and repeatability. RESULTS CGM was reliable with a Bland-Altman agreement between CGM and OGTT of 0.81 mmol/l (95% CI for bias ± 2.90 mmol/l) and good correlation between the two (r = 0.74–0.9; P < 0.01). CGM was reproducible with no significant differences in the coefficient of variation of the CGM assessment between visits and repeatable with a mean difference between CGM1 and CGM2 of 0.09 mmol/l (95% CI for difference ± 0.46 mmol/l) and a discriminant ratio of 13.0 and 15.1, respectively. CONCLUSIONS In this cohort of children and adolescents with cystic fibrosis, CGM performed on two occasions over a 12-month period was reliable, reproducible, and repeatable.

Cystic Fibrosis-Related Diabetes in Childhood

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.

Pubertal Presentation in Seven Patients with Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

Adolescents with oxidoreductase deficiency present with impaired pubertal development, manifesting in girls with hypergonadotropic hypogonadism and ovarian cysts while boys may show delayed but spontaneous pubertal progression.

A novel variant of familial glucocorticoid deficiency prevalent among the Irish Traveler population.

CONTEXT 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. AIMS 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. METHODS 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. RESULTS 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. CONCLUSION We report a high prevalence of FGD among Irish Travelers. Their subtle phenotype and initial normal biochemistry may delay the early diagnosis of FGD.

Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency

Objective  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.

A novel method for the direct measurement of urinary conjugated metabolites of α-tocopherol and its use in diabetes.

Over the past 50 years, a number of metabolites of vitamin E (a-tocopherol) have been described. These can be divided into two groups. The first include a-tocopherylquinone, a-tocopheronic acid and a-tocopheronolactone (a-TL), all of which result from the oxidation and opening of the chromanol ring of a-tocopherol [1, 2]. The second group result from the successive shortening of the phytyl side chain of a-tocopherol, initially by o-hydroxylation by a cytochrome P450-dependent mechanism followed by b-oxidation [3, 4] and include a-carboxymethyl-butylhydroxychroman and a-carboxy-ethyl-hydroxychroman (a-CEHC) [5–7]. The principal urinary metabolites of a-tocopherol are a-CEHC and aTL, both of which are excreted as their polar sulfate and glucuronide conjugates [5, 8]. There is, however, doubt in the literature whether the aTL observed in urine is real or an artifact produced from the oxidation of a-CEHC during the methodological work up [5]. Confirmation of the authenticity of aTL is important, as it could potentially be used as an ex vivo biomarker of oxidative stress. Published methods for the measurement of urinary vitamin E metabolites typically involve deconjugation, extraction and derivatization steps, which are time consuming and risk the artifactual formation of aTL from a-CEHC [9]. Our aim was to develop a new and rapid method for the direct assay of the conjugated vitamin E metabolites and to investigate whether there was evidence for increased urinary concentrations of aTL in conditions where oxidative stress may be implicated such as diabetes.