Genotypic spectrum of 21-hydroxylase deficiency in an endogamous population.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to autosomal recessive 21-hydroxylase deficiency (21-OHD) is caused by defects in the CYP21 (CYP21A2) gene. Several mutations have been identified in the CYP21 (CYP21A2) gene of patients with 21-OHD. We aimed at determining the frequency of these mutations among a group of Egyptian patients and studying the genotype-phenotype correlation. METHODS: Forty-seven patients with CAH due to 21-OHD from 42 different families diagnosed by clinical and hormonal evaluation and classified accordingly into salt wasting (SW) and simple virilizing (SV) phenotypes were enrolled. Their ages ranged between 1.78 and 18.99 years. Molecular analysis of the CYP21 (CYP21A2) gene was performed for the detection of eleven common mutations: P30L, I2 splice (I2 G), Del 8 bp E3 (G110del8nt), I172N, cluster E6 (I236N, V237E, M239K), V281L, L307 frameshift (F306 + T), Q318X, R356W, P453S, R483P by polymerase chain reaction (PCR) and reverse hybridization. RESULTS: Disease-causing mutations were identified in 47 patients, 55.31% of them were compound heterozygous. The most frequent mutations were I2 splice (25.43%), followed by cluster E6 (16.66%) and P30L (15.78%). Two point mutations (P453S, R483P) were not identified in any patient. In the SW patients, genotypes were more compatible with their phenotypes. CONCLUSION: Molecular characterization should be considered along with clinical and biochemical diagnosis of CAH since it could confirm the diagnosis, outline the treatment strategy and morbidity, and ensure proper genetic counseling.

Metabolic parameters and adipokine profile in growth hormone deficient (GHD) children before and after 12-month GH treatment.

It is a common knowledge that GH exhibits a large number of metabolic effects, involving lipid and glucose homeostasis. The aim of the study was to investigate the effect of one year GH therapy on metabolic parameters and adipokines in GH deficient (GHD) children. Sixteen prepubertal children (11 M and 5 F) with complete GHD (age range: 3.4-14.7 years) and 20 (13 M and 7 F) age and sex-matched healthy children (age range: 4.6-12.3 years) were studied. Blood was collected from patients before starting GH therapy (0.025 mg/kg/day) and one year later, and from healthy children to measure adiponectin, leptin, osteoprotegerin, resistin, interleukin (IL)-6, tumor necrosis factor (TNF)-α levels, and other glucose and lipid metabolism parameters. Adiponectin and resistin levels were significantly higher (49980 ng/ml vs. 14790 ng/ml and 11.0 pg/ml vs. 6.3, respectively) in GHD children before GH therapy than in controls. Serum IGF-I levels (p=0.0001) and height SDS (p<0.0001) significantly increased after 12 months' of GH therapy. There was a loss of body fat reflected by a significant decline in tricep (p=0.0003) and subscapular skinfold thickness SDS (p=0.0023). After 12 months, there was a significant rise in insulin (p=0.0052) and leptin levels (p=0.0048) and a significant decrease in resistin (p=0.0312) and TNF-α (p=0.0137). We observed that lipid and glucose metabolisms are only slightly affected in GHD children. Growth hormone replacement therapy affects some factors, such as leptin, resistin and fat mass, suggesting that also in children, GH treatment has a role in the regulation of factors secreted by adipose tissue.

Growth hormone deficiency in adults with thalassemia: an overview and the I-CET recommendations.

This review paper provides a summary of the current state of knowledge regarding GHD provides recommendations for the diagnosis and treatment of GHD in adult patients with thalassaemia major (TM). The reported prevalence of adult GHD and /or IGF-I deficiency in TM patients varies from 8% to 44 % in different centers. Because GH treatment requires analysis of many factors, including the effect of treatment on cardiac functions, metabolic parameters and psychosocial functioning, along with safety, ethical considerations, financial cost and other burdens of therapy, stringent diagnostic criteria are needed. The authors report the diagnostic recommendations of the International Study Group of Endocrine Complications in Thalassemia (I-CET) for adult TM patients.The pros and cons of GH treatment must be discussed with each patient, after which GH doses should be individualized and titrated to maximum efficacy with minimal side effects. Prospective studies to monitor potential benefits versus possible side-effects will enable endocrinologists to define recommendations on dosage and the long term effects, particularly on cardiovascular and bone status of GH therapy in adult TM patients.

Vitamin D status in healthy Egyptian adolescent girls.

Over the last decade there had been growing evidence of high prevalence of vitamin D deficiency especially among adolescents. Inadequate sun exposure is considered a precipitating factor. Females who remain fully covered seem to be at greatest risk. The aim of this study was to investigate the vitamin D status in adolescent females in Egypt. Seventy five healthy adolescent girls aged 14-17 years were recruited during the summer months. Anthropometric measures, calcium and vitamin D intake, sun exposure index, use of topical sun screen, and socioeconomic standard were all determined. Serum calcium, inorganic phosphate, alkaline phosphatase, and 25 hydroxycholecalceferol (25-OHD) were measured. Sixteen girls (21.3 %) had vitamin D deficiency, 18 were vitamin D insufficient (24 %), and 41 had adequate vitamin D levels (54.7 %). Both sun exposure index and daily sun exposure time were significantly higher in girls with adequate vitamin D levels compared to those with insufficient and deficient vitamin D. Exposure of at least 18% of BSA for at least 37 minutes/day is enough to achieve adequate vitamin D levels in a sunny climate as Egypt. Calcium intake was highest in girls with adequate 25-OHD, while there was no difference in vitamin D intake. Serum 25-OHD correlated positively with BMI, BMI standard deviation score (SDS), sun exposure index, sun exposure time, and daily calcium intake, and negatively with PTH level. Vitamin D deficiency is a common problem among Egyptian adolescent girls. Inadequate sun exposure, possibly related to cultural/social factors influence vitamin D levels. Insufficient dietary calcium is another contributing factor.

International network on endocrine complications in thalassaemia (I-CET): an opportunity to grow.

Most of the endocrine complications in thalassaemia are attributable to iron overload which may be the result of economic circumstances (expense of the chelation therapy), late onset of chelation therapy or poor compliance with the iron chelation therapy. The major difficulties reported by hematologists or pediatric endocrinologists experienced in thalassaemias or thalassaemia syndromes in following growth disorders and endocrine complications were: lack of familiarity with medical treatment of endocrine complications (40%), interpretation of endocrine tests (30%), costs (65%), absence of paediatric endocrinologist for consultation on growth disorders and endocrine complications (27%), facilities (27%), other (e.g. lack of collaboration and on-time consultation between thalassaemic Centers supervised by hematologists and endocrinologists) (17%). Because any progress we make in research into growth disorders and endocrine complications in thalassaemia should be passed on to all those suffering from it, guaranteeing them the same therapeutic benefits and the same quality of life, on the 8th of May, 2009 in Ferrara (Italy), the International Network on Endocrine Complications in Thalassemia (I-CET) was founded. The I-CET group is planning to conduct, in Ferrara in May 2012, a workshop, "MRI and Endocrine Complications in Thalassaemia", and in Doha (Qatar) in September 2012, a 3-day intensive course entitled, "Growth disorders and Endocrine Complications in Thalassaemia", to provide interested pediatricians, physicians and hematologists from all over the world with an in-depth approach to the diagnosis and management of growth and endocrine disorders in thalassaemic patients.

Growth hormone/IGF-I axis and growth hormone receptor mutations in idiopathic short stature.

BACKGROUND/AIMS: It was hypothesized that some children with idiopathic short stature (ISS) may have partial insensitivity to growth hormone (GH). In this study analysis of the GH/IGF-I axis as well as GH receptor (GHR) gene was done in children with ISS to determine the possible underlying factor(s) to their short stature. METHODS: Forty-eight patients with a diagnosis of ISS were studied; 33 boys and 15 girls aged 13.6 ± 3.7 years. Molecular analysis of the GHR was performed and GH sensitivity was tested by the IGF-I generation test. RESULTS: Basal IGF-I levels were <-2 SD in 22.9%, and 53.5% showed an IGF-I response below 40% (0-38%) to GH stimulation. GH-binding protein (GHBP) levels were below the normative mean in almost all patients. Mutations in the region of the GHR gene that codes for the extracellular domain of the receptor were found in 15.5%; one newly described mutation was recorded. CONCLUSION: With the possible exception of the novel G62V mutation, functional studies of the other 2 heterozygous mutations found in 6 of our patients are needed in order to prove their impact on short stature.

SOS1: a new player in the Noonan-like/multiple giant cell lesion syndrome.

Noonan-like/multiple giant cell lesion syndrome is a rare condition with phenotypic overlap with Noonan syndrome (NS) and cherubism. PTPN11 gene mutations were described in several individuals with this phenotype, and it is recently considered as a variant phenotype of NS. Gain-of-function mutations in the SOS1 gene were recently described as the second major cause of NS. Here, we report for the first time the involvement of SOS1 gene in a family with the Noonan-like/multiple giant cell lesion phenotype.