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D. H. Shah, S. R. Dandekar, R. K. Jeevanram, Ajay Kumar, S. M. Sharma and R. D. Ganatra


Serum thyroglobulin (tg) levels were measured in 112 patients with proved differentiated thyroid carcinoma (6 pre-operative, 32 post-operative and 74 in whom thyroidectomy was followed by radioiodine treatment). The tg levels were within the normal range in patients who had a residual mass in the neck region after surgery and who were in remission. The patients with metastases showed a wide range (undetectable to microgram quantities) of tg in circulation. The analysis of serum tg with respect to histology showed that the follicular variety of carcinoma tends to show higher tg in serum than the papillary type.

Metastatic involvement of bone was associated with much higher serum tg levels than other sites such as lung and lymph node.

Thirteen patients with bone metastases of non-thyroidal primary origin had tg levels within the normal range. Serum tg estimation is useful in excluding thyroid as a primary site in patients with bone metastases of unknown primary origin.

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Masanobu Fujimoto, Jane C Khoury, Philip R Khoury, Bhanu Kalra, Ajay Kumar, Patrick Sluss, Claus Oxvig, Vivian Hwa and Andrew Dauber


Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors.


Cross-sectional study at a single center.


PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3–18 years old) and an evaluation of the relationship between these proteins and anthropometric factors.


In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = −0.58, −0.65; P < 0.0001).


This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.

Open access

Roberto Salvatori, Serban Radian, Yoan Diekmann, Donato Iacovazzo, Alessia David, Plamena Gabrovska, Giorgia Grassi, Anna-Marie Bussell, Karen Stals, Astrid Weber, Richard Quinton, Elizabeth C Crowne, Valentina Corazzini, Lou Metherell, Tara Kearney, Daniel Du Plessis, Ajay Kumar Sinha, Atik Baborie, Anne-Lise Lecoq, Philippe Chanson, Olaf Ansorge, Sian Ellard, Peter J Trainer, David Balding, Mark G Thomas and Márta Korbonits


Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events.

Design and methods

Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments.


Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability.


The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability.