Neutropenia Occurs More Often Under Carbimazole than Under Methimazole Treatment in Pediatric Graves' Disease Patients.

Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10-1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger (p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD.

Hoffmann's syndrome and pituitary hyperplasia in an adolescent secondary to Hashimoto thyroiditis.

BACKGROUND: Diffuse muscle hypertrophy is a rare complication of acquired hypothyroidism. When accompanied by stiffness, weakness, and painful muscle cramps, the condition is known as Hoffmann's syndrome (HS). HS is usually seen in young adults due to long-standing untreated primary hypothyroidism. We report a very rare case of HS with muscle hypertrophy and pituitary hyperplasia complicating hypothyroidism in an adolescent. CASE: A 12-year-old male admitted with muscle pain, headache, and fatigue. He had marked hypertrophy of both calf and shoulder muscles. Laboratory tests indicated elevated muscle enzymes and lipids with an elevated thyrotropin and low thyroxine levels. Hashimoto thyroiditis was confirmed on thyroid studies. He had also papilledema bilaterally and magnetic resonance imaging showed an enlargement of the pituitary gland. Treatment with thyroid hormone resulted in complete improvement of symptoms within 3 months. CONCLUSIONS: HS is a rare but treatable form of acquired myopathies and can be seen in children due to untreated hypothyroidism. All patients with an acquired myopathy and muscular pseudohypertrophy should be screened regarding thyroid hormones.

Clinical features and management of diabetic ketoacidosis in different age groups of children: children less than 5 years of age are at higher risk of metabolic decompensation.

OBJECTIVE: To characterize the clinical features and biochemical status at presentation of diabetic ketoacidosis (DKA) in different age groups of children, and to analyze the outcomes of a certain treatment protocol. METHODS: We reviewed records of patients with DKA who were admitted to our hospital between January 2007 and December 2010. Patients were divided into three subgroups according to age, and the results were compared between these groups. RESULTS: One hundred thirty-four episodes in 111 patients (64 females, 47 males) were analyzed. Of these 134 episodes, 60% was in patients with new-onset diabetes and 40% was in those with established diabetes. Patients younger than 5 years had lower C-peptide and HbA1c levels than older patients at clinical onset. They were also given more alkali therapy. The initial conscious level was found closely related to plasma osmolality and serum sodium levels. Seven of 11 patients with recurrent DKA were females. No major complication was observed. CONCLUSION: Our study indicates that younger children are at higher risk for severe metabolic decompensation and require more attention and closer monitoring during treatment. We suggest the use of low-dose insulin in this subgroup of patients with DKA without slowing the correction of acidosis.

Evaluation of hydration status of children with obesity-a pilot study.

OBJECTIVES: To compare the hydration status between children with obesity and normal-weighted children and to determine whether obesity is related to less water consumption. METHODS: Children aged between 7 and 18 years with obesity (Group 1, n=31) were compared with nonobese healthy volunteers (Group 2, n=30) in terms of body composition analysis, urine density and daily fluid intake. RESULTS: The fluid intake per body surface of Group 1 was found significantly less than Group 2 (p<0.001). The urine density was found significantly higher in Group 1 (1020 (10) vs. 1015(10), p<0.001). Subjects in Group 1 had a higher percentage of body fat (p<0.001), lower percentages of total body water and fat-free mass (p=0.007 and <0.001, respectively). While 55% of subjects in Group 1 satisfied the recommended daily fluid intake, this was 80% in Group 2 (p=0.036). The consumption of SSBs was 71% in Group 1 and 20% in Group 2, with higher amount in Group 1 (median 200 vs. 0 mL, p<0.001). CONCLUSIONS: Children with obesity had less fluid consumption, lower TBW percentages and higher urine density. The results of this cross-sectional study showed that children with obesity were less hydrated than normal weighted children.

A Rare Cause of Autistic Regression in a Boy with Down Syndrome: Hashimoto Encephalopathy.

BACKGROUND: Hashimoto encephalopathy (HE) is a rare condition associated with autoimmune thyroid disease. We aimed to report the youngest patient with Down syndrome and HE with an unusual presentation. CASE REPORT: Six years and six months old boy with Down syndrome admitted due to loss of speech. His physical development was appropriate for his age and had no goiter. Neurological examination revealed the absence of eye contact and stereotypic movements. Autism spectrum disorder was considered based on his result on Gilliam autism evaluation scale. He had subclinical hypothyroidism with markedly elevated anti-thyroid peroxidase antibody level, rare spikes in the frontocentral area were found in electroencephalography, and cranial magnetic resonance imaging was normal. Neurologic improvement was observed to a treatment with glucocorticoid and thyroid hormone. CONCLUSION: HE might be considered in patients with Down syndrome along with progressive cognitive decline and autistic regression.

Identification of Three Novel and One Known Mutation in the WFS1 Gene in Four Unrelated Turkish Families: The Role of Homozygosity Mapping in the Early Diagnosis

Objective: Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by nonautoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing. Methods: Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of "in silico" analyses, protein prediction, and functional consequences. Results: Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, that was absent in their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c.1522_1523delTA) mutations in WFS1. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. Conclusion: Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets.

CONTEXT: Hypophosphatemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3. OBJECTIVE: A large kindred with 5 HR patients was recruited with dominant inheritance. The study was undertaken to investigate underlying genetic defects in HR patients. DESIGN: Patients and their family members were initially analyzed for PHEX and FGF23 mutations using polymerase chain reaction sequencing and copy number analysis. Exome sequencing was subsequently performed to identify novel candidate genes. RESULTS: PHEX and FGF23 mutations were not detected in the patients. No copy number variation was observed in the genome using CytoScan HD array analysis. Mutations in DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 were also not found by exome sequencing. A novel c.979-96 T>A mutation in the SGK3 gene was found to be strictly segregated in a heterozygous pattern in patients and was not present in normal family members. The mutation is located 1 bp downstream of a highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids, which is part of the protein kinase domain and contains a Thr-320 phosphorylation site that is required for its activation. Protein tertiary structure modelling showed significant structural change in the protein kinase domain following the deletion. CONCLUSIONS: The c.979-96 T>A splice mutation in the SGK3 gene causes exon 13 skipping and deletion of 29 amino acids in the protein kinase domain. The SGK3 mutation may cause autosomal dominant HR.

Clinical and Genetic Characteristics, Management and Long-Term Follow-Up of Turkish Patients with Congenital Hyperinsulinism.

OBJECTIVE: Mutations in the KATP channel genes is the most common cause of congenital hyperinsulinism (CHI) of infancy. Our aim was to report the clinical and genetic characteristics, treatment modalities, and long-term prognosis of patients with CHI. METHODS: Clinical and biochemical findings, operation procedures, and results of genetic analysis were retrospectively evaluated in 22 CHI patients from two pediatric endocrine centers in Turkey. RESULTS: Seven of the patients were born large for gestational age. Hypoglycemia was diagnosed within the first 24 hours of life in 9 patients and treatment with diazoxide (n=21) and/or somatostatin (n=8) had been attempted. Seven patients (31.8%) were unresponsive to medical treatment and underwent pancreatectomy. Histological examination of the pancreas confirmed diffuse disease in 6 patients. Diabetes developed in 3 patients following pancreatectomy (10 years, 2.5 years, and immediately after operation). The remaining four patients had neither recurrence of CHI nor of diabetes during the 3.67±0.7 years of follow-up. Sequence analysis identified mutations in 12 out of 19 patients (63%). Mutations in the ABCC8 gene were the most common finding and were found in 6 out of 7 patients who underwent pancreatectomy. Other mutations included a paternally inherited KCNJ11 mutation, a homozygous HADH mutation, and a heterozygous GLUD1 mutation. CONCLUSION: Mutations in the ABCC8 gene were the most common cause of CHI in our cohort. These mutations were identified in 85% of patients who underwent pancreatectomy. The development of diabetes mellitus after pancreatectomy may occur at any age and these patients should be screened regularly.

The debate on the link between subclinical hypothyroidism and childhood migraine: is initial endocrinological evaluation necessary for children with migraine?

Subclinical hypothyroidism (SH) is characterized by mildly elevated thyroid stimulating hormone (TSH) levels with normal serum-free thyroxine (fT4). While the prevalence of SH is 2 % in pediatric population, it has been reported much higher in children with migraine headache. In this study, the presence of subclinical hypothyroidism and associated endocrinological abnormalities in children with migraine naïve to treatment was investigated. Children with migraine who were diagnosed in Pediatric Neurology Clinic based on the second edition of the International Classification of Headache Disorders and who did not receive any medication were recruited in this cross-sectional study. All patients were examined by the same pediatric endocrinologist and anthropometric measurements, systemic blood pressure, pubertal stages were recorded. Fasting serum levels of thyroid function tests, lipids, glucose and insulin were obtained. Ninety-eight children (55 female) with a mean age of 11.45 ± 3.1 years were evaluated. Of those, 39 were prepubertal and 59 were pubertal. Subclinical hypothyroidism (TSH ≥ 5.0 mIU/L with normal fT4) was detected in five patients (5.1 %); none had positive thyroid antibodies. Other conditions were obesity (n = 6), hirsutism (n = 4), short stature (n = 3), polycystic ovaries (PCO, n = 3), precocious puberty (n = 2) and gynecomastia (n = 1). Of five patients with SH, only one had obesity. Our results revealed that the prevalence of SH in children with migraine is not as high as previously reported. Since no significant endocrinologic disturbance was found in those children, we suggest that the initial endocrinological evaluation or screening for SH is unnecessary.

Higher body fat and lower fat-free mass in girls with premature adrenarche.

OBJECTIVE: Idiopathic premature adrenarche (PA) refers to presence of androgenic signs before the age of eight years in girls in the absence of thelarche. In children with PA, increased adrenal androgens lead to changes in body composition and transient growth acceleration. Although the association between PA and some components of the metabolic syndrome is well known, body composition has not been extensively studied in these patients. METHODS: We examined 47 girls with PA with a median age of 7.39 years and 57 healthy controls with a median age of 7.11 years. For PA group, the inclusion criteria were appearance of pubic/axillary hair before 8 years of age, absence of findings of central puberty and absence of use of any medication. Patients with steroidogenic enzyme defects and virilizing tumors were excluded. Height, body weight, waist and hip circumference were measured. The bioelectrical impedance method was used for body composition analysis. RESULTS: In the PA group, both body weight standard deviation score (SDS) and height SDS were significantly higher than in the controls (p<0.001 for both). While total body fat percentage values were significantly higher in the PA group than in the controls (median 22.8% vs. 19.95%, p=0.049), fat-free mass (FFM) and total muscle mass percentages were significantly lower than in the controls (median 76.8% vs. 79.9%, p=0.024 and 72.6% vs. 75.7%, p=0.018, respectively). CONCLUSION: Our findings revealed that girls with PA have higher body weight and height for age values. They also show significant changes in body composition such as an increase in total body fat percentage with a concomitant decrease in the percentages of FFM, muscle mass and total body water.

Should patients with Down syndrome be screened for testicular microlithiasis?

BACKGROUND: Testicular microlithiasis (TM) is a rare condition characterized by asymptomatic calcification of seminiferous tubules and is considered as a precursor of testicular germ cell tumors. The prevalence of TM has been reported higher in patients with Down syndrome (DS) than general population. Our aim was to determine the prevalence of TM in our patients with DS. PATIENTS AND METHODS: Male patients with DS confirmed by chromosomal analysis were prospectively evaluated using high resonance ultrasound. For every patient with DS, an age-matched healthy non-DS volunteer was recruited and the results were compared. RESULTS: A total of 50 testes from 25 patients between the age of newborn and 19.3 years were studied. While nine patients with DS (36%) had TM, none of controls had TM. Mean testicular volumes (TVs) of patients with DS did not differ significantly from the control group. In DS group, patients with TM were significantly older than patients without TM (mean age was 8.44 years [range, 2.0-19.3 years] and 2.39 years [range, 0.1-12.1 years], respectively, p = 0.002). TM was found positively correlated with age (r = 0.568, p = 0.003). Cryptorchidism was found in five patients in DS group (three unilateral and two bilateral) and in two controls (one unilateral and one bilateral). Of the nine patients with TM, only one patient had cryptorchidism; thus, TM was not found to be related with cryptorchidism. All the nine patients with DS and TM had normal serum levels of α-fetoprotein and ß-human chorionic gonadotropin. CONCLUSION: On the basis of the high prevalence found in our study, we suggest that all male patients with DS should be screened for TM in childhood.

Epilepsy treatment by sacrificing vitamin D.

Epilepsy is one of the most common neurologic disorders in childhood that often requires long term treatment with antiepileptic drugs. Both antiepileptic treatment and the comorbidities associated with epilepsy have a negative impact on bone health in growing children. Given the fact that vitamin D deficiency is a major public health problem worldwide, clinicians caring for children with chronic diseases should be aware of effects of the medication on the bone metabolism. Yet, vitamin D deficiency due to antiepileptic treatment is an overlooked issue among neurologists. In this review, we briefly describe vitamin D metabolism and the effect of vitamin D in the brain. We also discuss the literature in terms of vitamin D deficiency and antiepileptic treatment in the pediatric population.

Profile of hypothyroidism in Down's syndrome.

OBJECTIVE: Although the association between Down's syndrome (DS) and thyroid dysfunction is well recognized, the cause of this condition is not known. METHODS: Hospital records of patients with DS and hypothyroidism referred to our clinic were retrospectively reviewed. Initial thyroid hormone and thyrotropin (TSH) levels, age at admission, initial anthropometric measurements, age at the beginning of therapy, initial L-thyroxine (L-T4) doses, time to normalization of the thyroid function tests, and L-T4 dose at last visit were recorded. Thyroid ultrasound imaging was used to measure the size of the gland. Descriptive data were expressed as mean±SD values. Skewed data were shown as median and interquartile ranges (IQR). RESULTS: There were 62 patients with DS (32 male and 30 female). Median TSH level at the first visit was 10.40 (19.4) µIU/mL and median free T4 level was 1.18 (0.43) ng/dL. There was no statistical difference in terms of age, hormone and antibody levels, thyroid volume and L-T4 doses between boys and girls. Thyroid volumes of 54 patients were measured. Only nine of these patients had a normal-sized thyroid gland. Median total thyroid volume was 0.89 (2.07) mL. Thyroid volume was negatively correlated to L-T4 dose at last visit (p=0.006, r=-0.387). CONCLUSIONS: We found a high prevalence of thyroid dysgenesis in patients with DS and hypothyroidism. This association has not been reported before. Further studies investigating the thyroid gland size in these patients need to be performed to confirm the results.

Remission with cabergoline in adolescent boys with Cushing's disease.

Cabergoline is a long-acting dopamine receptor agonist used for treatment of patients with uncured Cushing's disease (CD) and, as a first-line treatment, was used in only limited numbers of patients. This report presents two adolescent boys with CD who were treated with cabergoline. Two adolescent boys with clinical and laboratory findings of CD are presented. No pituitary adenoma was detected by radiological investigation in either patient. Adrenocorticotropic hormone (ACTH) hypersecretion and lateralization was found by inferior petrosal sinus sampling in both patients. The initial cabergoline dose was 1mg/week and was adjusted up to 1.5 mg/week in the second patient, based on his urinary free cortisol (UFC) level. The patients responded to cabergoline treatment with normal UFC levels on the 4th and 6th months of treatment. The boys reached complete remission at the end of the 17th and 24th months, respectively. Cabergoline is effective in the control of cortisol secretion and can be considered as a first-line treatment in cases of CD.

Delirium in diabetic ketoacidosis: a case report.

A 15-year-old female patient with known type 1 diabetes mellitus was referred because of abdominal pain. On admission, she was alert but dehydrated with marked Kussmaul breathing. Blood glucose was 414 mg/dL (23 mmol/L). Blood gas analysis revealed severe metabolic acidosis (pH: 6.99) with an elevated anion gap (29.8 mmol/L) and an increased base excess (-25.2 mmol/L). At the sixth hour of treatment with intravenous fluids and insulin, the patient became delirious. The delirium persisted despite the normalization of the acidosis and became difficult to manage. Brain imaging studies revealed neither brain edema nor other intracranial pathology. No evidence of intoxication could be found. The patient gradually regained consciousness and was diagnosed as a case of severe diabetic ketoacidosis (DKA) associated with infection. We were unable to find a similar case in the pediatric literature and thought that reporting this unusual case would be a contribution to the literature on DKA in children.

Developmental defects of the thyroid gland: relationship with advanced maternal age.

OBJECTIVE: Developmental defects of the thyroid gland are the most frequent causes of permanent congenital hypothyroidism. This study aimed to investigate the epidemiological features of patients with thyroid dysgenesis (TD). METHODS: Medical records of 234 patients with TD followed between the years 2008 and 2010 were evaluated retrospectively. Diagnosis was made by ultrasonography. RESULTS: Of 234 patients, 120 (51.3%) were male and 114 (48.7%) were female. Male to female ratio was 1.08 and there were no significant differences in epidemiologic and clinical findings between girls and boys. One hundred eighty-three patients (78.2%) were diagnosed as hypoplasia, 35 (14.9%) as thyroid agenesis, 4 as ectopic thyroid gland and 12 as hemiagenesis. The mean maternal age of the group was 28.9 ± 0.4 years (range 18 to 45 years), which is significantly higher than the recently reported mean maternal ages for Turkish women. CONCLUSIONS: Advanced maternal age was more prevalent in patients with TD. Our clinical and epidemiologic findings suggested no evidence of sexual dimorphism.

3M syndrome: a report of four cases in two families.

3M syndrome is a rare entity characterized by severe growth retardation, dysmorphic features and skeletal changes as its major components. It is differentiated from other types of dwarfism by its clinical features and by the typical slender long bones and foreshortened vertebral bodies that can be visualized radiographically. 3M syndrome has an autosomal recessive mode of inheritance. An early diagnosis is important for genetic counseling. In this report, we present four children (3 males, 1 female) from two families who were aged between 4(11/12) and 10(11/12) years and had clinical findings of 3M syndrome. One of these patients had received growth hormone (GH) treatment which was discontinued due to an inadequate height gain. Physicians should be aware of this entity in the differential diagnosis of children with severe short stature and mild skeletal changes.