Diagnostic challenges and considerations of cyclical Cushing's syndrome in a 15-year-old female.

Cyclical Cushing's syndrome (CS) is a rare disorder in which cortisol secretion is cyclical and intermittent. This phenomenon makes for a challenging diagnosis, as patterns of cycling can vary widely among patients and as patients with cyclical CS do not exhibit unique clinical features compared to those without cycling. Current research suggests that cyclical CS may be present in approximately 15% of adult cases, with an even lower reported prevalence in the pediatric population. In this case study, we describe a 15-year-old female with obesity and hypertension who was then diagnosed with cyclical CS after we pursued additional screening tests of urine creatinine and 24-hour urine cortisol, dexamethasone suppression tests, bilateral inferior petrosal sinus sampling, as well as MRI. We discuss the vari-ous diagnostic modalities in the challenging diagnosis of cyclical CS as well as the importance and modalities of post-operative monitor-ing in this patient population. From this case study, we emphasize that when CS is suspected and initial screening tests are negative, clinicians should be aware of the cycling phenomenon of CS in order to consider performing additional screening tests.

A novel mutation in the glucocorticoid receptor gene as a cause of severe glucocorticoid resistance complicated by hypertensive encephalopathy.

BACKGROUND: Glucocorticoid resistance syndrome (GRS) is caused by mutations of the glucocorticoid receptor (coded by the NR3C1 gene) and presents with signs of mineralocorticoid and/or androgen excess. PATIENT: A female patient presented at the age of almost 3 years with hypertensive and hypoglycemic seizure. She was diagnosed with GRS and was treated with antihypertensive medications and dexamethasone. She was later found to have MRI findings of punctuate microinfarcts at the basal ganglia, left thalamus and pons, possibly associated with uncontrolled hypertension. Increase of the dexamethasone dose up to 14 mg/day resulted in sufficient control of her symptoms. RESULTS: Two mutations in the NR3C1 gene were identified: a novel mutation in exon 2 (p.E198X), and a previously described mutation in exon 8 (p.R714Q). CONCLUSION: GRS may present with life-threatening complications; this is the first report of hypertensive encephalopathy in association with GRS. Successful management of patients might require high doses of dexamethasone to control blood pressure.

Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), ß (PHKB), É£ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. CONCLUSION: A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Validation of HbA1c of 6.5% for diagnosing diabetes mellitus via the use of taxometric analysis.

PURPOSE: Previous studies in which authors examined the internal and external validity of a glycemic cut-point for diagnosis of diabetes mellitus have provided mixed results. The purpose of the current study was to test the internal validity of the HbA1c 6.5% cut-point with taxometric analysis. METHODS: Data on 14,798 participants were obtained from the National Health and Nutrition Examination Survey, years 1999-2008. Fasting plasma glucose and HbA1c were submitted to the taxometric procedures MAMBAC (mean above minus below a cut) and MAXSLOPE (MAXimum SLOPE). The comparison curve fit index was the outcome measure, with values less than 0.40 and greater than 0.60 indicative of dimensional and categorical solutions, respectively. RESULTS: In the full sample, MAXSLOPE and MAMBAC procedures yielded CCFIs of 0.778 and 0.872, respectively. Analyses were repeated in subgroups by age, sex, fasting insulin level, ethnicity, and year; the lowest comparison curve fit index measurement from any analysis was 0.706. CONCLUSIONS: These results support a categorical overdimensional model of diabetes, consistent with the new HbA1c cut-point recommendation.

U.S. News and World Report's rankings of the top 50 children's hospitals for diabetes and endocrinology reflect reputation more than objective measures.

The objective of this short communication was to evaluate the roles of reputation and objective measures in U.S. News rankings of the top 50 children's hospitals for diabetes and endocrinology. Analysis was performed on data obtained from the 2011 to 2012 report. Reputation scores exhibited more variance (CV = 158%) compared to objective measures (average CV = 14%). Ranking hospitals based on reputation, compared to total score, identified the same top hospital, same top five hospitals, and 90% of the same top 10 hospitals. Ranking based on total objective score resulted in different top hospitals, 60% of the same top five hospitals, and 50% of the same top 10 hospitals. Hospital total rank was strongly associated with reputation rank (rho2 = 0.78) and moderately associated with objective rank (rho2 = 0.48). Objective rank was minimally associated with reputation rank (rho2 = 0.19). Among the top 50 children's hospitals in diabetes and endocrinology, standings reflect reputation more than objective measures.

I-131 treatment of graves' disease in an unsuspected first trimester pregnancy; the potential for adverse effects on the fetus and a review of the current guidelines for pregnancy screening.

Graves' disease is a thyroid-specific autoimmune disorder in which the body makes antibodies to the thyroid-stimulating hormone receptor leading to hyperthyroidism. Therapeutic options for the treatment of Graves' disease include medication, radioactive iodine ablation, and surgery. Radioactive iodine is absolutely contraindicated in pregnancy as exposure to I-131 to the fetal thyroid can result in fetal hypothyroidism and cretinism. Here we describe a case of a female patient with recurrent Graves' disease, who inadvertently received I-131 therapy when she was estimated to be eight days pregnant. This was despite the obtaining of a negative history of pregnancy and a negative urine pregnancy test less than 24 hours prior to ablation. At birth, the infant was found to have neonatal Graves' disease. The neonatal Graves' disease resolved spontaneously. It was suspected that the fetal thyroid did not trap any I-131 as it does not concentrate iodine until 10 weeks of gestation.

A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain.

CONTEXT: Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by partial insensitivity to glucocorticoids, caused by mutations in the glucocorticoid receptor (GR) gene. Most of the reported cases are adults, demonstrating symptoms associated with mineralocorticoid and/or adrenal androgen excess caused by compensatively increased secretion of the adrenocorticotropic hormone. PATIENT: We identified a new 2-yr-old female case of generalized glucocorticoid resistance syndrome. The patient (TJ) presented with a generalized seizure associated with hypoglycemia and hypokalemia. She also had hypertension and premature pubarche, whereas dexamethasone effectively suppressed these clinical manifestations. RESULTS: The patient's GR gene had a heterozygotic mutation (G-->A) at nucleotide position 2141 (exon 8), which resulted in substitution of arginine by glutamine at amino acid position 714 in the ligand-binding domain (LBD) of the GR alpha. Molecular analysis revealed that the mutant receptor had significantly impaired transactivation activity with a 2-fold reduction in affinity to ligand. It showed attenuated transactivation of the activation function (AF)-2 and reduced binding to a p160 nuclear receptor coactivator. Computer-based structural analysis revealed that replacement of arginine by glutamine at position 714 transmitted a conformational change to the LBD and the AF-2 transactivation surface, resulting in a decreased binding affinity to ligand and to the LXXLL coactivator motif. CONCLUSIONS: Dexamethasone treatment is effective in controlling the premature pubarche, hypoglycemia, hypertension, and hypokalemia in this child case, wherein arginine 714 plays a key role in the proper formation of the ligand-binding pocket and the AF-2 surface of the GR alpha LBD.

An infant with combination gene mutations for Monogenic Diabetes of Youth (MODY) 2 and 4, presenting with Diabetes Mellitus Requiring Insulin (DMRI) at 8 months of age.

Monogenic Diabetes of Youth (MODY) is an autosomal dominant form of diabetes. [Fajans SS, et al. NEJM 2001: 345: 971-980.] There are at least six different types of MODY, all of which involve a loss of function gene mutation that results in diminished insulin production. MODY2 results from a mutation in the glucokinase gene (GCK), which decreases enzyme activity. MODY4 results from a mutation in the insulin promoter factor-1 (IPF-1) gene, a transcription factor which regulates the transcription of insulin. [Sperling M, et al. NEJM 2006: 355: 507-510.] TJ presented at 8 months of age with diabetes mellitus requiring insulin (DMRI) with negative islet autoantibodies. She had a prolonged honeymoon period, as evidenced by her insulin requirement of 0.5 units/kg/day at three years of age. Genetic testing showed combination MODY2 (c.1019+18G >A) and MODY4 (c.226G>A) gene mutations. The father was homozygous for MODY2 and the mother was heterozygous for MODY4. [Athena Diagnostics Evaluations "2007 # 839 - Monogenic Diabetes (MODY) Evaluation for the patient, the patient's father, and the patient's mother] Neither parent had diabetes mellitus. The clinical course and negative islet autoantibodies support that the combination of benign MODY2 and MODY4 gene mutations in the parents resulted in DMRI in TJ.

Glycogen storage disease type IIIa presenting as non-ketotic hypoglycemia: use of a newly approved commercially available mutation analysis to non-invasively confirm the diagnosis.

Glycogen storage disease type III (GSD-III) is an autosomal recessive disorder caused by the lack of amylo-1,6-glucosidase (AGL), one of the catalytic domains of the glycogen debranching enzyme. Deficiency of this enzyme classically results in hepatomegaly and ketotic hypoglycemia. The diagnosis of the disorder was previously confirmed with a liver biopsy demonstrating abnormal liver glycogen content and absent enzyme activity. We describe an 11 month-old African-American Jehovah's Witness male with non-ketotic hypoglycemia (NKH), hepatomegaly, cardiomyopathy, and a flat glucagon response confirmed to have GSD-IIIa by mutation analysis of the AGL gene. The present case represents an unusual presentation (NKH) of GSD-IIIa and emphasizes the utility of the newly approved commercially available Clinical Laboratory Improvement Advisory Committee (CLIA) mutation analysis test.

Impact on bone of an estrogen receptor-alpha gene loss of function mutation.

CONTEXT: The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor (ER)-alpha. OBJECTIVE: Our objective was to assess the impact of a loss of function mutation in the ER-alpha gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-alpha heterozygosity on spine density and adult height in an extended pedigree. DESIGN AND PARTICIPANTS: A longitudinal follow-up of the propositus with homozygous loss of function mutation of ER-alpha and single contact evaluation of the kindred were performed. MAIN OUTCOME MEASURES: Iliac crest bone biopsy and peripheral quantitative computed tomography of propositus with serial measures of areal spine bone mineral density (aBMD) by dual-energy x-ray absorptiometry and bone age were performed. Members of pedigree were evaluated for ER-alpha mutation carrier status and spine aBMD. RESULTS: Bone biopsy revealed marked osteopenia (cortex: 641 microm), low trabecular volume (10.6%), decreased thickness (76.2 microm), normal trabecular number, and low activation frequency (0.099/yr). Radial periosteal circumference was similar, endosteal circumference larger, and trabecular and cortical volumetric bone mineral density markedly lower (158 and 1092 mg/cm(3), respectively) than controls. Spine aBMD at age 28.5 yr (0.745 g/cm(2)) decreased to 0.684 g/cm(2) (Z score -3.85) in 3.5 yr. Bone age advanced from 15-17.5 yr. Kindred analysis revealed that gene carriers had spine aBMD Z scores less than zero (P = 0.003), but carriers and nonmutant members were similar (-0.84 +/- 0.26 vs. -0.64 +/- 0.16). CONCLUSION: Homozygous ER-alpha disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER-alpha heterozygosity appears to not impair spine aBMD.

RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds.

BACKGROUND: Multiple endocrine neoplasia 2A (MEN 2A) is a genetic syndrome manifesting as medullary thyroid carcinoma (MTC), hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia 2A results from mutations in the RET proto-oncogene. Hirschsprung disease (HSCR) is a rare manifestation of MEN 2A and has been described in known MEN 2A families. METHODS: Here we describe 2 MEN 2A families that were only identified after the diagnosis of HSCR. RESULTS: Kindred 1: A boy presented in infancy with HSCR. Genetic screening revealed a C609Y mutation, which is consistent with MEN 2A. Evaluation of his sister, father, and grandmother revealed the same mutation. All 3 had thyroidectomies demonstrating C-cell hyperplasia. The grandmother had a microscopic focus of MTC. Kindred 2: An infant boy and his sister were diagnosed with HSCR as neonates. Genetic testing demonstrated a C620R gene mutation consistent with MEN 2A. Total thyroidectomies revealed metastatic MTC in the father and C-cell hyperplasia in both children. CONCLUSIONS: Hirschsprung disease can be the initial presentation of MEN 2A. We strongly recommend that genetic screening be performed in patients presenting with HSCR, looking for the known RET mutations associated with MEN 2A. If a mutation consistent with MEN 2A is detected, genetic screening of all first-degree relatives in the kindred is recommended.

Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations.

Although glycogen storage disease type 0 (GSD0) is included in the differential diagnosis of ketotic hypoglycemia, it usually is not considered in the evaluation of glucosuria or hyperglycemia. We describe two children with GSD0, confirmed by mutation analysis, who had glucosuria and hyperglycemia. Because of the variable presentation of this disorder and previous dependence on liver biopsy to confirm diagnosis, it is likely that GSD0 is underdiagnosed.