Investigation of SHOX Gene Mutations in Turkish Patients with Idiopathic Short Stature.

OBJECTIVE: The frequency of mutations in the short stature homeobox (SHOX) gene in patients with idiopathic short stature (ISS) ranges widely, depending mostly on the mutation detection technique and inclusion criteria. We present phenotypic and genotypic data on 38 Turkish patients with ISS and the distinctive features of 1 patient with a SHOX deletion. METHODS: Microsatellite markers (MSMs) DXYS10092 (GA repeats) and DXYS10093 (CT repeats) were used to select patients for fluorescent in situ hybridisation (FISH) analysis and to screen for deletions in the SHOX gene. The FISH analysis was applied to patients homozygous for at least one MSM. A Sanger sequencing analysis was performed on patients with no deletions according to FISH to investigate point mutations in the SHOX gene. RESULTS: One patient (2.6%) had a SHOX mutation. CONCLUSION: Although the number of cases was limited and the mutation analysis techniques we used cannot detect all mutations, our findings emphasize the importance of the difference in arm span and height when selecting patients for SHOX gene testing.

Gonadotropin-Releasing Hormone Analogue Treatment in Females with Moderately Early Puberty: No Effect on Final Height.

OBJECTIVE: To investigate the effects of treatment with gonadotropin-releasing hormone analog (GnRHa) on final height in girls who experienced moderately early puberty with symptoms beginning at 7-8.5 years of age. METHODS: Female cases diagnosed with moderately early puberty which had started between ages 7 to 8.5 years were included in the study. In the treatment groups, all cases with a bone age ≤10.5 years constituted group 1 (n=18) and those with a bone age >10.5 years constituted group 2 (n=23). The 8 patients for which treatment approval could not be obtained constituted group 3. The 49 cases in all three groups were observed until they reached their final height. RESULTS: Target height, target height standard deviation score (SDS), final height, and final height SDS values were similar in all 3 groups. Final height showed a significant positive correlation with target height (p=0.000, r=0.54) and height at diagnosis (p=0.003, r=0.467) in all groups. Linear regression analysis revealed that a 1 cm longer height at diagnosis increased the final height 0.213 fold, and a 1 cm longer target height at diagnosis increased the final height 0.459 fold. CONCLUSION: We found that GnRHa did not make a positive contribution to final height in cases of moderately early puberty.

Bone mineral density and growth in children with coeliac disease on a gluten free-diet.

BACKGROUND/AIM: To evaluate changes in growth and bone metabolism during consumption of a gluten-free diet (GFD) in children with coeliac disease (CD). MATERIALS AND METHODS: Thirty-seven children with CD (mean age of 8.8 ± 4.6 years, 21 girls) were enrolled. Anthropometric measurements, bone mineral density (BMD) in lumbar 2-4 vertebrae, and serum alkaline phosphatase, calcium, and phosphorus levels at diagnosis and at follow-up were recorded. RESULTS: The mean follow-up period was 3.5 ± 2.3 years. The BMD of patients was significantly lower than that of control subjects at the time of diagnosis but not after 1 year of the GFD. Incidence of low BMD with respect to z-scores for chronological age (CA) was significantly higher than z-scores for height age (HA) (P = 0.006). At the first year of GFD, BMD, BMD z-score, height-for-age z-scores, and weight-for-age z-scores were significantly increased compared with the baseline, but not after 1 year of the GFD. CONCLUSION: In CD, the first year of GFD is important in weight gain, linear growth, and improvement of BMD. A considerable relation of low BMD in children with CD, with respect to z-scores for CA, may be a result of misinterpretation of low BMD due to short stature.

Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development.

AIM: Androgen receptor (AR) gene mutations are the leading cause of 46,XY disorders of sex development (DSD) and are associated with varying degrees of androgen insensitivity. The aim of this study is to investigate AR gene mutations in 46,XY DSD patients with normal testosterone secretion, either normal or high testosterone/dihydrotestosterone (T/DHT) ratio and normal SRD5A2 gene analysis, collectively, suggestive of androgen insensitivity syndrome (AIS). METHODS: We direct sequenced all eight exons of the AR gene in 21 index patients with varying degrees of undervirilization. RESULTS: We detected AR gene alterations in five patients. In patients with complete AIS we found p.Val30Met in exon 1 and p.Gly689* in exon 4. One patient with partial AIS had p.Gln712Glu in exon 4. In two patients with partial phenotype, we found common p.Glu213Glu (c.639G>A) SNP, and an additional p.Ile817Ile (c.2451T>C) mutation was found in one of these two patients. DISCUSSION: Despite the fact that T/DHT ratio is frequently used in diagnosis of AIS, lack of precisely determined cutoffs compromises correct diagnosis. Hence, depending on clinical and biochemical findings solely may delay correct diagnosis. Direct sequence analysis of the AR is essential for precise diagnosis of AIS.

Clinical review of 95 patients with 46,XX disorders of sex development based on the new Chicago classification.

STUDY OBJECTIVE: The aim of our study was to determine the etiologic distribution of 46,XX disorder of sexual development (DSD) according to the new DSD classification system and to evaluate the clinical features of this DSD subgroup in our patient cohort. PARTICIPANTS: The evaluation criteria and clinical findings of 95 46,XX patients were described by clinical presentation, gonadal morphology, genital anatomy, associated dysmorphic features, presence during prenatal period with/without postnatal virilization, hormonal characteristics, and presence or absence of steroidogenic defects among 319 patients with DSD. RESULTS: Types and ratios of each presentation of our 95 patients with 46,XX DSD were as follows: 82 had androgen excess (86.3%): (74 had classical congenital adrenal hyperplasia, 2 had CAH variant possibility of P450-oxidoreductase gene defect), 6 had disorders of ovarian development (6.3%): (1 patient had gonadal dysgenesis with virilization at birth with bilateral streak gonad, 4 patients had complete gonadal dysgenesis, and 1 patient had ovotesticular DSD) and 7 had other 46,XX DSD. Two sisters, who had 46,XX complete gonadal dysgenesis,were diagnosed with Perrault Syndrome with ovarian failure due to streak gonads and associated with sensorineural deafness. CONCLUSION: 46,XX DSD are usually derived from intrauterine virilization and CAH is the most common cause of 46,XX DSD due to fetal androgen exposure.

Molecular analysis of PROP1, POU1F1, LHX3, and HESX1 in Turkish patients with combined pituitary hormone deficiency: a multicenter study.

To investigate the specific mutations in PROP1, POU1F1, LHX3, and HESX1 genes in patients with combined pituitary hormone deficiency (CPHD) in Turkey. Seventy-six patients with CPHD were included in this study. Based on clinical, hormonal, and neuro-radiological data, relevant transcription factor genes were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Total frequency of mutations was 30.9 % in patients with CPHD. Frequency was significantly higher in familial patients (p = 0.001). Three different types of mutations in PROP1 gene (complete gene deletion, c.301-302delAG, a novel mutation; IVS1+2T>G) were found in 12 unrelated patients (21.8 %). Mutations in PROP1 gene were markedly higher in familial than in sporadic cases (58.8 vs. 5.3 %, p < 0.001). Homozygous complete gene deletion was the most common mutation in PROP1 gene (8/12) and was identified in six familial patients. Four different homozygous mutations [p.Q4X, novel mutations; exons 1-2 deletion, p.V153F, p.I244S] were detected in POU1F1 gene. Central precocious puberty was firstly observed in a sporadic-male patient with homozygous POU1F1 (p.I244S) mutation. A homozygous mutation in HESX1 gene (p.R160H) was detected in one patient. This study is the first to investigate specific mutations in CPHD patients in Turkey. Complete deletion in PROP1 gene was the most common mutation encountered in patients with CPHD. We believe that the results of this study will contribute to the establishment of genetic screening strategies in Turkey, as well as to the studies on phenotype-genotype correlations and early diagnosis of CPHD patients.

Gastric carcinoid tumor in a 14-year old girl.

Gastric carcinoid tumors (GCT) are rare lesions that constitute 2.6-8.7% of all gastrointestinal carcinoids, mostly affect middle-aged females but the incidence in children is unknown. We present a 14-year-old girl, with GCT. She was treated with recombinant human growth hormone (GH) for complete GH deficiency, and endoscopy was performed to identify iron-deficiency anemia. Upper gastrointestinal endoscopy revealed a gastric polyp, and biopsies were compatible with GCT.

The evaluation of thyroid carcinoma in childhood and concomitance of autoimmune thyroid disorders.

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.

Preperitoneal fat tissue may be associated with arterial stiffness in obese adolescents.

Vascular aging is a chronic process, and many negative effects of obesity in this process have been well defined. We assessed arterial stiffness in obese adolescents and evaluated the relationship between intra-abdominal fat distribution and arterial stiffness. Arterial stiffness parameters and pulse wave velocity (PWV) were evaluated in 61 obese adolescents and 58 healthy controls. Carotid-femoral PWV was calculated by arterial tonometry. Additionally, all obese children were evaluated for metabolic syndrome and insulin resistance. Intra-abdominal fat distribution, including subcutaneous, preperitoneal and visceral fat thicknesses, was assessed by ultrasonography. PWVs of obese children were significantly higher than those of healthy controls (5.0 ± 0.7 m/s vs. 4.7 ± 0.5 m/s). Parameters affecting PWV were evaluated by regression analysis. The independent variable in the regression analysis model was PWV, and the dependent variables were age, metabolic syndrome, body mass index and Homeostasis Model Assessment--Insulin Resistance, as well as subcutaneous, preperitoneal and visceral fat tissue thicknesses measured by ultrasonography. The only parameter associated with PWV was preperitoneal fat tissue thickness. Vascular changes related to obesity may begin in adolescence, as illustrated by the increased PWV. Preperitoneal fat tissue may be related to arterial stiffness. Intra-abdominal fat distributions obtained by ultrasonography may provide clinicians with valuable information needed to determine cardiovascular disease risk factors in obese adolescents.

Adherence to growth hormone therapy: results of a multicenter study.

OBJECTIVE: To evaluate the adherence to growth hormone (GH) therapy and identify the influencing factors and outcomes in children. METHODS: A total of 217 GH-naïve patients in 6 pediatric endocrinology clinics were enrolled in the study. Structured questionnaires were filled out and patients were evaluated at the initiation and 3rd, 6th, and 12th months of therapy. Patients were categorized into 4 adherence segments based on percentage of doses omitted at each evaluation period, classified as excellent if 0%, good if 5%, fair if 5 to 10%, and poor if > 10%. RESULTS: There was a decrement in adherence to GH therapy during the study period (P = .006). Patients who showed excellent and good adherence to therapy had better growth velocity and growth velocity standard deviation scores (SDSs) (P = .014 and P = .015, respectively). A negative correlation between growth velocity SDS and number of missed injections was also observed (r = -.412; P = .007). A positive correlation between delta insulin-like growth factor-1 (IGF-1) SDS and growth velocity was demonstrated (r = .239; P = .042). IGF-1 levels were significantly higher in patients who showed excellent and good adherence to therapy (P = .01). Adherence was better in boys than in girls (P = .035), but adherence rates were not associated with age, cause of GH treatment, socioeconomic status, person who administered the injections, type of injection device, or GH product. CONCLUSION: Poor adherence to GH therapy was common in our group of patients and was one of the factors underlying suboptimal growth during therapy. Before considering other problems that can affect growth, clinicians should confirm good adherence to therapy.