Volume 25, Issue 3-4

Background: Peptide YY has been found to reduce food intake via the vagal-brainstem-hypothalamic pathway. There is some indication that PYY levels may differ in early childhood in comparison with adult studies. Studies of PYY in children have yet to be synthesized. Methods: This review synthesized 21 articles including studies with infants/newborns, primary school age children and populations with special health needs. Results: Some important differences emerge between studies of PYY in children in comparison to those with adults. In those studies with infants and newborns, there is a high level of PYY in preterm and full term neonates in comparison with school age children and adults. As children get older the relationship between PYY levels and body composition and obesity is more similar to that of adults. Fasting PYY levels may be lower in obese children in comparison with adults and weight loss may restore a higher postprandial level of PYY in contrast with adults whose levels remain low. Conclusions: Additional studies are needed to better understand the role of higher PYY in infancy and to assess the effectiveness of different diets on children throughout time-points in growth and development as well as those with different racial/ethnic background.

Brown adipose tissue (BAT) functions as a thermogenic organ by producing heat to maintain body temperature in many mammals, especially in the young. BAT is generally found in deep cervical, supraclavicular, interscapular, and paravertebral regions, as well as areas near large vessels. If not recognized, BAT activity can considerably interfere with 18 F-fluorodeoxyglucose position emission tomography (PET)/computed tomography (CT) image interpretation. BAT activation can be influenced by several factors and reduced by different methods. In this paper, we review BAT distribution and factors influencing BAT activity on FDG PET/CT scan. The purpose of this review is to enhance the recognition of pediatric-related physician of BAT on FDG PET/CT scan.

Context: Worldwide, only nine cases of slipped capital femoral epiphysis (SCFE) associated with primary hyperparathyroidism (PHP) have been reported. Case illustration: This is a report on adolescent subjects with SCFE associated with PHP exhibiting the leading pathogenesis and clinical course. Methods: Here, we reviewed all known cases and developed an effective approach to the management of SCFE and PHP. Results: In cases of emergency, SCFE fixation is primarily done regardless of any preexistent hypercalcemia due to PHP and is followed by parathyroidectomy as soon as possible. In cases of mild and moderate hypercalcemia, whether SCFE fixation is followed by parathyroidectomy and vice versa or resolved during a single operating session depends on the side effects of hypercalcemia. Severely hypercalcemic patients should undergo urgent parathyroidectomy followed by immediate orthopedic surgery or even as a simultaneous procedure. This is to avoid onset of hypercalcemic side effects or worsening of preexisting side manifestations resulting from hypercalcemia. Conclusion: Our report demonstrates that SCFE patients presenting with hypercalcemia, signs of low bone density, or with non-typical age of onset deserve further workup for secondary causes. In addition, the newly developed systematic approach toward achieving an effective, efficient management should help in improving the patients’ long-term outcome.

Background: Current pediatric normal values for thyroid function tests are based on data from relatively few patients. Objective: To develop new normal pediatric values based on a large sample of children. Patients and methods: Data were collected from a computerized database in Jerusalem, Israel, of thyroid function tests taken in community pediatric clinics. Samples from patients with antithyroid peroxidase antibodies and/or antithyroglobulin antibodies and from those treated with levothyroxine, methimazole, propylthiouracil, thyrotropin, lithium, phenobarbital, or glucocorticoids were excluded. The analysis included over 11,000 samples tested for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) with the ADVIA ® Centaur™ system. Results: The upper normal limit (UNL) for TSH increased by about 1 mIU/L and the lower normal limit (LNL) for FT3 increased by 0.5–2 pmol/L in different age groups. There was no significant change in FT4 values. Conclusions: These reference data should replace current normal values.

Objectives: To study iron metabolism and its association with thyroid function in infants with congenital hypothyroidism (CH). Study design: One hundred and twenty-three patients were recruited and matched with 110 controls. Serum levels of thyroid-stimulating hormone (TSH), thyroxine (T 4 ), free T 4 (FT 4 ), ferritin (SF) and soluble transferrin receptor (STfR), were measured. The STfR/lgSF ratio (the serum transferrin receptor-ferritin index, TfR-F index) was calculated. Between-group differences in laboratory parameters and the correlation of parameters of iron metabolism with T 4 were studied. Results: The CH group showed the following serum levels: SF=218.72±103.45 μg/L, STfR=5.19±1.58 mg/L, STfR/lgSF=2.29±0.72 and T 4 =38.39±19.11 nmol/L. The control group serum levels were: SF=182.44±96.17 μg/L, STfR=4.39±1.70 mg/L, STfR/lgSF=2.03±0.83 and T 4 =111.63±17.98 nmol/L. To adjust for an age mismatch between CH patients and controls, a subgroup analysis of all infants aged \u200a≤\u200a28 days at blood sampling was performed and showed: SF=214.26±99.43 μg/L, STfR=5.22±1.53 mg/L, STfR/lgSF=2.31±0.72 and T 4 =36.90±17.11 nmol/L for CH patients and SF=188.50±98.30 μg/L, STfR=4.56±1.72 mg/L, STfR/lgSF=2.10±0.87 and T 4 =112.27±23.87 nmol/L for controls, respectively. STfR was significantly elevated in CH patients. Significant negative correlations were found for STfR and TfR-F index with T 4 in CH patients only. Conclusions: Infants with CH did not show laboratory signs of iron deficiency. The observed elevation of STfR and its negative association with the severity of CH, suggest the presence of a self-regulating mechanism.

Background: There is a worsening high prevalence of global obesity. Special attention has been paid to the gut-endocrine system, represented by the regulators of appetite. In particular, it has been suggested that ghrelin (“hunger” peptide), and obestatin and glucagon-like peptide-1 (GLP-1) (“satiety” peptides) could play important roles in the pathogenesis of obesity. Objectives: The aims of this study were to compare fasting plasma ghrelin, obestatin, and GLP-1 levels between obese and nonobese prepubertal children, and to assess their relations with fatness indexes and insulin resistance (IR). Subjects and methods: Fifty-two prepubertal obese children and 22 controls were enrolled. Fasting levels of gastrointestinal hormones (ghrelin, obestatin, and GLP-1), glucose, and insulin were evaluated. IR was assessed using the homeostasis model assessment of IR (HOMA-IR) index. Analysis was performed by Mann-Whitney U-test, Kruskal-Wallis test, and Spearman’s correlation. Results: Obese prepubertal children and normal-weight controls had similar age distribution. Obese children were more insulin resistant when compared to controls (HOMA-IR: p<0.01). GLP-1 levels were significantly lower in obese children than in controls (p<0.01). Obestatin was significantly higher in obese than normal-weight children (p<0.01), while ghrelin was not different. There was a negative correlation between GLP-1 and standard deviation score-body mass index (r=–0.36, p=0.009) and between GLP-1 and waist circumference (r=–0.45, p=0.001), while no association was observed with HOMA-IR. Conclusions: GLP-1 levels have been shown to be correlated with adiposity indexes, but not with HOMA-IR, suggesting that this hormone could play an important role in the early development of obesity.

Background: In obese populations, oxidative stress plays a major role in the pathogenesis of serious diseases such as diabetes, coronary heart disease, and atherosclerosis. In this study, we investigated the status of oxidative stress in obese children as to nitrite/nitrate and glutathione peroxidase levels, and their relation with insulin resistance (IR). Methods: A total of 63 obese children were enrolled in the study. Each was relegated to one of three groups: 20 obese children without IR (11 adolescents, 9 prepubertal; mean age 10.27±2.36 years; 10 males, 10 females), 22 obese children with IR (13 adolescents, 9 prepubertal; mean age 11.26±2.52 years; 10 males, 12 females), and a control group of 21 children (14 adolescents, 7 prepubertal; mean age 11.41±2.00 years; 10 males, 11 females). Results: Glutathione peroxidase levels were lower in the obese group with IR than in either the control group or the obese group without IR (0.032±0.01 vs. 0.048±0.01 and 0.042±0.01, respectively). Nitrite/nitrate levels were higher in the obese group with IR than in the control group or the obese group without IR (89.83±25.00 vs. 66.00±21.75, and 68.65±28.98, respectively) and compared by pubertal status, adolescents’ results were similar. However, in prepubertal children, nitrite/nitrate and glutathione peroxidase levels were not significantly different between groups. Multiple regression analysis revealed that nitrite/nitrate levels were positively correlated with the homeostasis model assessment of IR (HOMA-IR) independent of body mass index, age, gender, serum lipids, and pubertal stages, and that glutathione peroxidase levels were negatively correlated with body mass index and HOMA-IR independent of age, gender, pubertal status, and serum lipids. Conclusion: This study demonstrates that oxidative stress exists even in populations of obese children, and that oxidative stress markers have a relation with the HOMA-IR, which was used as a surrogate marker of IR.

Objective: Elite male artistic gymnasts (AG) are exposed to high levels of physical and psychological stress during adolescence and experience a significant late maturation in both linear growth and pubertal development. The aim of the present study was to determine the impact of intensive physical training on the adult final height in elite male AG. Methods: This study is unique in character, as all variables were measured on the field of competition. The study was prospective and longitudinal; however, the current analysis of data is cross-sectional. Data from 86 elite male AG were obtained during the gymnastics competitions of European and World Championships. Clinical evaluation included height and weight measurements, as well as assessment of pubic hair and genital development according to Tanner’s stages of pubertal development. The laboratory investigation included determination of skeletal maturation. All athletes completed a questionnaire that included questions on personal (onset and intensity of training, number of competitions per year) and family data (paternal and maternal heights). Results: Male AG were below the 50th percentile for both final height and weight. Elite male AG had final height standard deviation score (SDS) lower than their genetic predisposition. Final height SDS was correlated positively with target height SDS (r=0.430, p<0.001) and weight SDS (r=0.477, p<0.001) and negatively to the intensity of training (r=–0.252, p=0.022). The main factors influencing final height, by multiple regression analysis were weight SDS (p<0.001) and target height SDS (p=0.003). Conclusion: In elite male AG, final height falls short of genetic predisposition, still well within normal limits. Considering medical and psychological risks in general, and based on the results of this research project, the International Federation of Gymnastics has increased the age limit for participants in international gymnastics competitions by 1 year.

Background/aim: Possible etiologies of idiopathic short stature (ISS) include a range of conditions, some of which may be caused by defects in the modulation of the growth hormone (GH)-signaling pathway. The Janus kinase/signal transducer and activator of transcription pathway is regulated by several mechanisms, including negative feedback regulation by the suppressors of cytokine signaling (SOCS). However, the specific induction of SOCS transcript levels in fibroblasts from ISS patients has not been studied. Methods: We determined the transcript levels of the SOCS1–3 genes under basal conditions, and in the presence or absence of stimulation with rhGH for 24 h in skin fibroblast cultures obtained from patients with ISS and children with normal height. Results: Under basal conditions, ISS patients express higher SOCS2–3 transcript levels than control children. After incubation with recombinant human GH (rhGH), the transcript levels of SOCS2 increased significantly in ISS patients compared to controls (0.79±0.06 vs. 0.55±0.07; p=0.03), a pattern which did not achieve statistical significance for SOCS3 transcript levels (0.55±0.08 vs. 0.40±0.07). Conclusion: The higher baseline transcript levels of the SOCS genes, and the increase observed for SOCS2 after rhGH treatment in ISS patients, suggest that growth retardation in some of these children may be mediated, at least in part, by intracellular overexpression of the SOCS genes.

Background: The growth assessment of bone age (BA) is an essential feature in diagnosing various diseases in children. In the clinic, the Tanner and Whitehouse (TW3) method and the Greulich-Pyle (GP) method are used to estimate bone age. Because those methods were developed for foreign children, it is necessary to evaluate the applicability of those methods to Koreans. Objectives: This study was designed (1) to compare the skeletal maturity score (SMS) in Koreans to the SMS in foreign children, and (2) to establish a correlation between the BA and chronological age (CA) on the basis of gender and age in normal Korean children. Material and methods: We estimated the SMS and BA for 378 healthy children (141 boys and 237 girls) who visited the pediatrics clinic in Ewha Womans University Mokdong Hospital (Seoul, Korea) from 2000 to 2009. The SMS and BA were estimated using the TW3 and GP methods. Results: The SMS in Koreans was higher than in foreign children, and on average, the BA measured by both methods was higher than the CA. The correlation between the BA and CA were different according to gender and age. Conclusions: We suggest that there are differences between the SMS in Korean and foreign children and between the BA and CA. Therefore, the results can be used in evaluating the skeletal maturity of Koreans, and a correlation between the BA and CA would be a useful reference in diagnosis.

Background: Growth hormone (GH) is used to treat growth failure in children and metabolic impairments in adults with GH deficiency (GHD). Treatment requires daily subcutaneous injections that may affect treatment outcomes, and subsequently efficacy outcomes. To enhance potential adherence, improved GH delivery device systems are being developed. Objective: To compare patient acceptability and usability of Norditropin ® FlexPro ® /FlexPro ® PenMate ® with Norditropin NordiFlex ® /NordiFlex PenMate ® for GH administration in children/adolescents with GHD. Methods: A multinational, open-label, uncontrolled study. Patients (n=50; 4–18 years) currently on GH therapy injected test medium into a foam pad. Ease-of-use and patient device preference were recorded by questionnaire. Results: The majority (80%) of patients preferred FlexPro ® PenMate ® over NordiFlex PenMate ® with 96% and 84%, respectively, reporting that they found the FlexPro ® PenMate ® system user-friendly and that they were highly confident using it. Conclusion: The FlexPro system was well accepted by patients. This may facilitate greater adherence to treatment and improve patient outcomes.

Objectives: To analyze the clinical manifestations of primary adrenal insufficiency in Chinese boys, to investigate the prevalence of DAX1 and SF1 gene mutations, and to explore the association between gene mutations and clinical manifestations. Subjects and methods: A total of 25 boys with primary adrenal insufficiency were enrolled. Mutational analysis of the DAX1 and SF1 genes was done by direct sequencing. Results: DAX1 gene mutations were found in 40% (10 of 25) of 46,XY phenotypic boys referred with adrenal insufficiency, and six of these were novel. One SF1 gene mutation was identified. These patients demonstrated diverse clinical presentations. There was no definite association between clinical manifestations and genetic mutations. Conclusions: DAX1 gene mutations are a relatively frequent cause of primary adrenal insufficiency. In contrast, mutation in the SF1 gene is seldom found. There is no definite relationship between gene mutations and clinical manifestations.

Nationally, newborn screening programs use 17-hydroxyprogesterone (17-OHP) as the biomarker to detect the rare but potentially fatal inherited disease, congenital adrenal hyperplasia. However, this biomarker is highly variable, with a high false-positive rate of detection, particularly in neonates born preterm. Several studies have examined various clinical and genetic factors to explain the variability of 17-OHP in preterm infants. The purpose of this study was to replicate previous clinical and genetic associations with 17-OHP in a well-characterized cohort of 762 preterm infants. We replicated previous findings that respiratory distress syndrome (p=2×10 –3 ) is associated with higher 17-OHP. Higher 17-OHP and false positives were significantly associated with lower gestational age and birth weight, as previously reported. Incorporating gestational age and birth weight together decreases the false-positive rate.

Background: Long-term treatment with glucocorticoids can induce bone loss and increase fracture risks. Aim: To compare the efficacy of a 12-month treatment between alfacalcidol and menatetrenone in preventing bone loss in children treated with long-term glucocorticoids. Patients and methods: Twenty children on a stable dosage of glucocorticoids were randomly divided into two groups (alfacalcidol or menatetrenone). Each group received the assigned treatment along with 400 mg of elemental calcium daily for 12 months. Patients receiving medications affecting bone metabolism or patients with impaired kidney function were excluded. Bone density parameters, including lumbar spine bone mineral content (BMC), bone mineral density (BMD), and BMD Z-score were assessed by dual-energy X-ray absorptiometry at baseline and at 12-month follow-up. Bone mineral apparent density (BMAD) was calculated as a size-adjusted measurement of BMD in growing children. Baseline characteristics and bone density parameters were similar between both groups. Results: After 12 months, BMC and BMD were significantly increased from baseline in both groups, but did not differ between the groups. The BMD Z-score at 12-month follow-up was significantly decreased from baseline in the menatetrenone group. BMAD was significantly increased from baseline in the alfacalcidol group. Conclusions: Administration of long-term glucocorticoids in children justifies an intervention to preserve bone mass. Calcium supplementation along with alfacalcidol can prevent further bone loss to a greater extent than menatetrenone in this group of patients.

Background: Onset of puberty is dependent on pulsatile secretion of gonadotropin releasing hormone (GnRH). The kisspeptin-GPR54 signaling system has a considerable role in GnRH physiology and induction of puberty. Objectives: To evaluate kisspeptin levels in girls with central precocious puberty (CPP) at the time of the diagnosis and during follow-up, to determine whether or not kisspeptin may serve as a marker for diagnosis and follow-up of CPP. Patients and methods: Kisspeptin levels of 28 girls with CPP were measured at the time of diagnosis and repeated at the 6th month of therapy after complete pubertal suppression and compared to kisspeptin levels of 13 age-matched prepubertal controls. Results: Kisspeptin levels of girls with CPP (10.2±2.6 pg/mL) were higher than those in controls (8.6±1.5 pg/mL (p<0.019). There was a significant decline in the kisspeptin levels (7.3±1.3 pg/mL) of girls with CPP after pubertal suppression (p<0.0001). Conclusion: These findings suggest that kisspeptin levels can be used as corroborative evidence for diagnosis of CPP and a valuable parameter for monitoring treatment efficacy.

Objectives: To investigate the risk of hypophosphatemia and hypercalcemia in small for gestational age (SGA) extremely low birth weight infants (ELBWI) receiving parenteral nutrition. Methods: A retrospective review of 58 ELBWI was conducted. Serum calcium (Ca) and phosphate (PO 4 ) concentrations on days 1 and 8 after birth were examined for associations with body measurements and nutritional factors in the 1st week of life. Results: Lower birth weight standard deviation (SD) scores were correlated with hypophosphatemia and hypercalcemia in SGA ELBWI on day 8. Higher parenteral amino acid (AA) administration was correlated with hypophosphatemia on day 8. SGA ELBWI exhibited lower serum PO 4 concentrations compared to appropriate for gestational age (AGA) ELBWI on day 8. Conclusions: This is the 1st study to report that parenteral nutrition, in the first 7 days after birth for the treatment of SGA ELBWI, was correlated with hypophosphatemia and hypercalcemia. It is important to determine an ideal nutrition protocol for treatment of SGA ELBWI.

We report a long-term follow-up on the use of anastrozole in the treatment of peripheral precocious puberty (PP) in McCune-Albright syndrome (MAS). A girl, age 3 years and 9 months, was diagnosed with MAS due to PP, café-au-lait spots, and polyostotic fibrous dysplasia. Serum estradiol was elevated, and gonadotropins were suppressed. Pelvic ultrasound showed an enlarged uterus and a follicle cyst (13 mm) in the left ovary. Bone scintigraphy showed osteogenic lesions on the skull, humerus, tibia, and acetabulum. Bone age was 3 years and 5 months at the chronological age of 3 years. After 36 months of treatment with anastrozole (1 mg/day), there was suppression of breast growth, normalization of growth velocity and serum estradiol, and disappearance of ovarian cysts. However, there was increase in uterine volume, advancement of bone age, and two episodes of vaginal bleeding (18th and 24th months). This report shows the partial benefit of anastrozole in the treatment of peripheral PP of girls with MAS.

Palmoplantar keratoderma (PPK) is a diverse group of disorders, characterized by thickening of the palms and soles, which are subdivided into focal or diffuse; it can be acquired or hereditary. Syndromic association of PPK is described in literature with all patterns of inheritance. Skin and nail changes, predisposition to malignancy, skeletal deformities, dwarfism and enamel abnormalities are rarely associated with PPK. In this case report, we present monozygotic twin sisters with palmoplantar keratoderma and growth hormone deficiency. We speculate a common mutation leading to these two apparently unrelated entities.

Antithyroid drugs (ATDs) have been widely and effectively used for the treatment of pediatric and adult thyrotoxicosis for more than a half century. Since the very beginning of ATD use, reports of hepatic dysfunction related to propylthiouracil (PTU) therapy have been published. We describe a case of a 12-year-old girl, who, after 4 weeks of therapy for Graves disease (GD) with PTU (300 mg/day at 100 mg given three times a day), developed fatigue, fever, diarrhea, nausea, and vomiting. The initial diagnosis was “viral gastrointestinal infection”. Few days after the initiation of her symptoms, the patient developed jaundice, hepatic tenderness, and dark urine. She was admitted to the hospital where, after an extensive investigation, it was found that serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were elevated (2312 and 1435 IU/L, respectively), alkaline phosphatase (ALP) was 171 IU/L and total bilirubin was 12.7 mg/dL, whereas direct bilirubin was 7.6 mg/dL and prothrombin time was 23.2 s (normal ratio, <14.5 s). Serology for hepatitis A and B was negative. The diagnosis of PTU-induced hepatitis was established. PTU was discontinued, and a treatment with prednisone (50 mg/day) and vitamin K was initiated. Four weeks after admission, her hepatic tests returned to normal. We searched the English literature and we present details of all cases with PTU-related hepatic toxicity in children and adolescents published so far. Also, we provide information regarding the mechanisms and treatment of this appalling clinical entity. Finally, after recent recommendations from American Thyroid Association (ATA) and European Thyroid Association (ETA), PTU should be administered only in the first trimester of pregnancy and in cases of drug allergy to methimazole.

Hyperthyroidism is rare in paediatric age group, the most common cause being Graves’ disease. Very few cases of autonomous functioning thyroid nodule (AFTN) as a cause of paediatric hyperthyroidism have been reported. We herein report a case of AFTN in a 3 and a half-year-old boy who had become symptomatic with a swelling in the neck and hypermetabolic features at the age of 8 months. He was successfully treated with 131 I radioablation, which rendered him euthyroid.

Ataxia telangiectasia is a rare genetic disease characterized by neurological manifestations, infections, and cancers. In addition to these cardinal features, different autoimmune diseases can be seen in patients with ataxia telangiectasia. Although there were reports of positive autoimmune thyroid antibodies associated with ataxia telangiectasia, to our knowledge, we report the first cases of nodular Hashimoto thyroiditis in two patients with ataxia telangiectasia in the English medical literature. These cases illustrate that despite the rarity of nodular Hashimoto thyroiditis associated with ataxia telangiectasia, physicians should be aware of this possibility. Furthermore, thyroid examination of patient with ataxia telangiectasia is recommended for early diagnosis.

Background: Activating mutations of the ABCC8 gene can lead to permanent neonatal diabetes mellitus (PNDM). Glucose variability in infants with NDM treated with insulin can be extreme. We report long-term glycemic control in a patient with PNDM on sulfonylurea therapy, despite initial allergic reaction. Methods: A Chinese girl presented on the first day of life with persistent hyperglycemia. Despite treatment with various insulin regimens, hemoglobin (Hb) A1c (normal 4.8%–6.3%) increased from 5.0% at 14 days of age to a peak of 9.7% at 15 months of age. Her average insulin dose was 0.5 units/kg/day. Genetic analysis revealed two novel ABCC8 gene activating mutations encoding the β-cell sulfonylurea-1 receptor of the ATP-sensitive potassium channel. At age 3 years 2 months, transition from insulin to the oral sulfonylurea glyburide was initiated. After 8 days, she developed urticaria, palmar erythema, and a diffuse maculopapular rash, which resolved when medication was discontinued. At age 3 years 11 months, glyburide was reintroduced at a very low dose and was increased with concomitant weaning of insulin over the following 6 months. Results: Normoglycemia (HbA 1c 5.6%) was achieved on glyburide without any further allergic reaction at the age of 4 years 5 months with improved metabolic control. For the next 3 years, HbA1c measurements, and glucose means and variability were significantly lower compared with values during insulin therapy. Conclusions: As compared with subcutaneous insulin, oral sulfonylureas improved long-term metabolic control in a patient with NDM caused by novel activating mutations in the ABCC8 gene. Desensitization permitted safe oral sulfonylurea therapy in our patient with NDM despite initial allergic reaction. Fewer episodes of hypoglycemia occurred on sulfonylurea than on insulin therapy, which is an advantage in a very young child.

Diabetes mellitus complicated by mixed diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome presents a special challenge to physicians. There is no standard protocol for the management of mixed hyperglycemic hyperosmolar syndrome and diabetic ketoacidosis in children. The commonest cause of neurological deterioration during an episode of diabetic ketoacidosis is cerebral edema, whereas hyperosmolality often leads to thrombosis. The risks for these complications are further increased in diseases associated with vasculopathies. We present the first case of complex cerebral arteriovenous thrombosis leading to stroke in a child with Adams-Oliver syndrome, a genetic condition that is associated with abnormal vasculogenesis. He presented with new-onset double diabetes complicated by a combination of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Magnetic resonance imaging, magnetic resonance angiography, and magnetic resonance venography provided evidence for an ischemic stroke. Children and adolescents who present with a combination of hyperglycemic hyperosmolar syndrome and diabetic ketoacidosis should be monitored for neurologic deficits and must be investigated for both stroke and cerebral edema in the event of neurological deterioration.

Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the αβ fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure.

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes diagnosed within the first 6 months of life. Heterozygous activation mutations in KCNJ11 , encoding the Kir6.2 subunit of the ATP-sensitive potassium (K ATP ) channel, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM. The majority of the patients represent isolated cases resulting from de novo mutations. Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome. Individuals with KCNJ11 mutations have been successfully transitioned from insulin to sulfonylurea (SU) therapy. Furthermore, there have been cases reported with variable improvement in neurological function following a successful switching. We describe a 12-year-old Portuguese girl with PNDM due to the previously reported R201C mutation in the KCNJ11 gene. Her medical history includes prematurity and moderate developmental delay. The mutation was inherited from her mother who has isolated PNDM. The patient was successfully transferred from insulin to SU, whereas her mother showed SU resistance. Despite good glycemic control, no improvements in the cognitive performance were verified. We present our experience in switching treatment from insulin to oral SUs in this family, and also discuss whether or not the girl’s developmental delay is related with the Kir6.2 mutation. To our knowledge, this is the first Portuguese patient reported with successful transition to SU treatment.

Classical citrullinemia generally involves hyperammonemic coma in the first few days of life and leads to neurological sequelae in survivors. We report a case of an elder sister who fell into a hyperammonemic coma on the fifth day after birth. She was successfully treated with intravenous benzoate and hemodialysis, and was subsequently diagnosed with citrullinemia on the basis of biochemical analysis. Two years later, a younger sister was born without prenatal diagnosis. We monitored plasma ammonia and citrulline levels after birth, and again diagnosed her with CTLN1 on the basis of biochemical and DNA analyses. There have been few reports of the prospective treatment of citrullinemia; however, our experience indicates the need for the prospective management and the rapid reduction of ammonia levels to avoid neonatal hyperammonemic coma and subsequent sequelae.

Acquired partial lipodystrophy (APL) is a rare disorder, mainly characterized by progressive loss of subcutaneous fatty tissue, starting from the face and spreading to the upper part of the body. The etiology of APL is unknown. It may be caused by mutations in the lamin B 2 ( LMNB2 ) gene on 19p13.3. We present a Chinese patient who had APL for 12 years, which initially affected her face. She also suffered from marked fatty liver and a mild metabolic disorder. We identified a heterozygous T to C transition in exon 5 of the LMNB2 gene (c.694T>C), and, consequently, tyrosine for histidine (p.Y232H). However, these features and the mutation were absent in her parents. The p.Y232H has not been described previously. We provide clinical data to the genotype-phenotype discussion and further expanded the number of LMNB2 mutations.

Micro syndrome is an autosomal recessive disorder characterized by severe intellectual disability, microcephaly, congenital cataract, microcornea, microphthalmia, agenesis, or hypoplasia of the corpus callosum and hypogenitalism. We report an 11-month-old boy who was referred for assessment of micropenis and cryptorchidism. Sequence analysis of exon 8 of the RAB3GAP1 gene confirmed the presence of a splice donor mutation (748+1G>A) in the homozygous state.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare syndrome characterized by complete or partial agenesis of the uterus and vagina, due to a congenital defect of the Mullerian duct. Affected individuals have a 46,XX karyotype and a normal female phenotype. MRKH syndrome may be isolated (type I MRKH syndrome) or associated with renal, cardiac, and skeletal anomalies, short stature, and auditory defects. The latter is defined as type II MRKH syndrome or the Müllerian duct aplasia/hypoplasia, renal agenesis/ectopy, and cervicothoracic somite dysplasia (MURCS) association. The majority of patients with MRKH syndrome present with primary amenorrhea. We report a case of type II MRKH syndrome who has been referred by a pediatric surgeon for detection of gonadal function. During an inguinal hernia operation, the left ovary had been observed in the hernia sac. Clinical and radiological evaluation of the patient showed an absence of the uterus and left kidney, and cervical hemi vertebra. Based on these findings, the patient was diagnosed as having type II MRKH syndrome.

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