Natural history of ENPP1 deficiency: Nationwide Turkish Cohort Study of autosomal-recessive hypophosphataemic rickets type 2.

OBJECTIVE: Autosomal-recessive hypophosphataemic rickets type 2 (ARHR2) is a rare disease that is reported in survivors of generalized arterial calcification of infancy (GACI). DESIGN, PATIENTS AND MEASUREMENT: The objective of this study was to characterize a multicenter paediatric cohort with ARHR2 due to ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) deficiency and with a diagnosis of GACI or GACI-related findings. The clinical, biochemical and genetic characteristics of the patients were retrospectively retrieved. RESULTS: We identified 18 patients from 13 families diagnosed with ARHR2. Fifteen of the patients had an ENPP1 variation confirmed with genetic analyses, and three were siblings of one of these patients, who had clinically diagnosed hypophosphataemic rickets (HRs) with the same presentation. From nine centres, 18 patients, of whom 12 (66.7%) were females, were included in the study. The mean age at diagnosis was 4.2 ± 2.2 (1.6-9) years. The most frequently reported clinical findings on admission were limb deformities (66.6%) and short stature (44.4%). At diagnosis, the mean height SD was -2.2 ± 1.3. Five of the patients were diagnosed with GACI in the neonatal period and treated with bisphosphonates. Other patients were initially diagnosed with ARHR2, but after the detection of a biallelic variant in the ENPP1 gene, it was understood that they previously had clinical findings associated with GACI. Three patients had hearing loss, and two had cervical fusion. After the treatment of HRs, one patient developed calcification, and one developed intimal proliferation. CONCLUSION: ARHR2 represents one manifestation of ENPP1 deficiency that usually manifests later in life than GACI. The history of calcifications or comorbidities that might be associated with GACI will facilitate the diagnosis in patients with ARHR2, and patients receiving calcitriol and phosphate medication should be carefully monitored for signs of calcification or intimal proliferation.

The clinical and demographical characteristics of Turkish pediatric lymphedema patients: a multicenter study.

BACKGROUND: Reducing lymphedema-associated burden and disability in the pediatric setting requires improved awareness and understanding clinical properties of the lymphedema. The aim of this study was to evaluate the clinical and demographic characteristics of patients with pediatric lymphedema presented to different lymphedema centers in Turkey. METHODS: The socio-demographic and clinical characteristics of the children including age, gender, presence of genetic syndromes, duration of edema, site and stage of lymphedema and the received therapies were determined. Parental and children education on self-management techniques were recorded. RESULTS: A total of 122 children (female: 66, male: 56) with a mean age of 120.7 ± 71.2 months were included from 7 centers. Of them; 92% had primary, 8% had secondary lymphedema mostly due to infection and trauma. Lymphedema was part of a syndrome in 18% of the children. The most common site of involvement was the lower extremity, followed by upper extremity and genital involvement. Lymphedema was complicated in 17 % of children, mainly with a clinical picture of cellulitis, infection, and pain. The median duration of lymphedema was 41 (5-216) months. Although most of the children had stage 2 lymphedema, only 40% of them received treatment. The most commonly received treatment was compression therapy. No family or child was educated for self- care management before. DISCUSSION: In conclusion, pediatric lymphedema has a comparable gender distribution and usually involves the lower extremities. Although most of the children had advanced disease, more than half of the patients did not receive any treatment indicating the unmet need for management of lymphedema. The education of patients and/or children about self-management methods were lacking. We suggest educational activities for both families of children with lymphedema and health care providers, in order to facilitate early reference to lymphedema units and to receive prompt preventive and therapeutic approaches for this suffering condition.

GPR30 Gene Polymorphisms Are Associated with Gynecomastia Risk in Adolescents.

AIM: The G protein-coupled receptor, GPR30, which is a third estrogen receptor, has been shown to mediate estrogenic effects on the essential features of human breast cancer cells. The aim of this study was to evaluate the association between GPR30 single nucleotide polymorphisms and gynecomastia in males. METHODS: This study included 109 male adolescents with gynecomastia and 104 controls. Follicle stimulating hormone, luteinizing hormone, total testosterone, estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), and prolactin levels were measured. DNA was extracted from whole blood using a GeneJET Genomic DNA purification kit. The genotypes of the GPR30 gene (rs3808350, rs3808351 and rs11544331) were studied using a tetra-primer ARMS (amplification refractory mutation system) PCR approach. RESULTS: The median E2 (11.80 vs. 16.86 IU/l, p < 0.001) and DHEAS levels (116.8 vs. 146.5 µg/dl, p = 0.044) were higher in the gynecomastia group. The G allele of rs3808350 and the A allele of rs3808351 were frequently observed in patients with gynecomastia. Gynecomastia was more common in patients with the GG genotype of rs3808350 and in patients with the AA genotype of rs3808351. CONCLUSIONS: Our results suggest that increased E2 levels, the G allele of rs3808350 and the A allele of rs3808351 might explain why certain adolescents are affected by gynecomastia.

Etiological evaluation of adolescents with primary amenorrhea.

OBJECTIVES: To determine causes of amenorrhea in adolescents with primary amenorrhea and to emphasize general approach to primary amenorrhea. METHODS: Thirty-nine patients, evaluated between January 2007 and May 2011, were divided into normogonadotropic hypogonadism, hypergonadotropic hypogonadism and hypogonadotropic hypogonadism groups. Means of age, height, weight, body mass index and standard deviation scores, gonadotropin levels, and accompanying diseases were evaluated. RESULTS: Mean values of age, height, height standard deviation score, weight and, weight standard deviation score were 15.54 ± 1.52 y. 152.0 ± 1.1 cm, -1.37 ± 1.3, 48.2 ± 14.3 kg, 0.96 ± 1.75, respectively. There were no statistical significances in the auxological parameters. Patients were distributed as 18 cases (46.1 %) with normogonadotropic hypogonadism, 12 cases (30.8 %) with hypergonadotropic hypogonadism, 9 cases (23.1 %) with hypogonadotropic hypogonadism. In the group of normogonadotropic hypogonadism, there were 6 patients with chronic diseases, 5 patients with insulin resistance, 4 patients with prolactinomas, 3 patients with müllerian agenesis. Of the hypergonadotropic hypogonadic patients, 3 were idiopathic primary ovarian failure, 3 were 46,XY disorders of sex development, 2 were Turner syndrome, 2 were ovarian insufficiency due to drug, one was 17 alpha-hydroxylase deficiency and one was autoimmune oophoritis. The group of hypogonadotropic hypogonadism included 5 patients with normosmic hypogonadism, 2 patients with constitutional delay of growth and puberty, 1 patient with panhypopituitarism and 1 patient with anosmic hypogonadism. CONCLUSIONS: Chronic diseases, prolactinoma, and insulin resistance may lead to hypogonadism without altering gonadotropin levels. Turner syndrome, primary ovarian failure, and autoimmune oophoritis should be investigated in cases with hypergonadotropic hypogonadism. 46, XY disorders of sex development also should be elucidated. Constitutional delay of growth and puberty should be distinguished from isolated hypogonadotropic hypogonadism.

Genetic variants of estrogen beta and leptin receptors may cause gynecomastia in adolescent.

OBJECTIVE: Gynecomastia is a benign breast enlargement in males that affects approximately one-third of adolescents. The exact mechanism is not fully understood; however, it has been proposed that estrogen receptors and aromatase enzyme activity may play important roles in the pathogenesis of gynecomastia. While many studies have reported that aromatase enzyme (CYP19) gene polymorphism is associated with gynecomastia, only one study has shown a relationship between estrogen receptor (ER) alpha and beta gene polymorphism and gynecomastia. Thus, the aim of this study was to evaluate the relationships between CYP19 (rs2414096), ER alpha (rs2234693), ER beta (rs4986938), leptin (rs7799039), and leptin receptor (rs1137101) gene polymorphisms and gynecomastia. METHODS: This study included 107 male adolescents with gynecomastia and 97 controls. Total serum testosterone (T) and estradiol (E2) levels were measured, and DNA was extracted from whole blood using the PCR-RFLP technique. The polymorphic distributions of CYP19, ER alpha, ER beta, leptin and leptin receptor genes were compared. RESULTS: The median E2 level was 12.41 (5.00-65.40) pg/ml in the control group and 16.86 (2.58-78.47) pg/ml in the study group (p<0.001). The median T level was 2.19 (0.04-7.04) ng/ml in the control group and 1.46 (0.13-12.02) ng/ml in the study group (p=0.714). There was a significant relationship between gynecomastia and leptin receptor rs1137101 (p=0.002) and ER beta receptor rs4986938 gene polymorphisms (p=0.002). CONCLUSIONS: According to our results, increased E2 level and ER beta gene rs4986938 polymorphism might explain why some adolescents have gynecomastia. Leptin receptor gene rs1137101 polymorphism might affect susceptibility to gynecomastia.

Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia.

OBJECTIVE: Early diagnosis and treatment of testicular adrenal rest tumors (TART) is important for gonadal functions and fertility protection in boys with congenital adrenal hyperplasia (CAH). In this descriptive study, we investigated the prevalence of TART in boys with 21-hydroxylase deficient (21OHD) CAH followed in our pediatric endocrine clinic. METHODS: The study group consisted of 14 male patients with a mean age of 9.6 ± 5.1 (range: 0.8-18.3) years. Six (42.9%) of the 14 patients were diagnosed as having salt-wasting type (SW) and eight (57.1%) patients - as having the simple virilizing (SV) form of 21OHD. Mean age at diagnosis was 2.9 ± 2.7 (range: 0.03-6.3) years. Two different radiologists performed scrotal ultrasonography. Chronological age, bone age, and anthropometric measurements were evaluated. Serum adrenocorticotropic hormone (ACTH), 17-alpha-hydroxyprogesterone (17OHP) and androstenedione levels were also evaluated in all patients during the follow-up period. RESULTS: Scrotal ultrasonography revealed bilateral TART in two patients (14.3%) and testicular microlithiasis (TM) in four patients (28.6%). One patient had both TART and TM bilaterally. During the follow-up period, the mean serum adrenocorticotropic hormone, 17OHP and androstenedione levels in the total group of patients were 130.0 ± 179.1 pg/mL (21.7-726.5), 5.8 ± 3.3 ng/mL (0.8-11.4) and 4.3 ± 4.1 (0.2-11.0) ng/mL, respectively. CONCLUSIONS: Microlithiasis or TART may be frequently encountered during the follow-up of patients with CAH. In order to prevent late complications including infertility, we suggest that ultrasonographic evaluations be performed yearly in all male CAH patients.

Clinical course of hyperprolactinemia in children and adolescents: a review of 21 cases.

OBJECTIVE: Hyperprolactinemia may be due to various etiological factors and may present with different signs and symptoms. It is relatively less frequent in childhood than in adulthood. The aim of this study was to evaluate retrospectively the clinical course and outcome of hyperprolactinemia in pediatric patients. METHODS: We investigated the records of 21 patients with hyperprolactinemia who attended a tertiary hospital. RESULTS: Menstrual problems, galactorrhea , and headache were the most common presenting symptoms. Hyperprolactinemia was due to microadenoma in 10, macroadenoma in 7, and was drug-induced in 4 patients. Bromocriptine and cabergoline were equally effective in lowering serum prolactin levels. Surgical treatment in children with macroprolactinoma was not curative and dopamine agonist therapy was required postoperatively. CONCLUSION: In the presence of any clinical symptom or sign suggestive of suppression of the pituitary-gonadal axis, hyperprolactinemia should not be forgotten as a probable diagnosis. Medical therapy seems effective in microadenoma. Surgical therapy may not be successful in macroadenoma and recurrence is frequent.

Resolution of autoimmune oophoritis after thymectomy in a myasthenia gravis patient.

Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies against acetylcholine receptors. MG is generally an isolated disorder but may occur concomitantly with other autoimmune diseases. We describe an eighteen-year-old girl with MG who was admitted to our clinic with secondary amenorrhea and diagnosed as autoimmune oophoritis. Since her myasthenic symptoms did not resolve with anticholinesterase therapy, thymectomy was performed. After thymectomy, her menses have been regular without any hormonal replacement therapy. To our knowledge, this is the first report on a patient with autoimmune ovarian insufficiency and MG in whom premature ovarian insufficiency resolved after thymectomy, without hormonal therapy.