Diazoxide-Induced Neutropenia and Long-Term Follow-up in a Patient with Hyperinsulinemia-Hyperammonemia due to GLUD1 Mutation.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic hypoglycemia, in addition to persistently elevated plasma ammonia levels. First-line treatment is diazoxide, and most patients respond well to this agent, however side effects may be observed. The most frequent side effect of diazoxide is fluid retention and hypertrichosis, while hyperuricemia and hematologic side effects are observed less often. Herein, we report a case who had a heterozygous mutation of GLUD1 gene and who developed diazoxide related neutropenia 8 years after the start of treatment. On follow-up, leucopenia and mild neutropenia persisted and the treatment was changed to somatostatin analogues. However, she developed persistent severe symptomatic hypoglycemia and required diazoxide retreatment. A lower dose of diazoxide (6 mg/kg/day) successfully controlled hypoglycemia and cell counts increased even though they were not normalized. Neutropenia in current case presented after a long period of time of diazoxide use and this period is the longest defined in the literature. Long-term endocrine and hematologic follow-up of this patient up to 18 years old will also be presented.

Genetic IGF1R defects: new cases expand the spectrum of clinical features.

PURPOSE: We aimed to identify the phenotypic variability of IGF1R defects in a cohort of short children with normal GH secretion gathered through the last decade. PATIENTS AND METHODS: Fifty children (25 girls) with short stature and a basal/stimulated growth hormone (GH) over 10 ng/ml having either a low birth weight or microcephaly were enrolled. MLPA and then Sanger sequence analysis were performed to detect IGF1R defects. The auxological and metabolic evaluation were carried out in index cases and their first degree family members whenever available. RESULTS: A total of seven (14%) IGF1R defects were detected. Two IGF1R deletions and five heterozygous variants (one frameshift, four missense) were identified. Three (likely) pathogenic, one VUS and one likely benign were classified by using ACMG. All children with IGF1R defects had a height < - 2.5SDS, birth weight < - 1.4SDS, and head circumference < - 1.36SDS. IGF-1 ranged from - 2.44 to 2.13 SDS. One child with a 15q terminal deletion had a normal phenotype and intelligence, whereas low IQ is a finding in a case with missense variant. Two parents who carried IGF1R mutations had diabetes mellitus, hypertension and hyperlipidemia, one of whom also had hypergonadotropic hypogonadism. CONCLUSION: We found a deletion or variant in IGF1R in 14% of short children. Birth weight, head circumference, intelligence, dysmorphic features, IGF-1 levels and even height are not consistent among patients. Additionally, metabolic and gonadal complications may appear during adulthood, suggesting that patients should be followed into adulthood to monitor for these late complications.

Acquired resistance to pamidronate treated effectively with zoledronate in juvenile Paget's disease.

Juvenile Paget's disease (JPD) is a rare autosomal recessive osteopathy. There is still a question about the most effective treatment modality in long-term prognosis. A 9-month-old boy who suffered from bone pain and deformities with a very high alkaline phosphatase level was diagnosed as JPD by radiographic findings. Genetic analysis showed a homozygous large deletion in TNFRSF11B gene encoding osteoprotegerin. Clinical improvement was observed with intravenous pamidronate therapy. However, the effect of drug reduced in time so the annual dose per kilogram body weight was increased after 2 years. Despite this increment, bone fractures developed and bone pain recurred with high-ALP levels, which suggested resistance to pamidronate. Switching to zoledronate resulted a significant improvement in bone findings radiographically and ALP level. Severe hypocalcemia requiring intravenous calcium treatment complicated the first dose of zoledronate, but not recurred thereafter. Intravenous pamidronate therapy is effective in reducing bone pain, improving bone deformities and motor development in infantile onset JPD. However, this effect can be transient. Switching to another bisphosphonate like zoledronate may provide long-term clinical and biochemical improvement as an alternative treatment in case of resistance to pamidronate therapy.

Risk factors for clavicle fracture concurrent with brachial plexus injury.

PURPOSE: The aim of this study was to evaluate the risk factors for clavicle fracture concurrent with brachial plexus injuries. METHODS: A retrospective study was conducted at a tertiary centre. The hospital records of 62,288 vaginal deliveries were evaluated retrospectively. There were 35 cases of brachial plexus injury. Of these patients, nine had brachial plexus injuries with clavicle fracture and 26 without clavicle fracture. The analysed risk factors for clavicle fracture concurrent with brachial plexus injury were gestational diabetes, labour induction and augmentation, prolonged second stage of labour, estimated foetal weight above 4000 g, birth weight above 4000 g, risky working hours, and the requirement of manoeuvres to free the impacted shoulder from behind the symphysis pubis. RESULTS: Labour augmentation with oxytocin increased the risk of clavicle fracture in cases of brachial plexus injury (OR 6.67; 95% CI 1.26-35.03). A birth weight higher than 4000 g also increased the risk of clavicle fracture. Risky working hours, gestational diabetes, estimated foetal weight higher than 4000 g, and requirement of shoulder dystocia manoeuvres did not increase the risk of clavicle fracture. CONCLUSIONS: Labour augmentation and actual birth weight higher than 4000 g were identified as risk factors for clavicle fracture in cases of brachial plexus injury.

Intrapartum, postpartum characteristics and early neonatal outcomes of idiopathic polyhydramnios.

This paper investigates the effect of idiopathic polyhydramnios on the intrapartum and postpartum characteristics of labour and early neonatal outcomes. In this study, intrapartum and early neonatal outcomes of 207 women with idiopathic polyhydramnios and 336 matched healthy pregnant patients were evaluated. In the case of idiopathic polyhydramnios, the active phase of labour became longer when compared to the control group (5.76 ± 3.56 h vs. 4.38 ± 2.8 h, p: 001). The risk of preterm birth (OR 5.23; 95% CI: 2.04-13.42) and caesarean section (OR 2.26; 95% CI: 1.56-3.28) was higher in women with IP. Patients with IP had a higher rate of transcient tachypnoea of the newborn (TTN), newborn resuscitation, admission to neonatal intensive care unit (NICU), ventilator requirement, newborn jaundice, newborn hypoglycaemia and structural anomalies. IP did not cause any appreciable maternal risk during the intrapartum or postpartum periods. However, neonatal morbidity and post-natal anomaly rates were higher in the case of IP.

Variations in tumor marker levels in metastatic breast cancer patients according to tumor subtypes.

PURPOSE: To investigate whether serum CA 15-3 and CEA levels show differences among subgroups of breast cancer patients at the time of diagnosis of early-stage disease and at disease relapse. METHODS: Patients with metastatic breast cancer diagnosed from 2000 to 2010 were retrospectively analyzed. Data were obtained from medical charts. CA 15-3 and CEA levels of patients with metastatic disease at the time of diagnosis or who relapsed during follow-up were evaluated. Four different breast cancer subtypes were defined: estrogen receptor (ER) and/or progesterone receptor (PR) positive and HER-2 negative (luminal A), ER and/or PR positive and HER-2 positive (luminal B), ER and PR negative and HER-2 positive (HER-2 overexpressing) and triple negative (ER, PR and HER-2 negative). Fifty-eight (13.7%) of the patients were metastatic at the time of diagnosis. RESULTS: 423 metastatic breast cancer patients were included. Of the patients, 232 (54.8%) had luminal A disease, 70 (16.5%) luminal B, 53 (12.5%) HER-2 overexpressing, and 68 (16.1%) triple negative disease. Preoperative CA 15-3 levels were raised in 48.1% of the luminal A group, in 42.8% of the luminal B group, in 26.0% of the HER-2 overexpressing group, and in 33.3% of the triple negative group. CA 15-3 levels after relapse were raised in 44.5% of the luminal A group, in 33.3% of the luminal B, in 28.9% of the HER-2 overexpressing, and in 38.8% of the triple negative group. Preoperative CEA levels were elevated in 44.3% of the luminal A group, in 28.5% of the luminal B, in 43.4% of the HER-2 overexpressing, and in 14.3% of the triple negative group. CEA levels after relapse were raised in 60.8%, 54.7%, 51.1%, and 36.0% of the patients in the 4 subgroups, respectively. CONCLUSION: This study showed that there are differences between the breast cancer subgroups in terms of tumor marker levels in metastatic breast cancer patients. Tumor marker elevation was lower in the triple negative group as compared to the luminal groups. Monitoring CEA levels in luminal A group may be beneficial in determining early relapses. However, this retrospective study requires further prospective confirmative cohort studies.

c-Kit (CD117) expression in classic Kaposi's sarcoma.

BACKGROUND: Kaposi's sarcoma is a multicentric, low-grade, vascular neoplasia. Human herpesvirus 8 is associated with all epidemiological forms of KS and has been shown in vitro to induce the tyrosine receptor kinase c-Kit in infected cells. AIM: To investigate the expression of c-Kit in cases of classic KS and to clarify its association with clinicopathological parameters and HHV8 latency-associated nuclear antigen-1 expression. METHODS: In total, 35 cases of classic KS at various histological stages were included in the study. Age and gender of the patients and location and histological stage of the tumours were recorded. Formalin-fixed, paraffin wax-embedded tissue sections were stained by immunohistochemistry with antibodies to c-Kit and HHV8. RESULTS: c-Kit immunoreactivity was found in 22 cases and HHV8 immunoreactivity was present in all cases. There was no correlation in c-Kit immunoreactivity between clinicopathological parameters and HHV8 immunoreactivity. CONCLUSIONS: The results of our study show that in cases of classic KS there is a high rate of c-Kit immunoreactivity, but c-Kit expression does not show any correlation with HHV8 immunoreactivity.

Anemia and neutropenic fever with high dose diazoxide treatment in a case with hyperinsulinism due to Munchausen by proxy.

BACKGROUND: The etiology of hyperinsulinemic hypoglycemia in adolescents is similar to that of adults. Patients resistant to medical treatment may undergo pancreatectomy. Diazoxide is the mainstay of medical treatment. Rarely bone marrow suppression is reported due to diazoxide. PATIENT: An adolescent with severe hyperinsulinemic hypoglycemia was referred for pancreatectomy after she was treated with high doses of diazoxide, octreotide and glucose. She developed anemia and febrile neutropenia in the course of diazoxide treatment that resolved with cessation of medication. The cause of the hyperinsulinemia proved to be classical Munchausen by proxy. CONCLUSION: This is the first report of bone marrow suppression involving erythroid series by diazoxide. Follow-up of blood count may be considered in patients on high dosages since anemia may be dose dependent. Munchausen by proxy poses a serious threat to children with significant morbidity and mortality. Awareness and a high index of suspicion in clinical settings with unusual causes are the mainstay for the diagnosis.

Assessment of thyroid function during the long course of Hashimoto's thyroiditis in children and adolescents.

CONTEXT: The prognosis of Hashimoto's thyroiditis (HT) in children and adolescents is not well known and studies reporting long-term outcome of the disease are scarce. OBJECTIVE: To assess the thyroid hormone status during long-term follow-up and to establish the prognosis of children and adolescents with HT. PATIENTS: One hundred and twenty-nine patients with HT were re-evaluated for thyroid hormone status after a mean follow-up period of 50 months. RESULTS: Seventy-seven per cent of the euthyroid patients were still euthyroid, while 21.1% of these patients became hypothyroid at the time of re-evaluation. However, 69.5% of hypothyroid patients remained hypothyroid (overt or subclinical) and 30.5% recovered. CONCLUSION: HT is a dynamic process. Thyroid functions can show variation during follow-up. Therefore, thyroid function tests should be repeated periodically to detect progression to hypothyroidism in initially euthyroid patients as well as reversibility of hypothyroidism.

Hashimoto's thyroiditis in children and adolescents: a retrospective study on clinical, epidemiological and laboratory properties of the disease.

UNLABELLED: Hashimoto's thyroiditis (HT) is the most common cause of goiter and acquired hypothyroidism in children and adolescents in iodine replete areas. To find out the clinical, epidemiological and laboratory characteristics of the disease in childhood, we reviewed files of 162 children and adolescents with HT followed in the Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine. RESULTS: Female patients constituted 86.4% (n = 140) of all patients with a female:male ratio of 6.4. Mean age at diagnosis was 11.4 +/- 2.97 years (age range 4.4-16.5 years). At the time of diagnosis 43.2% of the patients (n = 70) were euthyroid, 24.1% (n = 39) had subclinical hypothyroidism, 21% (n = 34) had overt hypothyroidism, and 8.6% (n = 14) had overt and 3.1% (n = 5) subclinical hyperthyroidism. CONCLUSIONS: Autoimmune thyroiditis is more frequent in females, and increases in frequency over age during childhood and adolescence. At the time of diagnosis, frequency of overt and subclinical hypothyroidism is similar to that of euthyroid goiter.

A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis.

The rare bone thickening disease osteopetrosis occurs in various forms, one of which is accompanied by renal tubular acidosis (RTA), and is known as Guibaud-Vainsel syndrome or marble brain disease. Clinical manifestations of this autosomal recessive syndrome comprise increased bone density, growth failure, intracerebral calcification, facial dysmorphism, mental retardation, and conductive hearing impairment. The most common cause is carbonic anhydrase II (CAII) deficiency. Several different loss of function mutations in CA2, the gene encoding CAII, have been described. To date, there have been no exceptions to the finding of CAII deficiency in patients with coexistent osteopetrosis and RTA. Most often, the RTA is of mixed proximal and distal type, but kindreds are reported in which either distal or proximal RTA predominates. We report the molecular genetic investigation of two consanguineous kindreds where osteopetrosis and distal RTA (dRTA) were both manifest. One kindred harbours a novel homozygous frameshift alteration in CA2. In the other, CAII levels were normal despite a similar clinical picture, and we excluded defects in CA2. In this kindred, two separate recessive disorders are penetrant, each affecting a different, tissue specific subunit of the vacuolar proton pump (H(+)-ATPase), providing a highly unusual, novel genetic explanation for the coexistence of osteopetrosis and dRTA. The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H(+)-ATPase. This kindred is exceptional firstly because the coinheritance of two rare recessive disorders has created a phenocopy of CAII deficiency, and secondly because these disorders affect two different subunits of the H(+)-ATPase that have opposite effects on bone density, but which have only recently been determined to possess tissue specific isoforms.

Nine novel growth hormone receptor gene mutations in patients with Laron syndrome.

The GH receptor (GHR) is a member of the cytokine receptor superfamily; GH binding protein is the solubilized extracellular domain of the GHR. Abnormalities in the GHR produce an autosomal recessive form of GH resistance, the Laron syndrome, characterized by growth failure and the clinical appearance of severe GH deficiency despite elevated circulating GH levels. In 13 unrelated patients with undetectable levels of GH binding protein, we characterized nine novel mutations in the GHR gene. These molecular defects comprise three nonsense mutations (Q65X, W80X, and W157X), one frameshift (36delC), two splice defects (G-->A at 70 + 1, C-->T at 723), and three missense mutations (C38S, S40L, and W50R) located in the extracellular domain of the receptor, and thus would be expected to interfere with GH binding activity. These results further confirm the broad heterogeneity of mutations underlying this rare GH resistance syndrome.

Review of Turkish patients with growth hormone insensitivity (Laron type).

Clinical spectrum and endocrine details of thirteen Turkish children (age 0.3-14.2 years; eight females and five males; ten prepubertal, three pubertal) with growth hormone insensitivity are presented. All patients display phenotypical features of severe growth hormone deficiency. The diagnosis based on height standard deviation score (SDS), basal growth hormone (GH), basal insulin-like growth factor I (IGF-I, IGF-I response in an IGF generation test and growth hormone binding protein (GHBP) measurements. The median height SDS was -7.4 (range -3.2 to -10), weight for height index was 100 (range 81-152) and bone age/height age ratio was 2 (range 1.6-3.3). Endocrine investigations showed a median basal GH concentration of 61.4 mU/l (range 23.5-120 mU/l). Basal IGF-I level was below 10 ng/ml in all patients except one. None of the patients showed a significant IGF-I response to injections of GH (0.1 U/kg body weight for 4 days). The median IGFBP-3 level was 0.23 mg/l (range 0.1-0.56 mg/l). The GHBP level was undetectable in all of 10 patients. The high number of patients in our center may be due to the high rate of consanguinity among the Turkish population and the referral facility of our center in the area. These patients may benefit from the new therapy with recombinant human IGF-I.

mtDNA nt3243 mutation, external ophthalmoplegia, and hypogonadism in an adolescent girl.

A 14-year-old girl presented with a 3-month history of easy fatigue and exercise intolerance, especially when climbing stairs. She had a mild ptosis and mild limitation of upward gaze. Her puberty was delayed, and she manifested hypogonadotrophic hypogonadism. Serum lactic and pyruvic acids were elevated. Cranial magnetic resonance imaging was normal. Muscle biopsy documented typical ragged-red fibers. A point mutation at nucleotide 3243 in the tRNALeu(UUR) (typical mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation) was detected in mitochondrial DNA from both blood and muscle tissues, indicating that our patient was suffering from a mitochondrial myopathy. Hypogonadism may be a manifestation of the MELAS nucleotide 3243 mutation.

Age-related differences in serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels in congenital hypothyroidism.

It is well established that thyroid hormones play a fundamental role in normal growth and development. The complex relationship between thyroid hormone and the growth hormone-insulin-like growth factor axis is not completely understood. We investigated age-related differences in serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels in 43 patients with primary congenital hypothyroidism. These patients were classified into five age groups (Group I: 0-1 month, Group II: 1 month-1 year, Group III: 1-5 years, Group IV: 5-9 years, Group V: 9-13 years). Patients diagnosed in the first month of life did not display a significant difference in serum IGF-I and IGFBP-3 levels compared to age-matched controls (p > 0.05). However, in groups II to V, IGF-I and IGFBP-3 levels were significantly lower than in controls (p < 0.05). Thyroid hormone replacement therapy increased serum IGF-I and IGFBP-3 levels significantly in 26 hypothyroid children (p < 0.05). Although serum IGF-I and IGFBP-3 levels increase in an age dependent manner in normal children, this increment was not observed in hypothyroid children.

Magnetic resonance imaging in growth hormone deficiency: relationship between endocrine function and morphological findings.

Magnetic resonance imaging (MRI) using gadopentetate dimeglumine (Gd-DTPA) improves the delineation of hypothalamic-pituitary structures and facilitates the detection of anatomical abnormalities which are indicators of permanent growth hormone deficiency (GHD). The aim of this study was to determine the frequency of neuroradiological abnormalities in 85 (52 M, 33 F) patients with hereditary or idiopathic forms of isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) and also to investigate the relationship between anatomical findings and hormonal status. Pituitary hypoplasia with absent or thin infundibulum and ectopic posterior pituitary (EPP) were the most frequent findings in 39 patients with MPHD, whereas in 46 patients with IGHD the most frequent finding was pituitary hypoplasia without neuroradiological abnormalities. All patients whose infundibulum was not visualized after Gd-DTPA injection belonged to the MPHD group; therefore, absence of pituitary stalk can be a good indicator of the severity of hormonal deficiencies. Pituitary hypoplasia was found in all patients with familial IGHD. Among patients with abnormalities of the hypothalamic pituitary area on MRI, normal or breech delivery frequency distributed equally. Therefore it seems that mechanical or hypoxic prenatal events cannot be the primary etiological factor in all patients with neuroradiological abnormalities since half of these patients had normal delivery and birth history. The localization of the bright spot of the posterior pituitary at the level of the median eminence, midstalk position or at the end of the infundibulum may suggest a neuronal migration defect which may occur during early embryogenesis. In conclusion, in children with GHD a careful examination of the hypothalamic pituitary area by MRI after enhancement helps to establish the diagnosis and predicts the prognosis.

True hermaphroditism: clinical features, genetic variants and gonadal histology.

True hermaphroditism is a rare cause of intersexuality in which both ovarian and testicular tissue is present in the same individual. We present the clinical findings, karyotype, gonadal histology and management of eight patients with true hermaphroditism. Their ages ranged from 43 days to 12 years at the first evaluation. The presenting symptoms were ambiguous genitalia (6 patients), isolated clitoromegaly (1 patient) and hypospadias (1 patient). The most common karyotype was 46,XX (6 patients). In one patient the karyotype was 46,XY and in another 45,XO/46,XY mosaicism, which is rare in the literature. A vagina was found by genitography in all patients, and at laparotomy the uterus was found normal in five patients, hypoplastic in one patient, as a fibrous band in one, and absent in the remaining patient. Histological investigation of the gonads revealed bilateral ovotestis in two patients, ovotestis plus ovary in two patients, and ovary on one side and testis on the other side in three patients. Five patients were assigned to the female sex, and three to the male sex. One of these patients was changed from male to female after evaluation.

Height prognosis in children with late-diagnosed congenital hypothyroidism.

It is a general belief that early and adequate thyroid hormone replacement achieves normalization of growth as well as disappearance of clinical sings and symptoms of hypothyroidism. Due to the lack of comprehensive growth studies, height prognosis has remained controversial in late-diagnosed hypothyroidic children. The limited number of previous studies have suggested permanent height deficit in these children. In this study we present longitudinal growth and final height of 20 children (14 females and 6 males) in whom the duration of hypothyroidism before onset of therapy varied from three to 12.6 years. The etiological distribution of cases revealed ectopic thyroid tissue in nine cases, agenesis in seven, and dyshormonogenesis in four cases. At the time of the diagnosis all hypothyroidic children had severe growth retardation (mean height SDS +/- SD -3.95+/-1.07) due to prolonged hypothyroidism. Although the catch-up spurt corrected an important part of the initial height deficit in all patients, only nine patients reached or exceeded their target height, and the final height of five patients remained below 2 SD of mean. Despite treatment, prolonged hypothyroidism may result in compromised adult height in some patients. The contributing factors to this height deficit may include the duration of hypothyroidism, the height deficit at the time of the diagnosis, etiological differences and the diminished potential for catch-up growth in late-diagnosed hypothyroidism.

The epidemiology of juvenile-onset insulin-dependent diabetes mellitus in Turkish children. A retrospective analysis of 477 cases.

The hospital records of 477 patients under 18 years of age with insulin-dependent diabetes mellitus (IDDM) who were followed in the Endocrinology Unit of Hacettepe University Children's Hospital between the years 1969 and 1991 were analyzed for age, sex, residence at time of diagnosis, date of onset of symptoms, date of diagnosis, family history of IDDM, and consanguinity between parents. The distribution of age at diagnosis showed a small peak between 4 and 6 years of age and a main peak between 12 and 14 years. In girls, the main peak appeared between 10 and 12 years, and in boys between 12 and 14. A significant difference was not seen between sexes (239 males and 236 females). The frequency of diagnosis showed seasonal variations the lowest in autumn and the highest in winter. Consanguinity between parents was 23.9 percent, and 10.3 percent of the patients had IDDM in first degree relatives.

The results of long-term growth hormone replacement therapy in Turkish children with growth hormone deficiency.

From a total of 118 patients treated for growth hormone deficiency, 37 (23 boys, 14 girls) have reached their final height. Twenty-five patients had isolated growth hormone deficiency (IGHD) and 12 had multiple pituitary hormone deficiency (MPHD). Growth hormone deficiency was diagnosed and treated late in both boys and girls. The mean height standard deviation score (SDS) for chronological age (CA) increased significantly from -4.43 to -1.94 during the therapy. The target height was not achieved in boys or girls nor in MPHD and IGHD groups, although they have reached the third percentile of the normal Turkish population. The height and chronological age of the patients at the start of the treatment correlated significantly with final height in all patients. Therefore, early diagnosis and treatment is important to complete catch-up growth in growth hormone deficient patients. The height prognosis is improved with administration of a recombinant form of human growth hormone (GH) as daily subcutaneous injections with a dose of 0.1 IU/kg, when compared to the earlier studies with pituitary GH.