Band 27, Heft 9-10

Children with thalassemia are living longer due to better care. Physicians dealing with this group of patients now have to contend with new challenges resulting from iron overload. Endocrine complications represent the most common morbidities encountered. To provide a better quality of life, these complications have to be addressed in a consistent way. For this purpose, we have compiled a set of recommendations to help physicians provide the best care possible to these patients.

Objective: Hashimoto’s thyroiditis (HT) is the most common cause of thyroid disease in children and adolescents, but little is known about the long-term follow-up of HT. The aim of this study was to analyze the clinical and laboratory characteristics and to observe the natural course of HT in children and adolescents. Methods: We retrospectively reviewed 153 patients with HT diagnosed before 18 years of age. Subjects were grouped into euthyroid, subclinical hypothyroidism, overt hypothyroidism, and hyperthyroidism on the basis of the thyroid function test. Of the 153 subjects, 133 were followed up (range 6∼181 months) at our clinic every 6 months for evaluation of goiter size, thyroid function, thyroid peroxidase antibodies (TPO Ab), and thyroglobulin antibodies (TG Ab) serum concentration. Results: Thyroid function tests at the time of presentation revealed euthyroid in 72 patients (47.1%), subclinical hypothyroidism in 48 (31.4%), overt hypothyroidism in 22 (14.4%), and hyperthyroidism in 11 (7.2%). Serum TPO Ab and TG Ab significantly decreased in the subclinical hypothyroidism group with levothyroxine treatment. Also, there was a significant decrease in the mean serum TG Ab levels among the overt hypothyroid patients during the follow-up period, although TPO Ab levels were not significantly different when compared to their baseline TPO Ab levels. Conclusion: Most children with HT were euthryoid and remained euthyroid during follow-up. However, thyroid function should still be monitored periodically for early detection and treatment of overt hypothyroidism. Our data also showed that levothyroxine treatment may have beneficial effects on the thyroid antibody titers.

We assessed body composition and muscle strength during the transition phase in 18 growth hormone (GH) deficient males treated with recombinant GH to final height and 18 controls. According to peak-stimulated GH and basal insulin-like growth factor-1 (IGF-1) during the transition phase, patients were subdivided into GH deficient (GHD-TP, n=9) and GH sufficient (GHS-TP, n=9) groups. Assessments included lean and fat body mass and bone mineral density (BMD), all measured by dual-energy X-ray absorptiometry, and dynamic knee muscle strength, assessed by isokinetic dynamometer. Total body and lumbar spine BMD and muscle strength were lower in GHD-TP patients when compared with GHS-TP and controls (all p<0.05), whereas lean and fat body mass were lower in both GHD-TP and GHS-TP patients when compared with controls (p<0.05). These findings suggest that administration of recombinant GH to final height is not sufficient to provide normal body composition and muscle strength in young male patients with GH deficiency.

Objective: Premature menarche is an uncommon, benign condition characterized by isolated or recurrent menstrual bleeding in the absence of secondary sexual characteristics. Methods: We performed an observational retrospective study to further characterize the clinical, biochemical and imaging features of benign prepubertal vaginal bleeding (BPVB). Out of 1037 girls evaluated for precocious puberty over a 5-year period, 24 girls with BPVB were identified based on ≥1 episodes of vaginal bleeding, Tanner I or non-progressive Tanner II breast development, and lack of physical findings suggesting genital infection, trauma or foreign body. Results: Age at presentation ranged from 3 years 2 months to 9 years 11 months. Ten patients (42%) had one episode of vaginal bleeding, six (25%) had two episodes and eight patients (33%) had three or more. First bleeding episode lasted 3 days (range; 1–30 days). Six girls had intermittent spotting for up to 1 year. No breast development was noted in 19 (79%) patients. Minimal breast was present in five girls; early pubic hair was present in 2. LH and FSH were prepubertal; estradiol was >20 pg/mL in two girls. Pelvic ultrasound, performed in 11 patients, showed pre-pubertal uterus and ovaries without adnexal masses. Conclusion: Isolated prepubertal vaginal bleeding is typically benign and self-limited, in the absence of sexual precocity signs or other vaginal pathology. Laboratory and imaging studies are generally unrevealing.

Background: Childhood obesity is a cardiovascular risk factor. Objective: Epicardial adipose tissue (EAT) thickness, carotid intima-media thickness (IMT) and cardiac functions of obese children and their correlations were evaluated. Subjects: Five hundred obese children and 150 age- and sex-matched healthy controls. Methods: Anthropometric, laboratory data and echocardiographic measurements of IMT, EAT and cardiac functions were determined. Results: Increased M-mode echocardiographic measurements, E/e′ ratios, Tei index values and decreased E/A and e′/a′ ratios (where E and A are early and late mitral/tricuspid diastolic velocities, respectively, and e′ and a′ are peak early diastolic and peak atrial systolic myocardial velocities, respectively), were determined in the obese group. Also, carotid artery IMT and EAT thickness were significantly higher in obese children. Carotid artery IMT, EAT thickness and left ventricular mass (LVM) were found to be strongly associated with Tei index values. Conclusion: Obesity is a major risk factor for cardiovascular diseases. In our study, we showed that obese children have early subclinical systolic and diastolic dysfunctions. Also, these cardiac impairments are correlated with the increase in IMT, EAT thickness and LVM.

The discovery that mutations in the succinate dehydrogenase ( SDH ) complex subunit ( SDHA, B/C/D/AF2 ) genes predispose patients to the development of tumors has led to the identification of a large population of patients and relatives at risk for developing malignancies. The most frequent conditions associated with these mutations are the familial paraganglioma syndromes. Other tumors that are frequently associated with SDH mutations ( SDHx ) are gastrointestinal stromal tumors and renal cell carcinomas. A number of other rare associations have also been described. SDHx mutations are often clinically silent and metastatic, but they may also be aggressive in their presentation. The penetrance of these mutations is beginning to be understood, and the characteristics of the phenotype are being elucidated. However, the inability to accurately predict the appearance, nature, and location of tumors as well as their tendency to recur or metastasize pose challenges to those who counsel and manage patients with SDHx mutations. In this work, we present our approach for counseling these families in the context of the current uncertainties, while striving to maintain patient autonomy.

Introduction: Puberty can be divided into two independent events: adrenarche and gonadarche. In healthy children, adrenarche is followed by gonadarche, but in patients with gonadal dysgenesis there is partial or complete dissociation between these two events. Objective: To evaluate the age and chronology of the development of secondary sexual characteristics and occurrence of these events and their relationship to the induction of puberty in patients with Turner syndrome (TS). Materials and methods: A descriptive analysis with historical records of the patients with clinical and cytogenetic TS was conducted. The following variables were recorded: karyotype; age of thelarche, pubarche, and menarche; occurrence of spontaneous puberty; maintenance of puberty or secondary failure; and the onset of hormone replacement therapy (HRT) with estrogen. Results: We evaluated 123 medical charts. Seven (5.7%) patients were prepubertal, 10 (8.1%) had only pubarche, and 5 (4%) had only thelarche. Forty-seven (38.2%) patients entered puberty spontaneously. Among these, 35 (28.5%) remained in puberty, and 12 (9.8%) required subsequent HRT; 54 (44%) had puberty induced. Sixty-six (56.9%) patients had pubarche started before thelarche. Menarche occurred in 67 patients, spontaneously in 19. Pubarche spontaneously presented in 91 (78.4%) patients, and in 25 (21.5%) after HRT introduction. Conclusions: Spontaneous puberty occurred in approximately one-third of the patients. Pubarche was the first feature in most patients and about 20% showed pubarche only after estrogen therapy.

Background: Neonatal severe primary hyperparathyroidism (NSHPT, MIM 239200) is most often an isolated disorder that is due to biallelic inactivating mutations in the CASR , the gene encoding the calcium sensing receptor; NSHPT is inherited from parents with familial hypocalciuric hypercalcemia, each of whom has one mutated CASR allele. Objectives: To report clinical and genetic findings in a brother and sister with NSHPT due to a novel mutation in the CASR transmitted as an autosomal recessive trait and to examine the functional effect of the mutation. Subjects and methods: A brother and sister with marked hypercalcemia due to NSHPT were identified; the boy also had craniosynostosis requiring surgical repair. The genotyping of the CASR in both children and their parents who were eucalcemic and normophosphatemic was undertaken. In order to examine the significance of the variant CASR identified, the CASR variant was expressed in vitro and examined by three computer computational programs [PolyPhen2, MutationTaster, Sorting Intolerant From Tolerant (SIFT)] designed to evaluate the effect of a nucleotide variant on the structure and likely functional consequence upon the protein product. Results: A sequence variant in the CASR was identified [G>T point mutation at nucleotide c.2303 in exon 7 (c.2303G>T) resulting in the replacement of glycine by valine at codon 768 (p.Gly768Val)]. Two copies of this CASR variant were present in the genome of the siblings while a single copy of the CASR variant was present in both of the clinically and biochemically normal parents, a pattern of transmission consistent with autosomal recessive inheritance of NSHPT in this family. When expressed in HEK293 cells in vitro, the novel Gly768Val variant did not interfere with protein generation or migration to the cell membrane in vitro. The analysis of the functional effect of the Gly768Val CASR variant by the PolyPhen2, MutationTaster, and Sorting Intolerant From Tolerant computer programs revealed that this mutation was very likely to be deleterious. Conclusion: The NSHPT associated with biallelic Gly768Val mutations of the CASR in two siblings with severe hypercalcemia and hyperparathyroidism and their clinically and biochemically normal heterozygous parents was transmitted as an autosomal recessive disorder in this family.

Increasing evidence suggests a role of the IGF axis in the maintenance of normal glucose and lipid metabolism. The local IGF-IGFBP environment changes significantly in response to the diabetes milieu. We aimed at determining serum IGF-1 and IGFBP-3 levels in children with type 1 diabetes mellitus (T1DM) and their relationship with clinical variables. Seventy-eight patients with T1DM and 47 healthy control subjects were included in this study. Significant reduction for concentration of serum IGF-1 was observed in patients with T1DM compared to healthy controls. However, serum IGFBP-3 levels were similar in patients with T1DM compared to controls. Both serum IGF-1 and IGFBP-3 levels were significantly correlated with age, BMI, and serum c-peptide levels. In addition, serum IGFBP-3 levels showed significant positive correlation with HbA1c, total cholesterol, and LDL-cholesterol in the uncontrolled diabetic patients. These findings suggest that IGFBP-3 may be involved in the glucose control and lipid metabolism in those with uncontrolled T1DM. Further studies are needed to document their roles on glucose and lipid metabolism in T1DM.

Phenylketonuria (PKU) is one of the most prevalent inherited metabolic diseases and is accountable for a severe encephalopathy by progressive intoxication of the brain by phenylalanine. This results from an ineffective L-phenylalanine hydroxylase enzyme (PAH) due to a mutated phenylalanine hydroxylase ( PAH ) gene. Neonatal screening programs allow an early dietetic treatment with restrictive phenylalanine intake. This diet prevents most of the neuropsychological disabilities but remains challenging for lifelong compliance. Adult-derived human liver progenitor cells (ADHLPC) are a pool of precursors that can differentiate into hepatocytes. We aim to study PAH expression and PAH activity in a differenciated ADHLPC. ADHLPC were isolated from human hepatocyte primary culture of two different donors and differenciated under specific culture conditions. We demonstrated the high expression of PAH and a large increase of PAH activity in differenciated LPC. The age of the donor, the cellular viability after liver digestion and cryopreservation affects PAH activity. ADHLPC might therefore be considered as a suitable source for cell therapy in PKU.

Background: Life threatening conditions are associated with atypical genitalia in newborns. Analysis of genetic sex provides a clue to the underlying etiology in newborns with disorders of sex development (DSD) and can guide further endocrine investigations. Rapid diagnosis of genetic sex would be immensely useful in this situation. Traditionally used methods such as karyotype and fluorescence in situ hybridisation are time-consuming. Objectives: To study the clinical applicability of an indigenously developed rapid real-time polymerase chain reaction (RT-PCR) assay for the sex determining region on the Y chromosome ( SRY gene) and the DYS14 locus in newborns with DSD. Methods: Clinical examination, endocrinological tests, RT-PCR analysis of SRY and DYS14 and karyotype was performed in 15 newborns with DSD. Results: Results of PCR were available within 4 h. Based on this report, in SRY / DYS14 positive cases, further tests for assessment of testicular function were done. In SRY negative cases, tests for congenital adrenal hyperplasia were done. On comparing PCR results with other tests, the Y chromosome was present on karyotype and testicular tissue was detected by endocrinological and/or histological methods in all (8/15) SRY positive cases. The SRY and DYS14 negative cases (7/15) did not have Y chromosome in the karyotype. Congenital adrenal hyperplasia (CAH) was the most common diagnosis in this group. Conclusions: The indigenously developed PCR for dual Y chromosome markers is rapid and sensitive. Further endocrine evaluation of newborns with DSD can be based on these results. Information of genetic sex partly allays the psychosocial distress associated with the condition.

Objective: To study the vitamin D receptor ( VDR ) gene in five Egyptian patients with severe rickets and the clinical features of hereditary vitamin D-resistant rickets, including hypocalcemia, hypophosphatemia, total alopecia, and elevated serum levels of 1,25-dihydroxyvitamin D. Study design: We amplified and sequenced DNA samples from blood from the patients, their parents, and available family members. Results: DNA sequence analyses of the VDR gene showed three novel mutations (p.Y295X, p.R343C, and p.R391H) and a previously reported one (p.R30X) in four patients, whereas no mutation was found in one patient. Mutations cosegregated perfectly with affected individuals in all families, and did not exist in unaffected family members or 200 ethnically matched chromosomes. Conclusion: Three novel deleterious mutations in the VDR ligand-binding domain were identified, which are expected to render the VDR nonfunctional. Successful treatment with frequent high doses of oral calcium and calcidol was evident in all patients; however, hair growth occurred only in one patient.

Objective: Permanent neonatal diabetes mellitus (PNDM) is a rare heterogeneous form of diabetes that develops within the first 6 months of life. The objective of this study is to define the genetic etiology and incidence of permanent neonatal diabetes mellitus in Jordan. Methods: This study was conducted in Jordan at the National Center of Diabetes, Endocrinology and Genetics, Amman, between 2006 and 2012. The study included 22 cases diagnosed with diabetes within the first year of life. Results: The incidence of PNDM in Jordan was calculated as one case for every 203,221 live births. Mutations were found in six out of ten cases diagnosed before 6 months and included one homozygous ABCC8 p.R826W mutation, three cases with a heterozygous KCNJ11 p.R201C mutation, and two cases with a homozygous EIF2AK3 splicing mutation. Conclusion: The genetic etiology of PNDM in Jordan is different from that seen in European countries and more similar to other Arab countries.

Aim: The purpose of this study was to search for the effects of adenotonsillectomy (A&T) on height, weight, and body mass index (BMI), as well as changes in ghrelin, leptin, and insulin-like growth factor 1 (IGF-1) levels in children with adenotonsillar hypertrophy (ATH)-related sleep-disordered breathing (SDB). Methods: A study cohort of 39 children clinically diagnosed with ATH-related SDB was included in this study. Twenty-three healthy children were included as controls. Height and weight standard deviation scores (SDS) and ghrelin, leptin, and IGF-1 levels of the controls were determined once; in the study group, they were determined preoperatively and in the third month postoperatively. Results: Preoperative IGF-1 (ng/mL) and ghrelin (pg/mL) levels were significantly higher in the patients than in the controls (322.51±113.10 vs. 256.96±176.73, p<0.05 and 106.08±9.75 vs. 80.11±28.50, p<0.001, respectively). The preoperative height and weight SDS values of the patients were lower than those of the controls (–0.67±1.36 vs. 0.13±1.13, p<0.05 and –0.38±1.35 vs. –0.20±1.29, respectively). The patients’ postoperative height and weight SDS values were significantly higher than their preoperative values (–0.05±1.08 vs. –0.67±1.36, p<0.0001 and 0.00±1.28 vs. –0.38±1.35, p<0.0001, respectively). The mean postoperative IGF-1 levels also were significantly higher than preoperative levels (386.05±130.06 vs. 322.51±113.10, p<0.05, respectively). Conclusion: Plasma IGF-1 levels are lower in malnourished children, and plasma ghrelin levels are decreased after acute oral food intake and are increased in cachexia and fasting. Therefore, increased serum IGF-1 levels, height and weight SDS values, and decreased ghrelin levels detected postoperatively are useful parameters that help to monitor the development of children with adequate oral intakes.

Objective: To assess the sensitivity and specificity of anti-Mullerian hormone (AMH) and inhibin B for diagnosis of 46,XY disorders of sex development (DSD). Patients and methods: The study included 43 patients of 46,XY DSD and compared them with 43 healthy, male, age matched controls. All patients underwent karyotyping, assessment of testosterone, dihydrotestosterone (DHT) and Δ4-androstendione (Δ4A) basal and after human chorionic gonadotropin (HCG) testing. Basal dehydroepiandrosterone (DHEA) was measured. Ultrasonograghy was also done and some cases underwent laparoscopy or gonadal biopsies. Basal AMH and inhibin B were measured in both cases and controls. Results: The mean age of patients was 5.16±4.24 years. There were significant correlations between basal AMH and HCG stimulated testosterone and DHT (r=0.64; p<0.001 and r=0.52; p<0.001, respectively). Also, significant positive correlations were found between inhibin B and HCG as well as stimulated testosterone and DHT (r=0.62; p<0.001 and r=0.44; p=0.003, respectively). A highly significant correlation was found between AMH and inhibin B (r=0.78; p<0.001). The sensitivity of AMH was (96.6%), specificity (60.7%), NPV (89.5%) and PPV (83.6%). Best cut-off value was (27.11 IU/mL) while overall accuracy was (85%). The sensitivity of inhibin B was (96.6%), specificity (67.9%), NPV (90.5%), PPV (86.2%), and best cut-off value was (41.9 IU/mL) with an overall accuracy (87%). Conclusion: AMH and inhibin B are valuable, and reliable noninvasive parameters for the detection of functioning testicular tissues in prepubertal patients.

Autoimmune thyroiditis has been suggested as a precancerous condition in some adult studies, but there is still controversy. The importance of autoimmune thyroiditis in childhood thyroid cancer is not yet completely clear. We aimed to evaluate in this study the characteristics of childhood thyroid cancer in patients particularly in terms of coexisting factors including autoimmune thyroid disorders (ATD). Twenty patients diagnosed with primary thyroid cancer were evaluated retrospectively in a Pediatric Endocrinology clinic for 10 years. Patients were followed up for 57.22±11 months. Concomitant conditions (thyroidal and/or extra thyroidal) were determined. Most of the patients (80%) had a coexisting factor. ATDs are the most frequently encountered among them (40%). The ages at the time of diagnosis were older; and the tumor sizes were smaller in patients with concomitant ATDs than without autoimmune thyroid disorders. The follow-up characteristics were similar in both groups. In conclusion, ATDs are frequently encountered in association with thyroid cancer during childhood and adolescence. A thyroid autoimmunity may facilitate the development of a malignant thyroid tumor; on the other hand, increased attention to the thyroid gland may facilitate frequent diagnosis of thyroid cancer. A close follow-up of ATD patients should also include the evaluation of the development of thyroid malignancy.

Context: Previous studies in adults with growth hormone (GH) deficiency have substantiated an increased risk of cardiovascular events. This risk has been attributed to an unpropitious lipid profile, increased abdominal mass, and higher incidence of metabolic syndrome. In these studies, a collateral observation has been a negative correlation between IGF-1 levels and lipid profiles. Longitudinal studies are lacking in children with GH-deficiency wherein the various lipid subfractions after GH treatment were compared to matched GH-sufficient short stature controls. Our study examined changes in small lipid particles following GH treatment. Objective: The primary objective was to determine the effect of GH treatment on serum lipids in GH-deficient patients vs. short controls. Design, setting, and participants: This was a prospective, unblinded, case-controlled, 6-month trial conducted at a tertiary pediatric referral center. Patients were referred for short stature. Incorporating accepted criteria, the treatment group (n=18) was found to be GH-deficient, whereas the control group (n=13) was GH-sufficient. The two groups had near-identical short stature along in addition to baseline measurements of weight and BMI. Interventions: The treatment arm received 6 months of recombinant GH at standard doses. Main outcome measures: The primary endpoint was the comparison of the lipoprotein subclasses and lipids between the two groups after 6 months. Results: With the exception of the intermediate density lipoprotein (IDL), there were no significant differences at baseline in serum lipid profiles between the GH-deficient children and the controls. After 6 months of therapy, there were statistically significant differences in Apo-B, LDL, and smaller lipoparticles (LDL-3 and non-HDL) in GH-treated children compared to untreated GH-sufficient short children. Conclusions: Our findings indicate that GH replacement may improve cardiovascular outcome by favorably altering lipid profiles.

Aim: The aim of this study was to evaluate the morphology and elastic properties of the aorta in children and adolescents with Ullrich-Turner syndrome (UTS) treated with growth hormone, by using magnetic resonance imaging (MRI). Methods: Thirty-seven conscious UTS patients were examined using a 1.5-T whole-body MRI. Contrast-free three-dimensional (3D)-MR angiographies were performed, including 2D cine MRI, to calculate the aortic compliance (C) and cine of the aortic valve. Results: Changes of aortic morphology were evident in 40% of the patients, whereas six had more than one alteration. A bicuspid aortic valve was identified in three patients that were missed by previous echocardiography. The aortic compliances in UTS patients were similar to those in healthy persons. Conclusion: This study shows that aortic morphology and compliance can be assessed by MRI without using contrast agents and without sedation in children and adolescents with UTS.

Aim: To assess the efficiency of oral desmopressin lyophilisate (ODL) in neonatal central diabetes insipidus (CDI). Methods: The characteristics of four newborns with CDI treated with ODL were evaluated. Results: Four newborns with polyuria and hypernatremia were included [male, 2 (50%); mean postnatal age, 19±17 days]. At the time of hypernatremia, the mean serum and urine osmolality values were 310±16 and 179±48 mOsm/kg, respectively. Antidiuretic hormone levels were undetectable (<0.5 pmol/L) in all cases. Magnetic resonance imaging revealed anatomical malformations in all cases. ODL (60 μg/tablet) dissolved in water (3–5 mL) was initiated with a dose of 5 μg/kg/day in two equal doses, together with limitation of water intake to avoid hyponatremia. Serum sodium levels returned to normal in a mean duration of 58±9.9 h with a mean decline rate of 0.37±0.1 mEq/L/h after desmopressin administration. Rehospitalization was required for one of the infants because of hypernatremia due to non-compliance. No episode of hyponatremia was encountered. Weight gain and growth of the infants were normal during the mean follow-up duration of 8.5±1 months. Conclusions: ODL appears to be practical and safe in the treatment of CDI during the first year of life.

Thyroid hormones are important regulators of fetal neurodevelopment. Among preterm infants, thyroid stimulating hormone (TSH) is highly variable. Understanding this variability will further improvements in screening for thyroid disorders in preterm infants. We examined 61 maternal and infant clinical and demographic factors for associations with neonatal TSH levels in 698 preterm neonates. TSH was measured as part of routine State-mandated newborn screening in Iowa. Of the maternal characteristics, nulliparous women (p=8×10 –4 ), women with preeclampsia (p=2×10 –3 ), and those with induced labor (p=3×10 –3 ) had infants with higher TSH levels. TSH levels at the time of newborn screening were associated with respiratory distress syndrome (RDS) (p<0.0001) and sepsis (p=3×10 –3 ). We replicated findings between parity and preeclampsia previously observed in primarily term infants. We also observed strong relationships between neonatal TSH and complications of prematurity including RDS and sepsis, which have implications for future studies examining this relationship both prenatally and longitudinally after birth.

Pituitary infarction or apoplexy with spontaneous cure of the underlying pituitary adenoma is rare. In the paediatric population, we found only a few reported cases. We report a rare case of pituitary infarction progressing to CSF-sella syndrome (or empty sella) in an 11-year-old girl. She presented with sudden onset vomiting, moderate headaches, lethargy, weight loss, and tall stature above her mid-parental height. She did not have any severe symptoms of apoplexy. Her clinical and radiological findings suggested infarction of a pituitary lesion, such as a pituitary adenoma or infarction of a cystic lesion, such as a Rathke’s cleft cyst. In this report, we discuss her case of probable infarction of a growth hormone secreting adenoma with a phase of accelerated growth ending up with total anterior pituitary insufficiency. The differential diagnosis and review of the rare cases of paediatric pituitary infarction in the literature will be discussed.

We present a rare case of galactosemia identified by a positive screening test. A 20-day-old female infant was admitted with jaundice and bloody stained diarrhea. There was no history of fever, convulsions, abdominal distention, or bleeding from other sites. Laboratory findings indicated elevated total billirubin, alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. International normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged. Total vitamin D was low. Quantitative assay for GALT in hemolysates of RBC: 17 μmol/min/mg protein (normal values: 20–35) (compound heterozygous for D2/N: 16–19). GALE level in RBC hemolysate: 11.5 μmol/h/g Hb (normal values 19–35). Our patient was homozygous for the peripheral form of epimerase deficiency galactosemia, as well as heterozygous for GALT/(D2) deficiency. She was started on galactose restricted diet and vitamin supplementation. At the age of 10 months, the patient appeared normal with no signs of developmental delay or eye-cataract.

Congenital hyperinsulinism (CHI) is a rare metabolic disease characterized by inappropriate insulin secretion in the presence of hypoglycemia. We describe the clinical presentation and management of congenital hyperinsulinism and persistent hypoglycemia in two infants. Both patients had an initial clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) but normal methylation analysis for LIT1 and H19 status. Both patients were eventually found to have mosaic uniparental disomy 11p diagnosed by single nucleotide polymorphism (SNP) array in DNA isolated from lymphoblasts and fibroblasts, respectively. We report that patients with mosaic BWS are at increased risk for both transient and refractory hypoglycemia that may need aggressive management with diazoxide, octreotide, high glucose infusion rates, and a frequent feeding regime. Our patient experience supports the case for pursuing further testing in patients with features of BWS with normal methylation studies, karyotype, and SNP arrays on blood. The next logical step is SNP array on skin biopsy to rule out mosaicism.

A female patient with known Hurler-Scheie syndrome, who underwent hematopoietic cell transplantation, presented with growth retardation and delayed puberty. She started growth hormone (GH) treatment at age 12.33 years, resulting in significantly improved linear growth and predicted adult height. We describe details of her clinical course and literature review of growth pattern as well as GH use in patients with mucopolysaccharidosis I.

Hypoparathyroidism, sensorineural deafness and renal dysplasia syndrome (HDRS) is comprised of a triad of conditions. It is an autosomal dominant condition caused by mutations in the GATA3 gene, located at 10p15, a critical region in the development of the embryonic parathyroid glands, inner ear, and kidneys. Here we describe the case of a patient with all three components of HDR syndrome diagnosed in the neonatal period who presented with cerebral infarction, hypocalcemia, and renal anomalies. Upon chromosomal microarray he was found to have an interstitial deletion at 10p, which produced a partial deletion in the GATA3 gene.

Wolcott-Rallison syndrome (WRS) is a very rare genetic disorder, which is transmitted by autosomal recessive inheritance and results from mutations in the gene encoding the eukaryotic initiation factor 2-α kinase-3 ( EIF2AK3 ). The cardinal features of the syndrome include early-onset insulin-dependent diabetes mellitus, multiple epiphyseal dysplasia, and growth retardation. We present the case of a 13-year-old Greek boy with a known history of infancy-onset diabetes mellitus and was found to have WRS at the age of 4 years. He presented with acute liver and renal insufficiency in addition to skeletal dysplasia and neurodevelopmental retardation. The clinical suspicion of WRS was confirmed by molecular analysis of the EIF2AK3 gene. The patient was found to be a compound heterozygote with two different novel mutations (c.2776C>T, p.R902X and c.3038A>G, p.Y989C). The current patient is one of the longer survivors.

We report the case of an infant boy with polyuria and a familial history of central diabetes insipidus. Laboratory blood tests disclosed hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism. Plasma magnesium concentration was slightly low. Urine analysis showed hypercalciuria, hyposthenuria, and high excretion of potassium. Such findings oriented toward type III Bartter syndrome (BSIII). Direct sequencing of the CLCNKB gene revealed no disease-causing mutations. The water deprivation test was positive. Magnetic resonance imaging showed a lack of posterior pituitary hyperintensity. Finally, direct sequencing of the AVP-NPII gene showed a point mutation (c.1884G>A) in a heterozygous state, confirming an autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). This condition did not explain the patient’s phenotype; thus, we investigated for Gitelman syndrome (GS). A direct sequencing of the SLC12A3 gene showed c.269A>C and c.1205C>A new mutations. In conclusion, the patient had a genetic combination of GS and adFNDI with a BSIII-like phenotype.

Iatrogenic Cushing’s syndrome in children may occur as a result of the application of exogenous steroids. Prolonged use of powerful corticosteroids suppresses adrenal functions and iatrogenic Cushing’s syndrome may develop particularly in infants who are given topical corticosteroids. We report here a case on three infants having Cushing’s syndrome with similar clinical presentations due to overuse of topical steroids for diaper dermatitis. The importance of exercising caution during the use of topical steroids is underlined in this study.

Objective: To describe the case of a male Prader-Willi syndrome (PWS) patient with atypical development features. Description: We report the case of a male adolescent with confirmed diagnosis of PWS which presents atypical phenotype. The patient progressed with spontaneous and complete pubertal development, stature in the normal range, and weight control without any pharmacological treatment, except metformin. Comments: PWS is an imprinting paternally inherited disorder of 15q11–13 characterized by hypotonia in infant age, hyperphagia, varied degrees of mental retardation, behavior problems, hypogonadism, short stature, and other less common findings.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive disorder characterized by a nearly complete absence of adipose tissue and generalized muscular appearance. This condition is associated with various dermatological and systemic manifestations. We report a 5-year-old boy, with clinical and metabolic presentation resembling BSCL and unusual features, such as diabetes detected at an early age and multiple duodenal and colonic polyps.

We describe a 13-year-old male with multiple endocrine neoplasia syndrome type 2B with medullary thyroid carcinoma who was diagnosed with ectopic adrenocorticotropin-dependent Cushing syndrome. This report highlights the importance of monitoring for paraneoplastic syndrome in MEN and clues to the diagnosis of this complication provided by growth patterns.

The activation of the hypothalamic-pituitary-gonadal axis observed during the first month of life is thought to be a significant phase in the maturation of gonads and potentially be important for the development of reproductive functions. The preterm ovarian hyperstimulation syndrome (POHS) was first detected at postconception 36–39 weeks in a preterm female newborn with edema developing in the vulva, the hypogastric site, and the upper leg. The pathophysiology of this postnatal hormonal change is obscure. In this paper we would like to present a case developing POHS and to discuss possible pathophyslogical mechanisms.

Background: Diabetic ketoacidosis (DKA) is a common initial presentation of pediatric type 1 diabetes mellitus. Intracerebral complications of DKA pose significant mortality and morbidity rates. Objective: Our aim is to emphasize the importance of early identification, investigation, and treatment for patients who present with DKA and stroke. Case report: Here, we report a case of a 4-year-old female patient who presented with ischemic-hemorrhagic stroke as a complication of DKA. Conclusion: Cerebrovascular complications of DKA in children are a rare condition; however, higher risks take place in their youngest age. Clinicians should be aware of these complications so as to develop appropriate approach for its management.

Background: Cushing’s syndrome (CS) is uncommon in childhood and adolescence. Variable presentation with subtle symptoms and signs can make diagnosis difficult. Case report: We report the case of a 17-year-old girl referred for acne and progressive weight gain with an adrenocorticotropic hormone-independent CS. A computed tomography scan of the adrenals showed normal-sized adrenal glands with discrete bilateral shape irregularity. Bilateral adrenalectomy was performed and the histopathological findings were characteristic of primary pigmented nodular adrenocortical disease (PPNAD). Genetic analysis confirmed a germline mutation of the PRKAR1A gene. The same mutation was found in her sister, mother, and maternal grandfather. Endocrine tests showed that the sister of our patient also presented PPNAD requiring bilateral adrenalectomy and a similar histopathological pattern was observed. No other features of Carney complex was found among all affected members of the family. Conclusion: It is exceptional for PPNAD to be an isolated phenomenon as well as being revealed by progressive weight gain in adolescence.

Type 1 diabetes mellitus (T1DM) is characterized by selective autoimmune destruction of pancreatic b-cells, resulting in insulin deficiency. Associated autoimmune disorders, such as celiac disease, autoimmune thyroiditis, and gastritis, can coexist in patients with T1DM. These disorders are characterized by the presence of antibodies against tissue transglutaminase (anti-tTG-IgA), thyroglobulin, and thyroid peroxidase (anti-TG, anti-TPO), as well as antibodies against gastric parietal cells. Children with T1DM may also develop organ-specific multiple autoimmunity, with the coexistence of one or more autoimmune disorders. Furthermore, there is a lot of controversy regarding the role of thyroid autoimmunity in the pathogenesis of thyroid cancer. We present a child with T1DM and multiple autoimmunity including autoimmune Hashimoto’s thyroiditis (HT), who developed thyroid cancer. The literature on the prevalence of associated autoimmunity in children with T1DM and the prevalence, pathogenesis, and timely diagnosis of thyroid cancer among patients with HT is also reviewed.

Hepatic dysfunctions are not infrequent in patients with hyperthyroidism. These disorders may be related to the effects of the excess thyroid hormone secretion, to the uses of antithyroid drugs, or to the presence of concomitant hepatic diseases. Our aim is to describe the clinical and biochemical features of liver dysfunction related to thyrotoxicosis. We report here a case of a 6-year-old girl who was admitted for jaundice and pruritus as a result of the development of hyperthyroidism due to Graves’ disease. On physical examination at admission, she was found to have jaundice and hepatomegaly. Laboratory data show cholestasis and protein-losing enteropathy. Investigations exclude other causes of hepatic disorder. One month after the initiation of antithyroid drug, the patient became euthyroid with improvement in jaundice and pruritus and normalization of hepatic tests and alpha antitrypsine clearance. In conclusion, the diagnosis of hyperthyroidism may be delayed in patients in whom the primary manifestations were pruritus and jaundice. The physician should suspect thyrotoxicosis prior to hepatitis or skin manifestations.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. Because CH is often inherited in autosomal recessive manner in consanguineous/multicase-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene. The family showed potential linkage to the TSHR locus, and we detected an essential splice site mutation (c.317+1G>A) in both siblings. RT-PCR analysis confirmed the functionality of the mutation. The mutation was homozygous in the cases whereas heterozygous in carrier parents and an unaffected sibling. Here we conclude that thyroid agenesis in both siblings in this study originates from c.317+1G>A splice site mutation in the TSHR gene, and this study underlines the importance of detailed molecular genetic studies in the definitive diagnosis and classification of CH.