Band 26, Heft 5-6

Purpose of review: What controls puberty remains largely unknown, and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately, important developments have occurred in this field. Recent findings: The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that control the activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann syndrome, or with a normal sense of smell, termed normosmic idiopathic hypogonadotropic hypogonadism, has proven to be important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.

We report 20 infants aged between 1 month and 6 months found to have subdural bleeding and also multiple unexplained fractures in a pattern similar to that described earlier as temporary brittle bone disease. Child abuse seemed unlikely as a cause of the fractures as in no case was there clinical evidence of injury commensurate with the fracturing, as some patients had fractures while in hospital and as metaphyseal lesions, when present, were often symmetrical in distribution. Abuse seemed unlikely to have been the cause of the subdural bleeding in several patients; three had clear histories of accidental injury and five had evidence that the initial bleeding was likely to have taken place at birth. Abuse also seemed unlikely as the cause of the syndrome; the nine patients who were returned to their parents had no subsequent allegations of abuse with a mean follow-up period of 15.8 years. The finding of hypermobile joints in the parents of eight of the children is an additional pointer to a natural cause for this condition. The cause of this combination of fractures and subdural bleeding is not yet clear but it is important to be aware that it can result from natural disease.

Patients with glycogen storage disease type I (GSD-I) often have marked hyperlipidemia with abnormal lipoprotein profiles. This metabolic abnormality improves, but is not fully corrected, with dietary therapy; therefore, these patients may be at high risk for the development of atherosclerosis. A recently discussed cardiovascular risk factor, asymmetric dimethylarginine (ADMA), a naturally occuring product of asymmetric methylation of proteins, is an endogenous inhibitor of endothelial nitric oxide synthase. ADMA causes endothelial dysfunction, vasoconstriction, blood pressure elevation, atherosclerosis, and kidney disease progression. A high prevalence of elevated plasma ADMA levels is observed in adults with hypercholesterolemia, hypertension, chronic kidney disease, diabetes mellitus, peripheral arterial disease, coronary artery disease, preeclampsia, heart failure, liver disease, stroke, and many other clinical disorders. Therefore, we aimed to evaluate the endothelial function in patients with GSD-I by using ADMA levels. High-performance liquid chromatography – based method was used for measuring ADMA and L-arginine levels in plasma. The ADMA level was similar between children with GSD-I and the age-matched healthy control group (0.9±0.28 vs. 1.1±0.45 μmol/L; p=0.18). The L-arginine plasma levels in patients with GSD-I were found to be 55.7±41.3 and 91.6±50.2 μmol/L in healthy controls. The preservation of normal endothelial function may result from diminished platelet aggregation, increased levels of apolipoprotein E, decreased susceptibility of low-density lipoprotein to oxidation (possibly related to the altered lipoprotein fatty acid profile in GSD-I), and increased antioxidative defenses in plasma protecting against lipid peroxidation.

Background: Maple syrup urine disease (MSUD) is an inherited disorder caused by a deficiency of the mitochondrial branched-chain keto acid dehydrogenase complex. We investigated whether liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a more reliable and accurate method than MS/MS in the diagnosis and management of patients with MSUD in a Chinese population. Methods: A total of 370 dried blood spots (DBS) from healthy neonates, 44 DBS specimens from phenylketonuria neonates, and 38 DBS samples from 10 MSUD patients were retrospectively tested using the LC-MS/MS method. The results were compared with those obtained by the MS/MS method. Results: The reference intervals of branched-chain amino acids (BCAAs) and alloiosleucine (Allo-Ile) were estimated for both sexes. In classic MSUD patients, Allo-Ile was markedly elevated (average of 136 μmol/L, which was significantly higher than the normal value, <5 μmol/L). The averages of BCAAs were also markedly elevated continually during the treatment. Conclusions: The application of the LC-MS/MS method in the measurement of Allo-Ile and BCAAs in DBS is more useful for diagnosing and managing classic MSUD than the MS/MS method.

Aim: Uncoupling protein (UCP) genes, which may contribute to energy metabolism in mitochondria, may be involved in the pathogenesis of obesity. We analyzed the differences in energy expenditure between single nucleotide polymorphisms (SNPs) UCP3 - 55C/T , UCP3 Y210Y , and UCP2 A55V among Indonesian children. Methods: The study included 76 schoolchildren (36 obese and 40 healthy; mean age, 12.8 years) in Semarang, Indonesia. Body composition was measured by bioelectrical impedance analysis; resting energy expenditure (REE) by indirect calorimetry; physical activity by uniaxial accelerometer; and total energy expenditure (TEE) by the equations extrapolated from REE and physical activity. UCP3-55C/T , UCP3 Y210Y , and UCP2 A55V were examined by restriction length fragment polymorphism analysis. Results: The TEE of the subjects with the T/T genotype at UCP3-55C/T after adjusting for fat-free mass (63.2±7.2 kcal/kg/day) and T/T at UCP2 A55V (62.8±5.6 kcal/kg/day) was lower than that of the subjects with the C/C and C/T genotypes (p<0.05). The REE of the subjects with these T/T genotypes tended to be lower than that of the subjects with C/C and C/T (p≥0.05). No significant differences in REE or TEE were found between the UCP3 Y210Y genotypes. Conclusions: The subjects with the T/T genotypes of UCP3-55C/T or UCP2 A55V had lower TEE than those with other genotypes.

Background: Thyroid dysfunction is very common and is associated with neurodevelopmental impairments in preterm infants. Objectives: This study was conducted to determine the incidence and natural course of various thyroid dysfunctions and their impacts on neurodevelopmental outcomes among premature infants. Methods: A total of 177 infants were enrolled who were born at <34 weeks or whose birth weight was <1500 g and who underwent repeat thyroid function tests. We analyzed how various thyroid dysfunctions affected neurodevelopmental outcomes at 18 months of corrected age. Results: Thyroid dysfunction was noted in 88 infants. Hypothyroxinemia was observed in 23 infants, and their thyroid function was influenced by variable clinical factors. Free T4 levels were all normalized without thyroxine medication, and neurodevelopmental outcomes were not affected. In contrast, hyperthyrotropinemia was not associated with other clinical factors. Among 58 subjects who had hyperthyrotropinemia, only 31 infants showed normal thyroid-stimulating hormone (TSH) levels at follow-up tests. The remaining 27 infants had persistently high TSH levels, which significantly and poorly influenced the neurodevelopmental outcomes. Conclusions: Thyroid dysfunction is common among preterm infants. With the exception of persistent hyperthyrotropinemia, it generally does not affect neurodevelopmental outcomes. However, the beneficial effects of thyroid hormone therapy in patients with persistent hyperthyrotropinemia merits further study.

Background: The E23K variant of the KCNJ11 gene is possibly responsible for changes in insulin secretion during the fetal life. We tried to assess the influence of the E23K variant on birth weight and metabolic profile in prepubertal children born small for gestational age (SGA). Subjects: One hundred and twenty-three SGA and 132 born appropriate for gestational age (AGA) children were genotyped for the E23K variant. Lipids, glucose, and insulin concentrations during oral glucose tolerance test were assessed in 112 SGA prepubertal children. Results: There were no significant differences between the frequency of the E23K variant in SGA and AGA children. In SGA children with E23K, the mean birth weight was significantly higher than in the E23E group. Body mass index, glucose, insulin, and lipids were not different between the E23K, E23E, and K23K groups. Conclusions: The higher birth weight in SGA children with the E23K variant may be related to higher insulin concentrations in the fetal period. The E23K variant did not affect metabolic disorders in prepubertal SGA children.

Objective: In our study, the reference intervals of serum thyroid hormones were established in 247 hospitalized preterm infants from 28 to 36 weeks of gestation at 8–15 postnatal days. The thyroid hormones were serum triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), free thyroxine (FT4), and thyrotropin (TSH). Methods: Electrochemiluminescence immunoassay was used to examine the thyroid hormone levels of serum samples from 247 preterm infants, who were grouped on sampling by gestational age. SPSS 16.0 was used to calculate the population-based reference intervals, in comparison to the manufacturer’s suggested reference intervals. Results: Kruskal-Wallis H tests could not determine the difference in TSH levels among groups, which allowed us to develop a single interval for the study population. ANOVA determined the differences in T3, FT3, T4, and FT4 levels among groups, which allowed us to define reference intervals for preterm infants according to their gestational age. Conclusion: Developed reference intervals are useful for clinical diagnosis; however, there is a lack of consensus. These values could be used to assess the thyroid status of preterm infants and provide a foundation for clinical therapy. The results emphasized the importance of establishing gestational age-based reference intervals for the clinical laboratory.

Aim: To evaluate the clinical and biochemical findings of the children and adolescents with vitamin D deficiency and insufficiency in order to determine the clinical and biochemical presentation differences between age groups. Methods: This retrospective study included a review of medical reports of 543 patients (aged between 1–17 years) who were referred to our hospital between October 2011 and May 2012 with symptoms related to vitamin D deficiency or insufficiency. The patients were divided into four groups by age: 1–3 years (Group 1), 4–6 years (Group 2), 7–11 years (Group 3) and 12–17 years (Group 4). Patients diagnosed with vitamin D deficiency or insufficiency were evaluated as to their clinical and biochemical findings. Results: Gender distribution were not statistically different between the four groups. The mean ages of Groups 1–4 were 1.9±0.7, 5.1±0.9, 8.9±1.3, 13.1±1.1, respectively. Major complaints on admission were muscle weakness (91%), low weight gain (failure to thrive) (89%), head deformity (frontal bossing) (35.6%), bone deformity (enlargement of wrist and ankles) (29.7%) for Group 1. Muscle weakness (76%) and low weight gain (failure to thrive) (68%) for Group 2. Leg and chest pain were the major symptoms in Group 3 (57% and 28%, respectively) and in Group 4 (26% and 55%, respectively) as well as high rates of obesity (31% and 63%). The biochemical findings of vitamin D deficiency mostly appeared in the first group who developed vitamin D deficiency due to the lack of vitamin D supplementation. However, in older children, the majority of the patients had low 25 hydroxyvitamin D (25 OHD) values without evidence of biochemical findings of osteomalacia. Conclusion: Depending on the degree of deficiency and insufficiency, and the age of the patients, the clinical and biochemical findings varied widely. Children under the age of 3 who either never received vitamin D supplementation or who had been receiving supplementation that was stopped too early were at a greater risk for developing clinically and biochemically proved vitamin D deficiency. In older children, low vitamin D levels mostly resulted in subtle complaints without abnormal biochemical findings.

Objective: To develop a clinical risk scoring system for identifying adolescents with dysglycemia (prediabetes or diabetes) who need further confirmatory testing and to determine whether the addition of non-fasting tests would improve the prediction of dysglycemia. Study Design: A sample of 176 overweight and obese adolescents (10–17 years) had a history/physical exam, a 2-h oral glucose tolerance test, and non-fasting tests [hemoglobin A1c, 1-h glucose challenge test (GCT), and random glucose test] performed. Given the low number of children with diabetes, we created several risk scoring systems combining the clinical characteristics with non-fasting tests for identifying adolescents with dysglycemia and compared the test performance. Results: Sixty percent of participants were white and 32% were black; 39.2% had prediabetes and 1.1% had diabetes. A basic model including demographics, body mass index percentile, family history of diabetes, and acanthosis nigricans had reasonable test performance [area under the curve (AUC), 0.75; 95% confidence interval (95% CI), 0.68–0.82]. The addition of random glucose (AUC, 0.81; 95% CI, 0.75–0.87) or 1-h GCT (AUC, 0.82; 95% CI, 0.75–0.88) to the basic model significantly improved the predictive capacity, but the addition of hemoglobin A1c did not (AUC, 0.76; 95% CI, 0.68–0.83). The clinical score thresholds to consider for the basic plus random glucose model are total score cutoffs of 60 or 65 (sensitivity 86% and 65% and specificity 60% and 78%, respectively) and for the basic plus 1-h GCT model are total score cutoffs of 50 or 55 (sensitivity 87% and 73% and specificity 59% and 76%, respectively). Conclusions: Pending a validation in additional populations, a risk score combining the clinical characteristics with non-fasting test results may be a useful tool for identifying children with dysglycemia in the primary care setting.

Objective : To investigate the changes in thyroid function and morphology in overweight and obese school-aged children and adolescents in Chinese population. Methods: Altogether, 880 children and adolescents were enrolled in a cross-sectional survey in Anhui Province and we assessed thyroid function, thyroid ultrasound, metabolic indicators and high-sensitivity C-reactive protein (hs-CRP) levels in 781 subjects, which were divided into obesity (n=327), overweight (n=242), and normal-weight (n=212) groups. Overweight and obese subjects were further divided into four subgroups according to thyroid peroxidase antibody and ultrasound pattern to compare thyroid function and morphology with or without thyroid autoimmune evidence. Results: Thyroid-stimulating hormone (TSH) and free 3,5,3′-triiodothyronine (FT 3 ), as well as thyroid volume, were found to be positively associated with body mass index Z-score, waist/hip ratio, waist/height ratio and/or waist circumference (WC). Conversely, free thyroxine was negatively associated with WC. The detection rates of thyroid nodules among these groups were not significantly different (p=0.828). Among the four subgroups in 569 overweight or obese subjects, the changes in thyroid function and volume were more obvious in group D which showed no autoimmune evidence. The levels of hs-CRP were also higher in the overweight and obese groups with or without autoimmune evidence than in the normal-weight group (p<0.05). Conclusion: Thyroid function and morphology may be affected in obese and overweight children and adolescents with elevated TSH, FT 3 and thyroid volume. The detection rates of thyroid nodules may not be affected by obesity. Alterations in thyroid function and morphology cannot be completely explained by local autoimmune responses. Low-grade inflammation may be involved in the changes in thyroid function and morphology in obesity.

Background: Propionic acidaemia is a global, metabolic disease, highly prevalent in Kingdom of Saudi Arabia. It may produce an array of complications which significantly deteriorate the patient’s quality of life. Objectives: To find out the demographic characteristics and complications of patients with propionic acidemia. Methods: The records of diagnosed cases of propionic acidaemia were reviewed, retrospectively. Results: Of 24 patients, 16 (67%) were male. Consanguineous parents were 16 (67%). Ten (42%) patients had diseased siblings. Mean age at diagnosis was 0.13±0.27 year. Twenty-two (92%) patients had early onset and 2 (8%) had late onset disease. Eighteen (75%) patients had developmental delay, 11 (46%) had hypotonia, 3 (12%) had hypertonia, 13 (54%) had hyperreflexia and 12 (50%) had seizures. Two (8%) children each, had intracranial haemorrhage, spastic quadriplegia, hemiplegia and 1 (4%) had paraplegia. Cerebral atrophy and nasogastric/gastrotomy, tube feeding, each was found in 6 (25%) patients. Under nutrition was revealed in 20 (83%), short stature in 18 (75%), rickets in 1 (4%) and pancreatitis in 2 (8%) patients. During metabolic crisis, cerebral oedema and pancytopenia each were found in 4 (17%), hypoglycaemia in 6 (25%), hyperglycaemia in 2 (8%), hyperammonaemia in all 24 (100%) and metabolic acidosis in 20 (83%) cases. Conclusion: Propionic acidaemia is a rare hereditary disorder that has wide spectrum of neurological and other complications, which perhaps with early diagnosis and intervention may be preventable, more effectively.

Background/Aims: Some markers of inflammation have been found to be associated with cardiorespiratory fitness levels, but only few studies have studied this in overweight children. The aim of this study was to investigate associations between markers of inflammation and the fitness levels measured by peak oxygen consumption (VO 2peak and VO 2peak /kg) in boys with increased body mass index (BMI) and with normal BMI. Participants/Methods: Subjects were 38 boys with BMI above 85th percentile (OWB) and 38 boys with normal BMI (NWB) at the age of 10 to 11 years. Serum concentrations of IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFNγ, TNF-α, IL-1α, IL-1β, MCP-1, EGF, CRP and associations with measured cardiorespiratory fitness levels were studied. High-sensitive chips were used to measure 13 markers of inflammation. Results: Mean VO 2peak was significantly higher (2.1±0.3 vs. 1.8±0.3 L/min; p<0.05) and mean VO 2peak /kg significantly lower (33.7±4.7 vs. 48.9±6.4 mL/min/kg; p<0.05) in OWB than in NWB group. Out of 13 measured biochemical markers IL-6 correlated with VO 2peak /kg (r=–0.37; p<0.05) and TNF-α with VO 2peak (r=0.41; p<0.01) in OWB. BMI and IL-6 together explained 44.5% of the variability of VO 2peak /kg in the OWB group. Conclusions: Overweight boys had lower cardiorespiratory fitness level measured by VO 2peak /kg and this was negatively correlated with serum IL-6 level. Measurement of serum IL-6 level in overweight boys may help to identify subjects who need specific exercise formats to achieve maximal beneficial health effects and to reduce their risk for the development of type 2 diabetes and atherosclerosis later in life.

This is an attempt to establish the normal stretched penile length and prevalence of male genital anomalies in full-term neonates and whether they are influenced by prenatal parental exposure to endocrine-disrupting chemicals. A thousand newborns were included; their mothers were subjected to the following questionnaire: parents’ age, residence, occupation, contact with insecticides and pesticides, antenatal exposure to cigarette smoke or drugs, family history of genital anomalies, phytoestrogens intake and history of in vitro fertilization or infertility. Free testosterone was measured in 150 neonates in the first day of life. Mean penile length was 3.4±0.37 cm. A penile length <2.5 cm was considered micropenis. Prevalence of genital anomalies was 1.8% (hypospadias 83.33%). There was a higher rate of anomalies in those exposed to endocrine disruptors (EDs; 7.4%) than in the non-exposed (1.2%; p<0.0001; odds ratio 6, 95% confidence interval 2–16). Mean penile length showed a linear relationship with free testosterone and was lower in neonates exposed to EDs.

Aim: Vitamin D deficiency (VDD) among adolescents is a major health problem in India. The aim of this study was to assess the efficacy of therapeutic/loading doses of vitamin D supplementation on serum 25-hydroxy vitamin D (25OHD) levels in vitamin D deficient adolescents. Methods: A total of 482 out of the 511 subjects recruited for the study were divided into three groups, each group receiving 60,000 IU of vitamin D3 weekly for 4, 6 and 8 weeks followed by 600 IU daily for 12 weeks, respectively. Clinical evaluation was followed by estimation of biochemical markers and serum 25OHD levels. Results: VDD was observed in 94.8% of adolescents. All three vitamin D loading doses were equally efficacious in achieving vitamin D sufficiency >75 nmol/L (>30 ng/mL) in more than 90% subjects in the three groups. Mean 25OHD levels in groups 2 and 3 following maintenance therapy were 67.5±16.5 nmol/L (27.0±6.6 ng/mL) and 70.0±21.8 nmol/L (28.0±8.7 ng/mL), respectively. Conclusion: Supplementing 60,000 IU of vitamin D3 per week for 4–8 weeks, followed by 600 IU daily through fortified milk, is an effective strategy for achieving vitamin D sufficiency in Indian adolescents.

Background: Neonatal hypoglycemia is a common symptom in early infant life. The currently available literature identifies the risk factors but not the degree to which each factor lends itself to the development or severity of an ensuing hypoglycemia. Methods: A retrospective electronic chart review of near-term and term infants (>35 weeks’ gestation) admitted to a tertiary-level neonatal unit over 16 months was carried out from the initiation of electronic record keeping. Results: Ninety-five infants admitted with hypoglycemia to the unit were identified with complete records available. Fifty-eight percent of the infants were males, and the median gestation was 38 weeks. Twenty-two percent of the infants were premature, whereas 18% were macrosomic. Maternal diabetes was present in 27% infants. Comorbidities were common in this cohort, with approximately two-thirds of infants having multiple morbidities. The majority of which were jaundice and infection, whereas the minor ones were respiratory distress, initial lactic acidosis, feeding issues, and temperature instability. Conclusions: Neonatal hypoglycemia continues to be a significant morbidity in near-term and term infants. The presence of multiple morbidities is common in the setting of hypoglycemia and is the main determinant of the length of stay in the neonatal unit in this study population.

Background: Contrasting data exist regarding the relationship between thyroid-stimulating hormone (TSH) and obesity-related risk factors in children. In the present study, we investigated the association between TSH, free T4 (fT4) and cardiometabolic risk factors in euthyroid obese children and adolescents. Methods: A retrospective analysis of patient records was performed on data from 703 multi-ethnic obese children and adolescents who visited an obesity-outpatient clinic. We performed anthropometric measurements, an oral glucose tolerance test, and measured serum TSH, fT4 and lipid levels. Results: A positive association between TSH and the standard deviation score of the body mass index (BMI-Z) was found. After adjustment for ethnicity, sex, pubertal stage and BMI-Z, logistic regression analysis showed significant associations between TSH levels and impaired fasting glucose, impaired glucose tolerance, high total cholesterol, high low-density lipoprotein cholesterol and high triglycerides. No significant associations between fT4 levels and cardiometabolic risk factors were found in linear/logistic regression analysis. Conclusion: In our multi-ethnic cohort of euthyroid obese children and adolescents increasing TSH was associated with impaired glucose metabolism and dyslipidemia.

Aim: We aimed to study the influence of the fat mass and obesity-associated ( FTO ) gene on eating behavior in 412 obese Sardinian children and adolescents. Genome-wide association studies (GWAS) have identified several susceptibility loci for obesity. Among these, the polymorphisms in the intron 1 of the FTO gene has been found associated to weight gain and obesity in various populations. Methods : All obese patients were genotyped for the FTO single nucleotide polimorphysm (SNP) rs9939609. In all subjects we evaluated eating behavior using the Child Eating Behaviour Questionnaire (CEBQ). Results: We found no differences in eating behavior according to the genotype, either in the entire cohort, or when subjects were subdivided into four different age groups. Conclusions: FTO genotype is associated with body mass index but does not influence eating behavior in a selected cohort of obese children from the isolated genetic population of Sardinia.

Our study aimed to investigate: the prevalence of autoantibodies related to organ-specific disease; the prevalence of some autoimmune diseases (AID) in Egyptian Turner syndrome (TS) patients; and the association of autoimmunity with patients’ karyotypes. Eighty TS patients were subjected to history, auxological assessment and measurement of antithyroid peroxidase antibody (ATPOAb), antithyroglobulin antibody (ATGAb), anti-tissue transglutaminase IgA antibodies (ATTIgAAb), anti-glutamic acid decarboxylase-65 antibodies (GAD-65-Ab) and anti-adrenal cortex antibodies (AACAb). Of the 80 TS patients, 54 (67.5%) were seropositive for one or more autoantibodies. Thirty-five percent were positive for ATPOAb, 15% for ATGAb, 12.5% for ATTIgAAb, 3.75% for Anti-GAD-65Ab and 1.25% for AACAb. There was a non-significant association between the 45,X karyotype and overall prevalence of autoantibodies (p=0.20), while IsoXq was associated with increased prevalence of ATPOAb (p<0.01), ATGAb (p=0.01) and anti-GAD-65Ab (p=0.02). Thus, female TS patients face a high prevalence of autoimmunity and associated AID.

Patients with DAX-1 gene mutations on chromosome Xp21 usually present with adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Yet, neither correlation between the type of mutation and the age of onset of the disease nor mechanism of the mutation on puberty is fully understood. Here, we report a novel non-sense p.Gln208X mutation in the amino terminal domain of the DAX-1 gene observed in a large family with three boys presenting with adrenal manifestations at different ages. Furthermore, two boys developed spontaneous puberty that failed to progress at similar ages, whereas the other boy developed precocious puberty at 10 month of age. The unique structure of the DAX-1 gene may explain this phenotypic variability. However, more studies are needed to understand the role of the DAX-1 gene on development of the adrenal gland and hypothalamus-pituitary-gonadal axis.

Pseudohypoparathyroidism type Ia (PHP Ia) is a rare disease characterized by an elevated parathyroid hormone due to the resistance to its action in target tissues. We report a new GNAS mutation causing PHP Ia and an atypical early-onset primary hypothyroidism. A 3-year-old boy was diagnosed with obesity, delayed pyschomotor development, and round face. The laboratory evaluation at the age of 1 year showed primary hypothyroidism, hypocalcemia, hyperphosphatemia, elevated alkaline phosphatase, and parathyroid hormone. These data led to the diagnosis of PHP Ia. Molecular analysis revealed a novel missense mutation in GNAS exon 1 (TCG→CGC, Cys3→Arg) in both the child and his mother. Although previously reported cases described delayed subclinical hypothyroidism as the more common thyroid abnormality, we report a not previously described GNAS mutation associated with an atypical early-onset primary hypothyroidism. These observations broaden the clinical spectrum of PHP Ia and its associated mutations.

Background : Diabetic ketoacidosis (DKA) is one of the most common and harmful complications of type 1 diabetes in children. The neurologic morbidities, including seizure activity, motor/sensory deficit, and coma, can be seen secondary to cerebral edema, hemorrhage, or ischemia. Alpha-frequency is a normal 8–13 Hz physiologic electroencephalogram rhythm that is seen most prominently in the occipital region of awake people and is augmented by eye closure. In the comatose patient, alpha-rhythm is not usually seen. Alpha-frequency coma (AC) is a rare finding in comatose patients and is generally associated with a poor prognosis. Case report : We report an adolescent with severe DKA, intraparenchymal cerebral hemorrhage, and AC, who had a rapid resolution of the neurologic symptoms. Conclusions : Similar to other reported cases, our case suggests that the prognosis for patients with AC may not be always poor when it is associated with DKA.

A 3-year-old girl had global developmental delay with dysmorphic facies. In addition, she was found to have congenital hypothyroidism. In view of the associated dysmorphism, a karyotype analysis was done. It revealed a novel translocation mutation, 46XX t(1;14) (p22;q32). The association of this mutation with congenital hypothyroidism has been postulated in our case report. To the best of our knowledge, this mutation has never been described before in cases of congenital hypothyroidism.

The tricarboxylic acid (TCA) cycle represents the key enzymatic steps in cellular energy metabolism. Once the TCA cycle is impaired in case of inherited metabolic disorders, life-threatening episodes of metabolic decompensation and severe organ failure can arise. We present the case of a 6 ½-year-old girl with propionic acidaemia during an episode of acute life-threatening metabolic decompensation and severe lactic acidosis. Citric acid given as an oral formulation showed the potential to sustain the TCA cycle flux. This therapeutic approach may become a treatment option in a situation of acute metabolic crisis, possibly preventing severe disturbance of energy metabolism.

Osteopetrosis is a rare genetic disorder characterized by increased bone mineral density (BMD) due to osteoclast failure. T-cell immune regulator 1 (TCIRG1) plays crucial roles on osteoclast function, and its mutation causes autosomal recessive osteopetorosis. However, mutations in TCIRG1 have never been identified in autosomal dominant osteopetrosis (ADO). A 3-year-old boy was first presented to the clinic because of spontaneous radius and femur fractures. He has optic atrophy. The areal BMD at the lumbar spine was 1274 g/cm 2 (233% of normal). Laboratory tests revealed no remarkable abnormal findings, including anemia, except for extremely elevated serum tartrate-resistant acid phosphatase-5b (14,600 mU/dL). Radiographically, the skull base, pelvis, and vertebrae showed a focal sclerosis. Genetic analysis revealed a novel de novo heterozygous missense mutation (His242Arg). Taken together with the mutation, his mild clinical features were diagnosed as ADO. This case implies that TCIRG1 could become a genetic candidate for ADO in addition to malignant forms such as ARO.

Primary adrenal insufficiency, or Addison’s disease, is very rare in the pediatric population. The diagnosis of Addison’s disease is usually suspected in the presence of hyponatremia and hyperkalemia, or when adrenal crisis develops. Pediatricians often are unaware of other presenting symptoms of the disease. As a consequence, diagnosis is often delayed by months and even years. One of the presenting signs of adrenal insufficiency is hyperpigmentation. We present the diagnosis of Addison’s disease in an 11-year-old boy complaining of skin color changes that were misinterpreted as “progressive cyanosis”. When skin color changes occur in a child, pediatricians should think of hyperpigmentation as a presenting sign of adrenal insufficiency.

Hyperthyrotropinaemia [mildly elevated thyrotropin (TSH) with normal thyroxine (T4) levels] demands a full assessment, including clinical examination, thyroid imaging and, where indicated, molecular genetic investigations. A male infant, both of whose parents were on T4 treatment, was referred at age 57 days with mild but persistent TSH elevation (12.7 mU/L) and normal free T4 (19.6 pmol/L), following notification by the screening laboratory of a capillary TSH of 10.7 mU/L (reference range, 1.7–9.1 mU/L) on day 8. Assessment showed a venous free T4 level of 15 pmol/L, venous TSH of 20.9 mU/L, serum thyroglobulin of 63 μg/L (reference range, <50 μg/L), and negative thyroglobulin and thyroid peroxidase antibodies. Thyroid ultrasound showed a eutopic, slightly small gland with heterogeneous texture; however, there was no uptake on radioisotope scan. Molecular genetic studies demonstrated a novel missense heterozygous mutation in the TSH receptor ( TSHR ) gene (c.1169G>T;p.Cys390Phe) in the child, mother and maternal grandmother, but not in the father. The infant was treated with T4 but this was discontinued at age 3 years when repeat testing showed a free T4 of 16.7 pmol/L (reference range, 9–23 pmol/L) and TSH of 8.5 mU/L (reference range, 0.3–5.5 mU/L). A heterozygous TSHR mutation should be considered in the context of hyperthyrotropinaemia and reduced/absent uptake on radioisotope scan. Detection of this mutation has allowed our patient to discontinue T4 treatment for the moment, with a view to staying off treatment in the long-term.

We report on a patient who initially presented with delayed puberty and an absent uterus on imaging with ultrasound and MRI. She was subsequently diagnosed with Turner Syndrome. Turner Syndrome typically presents with early loss of ovarian function and should be considered when primary ovarian insufficiency is present with apparent absent uterus on imaging. Follow-up imaging of the apparent absent uterus post-estrogen replacement therapy is important to confirm a normal uterus. A diagnosis of an absent uterus can be psychologically traumatic for patients and families, and can have significant implications for future fertility options.

We present a 4-month-old girl who showed vaginal bleeding and breast development. She was born preterm at 25 weeks and 4 days of gestation. Luteinizing hormone and follicle-stimulating hormone levels were extremely elevated. Magnetic resonance imaging showed a lesion of unknown nature in the pituitary gland, most likely a Rathke’s cleft cyst. Because central precocious puberty (CPP) was suspected, a gonadotropin-releasing hormone analogue was started. At the age of 18 months, the treatment was stopped. Thereafter, no signs of puberty developed. The pituitary lesion remained unchanged. Therefore, the initial diagnosis of CPP was incorrect, and instead, an extreme minipuberty had occurred. If treatment for idiopathic CPP in girls younger than 2 years is started, we recommend the treatment be stopped after a certain period, for reevaluation of the diagnosis of CPP.

Adrenocortical carcinoma (ACC) is a rare malignancy in children. Most of these are endocrinologically active tumors, with virilizing features being typically dominant. Its presentation with isolated Cushing syndrome is rare. We report a 3-month-old infant with Cushing syndrome without the clinical features of androgen or mineralocorticoid excess consequently diagnosed with ACC. We discuss the different presentations, diagnosis, and management of this rare tumor with a rarer presentation.