Clinical, biochemical, and echocardiographic evaluation of neonates with vitamin D deficiency due to maternal vitamin D deficiency.

OBJECTIVE: There are a few number of case reports and small-scale case series reporting dilated cardiomyopathy due to vitamin D-deficient rickets. The present study evaluates the clinical, biochemical, and echocardiographic features of neonates with vitamin D deficiency. PATIENTS AND METHODS: In this prospective single-arm observational study, echocardiographic evaluation was performed on all patients before vitamin D3 and calcium replacement. Following remission of biochemical features of vitamin D deficiency, control echocardiography was performed. Biochemical and echocardiographic characteristics of the present cohort were compared with those of 27 previously published cases with dilated cardiomyopathy due to vitamin D deficiency. RESULTS: The study included 148 cases (95 males). In the echocardiographic evaluation, none of the patients had dilated cardiomyopathy. All of the mothers were also vitamin D deficient and treated accordingly. Comparison of patients with normocalcaemia and hypocalcaemia at presentation revealed no statistically significant difference between the ejection fraction and shortening fraction, while left ventricle end-diastolic diameter and left ventricle end-systolic diameter were higher in patients with hypocalcaemia. Previously published historical cases were older and had more severe biochemical features of vitamin D deficiency. CONCLUSION: To the best of our knowledge, in this first and largest cohort of neonates with vitamin D deficiency, we did not detect dilated cardiomyopathy. Early recognition and detection before developing actual rickets and preventing prolonged hypocalcaemia are critically important to alleviate cardiac complications.

A major health problem facing immigrant children: nutritional rickets.

OBJECTIVES: Nutritional rickets (NR) is still an important problem and one which increasing influxes of immigrants are further exacerbating. This study evaluated cases of mostly immigrant children followed up with diagnoses of NR in our pediatric endocrinology clinic. METHODS: Details of 20 cases diagnosed with NR between 2017 and 2020 were retrieved from file records. RESULTS: Twenty (11 male) cases were included in the study. Three (15%) were Turkish nationals and the others (85%) were immigrants. Hypocalcemia and hypophosphatemia were detected in 17 and 13, respectively. Alkaline phosphatase (ALP) values were normal in two cases, while ALP and parathyroid hormone (PTH) values were elevated in all other cases, and PTH levels were very high (473.64 ± 197.05 pg/mL). 25-hydroxyvitamin D levels were below 20 ng/mL in all cases. Patients with NR received high-dose long-term vitamin D or stoss therapy. Six patients failed to attend long-term follow-up, while PTH and ALP levels and clinical findings improved at long-term follow-up in the other 14 cases. CONCLUSIONS: The elevated PTH levels suggest only the most severe cases of NR presented to our clinic. Clinically evident NR is therefore only the tip of the iceberg, and the true burden of subclinical rickets and osteomalacia remains unidentified. Public health policies should therefore focus on universal vitamin D supplementation and adequate dietary calcium provision, their integration into child surveillance programs, adequate advice and support to ensure normal nutrition, exposure to sunlight, and informing families of the increased risk not only for resident populations but also for refugee and immigrant children.

First Report of a de novo 10q23.31q23.33 Microdeletion: Obesity, Intellectual Disability and Microcephaly.

Intellectual disability (ID) is characterized by limited or insufficient development of mental abilities, including intellectual functioning impairments, such as learning and understanding cause-effect relationships. Some cases have ID as the only finding and are called isolated cases. Conversely, cases accompanied by facial dysmorphism, microcephaly, autism spectrum disorder, epilepsy, obesity, and congenital anomalies are called syndromic developmental delay (DD)/ID. Isolated and syndromic DD/ID cases show extreme genetic heterogeneity. Genetic etiology can be detected in approximately 40% of the cases, whereas chromosomal abnormalities are observed in 25%. Obesity is a multifactorial disease in which both genetic and environmental factors play important roles. The role of heredity in obesity has been reported to be between 40 and 70%. Array-based comparative genomic hybridization (array-CGH) can detect CNVs in the whole genome at a higher resolution than conventional cytogenetic methods. Array-CGH is currently recommended as the first-tier genetic test for ID cases worldwide. In the present study, we aimed to evaluate clinical, radiological, and genetic analyses of a 12-year and 4-month-old girl with microcephaly, ID, and obesity. In the array-CGH analysis, a 3.1-Mb deletion, arr[GRGh37] 10q23.31g23.33 (92745793_95937944)×1 was detected, and this alteration was evaluated to be pathogenic. We consider that haploinsufficiency of the candidate genes (GPR120, KIF11, EXOC6, CYP26A1, CYP26C1, and LGI1) in the deletion region may explain microcephaly, ID, obesity, seizures, and ophthalmological findings in our patient. The investigation of 10q23.31q23.33 microdeletion in cases with syndromic obesity may contribute to molecular genetic diagnosis.

The Spectrum of Low-Density Lipoprotein Receptor Mutations in a Large Turkish Cohort of Patients with Familial Hypercholesterolemia.

Background: Monogenic hypercholesterolemia with Mendelian inheritance is a heterogeneous group of diseases that are characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) levels, and the most common form of this disorder is autosomal-dominant familial hypercholesterolemia (FH). Methods: A total of 104 index cases with the clinical diagnosis of FH were included in this study. Low-density lipoprotein receptor (LDLR) was sequenced using the Sanger sequencing method. Results: Pathogenic/likely pathogenic variants were detected in LDLR in 55 of the 104 cases (mutation detection rate = 52.8%). Thirty different variants were detected in LDLR, three of which were novel. The total cholesterol and LDL-C values of the patients in the group of premature termination codon (PTC) mutation carriers were significantly higher than those of the patients in the group of non-PTC mutation carriers. A total of 87 patients (17 pediatric and 70 adult cases) were diagnosed with cascade genetic screening. Statin treatment was recommended to all 87 patients and was accepted and initiated in 70 of these patients. Conclusions: This study is the largest patient cohort that evaluated FH cases in the Turkish population. Herein, we revealed the LDLR mutation spectrum for a Turkish population and compared the cases in the context of genotype-phenotype correlation. Genetic screening of individuals with suspected FH not only helps to establish their diagnosis, but also facilitates early diagnosis and treatment initiation in other family members through cascade screening.

Clinical characteristics and molecular genetic analysis of a cohort with idiopathic congenital hypogonadism.

OBJECTIVES: Hypogonadism is defined as inadequate sex hormone production due to defects in the hypothalamic-pituitary-gonadal axis. In recent years, rare single gene defects have been identified in both hypergonadotropic hypogonadism (Hh), and hypogonadotropic hypogonadism (HH) cases with no chromosomal anomalies. The aim of the present study is to investigate the underlying molecular genetic etiology and the genotype-phenotype relationship of a series of patients with Hh and HH. METHODS: In total, 27 HH and six Hh cases were evaluated. Clinical and laboratory features are extracted from patients' hospital files. Whole exome sequencing (WES) analysis was performed. RESULTS: A total of 27 HH cases (15 female) (mean age: 15.8 ± 2.7 years) and six Hh patients (six females) (mean age: 14.9 ± 1.2 years) were included. In molecular genetic analysis, a pathogenic/likely pathogenic variant was identified in five (two patients from the same family) of 27 HH cases (two novel) and three of the six Hh. In HH group variants (pathogenic, likely pathogenic and variant of uncertain significance) were identified in KISS1R (n=2), PROK2 (n=1), FGFR1 (n=1), HS6ST1 (n=1), GNRH1 (n=1) genes. In the Hh group, splice-site mutations were detected in DCAF17 (n=1) and MCM9 (n=2) genes. CONCLUSIONS: HH and Hh cases are genetically heterogeneous diseases due to oligogenic inheritance, incomplete penetrance, and variable expressivity. We found rare variants in CHH related genes in half of our HH cases, whereas they classified as pathogenic/likely pathogenic according to ACMG criteria in only about 15% of HH cases. Using advanced genetic analysis methods such as whole-genome sequencing and long-read sequencing may increase the mutation detection rate, which should always be associated with and expert genetic counseling to interpret the data.

Evaluation of the pathophysiological role of Fetuin A levels in adolescents with polycystic ovary syndrome.

OBJECTIVES: Polycystic ovary syndrome (PCOS) is an endocrinopathy, in which hyperandrogenism and hyperinsulinism have both occurred. Fetuin-A, a natural inhibitor of tyrosine kinase, leads to insulin resistance. The aim was to evaluate the relationship between fetuin-A and hyperandrogenism and hyperinsulinism and the role of fetuin-A in the pathophysiology of PCOS. METHODS: Thirty-eight cases with PCOS and 40 healthy adolescents were included in the study. PCOS and controls were divided into obese/non-obese subgroups. LH, FSH, total and free testosterone (TT, FT), SHBG, androstenedione, DHEAS were measured in patients with PCOS. Fasting glucose, insulin, lipid profile, AST, ALT, HsCRP, and fetuin levels of PCOS patients and healthy controls were also measured. RESULTS: Fetuin-A levels were higher in PCOS patients than in controls. In the obese-PCOS group, when compared to non-obese PCOS patients; the levels of SHBG and HDL were low while cholesterol, LDL, triglyceride, HOMA-IR, FT, FAI, and HSCRP levels were high, but Fetuin-A levels were similar. In the obese-PCOS group, fetuin-A levels were higher than in obese-controls. HOMA-IR and fetuin-A levels were higher in non-obese PCOS patients than in non-obese controls. In the PCOS group, fetuin-A was positively correlated with TT, FT, FAI and androstenedione and negatively correlated with SHBG. Regression analysis demonstrated that FT, SHBG, and androstenedione significantly predicted fetuin-A levels (R2=54%). In non-obese PCOS patients and controls, fetuin-A was positively correlated with insulin and HOMA-IR. CONCLUSIONS: These results suggest a relationship between androgen levels and fetuin-A in PCOS cases, independent of insulin resistance, and may shed light on further studies.

Serum Fetuin-A and Insulin Levels in Classic Congenital Adrenal Hyperplasia.

Androgens play a pivotal role in non-reproductive organs such as the kidney, heart, liver, and pancreas. As androgen receptors are expressed in pancreatic and liver cells, excess testosterone can result in hypersecretion of insulin and fetuin-A, a protein produced in the liver. The expression of fetuin-A, a natural inhibitor of tyrosine kinase activity in muscle and liver, leads to insulin resistance. In addition, insulin and fetuin-A levels are thought to be affected by drugs such as glucocorticoids (GCs) and fludrocortisone. However, whether fetuin-A and insulin levels are affected by androgens and GCs in patients with classic congenital adrenal hyperplasia (CAH) is unknown. This cross-sectional study included 56 CAH patients and 70 controls. Analyses were stratified by sex and prepubertal/pubertal status to control for potential changes in serum metabolic/inflammatory markers associated with the production of sex steroids. Fasting blood glucose, insulin, triglyceride, total cholesterol, high density lipoprotein-cholesterol, aspartate aminotransferase, alanine aminotransferase, fetuin-A, and high-sensitivity C-reactive protein (hs-CRP) levels were measured in blood samples. In addition, 17α-hydroxyprogesterone, androstenedione, total testosterone, free testosterone, and dehydroepiandrosterone sulfate levels were measured before medication was administered. Insulin and fetuin-A levels were significantly higher in CAH patients than in controls. The unfavourably high levels of these substances exhibited a positive correlation with total and free testosterone. Regression analysis revealed that fetuin-A and free testosterone were the only independent predictors of the insulin level, while insulin and free testosterone levels significantly predicted the fetuin-A level (R2=42.7% and 59.8%). Differences were also observed in triglyceride and hs-CRP levels between the pubertal and prepubertal groups. We conclude that serum fetuin-A and insulin levels may be associated with androgens in CAH patients.

Genotypic Sex and Severity of the Disease Determine the Time of Clinical Presentation in Steroid 17α-Hydroxylase/17,20-Lyase Deficiency.

CONTEXT: Steroid 17α-hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol, and excessive mineralocorticoid action. The clinical symptoms of hypocortisolemia are subtle. AIM: The clinical, biochemical, and molecular characteristics of patients with 17OHD were evaluated to determine the factors influencing the time of diagnosis and the management. PATIENTS AND METHODS: Clinical data, steroid profiles by liquid chromatography-tandem mass spectrometry, and Sanger sequencing of the CYP17A1 gene was evaluated in 12 patients with 17OHD diagnosed between 2004 and 2020. RESULTS: Median age of diagnosis was 13.9 (range: 0.04-29.5) years. Ten of 12 patients had 46,XY karyotype. Except for one boy with partial 17OHD, all patients had female external genitalia hence raised as females. The clinical presentation of 17OHD was earlier (median age: 7 years) in patients, who presented with severe hypertension, atypical genitalia, or positive family history (n = 6, 50%) than those without (median age: 15.3 years; p = 0.0005). The latter group presented with amenorrhea (n = 6, 50%). Steroid profile of patients uniformly showed a typical pattern of 17OHD regardless of the age at diagnosis. Serum gonadotropin concentrations were elevated in patients >12 years (n = 7), normal in pre-adolescents (n = 4), and low in a patient, who had a digenic inheritance of homozygous CYP17A1 and KISS1R mutations. CONCLUSIONS: Early clinical presentation and diagnosis in 17OHD are associated with symptomatic hypertension in both 46,XX and 46,XY patients or inadequate virilization of external genitalia in 46,XY partial 17OHD. In the absence of these, the clinical presentation is at late pubertal ages at which time amenorrhea and elevated gonadotropins are the hints for diagnosis.

Functional assessment of variants associated with Wolfram syndrome.

Wolfram syndrome (WS) is a heterogeneous multisystem neurodegenerative disorder with two allelic variations in addition to a separate subtype known as WS type 2. The wide phenotypic spectrum of WS includes diabetes mellitus and optic atrophy which is often accompanied by diabetes insipidus, deafness, urological and neurological complications in combination or in isolation. To date, the understanding of the genotype-phenotype relationship in this complex syndrome remains poorly understood. In this study, we identified and explored the functionality of rare and novel variants in the two causative WS genes WFS1 and CISD2 by assessing the effects of the mutations on the encoded proteins Wolframin and ERIS, in a cohort of 12 patients with autosomal recessive WS, dominant WS and WS type 2. The identified pathogenic variants included missense changes, frameshift deletions and insertions in WFS1 and an exonic deletion in CISD2 which all altered the respective encoded protein in a manner that did not correlate to the phenome previously described. These observations suggest the lack of genotype-phenotype correlation in this complex syndrome and the need to explore other molecular genetic mechanisms. Additionally, our findings highlight the importance of functionally assessing variants for their pathogenicity to tackle the problem of increasing variants of unknown significance in the public genetic databases.

A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature.

Background Woodhouse-Sakati syndrome (WSS) (OMIM#241080) is an extremely rare multisystemic disease. Alopecia, hypogonadism, loss of hearing, hypothyroidism, diabetes mellitus (DM) and neurological disorders are the components of this syndrome. The syndrome is caused by homozygous or compound heterozygous mutations in DCAF17, and has recently been implicated in the development of both male and female gonads, thus resulting in hypogonadism. Case report A 16-year-old girl with consanguineous parents was admitted to our hospital with absence of breast development and amenorrhea. Hypogonadism was detected, in the form of hypergonadotropic hypogonadism. Whole-exome sequencing was used to identify the genetic etiology underlying the hypogonadism. A novel homozygous variant c.1091 + 1G > A was detected in DCAF17. Both parents were sequenced and identified as heterozygous for the same mutation. Conclusions We report a novel mutation detected in the DCAF17 gene and discuss the clinical findings in patients with previously reported mutations. Various manifestations of WSS, such as alopecia, endocrinological and neurological disorders, do not emerge until later in life, and therefore this situation can be challenging to diagnose particularly in pediatric cases, as in the present report. Careful attention should be paid to these additional findings, which may lead to early diagnosis and reduced genetic analysis costs, in patients with hypogonadism. In addition, there was no obvious genetic-phenotype correlation in reported cases.

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.

Experience of intravenous calcium treatment and long-term responses to treatment in a patient with hereditary vitamin D-resistant rickets resulting from a novel mutation.

Background Vitamin D resistant rickets (HVDRR), is a rare autosomal recessive disorder caused by vitamin D receptor (VDR) gene mutations. There is no standard treatment in HVDRR. Case report The patient was a 3-year-old girl presenting with short stature, genu varum deformity, waddling gait and alopecia. She had hypocalcemia, hypophosphatemia, hyperparathyroidism and normal 1.25-(OH)2D levels. The patient was initially treated with calcitriol and high-dose oral calcium (Ca) for 22 months. The patient was treated with continuous high dose intravenous (i.v.) Ca therapy for 4 months, following initial lack of response to oral Ca and calsitriol. At the end of the 4 months, rickets was dramatically improved and did not recur for 3 years after i.v. Ca therapy. DNA sequence analyses of the VDR gene showed a homozygous novel mutation. Conclusions We identified a novel VDR gene mutation, and we concluded that i.v. Ca therapy from the central catheter is a safe treatment in HVDRR.

Systemic Pseudohypoaldosteronism Type 1 due to 3 Novel Mutations in SCNN1Aand SCNN1BGenes.

OBJECTIVE: The systemic form of pseudohypoaldosteronism type 1 (PHA1) is an autosomal recessive disorder characterized by defective sodium transport in multi-organ systems. Mutations in the genes encoding the amiloride-sensitive epithelial sodium channel, ENaC, account for genetic causes of systemic PHA1. We describe systemic PHA1 due to 4 novel variants detected in SCNN1A and SCNN1B in 3 cases from 3 unrelated consanguineous families. PATIENTS AND METHODS: We evaluated the clinical presentations, biochemical and hormonal characteristics, and molecular genetic analysis results of 3 patients from 3 unrelated consanguineous families and parents from whom samples were available. RESULTS: The ages at presentation were postnatal days 9, 10, and 5. The main presentation symptoms were vomiting, poor feeding, weakness, weight loss, and skin rash. All patients exhibited laboratory characteristics including severe hyponatremia, hyperkalemia, metabolic acidosis, elevated plasma renin, elevated aldosterone, and positive sweat tests, suggesting a diagnosis of systemic PHA1. Molecular genetic analysis revealed 2 novel pathogenic variants [c.87C>A(p.Tyr29*)/IVS9 + 1G>A (c.1346 + 1G>A)] in SCNN1Bin case 1, a novel homozygous pathogenic variant [p.His69Arg(c.206A>G] in SCNN1Ain case 2, and a homozygous one-base duplication, p.A200Gfs*6 (c.598dupG), in SCNN1A in case 3. CONCLUSION: PHA1 should be considered at differential diagnosis in patients presenting with hyponatremia, hyperkalemia, and metabolic acidosis. The cases in this report involving 4 novel variants will add valuable insights into the phenotype-genotype relationship and will expand the mutation database.

Antimüllerian Hormone Levels of Infants with Premature Thelarche

Objective: Antimüllerian hormone (AMH) concentrations in mini puberty are higher than those reported for the prepubertal period. In this study we investigated AMH concentrations in infants with premature thelarche (PT). A healthy control group was used for comparison. Methods: Forty five female infants with PT, aged between one and three years and a control group consisting of 37 healthy girls in the same age range were included in the study. Bone age, pelvic ultrasonography, and concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), estradiol and AMH of the patient group were evaluated. Only serum AMH concentration of the control group was evaluated. Results: Median (range) serum AMH concentrations in the subjects were 1.66 ng/mL (11.85 pmol/L) [0.15-6.32 ng/mL (1.07-45.12 pmol/L)] and were significantly lower (p=0.025) than for the control group; 1.96 ng/mL (13.99 pmol/L) [0.60-8.49 ng/mL (4.28-60.64 pmol/L)]. AMH and FSH were negatively correlated (r=-0.360, p=0.015) in infants with PT. There was no correlation between AMH and uterine size, uterine volume, endometrial thickness, fundocervical ratio, ovarian size or volume, follicle size and follicle number. Conclusion: This is the first study that investigates AMH concentrations in infants with PT. The low AMH levels in these infants and the negative correlation between AMH and FSH suggests that AMH may play a role in suppressing pubertal findings during infancy and that decreased AMH may cause PT in infancy.

Detection of the SRY gene in patients with Turner Syndrome.

BACKGROUND: If turner syndrome (TS) patients have a Y-containing cell line, they have an increased risk for gonadal tumors. TS patients are therefore screened for Y-chromosome and Y-specific sequences, such as SRY, DYZ1, DYZ3, DYS132, ZFY, TSPY, etc. In addition, since the dysgenetic gonad may include the stroma and granulosa/sertoli cells, which produce androgens, virilization can seen in girls with Y-chromosomal material. Prophylactic gonadectomy may therefore be required for optimal management in such patients. Our aim is to discuss our observations in the follow-up of TS patients. METHODS: SRY was investigated in 71 out of 85 TS cases (aged 3 months-27 years) between 2005 and 2017. Fluorescent in situ hybridization (FISH) was used until 2014, after which SRY analysis was performed using the polymerase chain reaction (PCR) method. SRY analysis was performed a second time using PCR in 25 cases previously investigated with FISH. RESULTS: We identified no positive cases. No pathological findings in terms of virilization, clitoromegaly, or posterior labial adhesions were also determined in our TS cases. Further studies were not required since no pathological findings also were detected at ultrasonography. CONCLUSION: If Y-chromosome material has not been detected by conventional cytogenetic methods in TS patients with masculine features, further techniques should be applied to prevent the risk of invasive tumors, such as multiple sequences beside the Y centromere. This approach will prevent overtreatment.

Congenital long-QT syndrome in type 1 diabetes: a unique association.

Kurnaz E, Savas Erdeve S, Özgür S, Keskin M, Özbudak P, Çetinkaya S, Aycan Z. Congenital long-QT syndrome in type 1 diabetes: a unique association. Turk J Pediatr 2019; 61: 791-793. In contrast to acquired long QT syndrome (LQTS), congenital LQTS is a relatively rare channelopathy with an incidence of 1/2,500. We describe a patient found to have a prolonged QTc in the setting of newly diagnosed Type 1 DM. To the best of our knowledge, this unique association has not been previously reported. Currently, it is shown that glucose ingestion aggravated cardiac repolarization disturbances in LQT2 patients and prolonged the cardiac repolarization phase in healthy controls. Our case presented to the hospital with syncope after increased glucose level. Therefore, it seems that increased glucose level may have prolonged QTc interval and aggravated cardiac repolarization disturbances in the presented case. By this report, we want to emphasize the importance of hyperglycaemia in congenital LQTS.

Rare Cause of Infantile Hypercalcemia: A Novel Mutation in the SLC34A1 Gene.

BACKGROUND: Under physiological conditions, proximal tubular phosphate reabsorption via NaPi-IIa (and NaPi-IIc) ensures the maintenance of phosphate homeostasis. Impairment of NaPi-IIa, encoded by SLC34A1, is associated with various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi's syndrome with chronic kidney disease, and idiopathic infantile hypercalcemia and nephrocalcinosis. METHODS: A patient was referred to our hospital due to hyponatremia, hyperkalemia, and hypophosphatemia, as well as persistent hypercalcemia after fluid therapy and sodium replacement. At admission to our hospital, potassium and sodium values were normal. After initiation of phosphorus therapy, hypokalemia and metabolic alkalosis were observed. Renal sonography showed bilateral medullary nephrocalcinosis. Analyses of the SLC34A1 gene were performed due to hypercalcemia and hypophosphatemia. RESULTS: Gene analyses identified a novel homozygous c.682T>C (p.W228R) (p.Trp228Arg) mutation. There are no previous reports of patients with SLC34A1 gene mutations presenting with hypokalemia and metabolic alkalosis. CONCLUSION: Herein, we present a case of infantile hypercalcemia 2 with a very different phenotype from that of previously described patients. Our findings provide further evidence for the wide range of phenotypic heterogeneity associated with NaPi-IIa impairment.

SHOX gene deletion screening by FISH in children with short stature and Madelung deformity and their characteristics.

Background The short stature homeobox-containing (SHOX) gene strongly affects height. Therefore, a better understanding of SHOX haploinsufficiency could be advantageous to early diagnosis and treatment. We investigated the rate of SHOX haploinsufficiency in patients of short stature and documented their anthropometric measurements. Methods Between 2010 and 2017, we evaluated 86 patients (70 females, 16 males; age 4.3-18 years) with clinical diagnoses of short stature and Madelung deformity (MD). Clinical abnormalities are presented for patients with MD with and without SHOX haploinsufficiency as determined by fluorescence in situ hybridisation (FISH). Results According to our inclusion criteria, 78 of 86 patients (70 females, 16 males) had short stature (height <-2.5 standard deviation [SD]) and a family history suggestive of short stature. Eight patients had short stature, a family history suggestive of short stature and MD. MD was obvious in eight children in radiographic examinations. Although five of these had no deletion of SHOX, three had deletion of this gene. The deletion detection rate was 37.5% in the individuals with short stature and MD, i.e. Leri-Weill dyschondrosteosis syndrome (LWS), whilst no deletions were detected in the individuals with only short stature. One individual responded well to growth hormone (GH) treatment for the first 2 years but then developed an intolerance with persistently elevated insulin-like growth factor-1 (IGF-1) levels. Conclusions As we likely missed cases due to our methodology, the routine analysis for SHOX screening should be firstly multiplex ligation-dependent probe amplification (MLPA). The incidence of MD may have been higher in the cohort if X-rays were performed in all individuals. GH treatment was not well tolerated in one case due to persistently elevated IGF-1 levels, and long-term evaluations of patients with SHOX deficiency are required.

Follow-up in children with non-obese and non-autoimmune subclinical hypothyroidism.

Background The aim of our study was to evaluate clinical, laboratory and imaging findings and to have an idea about the clinical course of subclinical hypothyroidism in children. Methods Our study included 25 patients who were diagnosed with non-autoimmune subclinical hypothyroidism without goitre, between the ages of 3 and 18 and with body mass index (BMI) below the 85th percentile. Results The mean thyroid-stimulating hormone (TSH) level was 6.92±0.92 µIU/mL at diagnosis, 4.77±1.57 µIU/mL in the third month and 4.51±1.79 µIU/mL in the first year of follow-up. About 73.7% of subclinical hypothyroidism was recovered. There was no statistically significant difference between heart rate, diastolic blood pressure, lipid profile, fasting blood glucose (FBG), fasting insulin level, homeostatic model assessment of insulin resistance (HOMA-IR), hemoglobin, white blood cell, platelet, C-reactive protein (CRP) levels and thyroid volume at diagnosis and in the first year of follow-up. In the first year of follow-up, systolic blood pressure and high-sensitivity CRP value were significantly higher than at diagnosis. However, it was observed that these values were similar in the present group with subclinical hypothyroidism. Conclusions We concluded that there was no progression to overt hypothyroidism during 1-year follow-up and that subclinical hypothyroidism had no effect on height standard deviation score (SDS), BMI SDS, blood pressure, glucose and lipid metabolism during follow-up without treatment.

Near final height in patients with idiopathic growth hormone deficiency: A single-centre experience.

AIM: We analysed near final height (NFH) data in children with growth hormone deficiency (GHD) treated with recombinant human GH (rhGH). METHODS: We divided the idiopathic GHD patients into two groups, isolated GHD (IGHD) and multiple pituitary hormone deficiency, to evaluate NFH. Then, data were grouped according to gender, pre-pubertal/pubertal status and spontaneous or induced puberty. The trial was performed as a retrospective study. Median values are given, and measurements are expressed as standard deviation scores (SDSs). RESULTS: rhGH therapy was started at a median age of 12.1 (range 9.1-14.9) years in the IGHD group (n = 162, 83 males) and 9.1 (range 4.9-13.4) years in the multiple pituitary hormone deficiency group (n = 33, 22 males) at a median dose of 0.20 mg/kg/week. Height SDSs at the onset of therapy were -3.2 (range -4.4 to -2.6) and -3.9 (-6.8 to -2.8) in the two groups, respectively (P < 0.001). NFH SDSs were -1.8 (-2.9 to -1) and -1.6 (-3.1 to -0.4) (P = 0.139), and delta height SDSs (finish - start) were 1.4 (0.3-2.5) and 2.6 (1.5-4.6) (P < 0.001), respectively. Total delta height was 1.4 SDS (0.4-3.1) in patients who started rhGH treatment in the pre-pubertal period and 1.3 SDS (0.3-2.4) (P = 0.106) in those who started rhGH in the pubertal period. CONCLUSIONS: About 85% of the cases reached their genetic height potential. Delta height SDSs were higher than expected in cases that started treatment during the pubertal period. Therefore, it is possible to achieve NFH within the mid-parental height range in patients who start therapy during puberty.