Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin-melanocortin pathway in controlling energy balance, appetite and body weight . The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin-melanocortin signaling. These genes, however, only explain obesity in<5% of cases, predominantly from outbred populations . We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity. These data suggested that new monogenic forms of obesity could also be identified in this population. Here we identify and functionally characterize homozygous mutations in the ADCY3 gene encoding adenylate cyclase 3 in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent. These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity.

Syndactyly is a condition well documented in current literature due to it being the most common congenital hand defect, with a large aesthetic and functional significance.There are currently nine types of phenotypically diverse non-syndromic syndactyly, an increase since the original classification by Temtamy and McKusick(1978). Non-syndromic syndactyly is inherited as an autosomal dominant trait, although the more severe presenting types and sub types appear to have autosomal recessive and in some cases X-linked hereditary.Gene research has found that these phenotypes appear to not only be one gene specific, although having individual localised loci, but dependant on a wide range of genes and subsequent signalling pathways involved in limb formation. The principal genes so far defined to be involved in congenital syndactyly concern mainly the Zone of Polarizing Activity and Shh pathway.Research into the individual phenotypes appears to complicate classification as new genes are found both linked, and not linked, to each malformation. Consequently anatomical, phenotypical and genotypical classifications can be used, but are variable in significance, depending on the audience.Currently, management is surgical, with a technique unchanged for several decades, although future development will hopefully bring alternatives in both earlier diagnosis and gene manipulation for therapy.

3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7

Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r2 = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r2 = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.

Objective: To determine the frequency of common causes of short stature in children presenting to the Children’s Hospital & the Institute of Child Health, Multan. Methodology: This cross sectional study was done in Pediatric Endocrinology department, the Children’s Hospital & the Institute of Child Health, Multan, from March to September, 2011. One hundred and sixty nine children with short stature presenting to the outpatient department meeting inclusion criteria were recruited after taking an informed consent. The detailed history, physical examination including anthropometric measurements and relevant investigations were recorded. Causes of short stature (outcome variable) were recorded on a predesigned proforma for final analysis. Results: The common causes of short stature identified were; familial short stature (FSS) 36 cases (21.3%), hypothyroidism 29(17.2%), growth hormone deficiency (GHD) 18(10.7%), insulin dependent diabetes mellitus (IDDM) 16(9.5%) and constitutional delayed growth and maturation (CDGM) 11(6.5%) cases. This was followed by primary malnutrition 8(4.7%), celiac disease 6(3.6%),Turner syndrome 5(3%) cases and unknown syndromes 4(2.4%) followed by other rare causes. Conclusion: Common causes of short stature identified in this study were endocrine diseases followed by normal variant short stature (NVSS), while nonendocrine causes were the least.