Journal of Pediatric Endocrinology and Metabolism

Published by De Gruyter

Volume 27 Issue 1-2

Issue of Journal of Pediatric Endocrinology and Metabolism

Submit manuscript

Contents
Journal Overview

Masthead

Publicly Available November 27, 2013

Editorials

November 27, 2013

Editorial

Wieland Kiess

Page range: 1-2

November 27, 2013

Consensus, guidelines and reviews

Zvi Zadik

Page range: 3-3

Review article

June 29, 2013

Adaptation of glucose metabolism to fasting in young children with infectious diseases: a perspective

Wilco C.W.R. Zijlmans, Anne A.M.W. van Kempen, Mireille J. Serlie, Piet A. Kager, Hans P. Sauerwein

Page range: 5-13

Abstract

Hypoglycemia is a frequently encountered complication in young children with infectious diseases and may result in permanent neurological damage or even death. Mortality rate in young children under 5 years of age is increased four- to six-fold when severe infectious disease is complicated by hypoglycemia. Young age, prolonged fasting and severity of disease are considered important risk factors. This perspective describes the combined results of recently conducted studies on the effect of these risk factors on glucose metabolism in children with different infectious diseases. The results of these studies have nutritional implications for the approach in clinical practice towards young children with infectious diseases and specific recommendations are made. A unique finding is the existence of infectious disease-related differences in the adaptation of glucose metabolism during fasting in young children.

Images in pediatric endocrinology

September 13, 2013

Coexistence of testicular microlithiasis with parathyroid adenoma in an obese child

Beray Selver Eklioglu, Mehmet Emre Atabek, Nesibe Akyürek

Page range: 15-16

Original articles

August 14, 2013

Remission of hypertension and electrolyte abnormalities following renal transplantation in a patient with apparent mineralocorticoid excess well documented throughout childhood

Ahmed M. Khattab, Cedric H.L. Shackleton, Beverly A. Hughes, Jayesh B. Bodalia, Maria I. New

Page range: 17-21

Abstract

Apparent mineralocorticoid excess syndrome (AME) is an autosomal recessive genetic disorder caused by a deficiency in the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD). We report a 36-year-old male who was hypertensive from birth and was diagnosed with AME at 8 years of age. There was continuous documentation of his hypertension and hypokalemic alkalosis throughout childhood, during which spironolactone and supplemental potassium were administered. At 33 years of age, the patient received a renal transplant, and following this the AME appears to have been cured clinically with remission of his low renin hypertension and hypokalemic alkalosis despite termination of treatment with spironolactone and potassium supplements.

July 24, 2013

Effects of metformin in children and adolescents with Prader-Willi syndrome and early-onset morbid obesity: a pilot study

Jennifer L. Miller, Tiffany D. Linville, Elisabeth M. Dykens

Page range: 23-29

Abstract

Prader-Willi syndrome (PWS) is one of the most commonly recognized causes of early-onset childhood obesity. Individuals with PWS have significant hyperphagia and decreased recognition of satiety. The exact etiology of the hyperphagia remains unknown and, therefore, untreatable. We conducted a pilot, open-label study of response to metformin in 21 children with PWS and six with early morbid obesity (EMO). Participants had significant insulin resistance and glucose intolerance on oral glucose tolerance testing (OGTT) and were started on metformin for these biochemical findings. We administered the Hyperphagia Questionnaire to parents of patients before and after starting metformin treatment. Both the PWS and EMO groups showed significant improvements in food-related distress, anxiety, and ability to be redirected away from food on the Hyperphagia Questionnaire. In the PWS group, improvements were predominantly seen in females. Within the PWS group, responders to metformin had higher 2-h glucose levels on OGTT (7.48 mmol/L vs. 4.235 mmol/L; p=0.003) and higher fasting insulin levels (116 pmol/L vs. 53.5 pmol/L; p=0.04). Additionally, parents of 5/13 individuals with PWS and 5/6 with EMO reported that their child was able to feel full while on metformin (for many this was the first time they had ever described a feeling of fullness). Metformin may improve sense of satiety and decrease anxiety about food in some individuals with PWS and EMO. Positive response to metformin may depend on the degree of hyperinsulinism and glucose intolerance. Nonetheless, the results of this pilot study bear further investigation.

August 10, 2013

Glycemic control in familial vs. sporadic type 1 diabetes patients over 5 years

Sujana Reddy, Steven E. Reinert, Geetha Gopalakrishnan, Wendy Plante, Charlotte M. Boney, Jose Bernardo Quintos

Page range: 31-35

Abstract

Background: Studies have shown that familial type 1 diabetes patients (FTID) have less severe metabolic derangement at presentation compared to sporadic patients (ST1D), but data on long-term metabolic control are lacking. Objective/Hypothesis: (1) FT1D will have less severe presentation and better HbA 1c over 5 years compared to ST1D; (2) HbA 1c in the offspring will correlate with parent HbA 1c in parent-offspring group; and (3) HbA 1c of the second affected sibling (SP2) will correlate with the first affected sibling (SP1) in sib-pairs. Methods: Cohort of 33 parent-offspring and 19 sib-pairs; controls included 33 sporadic subjects matched by age, sex, ethnicity, puberty, and insulin regimen. Paired t-test and Pearson’s correlation were used for statistical analysis. Results: At diagnosis, mean age in FT1D vs. matched ST1D (7.7±4.9 vs. 7.6±4.5 years), mean HbA 1c (9.6% vs. 10.7%), HCO 3 (21 vs. 18 meq/L), glucose (428 vs. 463 mg/dL) and pH (7.35 vs. 7.36; p=ns) were not different. At 5 years, HbA 1c (8.9% vs. 8.8%; p=0.81), clinic visits (12 vs. 12.5, p=0.68) and emergency room visits (0.48 vs. 0.24, p=0.10) were not different. In affected siblings, only HCO 3 was different (SP1:18 vs. SP2: 24 meq/L; p<0.01). HbA 1c for SP2 correlated positively with SP1 (r=0.67, p<0.01). Offspring HbA 1c correlated positively with affected parents (9.3% vs. 8.6%, r=0.57, p=0.18) but was not significant. Conclusion: Metabolic control at diagnosis and at 5 years was similar in FT1D and ST1D. In sib-pairs, the second affected sibling had milder clinical presentation compared to the first affected sibling.

August 15, 2013

Clinical and laboratory features of temporary brittle bone disease

Colin R. Paterson, Elizabeth A. Monk

Page range: 37-45

Abstract

Temporary brittle bone disease has been described since 1990. It is a syndrome characterised by multiple unexplained fractures in early childhood. There is growing evidence that it has natural causes and does not represent inflicted trauma. We report the clinical and laboratory features of 104 patients investigated personally between 1985 and 2000. These patients had in aggregate 976 fractures or fracture-like lesions. Our patients included disproportionate numbers of infants born preterm or as a result of multiple pregnancy. The fractures were mainly identified in the first 6 months of life and entirely within the first year of life. Most fractures were asymptomatic, particularly the many rib fractures and metaphyseal lesions. Few patients had evidence of bruising at presentation; none had clinical evidence of inflicted injury commensurate with the fractures found. In 22 patients the fractures were found in the course of investigation for unrelated symptoms. In several cases fractures took place while the children were in hospital. Unexplained bruising and sub-conjunctival haemorrhages also occurred in hospital, suggesting collagen defects. Hernias were recorded; in most these resolved spontaneously, again suggesting transient collagen defects. Among the unexplained symptoms of the patients was a history of vomiting, often projectile vomiting. Some patients had unusually blue or grey sclerae for the child’s age. Many patients had abnormally large anterior fontanelles. Laboratory findings included anaemia, neutropenia and an exceptionally high serum alkaline phosphatase. Our findings reinforce the view that children with temporary brittle bone disease have a distinctive and identifiable syndrome which probably includes osteopathy of prematurity. These patients do not have osteogenesis imperfecta and are not the victims of non-accidental injury. While the causes of this syndrome remain uncertain, its distinctive features should now be more readily recognised.

August 17, 2013

Age of thelarche and menarche in contemporary US females: a cross-sectional analysis

Susanne M. Cabrera, George M. Bright, James W. Frane, Sandra L. Blethen, Peter A. Lee

Page range: 47-51

Abstract

Aim: A recent secular trend towards earlier thelarche has been suggested. The aim of this study is to examine normative ages of thelarche and menarche in contemporary US females. Methods : Trained physicians documented Tanner breast stage by observation in a cross-sectional cohort. Age of menarche was self-reported. The subjects were healthy female children and adolescents. The mean age of thelarche was determined by probit analysis and the mean age of menarche was determined by using a normal time-to-event model. Results: Mean age of thelarche was 9.7 years among 610 females aged 3.0–17.9 years (70% non-Hispanic Caucasian (NHC), 14% African-Americans, 7% Hispanic, 9% “other”). The mean age of menarche was 12.8 years for NHC, with African-Americans having menarche 0.6 years earlier. Conclusions: Thelarche occurred earlier than recently reported, while age of menarche remained unchanged, this supported a persistent secular trend towards earlier thelarche but stable age of menarche. This suggests that the observed thelarche is gonadotropin-independent or the tempo of pubertal advancement has slowed.

August 14, 2013

Teriparatide (rhPTH) treatment in children with syndromic hypoparathyroidism

Patrizia Matarazzo, Gerdi Tuli, Ludovica Fiore, Alessandro Mussa, Francesca Feyles, Valentina Peiretti, Roberto Lala

Page range: 53-59

Abstract

Background: Subcutaneous recombinant human parathormone [rhPTH (1–34)] has been introduced for hypoparathyroidism treatment, allowing avoidance of vitamin D and calcium side effects. Objective: Our objective was to evaluate rhPTH (1–34) safety and efficacy in pediatric patients with genetically proved syndromic hypoparathyroidism. Methods: The study was a 2.5-year self-controlled trial on six pediatric patients (four males, two females, age 9.8±5.1 years) with syndromic hypoparathyroidism including three with autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome, two with DiGeorge syndrome, and one with hypoparathyroidism-deafness-renal dysplasia syndrome. We compared patients’ clinical and biochemical outcome of conventional treatment based on oral administration of calcium (1–1.5 g/day in three doses) plus oral calcitriol (6.5–33 ng/kg per day in two to three doses) with the outcome obtained with rhPTH (1–34) (teriparatide, 12.5 μg bid). Therapy shift was conducted introducing rhPTH (1–34) while progressively withdrawing calcium and vitamin D. Blood calcium, phosphorus, alkaline phosphatase, and urinary calcium-to-creatinine ratio (mg/mg) before and during rhPTH therapy were compared. Results: rhPTH treatment allowed complete calcium and vitamin D withdrawal in two patients, calcium withdrawal in three and reduction of vitamin D dose in two. During rhPTH (1–34), mean blood calcium, phosphorus, and alkaline phosphatase were not significantly modified, whereas significant reduction of the calciuria-to-creatininuria ratio (0.55±0.31 vs. 0.1±0.1, p=0.02) was obtained. The number of tetanic episodes was reduced in four patients during teriparatide treatment compared to conventional treatment. Conclusion: In children with syndromic hypoparathyroidism, substitutive treatment with rhPTH (1–34) maintains adequate blood calcium levels and allows prompt normalization of urinary calcium excretion, through direct action on the kidney and through calcium and vitamin D therapy layoff.

August 14, 2013

Retinol and retinyl palmitate in fetal mice liver: sexual dimorphism

Olga Carvalho, Carlos Gonçalves

Page range: 61-67

Abstract

We determined retinoids liver content in male and female mice fetuses to study a possible sex difference during prenatal development, and to ascertain if vitamin A metabolism is similar in both sexes. The study was performed between developmental days E15-E19, and the fetuses were collected from two main groups: control (no manipulation) and vitamin A (administration of vitamin A on developmental day E14). Each group was subdivided by sex and retinoids were analyzed by high performance liquid chromatography (HPLC). The control group did not have any retinol in the liver of both sexes. Fetuses from the vitamin A group began to accumulate retinol on day E16, until E19 and sexual dimorphism was exhibited. Retinyl palmitate content in the control group showed sexual dimorphism on some developmental days, and in the vitamin A group these differences were more significant. In conclusion, our study showed sexual dimorphism in the retinoids liver content during mice development and evidences a sex difference in vitamin A metabolism, with different capacities to store and metabolize retinoids.

August 20, 2013

Skeletal maturation and predicted adult height in children with premature adrenarche

Shilpa Gurnurkar, Kristopher L. Arheart, Sarah E. Messiah, Aimee Mankodi, Adriana Carrillo

Page range: 69-74

Abstract

Objective: Premature adrenarche (PA) may be associated with obesity and advanced bone age. Our objective was to determine if children with PA had a predicted adult height less than target height. Methods: A retrospective chart review identified 100 children originating predominantly from South and Central America and the Caribbean region previously diagnosed with PA from one pediatric endocrinology clinic. Results: The majority (89.2%) of the sample had advanced bone age, while 43.4% were obese and 41.8% had a predicted height below target. There was a significant correlation between body mass index Z-score and bone age advancement among boys (r=0.67, p<0.001). The majority (72.7%) of those with a predicted height below target had a bone age advancement of two standard deviations or more. Conclusions: These findings suggest that PA and obesity are associated with rapid skeletal maturation and that significant bone age advancement in PA is associated with a sub-optimal adult height.

August 10, 2013

Homozygosity for a DTDST mutation in a child with multiple epiphyseal dysplasia

Dong Wang, Jie Qin, Chenguang Zhao, Xijing He

Page range: 75-80

Abstract

Background: Multiple epiphyseal dysplasia (MED) is one of the common hereditary osteochondrodysplasias. Mutations in diastrophic dysplasia sulfate transporter gene ( DTDST ) result in recessive MED. Objective: To investigate the possible gene mutation in a recessive MED patient. Subjects: A boy with typical clinical features of recessive MED and his parents. Methods: Clinical and radiological evaluations, DTDST gene sequence analysis, and sulfate uptake assay were performed on the patient and his parents. Results: The patient showed typical symptoms of recessive MED. The radiological evaluation confirmed dysplasia in multiple epiphysis of the patient, while his parents did not show the similar clinical and radiological features. Gene sequence showed the patient was homozygous of A2092T (T689S) mutation, while his parents were both of heterozygous of the same mutation. No such mutation in DTDST gene was found in 81 normal control individuals. The patient showed reduced sulfate uptake ability in dermal fibroblast compared with his parents and normal controls. Conclusion: The homozygous A2092T (T689S) mutation could be one of the mutations in the DTDST gene causing MED.

September 13, 2013

Body composition in young patients with galactose metabolic disorders: a preliminary report

Artemis Doulgeraki, Ioannis Monopolis, Domna Deligianni, Maria Kalogerakou, Kleopatra H. Schulpis

Page range: 81-86

Abstract

Aim: Body composition evaluation in patients with galactosemia and its variants. Methods: The body composition of young subjects with galactose metabolic disorders was analyzed with dual X-ray absorptiometry. The subjects were divided into the classic galactosemia (CG; n=14) group and the group with other galactose metabolic disorders (OGMD, e.g., epimerase deficiency; n=8). Results: In both groups, bone strength and bone mineral density Z-scores were normal. However, CG patients appeared sarcopenic (median muscle mass Z-score=–1.93), whereas OGMD subjects had low-normal muscle mass. In addition, approximately half of all patients were overweight. In CG patients, bone mass was strongly correlated to muscle mass (r=0.81), whereas in OGMD patients it was positively correlated to body mass index (r=0.78). Conclusions: An imbalance between muscle and fat mass, especially in patients with classic galactosemia, was observed. Given the observed strong correlation between bone and muscle mass, more effective lifestyle counseling is needed.

August 14, 2013

Detection of vascular risk markers in children and adolescents with type 1 diabetes

Heves Kırmızıbekmez, Ayla Güven, Metin Yıldız, Fatma Dursun, Nurcan Cebeci, Suna Hancili

Page range: 87-92

Abstract

Objectives: Type 1 diabetes is a chronic disease that causes persistent vascular injury. This study investigates the benefits of surrogate markers in early detection of vascular injury in children and adolescents with type 1 diabetes. Methods: Eighty-four patients (35 male, 49 female) with type 1 diabetes for 5 or more years were included. Serum lipid profile, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) (Lpa) and homocystein, were investigated. Patients were divided into two groups according to the duration of diabetes. Patients with and without microvascular complications were also compared. Results: Microvascular complications were present in 14 out of 48 patients in group-1 (29.1%; duration of diabetes: 5–10 years) and in 7 out of 36 patients in group-2 (19.4%; duration of diabetes: >10 years). Serum homocystein, Lpa, PAI-1 and serum lipids were not correlated with the duration of diabetes. Significantly increased triglyceride (TG) and HbA1C levels were associated with the presence of microvascular complications. Conclusion: Providing good glycemic control is very important for preventing vascular injury in children and adolescents with type 1 diabetes. It seems that traditional vascular surrogate markers like LDL/HDL ratio, triglycerides and HbA1C level correspond more to microvascular complications than newly defined surrogate markers that are not commonly available.

September 13, 2013

X-linked recessive nephrogenic diabetes insipidus: a clinico-genetic study

Che Ry Hong, Hee Gyung Kang, Hyun Jin Choi, Min Hyun Cho, Jung Won Lee, Ju Hyung Kang, Hye Won Park, Ja Wook Koo, Tae-Sun Ha, Su-Yung Kim, Hae Il Cheong

Page range: 93-99

Abstract

A retrospective genotype and phenotype analysis of X-linked congenital nephrogenic diabetes insipidus (NDI) was conducted on a nationwide cohort of 25 (24 male, 1 female) Korean children with AVPR2 gene mutations, comparing non-truncating and truncating mutations. In an analysis of male patients, the median age at diagnosis was 0.9 years old. At a median follow-up of 5.4 years, urinary tract dilatations were evident in 62% of patients and their median glomerular filtration rate was 72 mL/min/1.73 m 2 . Weights and heights were under the 3rd percentile in 22% and 33% of patients, respectively. One patient had low intelligence quotient and another developed end-stage renal disease. No statistically significant genotype-phenotype correlation was found between non-truncating and truncating mutations. One patient was female; she was analyzed separately because inactivation and mosaicism of the X chromosome may influence clinical manifestations in female patients. Current unsatisfactory long-term outcome of congenital NDI necessitates a novel therapeutic strategy.

September 20, 2013

Factors influencing neonatal thyroid-stimulating hormone concentrations as a measure of population iodine status

Helen Clapin, Barry D. Lewis, Lawrence Greed, Hugh Dawkins, Peter O’Leary

Page range: 101-106

Abstract

Background: The World Health Organization (WHO) has recommended measurement of neonatal thyroid-stimulating hormone (TSH) as a marker of population iodine status. A population is considered iodine sufficient when <3% of neonatal blood samples collected 3–4 days after birth have TSH concentrations >5 mIU/L. However, changes in technology and clinical practices have opened the WHO criteria to various interpretations. Aim: This study aimed to investigate the effects of time of sampling, weight, and sex on neonatal TSH concentrations by analyzing neonatal TSH data, based on the WHO criteria for population iodine sufficiency. Methods: We analyzed the Western Australian (WA) Newborn Screening Program records for 198,826 babies born in WA between 2005 and 2011, to determine the relationship between neonatal TSH concentrations and time of sampling, weight, and sex. Results: The proportion of TSH results above the WHO cut-off was higher for samples collected 48–72 h after birth rather than later, for males, for birth weights below 2500 g, and when a cut-off of 5.0 mIU/L was used. Conclusion: Following changes in newborn screening protocols and earlier collection of blood samples, the WHO criteria appear inappropriate. We recommend that WHO revise current guidelines regarding use of neonatal TSH for monitoring population iodine status.

September 11, 2013

Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study

Vincenzo Salpietro, Kshitij Mankad, Maria Kinali, Ashok Adams, Mariella Valenzise, Gaetano Tortorella, Eloisa Gitto, Agata Polizzi, Valeria Chirico, Francesco Nicita, Emanuele David, Anna Claudia Romeo, Carlo Attilio Squeri, Salvatore Savasta, Gian Luigi Marseglia, Teresa Arrigo, Conrad Earl Johanson, Martino Ruggieri

Page range: 107-115

Abstract

Aim: To unravel the potential idiopathic intracranial hypertension (IIH) endocrine-metabolic comorbidities by studying the natural (and targeted drug-modified) history of disease in children. IIH is a disorder of unclear pathophysiology, characterized by raised intracranial pressure without hydrocephalus or space-occupying lesion coupled with normal cerebrospinal fluid (CSF) composition. Methods: Retrospective study (years 2001–2010) of clinical records and images and prospective follow-up (years 2010–2013) in 15 children (11 girls, 4 boys; aged 5–16 years) diagnosed previously as “IIH”, according to the criteria for pediatric IIH proposed by Rangwala, at four university pediatric centers in northern, central, and southern Italy. Results: We identified six potential endocrine-metabolic comorbidities including, weight gain and obesity (n=5), recombinant growth hormone therapy (n=3), obesity and metabolic syndrome (n=1), secondary hyperaldosteronism (n=1), hypervitaminosis A (n=1), and corticosteroid therapy (n=1). Response to etiologically targeted treatments (e.g., spironolactone, octreotide) was documented. Conclusions: IIH is a protean syndrome caused by various potential (risk and) associative factors. Several conditions could influence the pressure regulation of CSF. An endocrine-metabolic altered homeostasis could be suggested in some IIH patients, and in this context, etiologically targeted therapies (spironolactone) should be considered

Patient reports

August 10, 2013

Hypothalamic hamartoma associated with central precocious puberty and growth hormone deficiency

Isabelle Rousseau-Nepton, Sagi Kaduri, Natasha Garfield, Preetha Krishnamoorthy

Page range: 117-121

Abstract

Hypothalamic hamartomas (HHs) are tumors generally associated with isolated central precocious puberty (CPP). To our knowledge, we report a unique case of a girl with HH associated with CPP and growth hormone deficiency. This case highlights the complex interaction between HHs and the hypothalamic-pituitary-gonadal axis. It also emphasizes the value of close follow-up of growth velocity in these patients even after treatment of the CPP.

August 14, 2013

A pediatric patient with Cushing syndrome caused by ectopic ACTH syndrome and concomitant pituitary incidentalomas

Alyse S. Goldberg, Robert Stein, Neil H. Merritt, Richard Inculet, Stan Van Uum

Page range: 123-128

Abstract

Ectopic ACTH syndrome is a rare but important cause of pediatric Cushing syndrome, for which management by a multidisciplinary team is required. Although diagnostic evaluation is similar to that in adults, the variation in epidemiology may sway investigations, leading to inappropriate and/or incomplete diagnostic interventions. We present a case of 15-year-old girl with symptoms of severe ACTH-dependent Cushing syndrome and two pituitary adenomas. The ectopic source of ACTH production was confirmed after petrosal venous sampling was performed. Diagnostics and perioperative management of a pulmonary carcinoid tumor producing ectopic ACTH is reviewed. In pediatric patients, as in adult patients, a pituitary lesion <6 mm on MRI is not sufficient confirmation of Cushing’s disease, and appropriate diagnostic work-up should be performed to assess the source of the ACTH overproduction.

July 11, 2013

A novel genetic mutation in a Portuguese family with GCK-MODY

Cláudia Almeida, Sónia Regina Silva, Elsa Garcia, Ana Luísa Leite, Andreia Teles, Rosa Arménia Campos

Page range: 129-133

Abstract

Introduction: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous form of diabetes mellitus, with autosomal dominant inheritance. It accounts for 2%–5% of all diabetes cases. Glucokinase-MODY is the second most frequent form, which has been shown to be the result of mutations in the glucokinase ( GCK ) gene. It mostly presents with mild hyperglycemia, and, usually, no diabetes-related complications occur. Case report: A 9-year-old female was admitted to the Endocrine Clinic to study her fasting hyperglycemia. Despite her obesity (body mass index 28 kg/m 2 ), her physical examination had no other abnormalities. Blood tests showed a 6.3% hemoglobin A 1c , with normal standard oral glucose tolerance test result, normal insulin value and normal C-peptide level. Insulin autoantibodies and antibodies against glutamate decarboxylase were negative. She began metformin and adequate diet. She had a strongly positive family history for diabetes. The patient’s mother, uncle, grandfather, great-aunt and great-grandfather on her mother’s side were diagnosed with diabetes. Complete sequencing of the GCK gene, carried out in the patient, identified a novel mutation c.1268T>A (p.Phe423Tyr) in exon 10 of the gene GCK in heterozygosity. Further studies revealed the same mutation in her mother and maternal grandfather. Conclusion: Finding the same mutation in three different generations of diabetic patients, in the same family, is highly suggestive of its pathogenicity. To the authors’ knowledge, this is the first time it is described in the literature. Correct molecular diagnosis of MODY predicts better the clinical course of diabetes and facilitates individualised management.

August 17, 2013

Permanent neonatal diabetes mellitus in monozygotic twins achieving low-dose sulfonylurea therapy

Kelly A. Hicks, Jake A. Kushner, Rubina Heptulla, J. Nina Ham

Page range: 135-138

Abstract

Although KCNJ11 mutations of the K ATP channel within the β cell are known to prevent insulin secretion and cause permanent neonatal diabetes mellitus, the genotype-phenotype correlation continues to be of clinical interest. We report the clinical outcomes in monozygotic twins with neonatal diabetes due to heterozygous mutations in KCNJ11 at R201H. The twins demonstrated concordant clinical outcomes after transitioning from insulin to oral sulfonylurea therapy at 4 months of age. Both twins remained on sulfonylurea therapy while achieving similar growth, development, and metabolic goals. They exhibit marked sensitivity to sulfonylurea therapy with current dosing at 0.05 and 0.06 mg/kg per day at age 5 years which deviates from the approximate maintenance dose of 0.4 mg/kg per day at the time of transition and subsequent follow-up. Metabolic control provided by low-dose sulfonylurea therapy is likely due to early age at transition from insulin to sulfonylurea therapy and possible preservation of endogenous insulin secretion.

August 10, 2013

Hypocalcemia in a paediatric case: from the clinical features to diagnosis

José Luis Gómez, Jerónimo Javier Momblán, María Mercedes Ibáñez, María José Pérez, María Isabel Garzón, Gema Martínez, Mercedes Alcalde

Page range: 139-142

Abstract

Pseudohypoparathyroidism refers to end-organ resistance that primarily impairs the renal actions of parathyroid hormone (PTH), a key regulator of calcium homeostasis. Its diagnosis is complex because of the multiple variants of this entity, and more so because intravenous PTH is not available for the Ellsworth-Howard test. We report a symptomatic paediatric case of hypocalcaemia, the clinical features of which, and the course after treatment, suggest that it is most probably a case of pseudohypoparathyroidism type Ib.

August 10, 2013

A rare case of osteogenesis imperfecta combined with complete tooth loss

Yanqin Lu, Fei Zhao, Xiuzhi Ren, Zhiliang Li, Xiaomeng Yang, Jinxiang Han

Page range: 143-147

Abstract

Osteogenesis imperfecta (OI) is a heritable disorder of the connective tissue characterized by blue sclerae, osteoporosis and bone fragility. Dentinogenesis imperfecta type I is commonly seen in OI patients, but other dental impairments, such as tooth agenesis or complete tooth loss, are rarely reported for these patients. Here, we report the case of a 37-year-old female Chinese OI patient who experienced complete tooth loss before puberty. The patient has a family history of OI and her father has a history of tooth loss. She showed obvious OI phenotypes, including a dwarfed stature, blue sclerae, scoliosis, pigeon chest and a history of fractures. Tooth loss began at the age of 6 years and continued until complete tooth loss at 20 years; this occurred in the absence of dental decay, gum disease, accidents or drug usage. Radiological studies revealed osteoporosis of the lower limbs and an underdeveloped scapula. Type I collagen gene analysis identified a known c.2314G>A (p.Gly772Ser) substitution in the COL1A2 gene, which we suggest affects the interaction between type I collagen and extracellular matrix proteins, including cartilage oligomeric matrix protein, phosphophoryn and SPARC (secreted protein acidic and rich in cysteine). In silico prediction indicated a relatively mild effect of the mutation, so it is conceivable that the severity of the clinical phenotype may result from additional mutations in candidate genes responsible for abnormal dental phenotypes in this family. To our knowledge, this is the first report of an OI patient with a phenotype of complete tooth loss at a young age.

August 10, 2013

Iatrogenic acute pancreatitis due to hypercalcemia in a child with pseudohypoparathyroidism

Francesca Feyles, Alessandro Mussa, Valentina Peiretti, Daniele Tessaris, Arianna Santanera, Andrea Corrias, Luisa de Sanctis, Luigi Calvo

Page range: 149-152

Abstract

Pancreatitis due to hypercalcemia is very rare in children, and its pathogenetic role is still debated. The following report describes a case of acute pancreatitis secondary to hypercalcemia in a 6-year-old boy with pseudohypoparathyroidism treated with calcium and vitamin D. Pseudohypoparathyroidism is characterized by parathormone (PTH) resistance, high PTH levels and hypocalcemia which need to be corrected with calcium and vitamin D supplementation. The patient was admitted for severe abdominal pain and vomiting associated with high plasma amylase, lipase and calcium levels. Hypercalcemia due to vitamin D and calcium overtreatment was probably responsible for the acute pancreatitis in this case. High serum calcium levels seem to sensitize patients to pancreatitis, even if the mechanism through which it happens is not completely understood. Moreover, the importance of concomitant predisposing factors, either acquired or especially genetic, needs to be further defined. Even though a rare occurance in childhood, hypercalcemia should be considered as a cause of pancreatitis and it should be examined together with the other etiologies that may contribute to the development of this disease.

September 20, 2013

Clinical expression of familial Williams-Beuren syndrome in a Turkish family

Mesut Parlak, Banu Güzel Nur, Ercan Mıhçı, Erdem Durmaz, Sibel Berker Karaüzüm, Sema Akcurin, İffet Bircan

Page range: 153-158

Abstract

Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by distinctive facial features, intellectual disability with a typical neurobehavioral profile, cardiovascular anomalies, and occasional infantile hypercalcemia. Majority of cases occur sporadically, and only a few cases of familial WBS have been reported. Although pre- and post-natal growth retardation is a common clinical feature of the syndrome, growth hormone deficiency is detected only in a few patients. To our knowledge, there has only been one report about familial Williams-Beuren syndrome in the Turkish population. Here, we report on the three molecular cytogenetically confirmed familial Williams-Beuren syndromes detected in a family with familial short stature. The father, daughter, and son analyzed with clinical and laboratory findings, and reasons of the short stature in Williams-Beuren syndrome are discussed through the literature.

August 14, 2013

The first report of cabergoline-induced immune hemolytic anemia in an adolescent with prolactinoma

Fatih Gürbüz, Begül Yağcı-Küpeli, Yılmaz Kör, Bilgin Yüksel, Suzan Zorludemir, Berrak Bilginer Gürbüz, Serhan Küpeli

Page range: 159-163

Abstract

Prolactinomas are common pituitary tumors that can cause gonadal dysfunction and infertility related to hyperprolactinemia. Dopamine agonists are the first-line treatment in these patients. Cabergoline leads to significant reduction in serum prolactin levels and tumor size in patients with prolactinoma. Dopamine agonists have been associated with adverse effects such as nausea, vomiting and psychosis. We report here a case with cabergoline-induced immune hemolytic anemia. The patient had cabergoline treatment history for prolactinoma and presented with weakness, fatigue, nausea, and paleness. Laboratory findings revealed severe anemia-related immune hemolysis. There were no causes identified to explain hemolytic anemia except cabergoline. Therefore, cabergoline therapy was stopped and subsequently hemolytic anemia resolved and did not occur again. This is the first reported pediatric case with prolactinoma and cabergoline-induced hemolytic anemia. Clinicians should be watchful for this rare side effect induced by cabergoline.

August 15, 2013

Low-level hyperinsulinism with hypoglycemic spells in an infant with mosaic Turner syndrome and mild Kabuki-like phenotype: a case report and review of the literature

Vera Pietzner, Johannes F.W. Weigel, Dorothea Wand, Andreas Merkenschlager, Matthias K. Bernhard

Page range: 165-170

Abstract

Background: Impaired glucose tolerance and type 2 diabetes are well-known features in patients with Turner syndrome. To the best of our knowledge, there is only one reported case of hyperinsulinemic hypoglycemia associated with a complex mosaic Turner syndrome available in the current literature. Patient: We report on the case of a 13-month-old girl with a complex mosaic Turner genotype and mild hyperinsulinemic hypoglycemia responsive to diazoxide therapy. Results: Cytogenetic analyses showed two or possibly three cell lines. Sixty percent of the cell lines had a 45,X genotype and the rest had 46,XX with a marker ring chromosome. Diagnosis of a mosaic Turner syndrome and mild Kabuki-like phenotype was confirmed. Conclusions: Despite the rareness of this case, clinicians should be aware of the possibility of hyperinsulinemic hypoglycemia in patients with Turner syndrome to prevent further brain damage caused by hypoglycemic episodes and seizures. Although the mechanism leading to hyperinsulinism in this condition is still unknown, the present report discusses this rare presentation and gives an overview on the current literature regarding this case.

September 11, 2013

Multiple cutaneous hemangiomas in a patient with combined pituitary hormone deficiency

Ayca Aykut, Samim Ozen, Damla Gokşen Sımsek, Huseyin Onay, Ozgur Cogulu, Sukran Darcan, Ferda Ozkinay

Page range: 171-174

Abstract

Combined pituitary hormone deficiency (CPHD) refers to a rare heterogeneous group of conditions in which there is a deficiency in at least two anterior pituitary hormones. Patients with POU1F1 mutations show a combined pituitary deficiency with low or absent levels of growth hormone, prolactin, and thyroid-stimulating hormone. In this study, a 7-month-old girl with a CPHD is presented. She had facial dysmorphologic features, hypertrichosis, and hypotonia. Additionally, she also presented with multiple cutaneous hemangioma that until now has not been reported in association with this disorder.

September 13, 2013

Premature thelarche related to fennel tea consumption?

Deniz Okdemir, Nihal Hatipoglu, Selim Kurtoglu, Leyla Akın, Mustafa Kendirci

Page range: 175-179

Abstract

Background: Isolated premature thelarche is the breast development in the absence of other secondary sex characteristics in prepubertal girls. Fennel is a plant which contains a phytoestrogen called anethole as an active ingredient. Case: Here, we report a case of a 12-month-old girl who showed breast development that became apparent in the last 3 months. Her medical history revealed that she was given two to three teaspoons of fennel tea by her mother every day for restlessness for the last 6 months. Isolated premature thelarche was diagnosed based on physical and laboratory findings. On follow-up, after cessation of fennel consumption, the breast development of the patient regressed gradually and became normal by the end of 1 year. Conclusion: Reporting this case, we want to emphasize the importance of awareness of fennel tea, a commonly used plant in babies, as a preventable cause of premature thelarche.

September 13, 2013

A novel insertion in the FOXL2 gene in a Chilean patient with blepharophimosis ptosis epicanthus inversus syndrome type I

Alejandro Martinez-Aguayo, Helena Poggi, Andreina Cattani, Marcela Molina, Eliana Romeo, Marcela Lagos

Page range: 181-184

Abstract

Objective: A novel insertion in the forkhead transcription factor 2 ( FOXL2) was identified in a Chilean patient with blepharophimosis, ptosis, and epicanthus inversus syndrome associated with premature ovarian failure (BPES type I). A clinical and molecular characterization of a patient with BPES type I was performed. Method: We present a 16-year-old adolescent girl with surgically treated blepharophimosis, ptosis, and epicanthus inversus that was associated with delayed puberty and secondary amenorrhea at the age of 15, indicators that suggested that the patient had BPES type I. The FOXL2 gene was analyzed by sequencing its coding region. Results: The sequence analysis of the FOXL2 gene revealed a novel heterozygous mutation: an 11 bp duplication (c.901_911dup11) that was predicted to encode a truncated protein (p.Pro305Argfs*54 ) . Conclusions: A novel out-of-frame duplication following the polyalanine domain in the FOXL2 gene was identified in a Chilean patient with BPES type I. This study characterized the molecular alterations in FOXL2 and confirmed the diagnosis, thereby providing information to allow for improved genetic counseling for the patient and her family.

September 13, 2013

Zellweger syndrome: prenatal and postnatal growth failure with epiphyseal stippling

Suresh Kumar, Renu Suthar, Sheetal Sharda, Inusha Panigrahi, Ram Kumar Marwaha

Page range: 185-188

Abstract

We present a 2-month-old male affected by Zellweger syndrome, a rare peroxisomal disorder. The diagnosis was supported by clinical and radiological findings and established by biochemical tests. The characteristic radiological features included anomalous ossification (epiphyseal stippling). We also discuss main differential diagnoses of epiphyseal stippling and a brief literature review.

September 20, 2013

Marine-Lenhart syndrome in a young girl

Yaşar Şen, Emine Ayça Cimbek, Sevil Arı Yuca, Gonca Kara Gedik, Oktay Sarı

Page range: 189-191

Abstract

Graves’ disease is the most common reason of hyperthyroidism in children. Graves’ disease with accompanying functioning nodules is defined as Marine-Lenhart syndrome. This syndrome has not been described in children before. Here, a 15-year-old girl with Graves’ disease and a coexisting cold nodule is presented. A thyroid scan showed diffuse uptake of Tc-99m pertechnatate in both lobes and decreased uptake in accordance with the left lobe nodule. The nodule was histologically diagnosed as benign. The patient was diagnosed with type 1 diabetes mellitus and polyglandular autoimmune syndrome during clinical follow-up. The differential diagnoses of Graves’ disease with coexisting nodules should include the Marine-Lenhart syndrome. Treatment options should be determined taking this rare condition into account.

August 15, 2013

Novel AQP2 mutation causing congenital nephrogenic diabetes insipidus: challenges in management during infancy

Rottanat Rugpolmuang, Asma Deeb, Yousef Hassan, Tawatchai Deekajorndech, Vorasuk Shotelersuk, Taninee Sahakitrungruang

Page range: 193-197

Abstract

Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, mostly caused by AVPR2 mutations. Less than 10% of cases are due to mutations in the aquaporin-2 ( AQP2 ) gene. Diagnosis and management of this condition remain challenging especially during infancy. Here, we report two unrelated patients, a 6-month-old Thai boy and a 5-year-old Emirati girl, with a history of failure to thrive, chronic fever, polydipsia, and polyuria presented in early infancy. The results of water deprivation test were compatible with a diagnosis of NDI. The entire coding regions of the AVPR2 and AQP2 gene were amplified by polymerase chain reaction and sequenced. Patient 1 was homozygous for a novel missense AQP2 mutation p.G96E, inherited from both parents. Patient 2 harbored a previously described homozygous p.T126M mutation in the AQP2 gene. Both patients were treated with a combination of thiazide diuretics and amiloride. Patient 1 developed paradoxical hyponatremia and severe dehydration 2 weeks after medical treatment began. In conclusion, we report a novel mutation of the AQP2 gene and highlight an important role of genetic testing for definite diagnosis. Vigilant monitoring of the fluid status and electrolytes after beginning the therapy is mandatory in infants with NDI.

Letter to the Editors

August 15, 2013

Mutational analysis of KISS1 and KISS1R in idiopathic central precocious puberty

Marina Krstevska-Konstantinova, Jana Jovanovska, Velibor B. Tasic, Luciana Ribeiro Montenegro, Daiane Beneduzzi, Leticia F.G. Silveira, Zoran S. Gucev

Page range: 199-201

Abstract

Aim: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood. The genetic activation of pubertal onset is thought to arise from the effect of multiple genes. Familial ICPP has been reported suggesting the existence of monogenic causes of ICPP. Kisspeptin and its receptor are found to be involved in gonadotropin-releasing hormone (GnRH) secretion and puberty onset. Mutations in their genes, KISS1 and KISSR , have been suggested to be causative for ICPP. Methods: ICPP was defined by pubertal onset before 8 years of age in girls, and a pubertal luteinizing hormone (LH) response to GnRH testing. Twenty-eight girls with ICPP were included in the study [age at diagnosis was 5.72±2.59, with a mean bone age advancement of 1.4 years (–0.1 to 2.8). Height at onset of therapy in SD score was 0.90±1.48 for age]. Luteinizing hormone-releasing hormone test was performed in all subjects, and all of them had a pubertal response (LH 20.35±32.37 mIU/mL; FSH 23.32±15.72 mIU/mL). The coding regions of KISS1 and KISS1R were sequenced. Results: No rare variants were detected in KISS1 or KISS1R in the 28 subjects with ICPP. Conclusions: We confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.

July 10, 2013

Carotid intima media thickness and echocardiography in risk stratification of obese adolescents with non-alcoholic fatty liver disease: what is the “right” approach?

Mehmet Emre Atabek

Page range: 203-204

September 11, 2013

Vitamin D and the heart: what is the truth?

Raffaella Mormile, Mario De Michele, Umberto Squarcia

Page range: 205-206

About this journal

Objective
The aim of the Journal of Pediatric Endocrinology and Metabolism (JPEM) is to diffuse speedily new medical information by publishing clinical investigations in pediatric endocrinology and basic research from all over the world. JPEM is the only international journal dedicated exclusively to endocrinology in the neonatal, pediatric and adolescent age groups. JPEM is a high-quality journal dedicated to pediatric endocrinology in its broadest sense, which is needed at this time of rapid expansion of the field of endocrinology. JPEM publishes Reviews, Original Research, Case Reports, Short Communications and Letters to the Editor (including comments on published papers). JPEM publishes supplements of proceedings and abstracts of pediatric endocrinology and diabetes society meetings.

Topics

Pediatric endocrinology
Pediatric diabetes
Inherited metabolic diseases

Article formats

Original Research, Reviews, Mini Reviews, Opinion Papers, Case Report, Short Communications, Letters to the Editor (including comments on published papers)