Decreased bone mineralization in children with Noonan syndrome: another consequence of dysregulated RAS MAPKinase pathway?

INTRODUCTION: Noonan syndrome (NS) is a disorder of RAS- mitogen activated protein kinase (MAPK) pathway with clinical features of skeletal dysplasia. This pathway is essential for regulation of cell differentiation and growth including bone homeostasis. Currently, limited information exists regarding bone mineralization in NS. MATERIALS AND METHODS: Using dual-energy X-ray absorptiometry (DXA), bone mineralization was evaluated in 12 subjects (mean age 8.7 years) with clinical features of NS. All subjects underwent genetic testing which showed mutations in PTPN11 gene (N=8) and SOS1 gene (N=1). In a subgroup of subjects with low bone mass, indices of calcium-phosphate metabolism and bone turnover were obtained. RESULTS: 50% of subjects had low bone mass as measured by DXA. Z-scores for bone mineral content (BMC) were calculated based on age, gender, height, and ethnicity. Mean BMC z-score was marginally decreased at -0.89 {95% CI -2.01 to 0.23; p=0.1}. Mean total body bone mineral density (BMD) z-score was significantly reduced at -1.87 {95% CI -2.73 to -1.0; p=0.001}. Mean height percentile was close to - 2 SD for this cohort, thus total body BMD z-scores were recalculated, adjusting for height age. Adjusted mean total body BMD z-score was less reduced but still significant at -0.82 {95% CI -1.39 to -0.25; p=0.009}. Biochemical evaluation for bone turnover was unremarkable except serum IGF-I and IGF-BP3 levels which were low-normal for age. DISCUSSION: Children with NS have a significantly lower total body BMD compared to age, gender, ethnicity and height matched controls. In addition, total BMC appears to trend lower in children with NS compared to controls. We conclude that the metabolic bone disease present resulted from a subtle variation in the interplay of osteoclast and osteoblast activity, without clear abnormalities being defined in the metabolism of either. Clinical significance of this finding needs to be validated by larger longitudinal studies. Also, histomorphometric analysis of bone tissue from NS patients and mouse model of NS may further elucidate the relationship between the RAS-MAPK pathway and skeletal homeostasis.

Clinical presentation of hypothyroidism: a case control analysis.

BACKGROUND: Hypothyroidism is a common endocrinological disorder. Its clinical presentation is variable but well established. However, clinical features vary significantly among different populations owing to their climate, education status and awareness about the disease. This study is designed to evaluate the difference in clinical presentation of our population from already available literature. METHODS: In this study we have compared the symptoms and signs of hypothyroid and euthyroid patients coming to a diagnostic centre (PINUM, Faisalabad) from January to July 1999. Of the 1594 patients coming to the centre, 394 were included in the study and were examined. After the laboratory investigations, 109 were identified as the cases of hypothyroidism, the rest were declared as euthyroid and selected as controls. We compared the 21 common signs and symptoms of hypothyroidism in our patients. RESULTS: Lethargy was the commonest symptom and facial oedema was the most prevalent sign in our population. Old age is reported to be a risk factor for hypothyroidism but in this study we could not find a rising trend with increasing age (odds ratio 1.15, p-value 0.71). We also compared the clinical presentation of our patients with the available literature. It was also proved that the signs elicited by the physicians were more reliable and specific for the identification of hypothyroidism. CONCLUSION: Thus, the presentation of hypothyroidism is non-specific and high degree of suspicion is required for its early diagnosis.