Abnormal uterine bleeding (AUB) is the most common gynecologic complaint of adolescents admitted to hospital. Heavy menstrual bleeding (HMB) is the most frequent clinical presentation of AUB. Anovulatory cycles, owing to immature hypothalamic-pituitary-ovarian axis, is the leading etiology of HMB and there is an accompanying bleeding disorder in almost 20% of patients with HMB. Additionally, endocrine disorders such as hypothyroidism, hyperprolactinemia and polycystic ovary syndrome are possible causes of AUB. Exclusion of bleeding disorders, especially of von Willebrand disease is important for diagnosis and treatment of HMB, particularly in cases with AUB, which has been present since menarche. Management of HMB is based on the underlying etiology and severity of the bleeding. After other causes are excluded, anovulatory heavy bleeding can be treated successfully with combined oral contraceptives and iron supplementation either as an outpatient or in hospital depending on the clinical findings and level of anemia. The epidemiology, clinical presentation, diagnostic approach and treatment of HMB is discussed and our clinical experience in this field is presented in this review.

Objective: In this study, we evaluated the frequency of euthyroid sick syndrome (ESS) among patients with childhood cancer and its association with the stage of disease, nutritional parameters and cytokines levels.
Methods: Eighty newly diagnosed children were included in the study. ESS was assessed in two different ways. According to criteria 1 ESS was present if free triiodothyronine (fT3) was below the lower limit and free thyroxine was within the normal or low limits, thyroid-stimulating hormone (TSH) was in the normal range. According to criteria 2, in addition to the above, it was required that reverse triiodothyronine (rT3) be performed and was higher than normal limits.
Results: Three of our pediatric patients had subclinical hypothyroidism and two had subclinical hyperthyroidism. Out of 75 patients, ESS was identified in 14 (17.3%) according to criteria 1 and in eight (10.6%) according to criteria 2. Only fT3 levels were significantly different in the ESS (+) and ESS (-) groups (p<0.05) according to criteria 1. A significantly negative correlation between interleukin (IL)-6 and fT3 was found, according to both sets of criteria. tumor necrosis factor alpha was negatively correlated with fT3 levels only in the criteria 1 group. There were no correlations between IL-1ß and fT3, free thyroxine, rT3 and TSH levels.
Conclusion: ESS may occur in childhood cancer and thyroid function testing should be performed routinely when cancer is diagnosed.

Objective: 17?-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), characterized by hypertension and varying degrees of ambiguous genitalia and delayed puberty. The disease is associated with bi-allelic mutations in the CYP17A1 gene located on chromosome 10q24.3. We aimed to present clinical and genetic findings and follow-up and treatment outcomes of 17OHD patients.
Methods: We evaluated six patients with 17OHD from five families at presentation and at follow up. Standard deviation score of all auxological measurements was calculated according to national data and karyotype status. CYP17A1 gene sequence alterations were investigated in all patients.
Results: The mean (±standard deviation) age of patients at presentation and follow-up time was 14.6±4.2 and 5.0±2.7 years respectively. Five patients were referred to us because of delayed puberty and primary amenorrhea and four for hypertension. One novel single nucleotide insertion leading to frame shift and another novel variant occurring at an ultra rare position, leading to a missense change, are reported, both of which caused 17OHD deficiency. Steroid replacement was started. The three patients with 46,XY karyotype who were raised as females underwent gonadectomy. Osteoporosis was detected in five patients. Four patients needed antihypertensive treatment. Improvement in osteoporosis was noted with gonadal steroid replacement and supportive therapy.
Conclusion: 17OHD, a rare cause of CAH, should be kept in mind in patients with pubertal delay and/or hypertension. Patients with 46,XY who are raised as females require gonadectomy. Due to late diagnosis, psychological problems, gender selection, hypertension and osteoporosis are important health problems affecting a high proportion of these patients.

Objective: Disorders of sex development (DSD) is a nomenclature intended to defeat the discomfort of families and patients and has found worldwide usage. The aim of this study was to address the perception and usage of terminology among the parents of DSD patients in a tertiary center in western Turkey.
Methods: The records of the DSD council (multidisciplinary team where each patient with DSD is discussed) between years 2008-2015 were reviewed retrospectively. Data including details of the management process, patient characteristics and follow-up details were noted. Then inquiries reflecting parental perception about terminology were implemented during clinical visits.
Results: In total, 121 patients were evaluated in monthly meetings of the DSD council and 79 inquiries were completed. Fifty-one percent of the families admitted knowing the terms DSD, ambiguous genitalia, “dubious genitals” and intersex. However, only 2% preferred using DSD, 6% intersex and 14% ambiguous genitalia. Fifty-two percent of the parents used a disease name in Latin (mostly hypospadias) addressing the disorder. The offspring of 69% of the parents who were familiar with the name “dubious genitals” were diagnosed in the neonatal period. The preferred terminology used by parents was strongly associated with the terminology used most commonly in the medical speciality their child most often attended.
Conclusion: Each country has its own social norms. We suggest therefore that local committees including medical professionals, patients and families should be employed to develop proper terminology.

Objective: There have been recent advances in the understanding of the etiology of idiopathic central precocious puberty (iCPP) including new genetic associations. The aim of this clinical study was to determine the frequency of MKRN3 mutation in cases of familial iCPP.
Methods: Potential sequence variations in the maternally imprinted MKRN3 gene were evaluated in 19 participants from 10 families using next-generation sequencing analysis.
Results: MKRN3 variation was found in only one of the 19 (5.3%) subjects. The male patient, who had a medical history of precocious puberty, had a heterozygous mutation, NM_005664.3: c.630_650delins GCTGGGC (p.P211Lfs*16). The father of this patient also had a history of precocious puberty and had the same mutation. p.P211Lfs*16 is a novel variant and it was identified as probably pathogenic by in silico analysis, consistent with the clinical findings.
Conclusion: Given that MKRN3 mutation was detected in only one patient, with a paternal history of precocious puberty, this reinforces the importance of accurate family history taking. The detected incidence of MKRN3 variants in our case series was much lower than reported elsewhere which suggests a need for further studies in Turkish iCPP patients.

Objective: A comprehensive survey was conducted to evaluate the shortcomings of clinical care in patients with Turner syndrome (TS) in Turkey.
Methods: A structured questionnaire prepared by the Turner study group in Turkey, which covered relevant aspects of patient care in TS was sent to 44 pediatric endocrinology centers.
Results: Eighteen centers (41%) responded to the questionnaire. In the majority of the centers, diagnostic genetic testing, screening for Y chromosomal material, protocols regarding the timing and posology of growth hormone (GH) and estrogen, thrombophilia screening, fertility information and screening for glucose intolerance, thyroid, and coeliac diseases in patients with TS were in line with the current consensus. Thirteen centers (72.2%) performed GH stimulation tests. Only four centers (22.2%) used oxandrolone in patients with TS with very short stature. The majority of the centers relied on bone age and breast development to assess estrogen adequacy, though together with variable combinations of oestrogen surrogates. Two centers (11.1%) reported performing serum estradiol measurements. Eight centers (44.4%) routinely conducted cardiac/thoracic aorta magnetic resonance imaging. Screening for hearing, dental and ophthalmologic problems were performed by thirteen (72.2%), six (33.3%) and ten (55.6%) centers, respectively. Psychiatric assessments were made by four centers (22.2%) at diagnosis, with only one center (5.6%) requiring annual reassessments.
Conclusion: Although we found some conformity between the current consensus and practice of the participating centers in Turkey regarding TS, further improvements are mandatory in the multi-disciplinary approach to address co-morbidities, which if unrecognized, may be associated with reduced quality of life and even mortality.

Objective: Data concerning subnormal growth velocity (GV) and factors that influence this during gonadotropin-releasing hormone analog (GnRHa) therapy for idiopathic central precocious puberty (ICPP) are scarce. We investigated the incidence of subnormal GV and associated factors in patients receiving GnRHa therapy for ICPP.
Methods: In this retrospective cohort study, the records of 50 girls who had been diagnosed with ICPP and started on GnRHa treatment before the age of eight years were investigated. Subnormal GV frequency, related factors during GnRHa therapy and the effect on final height were examined.
Results: During the treatment, a significant decrease in the annual GV and GV standard deviation score (SDS) of the patients was observed. In 16 (32%) patients GV never declined below -1 SDS, while a decline was noted once and twice in 19 (38%) and 15 (30%) patients respectively. The median age of detection of subnormal GV was 9.9 (4.9-10.9) years. Patients with pubic hair at diagnosis were found to have an increased risk of subnormal GV (p=0.016). There was a significant negative correlation between diagnostic basal luteinizing hormone (LH) level and the first and second year GV SDS (p=0.012 and 0.017 respectively). A significant negative correlation between bone age at diagnosis and 3rd year GV SDS, and 4th year GV SDS (p=0.002 and p=0.038) was also observed. LH suppression significantly increased during treatment (p=0.001).
Conclusion: In girls with ICPP the risk of subnormal GV appears highest at the 3rd year of GnRHa treatment, particularly in those patients with, at the time of diagnosis, pubic hair in conjunction with high baseline and peak LH and advanced BA and excessive LH suppression on follow-up.

Objectives: Continuation of growth hormone (GH) treatment in adolescents with severe childhood onset idiopathic GH deficiency (IGHD) during the transition period, irrespective of achievement of final height, is still debatable. We aimed to prospectively investigate the metabolic profile, bone mineral density (BMD) and body composition of patients with IGHD in whom GH treatments were terminated after they had reached their final height, six months after the cessation of therapy.
Methods: Twelve patients, six of whom had peak GH levels <5 ng/mL [permanent GH deficiency (GHD), group 1], and six who had peak GH levels >5 ng/mL (transient GHD, group 2) after insulin stimulation test were evaluated for anthropometric and laboratory parameters including fasting blood glucose (FBG), fasting insulin, lipid profile, BMD, body composition measurements and 24-hour ambulatory blood pressure monitoring before (baseline) and at six months after discontinuation of GH.
Results: No differences were found in clinical, laboratory, BMD and body composition measures between groups 1 and 2 at baseline. All IGHD patients had significant increments of body weight (BW), body mass index (BMI), BMD, total body fat (TBF), TBF%, truncal fat (TF) and TF% after GH cessation. Six months later BW, BMI, BMD and TF% was increased significantly while FBG and lipids showed no change in group 1. In group 2, TBF% and TF% were increased, FBG, total cholesterol and high-density lipoprotein decreased after six months. Changes in these parameters in group 2 were not statistically different from group1.
Conclusion: TF% increase in both groups after cessation of therapy. We did not observe a clinical condition requiring GH treatment in any of the study subjects during the follow-up period.

Objective: We aimed to investigate the prevalence of Turner syndrome (TS) in the Ukrainian population, the frequency of karyotype variants, the age of children at diagnosis, the degree of short stature and phenotypic features in TS girls.
Methods: A retrospective analysis was made in 538 TS girls aged 0.11-18.2 years within the time period of 2005-2015 with detailed examination of 150 patients.
Results: The prevalence of TS in Ukraine is 77.5 in 100.000 live female births. The average age at diagnosis is 9.33±4.93 years. The relative proportions of karyotypic abnormalities found were: 45,X (59.3%); mosaicism 45,X/46,XX (22.9%); and structural abnormalities in chromosome X (17.8%). The most frequently encountered findings were growth delay (98.8%), shortening of the 4th and 5th metacarpal bones (74.6%), abnormal nails (73.3%), broad chest (60.7%), short neck (58.6%), hypertelorism of nipples (51.4%), malformations of the cardiovascular (19.6%) and urinary systems (13.8%) and pathology related to vision (20.1%) and hearing (22.0%).
Conclusion: In the Ukrainian population, the highest proportion of patients with TS had a karyotype 45,X. TS was accompanied by a lower frequency of malformations of internal organs compared to other countries.

Objective: Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition.
Methods: Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire.
Results: Ninety patients (54 male-36 female) were seen between 1991-2015, most with paternal deletion (n=56) or maternal isodisomy (n=26). Features included cryptorchidism in 94% males, preterm birth (26%), birthweight <2500 g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) were reported in 82.5% patients compared with 4% healthy siblings. Of 35 children born since 1999, 23 were diagnosed clinically within 28 days while diagnosis in 12 was >28 days: 1-12 months in seven; and 3.75-10.5 years in five. Typical PWS features in these 12 infants included hypotonia (100%), feeding difficulties (75%), cryptorchidism (83% males) and reduced FM (66%). Causes other than PWS including neuromuscular disease were considered in nine patients.
Conclusion: Neonatal hypotonia, reduced FM, feeding difficulties and cryptorchidism should immediately suggest PWS, yet late diagnosis continues in some cases. Awareness of the typical features of PWS in newborn units is required to allow prompt detection even in the presence of confounding factors such as prematurity.

Monogenic obesity, caused by mutations in one of the genes involved in the control of hunger and satiety, is a rare cause of early onset obesity (EOO). The most common of the single gene alterations affect the leptin gene (LEP), resulting in congenital leptin deficiency that manifests as intense hyperphagia, EOO and severe obesity associated with hormonal and metabolic alterations. Only eight mutations of LEP associated with congenital leptin deficiency have been described in humans to date. In this study, we report a novel, homozygous, missense mutation in exon 3 of the LEP gene (chr7:127894610;c.298G>A) resulting in the amino acid substitution of asparagine for aspartic acid at codon 100 (p.Asp100Asn) in a 10-month-old infant who presented to us with severe hyperphagia and EOO. She was subsequently found to have low serum leptin concentrations. Additionally, a homozygous missense variation of unknown significance in exon 11 of Bardet-Biedl syndrome-1 gene (chr11:66291279; G>A; Depth 168x) was detected. Significant abnormalities of lipid parameters were also present in our patient. Both parents were thin but there was a family history suggestive of EOO in a paternal uncle and a cousin. In conclusion, we report the second patient from India with a novel mutation of the LEP gene associated with severe obesity.

Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects. Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment. A good response to sirolimus was observed. At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively]. In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days. Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases. In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days. When the dose was increased, enzymes increased within three days. Sirolimus was discontinued in both cases.
The rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis.
To the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI. Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.

Congenital isolated growth hormone deficiency (IGHD) type 1b is an autosomal recessive genetic condition caused by mutations of growth hormone (GH)-1 or the growth hormone releasing hormone receptor (GHRH-R) genes. Affected subjects present with symptoms of growth hormone deficiency (GHD) with low but detectable levels of growth hormone (GH), short stature and responsiveness to GH therapy. We describe a 13-month old girl with severe growth failure who showed a low GH response to two GH provocation tests and a modest increase of insulin-like growth factor-1 (IGF-1) to an IGF-1 generation test. Whole exome sequencing revealed a novel homozygous variant of the GHRH-R gene (c.97C>T), leading to a premature stop codon. Administration of recombinant human GH improved linear growth. This is the first report of a c.97C>T mutation of the GHRH-R gene.

Neurological complications of diabetic ketoacidosis are considered to be a serious clinical problem. The most common complication is cerebral edema. However, these neurological complications also include less common entities such as ischemic or hemorrhagic stroke, cerebral venous and sinus thrombosis or peripheral neuropathy.
We present a case of a 9-year old girl admitted to our intensive care unit with new onset type 1 diabetes, diabetic ketoacidosis, cerebral edema, multifocal vasogenic brain lesions and bilateral lower limb peripheral paresis. The patient developed polydipsia and polyuria one week before admission. The initial blood glucose level was 1136 mg/dL and severe acidosis was present (pH 7.1; BE-25.9). Computed tomography scan showed brain edema and a hypodense lesion in the left temporal region. Brain magnetic resonance imaging revealed more advanced multifocal brain lesions. Nerve conduction studies demonstrated damage of the motor neurons in both lower limbs with dysfunction in both peroneal nerves and the right tibial nerve. With treatment and physiotherapy, the patient’s health gradually improved.
Acute neuropathy after ketoacidosis is a rare complication and its pathogenesis is not clear. Patients with diabetic ketoacidosis require careful monitoring of neurological function, even after normalization of their glycemic parameters.

Infantile hepatic hemangiomas (IHH), particularly of the diffuse subtype can, in severe cases, be associated with hepatic and cardiac failure, compartment syndrome and consumptive hypothyroidism. Early recognition and treatment of these pathologies is paramount in order to minimise the risk of long-term sequelae.
We report an interesting case of a female infant who presented with systemic compromise, in the absence of large or obvious cutaneous infantile hemangiomas. Imaging identified innumerable hepatic hemangiomas, consistent with diffuse infantile hepatic hemangiomatosis. Subsequent to this, thyroid function tests confirmed an associated but comparatively rare form of hypothyroidism, known as consumptive hypothyroidism. Following joint consultation with dermatology and endocrinology she was promptly treated with oral propranolol and levothyroxine, with subsequent improvement in her clinical parameters.
This case reiterates the importance of aggressive investigation and management of consumptive hypothyroidism in any infant diagnosed with IHH, particularly when there is systemic compromise. We advocate propranolol as a single first line treatment for IHH, supported by thyroid replacement when appropriate.