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Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of patients with pituitary gigantism have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH-releasing hormone is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G-protein–coupled receptor, GPR101. This leads to the formation of a neo-TAD in which GPR101 overexpression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in 3 families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1, and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism. [ABSTRACT FROM AUTHOR]

Pituitary gigantism is a rare pediatric disorder caused by excess growth hormone (GH) secretion. In almost 50% of cases, a genetic cause can be identified, with pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene being the most common. We present a case of an 11-year-old boy who exhibited progressive vision loss, associated with accelerated linear growth, and weight gain. On physical examination, he had enlarged hands, right eye amaurosis, and was already above his target height. Increased GH and IGF-I concentrations confirmed the diagnosis of pituitary gigantism. Magnetic resonance imaging showed a giant sellar lesion with supra- and para-sellar extensions. He underwent two surgeries which did not achieve a cure or visual improvement. Histopathological analysis revealed a sparsely granulated tumor, negative for somatostatin receptor type 2 (SST2) and an immunoreactivity score of 6 for somatostatin receptor type 5 (SST5). Our published artificial intelligence prediction model predicted an 83% chance of not responding to first-generation somatostatin receptor ligands. Pasireotide was therefore prescribed, and afterward cabergoline was added on. IGF-I concentrations decreased but did not normalize. We discovered a novel germline single nucleotide variant in the splicing donor region of intron 2 of the AIP gene (NM_003977.4:c.279+1 G>A), classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines.

While not primarily a social theorist in the classical sense, E. F. Schumacher's interdisciplinary thought helped galvanise ecological social theory and the ecological movement more broadly. In this article, we introduce a special issue of the European Journal of Social Theory dedicated to engaging with E. F. Schumacher's Small is Beautiful on its 50th anniversary. We provide both an overview of his life and work before locating Small is Beautiful within both its contemporary context and within today's social theoretical literature. As we show, Schumacher was a fierce critic of capitalist modernity and its 'gigantist' tendencies. As we discuss below, he advocated a metaphysical turn in economics, the implementation of intermediate technology and a reorientation of social practices in line with a more ecologically attuned political economy. [ABSTRACT FROM AUTHOR]

Eurypterids—Palaeozoic marine and freshwater arthropods commonly known as sea scorpions—repeatedly evolved to remarkable sizes (over 0.5 m in length) and colonized continental aquatic habitats multiple times. We compiled data on the majority of eurypterid species and explored several previously proposed explanations for the evolution of giant size in the group, including the potential role of habitat, sea surface temperature and dissolved sea surface oxygen levels, using a phylogenetic comparative approach with a new tip-dated tree. There is no compelling evidence that the evolution of giant size was driven by temperature or oxygen levels, nor that it was coupled with the invasion of continental aquatic environments, latitude or local faunal diversity. Eurypterid body size evolution is best characterized by rapid bursts of change that occurred independently of habitat or environmental conditions. Intrinsic factors played a major role in determining the convergent origin of gigantism in eurypterids. [ABSTRACT FROM AUTHOR]

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The evolution of the extinct megatooth shark, Otodus megalodon, and its close phylogenetic relatives remains enigmatic. A central question persists regarding the thermophysiological origins of these large predatory sharks through geologic time, including whether O. megalodon was ectothermic or endothermic (including regional endothermy), and whether its thermophysiology could help to explain the iconic sharks gigantism and eventual demise during the Pliocene. To address these uncertainties, we present unique geochemical evidence for thermoregulation in O. megalodon from both clumped isotope paleothermometry and phosphate oxygen isotopes. Our results show that O. megalodon had an overall warmer body temperature compared with its ambient environment and other coexisting shark species, providing quantitative and experimental support for recent biophysical modeling studies that suggest endothermy was one of the key drivers for gigantism in O. megalodon and other lamniform sharks. The gigantic body size with high metabolic costs of having high body temperatures may have contributed to the vulnerability of Otodus species to extinction when compared to other sympatric sharks that survived the Pliocene epoch.

Abstract Belemnite rostra are very abundant in Mesozoic marine deposits in many regions. Despite this abundance, soft-tissue specimens of belemnites informing about anatomy and proportions of these coleoid cephalopods are extremely rare and limited to a few moderately large genera like Passaloteuthis and Hibolithes. For all other genera, we can make inferences on their body proportions and body as well as mantle length by extrapolating from complete material. We collected data of the proportions of the hard parts of some Jurassic belemnites in order to learn about shared characteristics in their gross anatomy. This knowledge is then applied to the Bajocian genus Megateuthis, which is the largest known belemnite genus worldwide. Our results provide simple ratios that can be used to estimate belemnite body size, where only the rostrum is known.

Sphenodontians are a group of vertebrates with a vast taxonomic diversity and worldwide distribution of their fossils. Although they have been the subject of many studies on their phylogeny and morphology, those focused on their paleobiology are still scarce. We present here the osteohistology of eleven postcranial elements corresponding to a single specimen of Priosphenodon avelasi, an eilenodontine sphenodontian from Cenomanian–Turonian rocks of Río Negro (Argentina). The bone samples described here share a parallel-fibered type of matrix. The degree of vascularization varies in all the samples, but none of them present a significant density of primary vascular canals. Lines of arrested growth were observed in all appendicular elements, being better preserved in the humerus, radius and fibula. Extrinsic fibers were observed only in reduced regions of the cortex of the ulna and in one of the phalanges. The primary bone tissue suggests that the specimen had a relatively low growth rate with alternation between slow and accelerated stages. The latter could explain why this taxon reached the largest sizes of all known sphenodontians.

Belemnite rostra are very abundant in Mesozoic marine deposits in many regions. Despite this abundance, soft-tissue specimens of belemnites informing about anatomy and proportions of these coleoid cephalopods are extremely rare and limited to a few moderately large genera like Passaloteuthis and Hibolithes. For all other genera, we can make inferences on their body proportions and body as well as mantle length by extrapolating from complete material. We collected data of the proportions of the hard parts of some Jurassic belemnites in order to learn about shared characteristics in their gross anatomy. This knowledge is then applied to the Bajocian genus Megateuthis, which is the largest known belemnite genus worldwide. Our results provide simple ratios that can be used to estimate belemnite body size, where only the rostrum is known. [ABSTRACT FROM AUTHOR]

Acromegaly and gigantism are disorders caused by hypersecretion of growth hormone (GH), usually from pituitary adenomas. Although somatostatin analogues (SSA), dopamine agonists, and GH receptor antagonists are important therapeutic agents, all of these have issues with their effectiveness, safety, and/or convenience of use. To overcome these, we developed a GH-specific potent neutralizing a mouse monoclonal antibody (mAb) named 13H02. 13H02 selectively bound both to human and monkey GH with high affinity, and strongly inhibited the biological activity of GH in the Nb2 rat lymphoma cell proliferation assay. In hypophysectomized/GH-supplemented rats, a single subcutaneous administration of 13H02 significantly and dose-dependently lowered the serum insulin-like growth factor-1 levels. To pursue the therapeutic potential of this antibody for acromegaly and gigantism, we humanized 13H02 to reduce its immunogenicity and applied a single amino acid mutation in the Fc region to extend its serum half-life. The resulting antibody, Hu-13H02m, also showed GH-specific neutralizing activity, similar to the parental 13H02, and showed improved binding affinity to human FcRn. [ABSTRACT FROM AUTHOR]

Terror birds (Aves, Phorusrhacidae) were large flightless apex predators in South America during the Cenozoic. Here, we estimate a new phylogeny for phorusrhacids using Bayesian inference. We demonstrate phylogenetic evidence for a monophyletic Patagornithinae and find significant support for a distinct crown group associated with the quintessential 'terror bird' characteristics. We use this phylogeny to analyse the evolution of body size and cursoriality. Our results reveal that size overlap was rare between co-occurring subfamilies, supporting the hypothesis that these traits were important for niche partitioning. We observe that gigantism evolved in a single clade, containing Phorusrhacinae and Physornithinae. The members of this lineage were consistently larger than all other phorusrhacids. Phorusrhacinae emerged following the extinction of Physornithinae, suggesting the ecological succession of the apex predator niche. The first known phorusrhacine, Phorusrhacos longissimus, was gigantic but significantly smaller and more cursorial than any physornithine. These traits likely evolved in response to the expansion of open environments. Following the Santacrucian SALMA, phorusrhacines increased in size, further converging on the morphology of Physornithinae. These findings suggest that the evolution and displacement of body size drove terror bird niche partitioning and competitive exclusion controlled phorusrhacid diversity. [ABSTRACT FROM AUTHOR]

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4Cseq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of firstgeneration somatostatin analogs. [ABSTRACT FROM AUTHOR]

Objectives Increased height in patients with acromegaly could be a manifestation of growth hormone (GH) excess before epiphysis closure. The aim of this study was to evaluate the relationship between the height of adult patients with GH excess related to mid-parental height (MPH) and population mean and to find whether taller patients with acromegaly come from tall families. Methods This is a single-centre, observational study involving 135 consecutive patients with acromegaly diagnosed as adults and no family history of GH excess. We established three categories for height for patients with acromegaly: normal stature, tall stature (TS, height above the 97th percentile (1.88 standard deviations (SD)) to <3 SD for gender- and country-specific data or as a height which was greater than 1.5 SD but less than 2 SD above the MPH) and gigantism (height which was greater than 3 SD) above the gender- and country-specific mean or greater than 2 SD above MPH). Results Thirteen percent (17/135) of patients (53% females) met the criteria for gigantism, 10% (14/135) fulfilled the criteria for TS (57% females). Parents and adult siblings were not taller than the population mean. Conclusion In a group of 135 consecutive adult patients with acromegaly, 23% had increased height based on country-specific and MPH data: 13% presented with gigantism while 10% had TS. The frequency of gigantism and TS in patients diagnosed with GH excess as adults is not higher in males than in females. Patients with acromegaly come from normal-stature families. [ABSTRACT FROM AUTHOR]

Sphenodontians are a group of vertebrates with a vast taxonomic diversity and worldwide distribution of their fossils. Although they have been the subject of many studies on their phylogeny and morphology, those focused on their paleobiology are still scarce. We present here the osteohistology of eleven postcranial elements corresponding to a single specimen of Priosphenodon avelasi, an eilenodontine sphenodontian from Cenomanian–Turonian rocks of Río Negro (Argentina). The bone samples described here share a parallel-fibered type of matrix. The degree of vascularization varies in all the samples, but none of them present a significant density of primary vascular canals. Lines of arrested growth were observed in all appendicular elements, being better preserved in the humerus, radius and fibula. Extrinsic fibers were observed only in reduced regions of the cortex of the ulna and in one of the phalanges. The primary bone tissue suggests that the specimen had a relatively low growth rate with alternation between slow and accelerated stages. The latter could explain why this taxon reached the largest sizes of all known sphenodontians. [ABSTRACT FROM AUTHOR]

Baleen whales (mysticetes) include the largest animals on the Earth. How they achieved such gigantic sizes remains debated, with previous research focusing primarily on when mysticetes became large, rather than where. Here, we describe an edentulous baleen whale fossil (21.12–16.39 mega annum (Ma)) from South Australia. With an estimated body length of 9 m, it is the largest mysticete from the Early Miocene. Analysing body size through time shows that ancient baleen whales from the Southern Hemisphere were larger than their northern counterparts. This pattern seemingly persists for much of the Cenozoic, even though southern specimens contribute only 19% to the global mysticete fossil record. Our findings contrast with previous ideas of a single abrupt shift towards larger size during the Plio-Pleistocene, which we here interpret as a glacially driven Northern Hemisphere phenomenon. Our results highlight the importance of incorporating Southern Hemisphere fossils into macroevolutionary patterns, especially in light of the high productivity of Southern Ocean environments. [ABSTRACT FROM AUTHOR]

Background and Aims Gigantism is a key component of the domestication syndrome, a suite of traits that differentiates crops from their wild relatives. Allometric gigantism is strongly marked in horticultural crops, causing disproportionate increases in the size of edible parts such as stems, leaves or fruits. Tomato (Solanum lycopersicum) has attracted attention as a model for fruit gigantism, and many genes have been described controlling this trait. However, the genetic basis of a corresponding increase in size of vegetative organs contributing to isometric gigantism has remained relatively unexplored. Methods Here, we identified a 0.4-Mb region on chromosome 7 in introgression lines (ILs) from the wild species Solanum pennellii in two different tomato genetic backgrounds (cv. 'M82' and cv. 'Micro-Tom') that controls vegetative and reproductive organ size in tomato. The locus, named ORGAN SIZE (ORG), was fine-mapped using genotype-by-sequencing. A survey of the literature revealed that ORG overlaps with previously mapped quantitative trait loci controlling tomato fruit weight during domestication. Key Results Alleles from the wild species led to lower cell number in different organs, which was partially compensated by greater cell expansion in leaves, but not in fruits. The result was a proportional reduction in leaf, flower and fruit size in the ILs harbouring the alleles from the wild species. Conclusions Our findings suggest that selection for large fruit during domestication also tends to select for increases in leaf size by influencing cell division. Since leaf size is relevant for both source–sink balance and crop adaptation to different environments, the discovery of ORG could allow fine-tuning of these parameters. [ABSTRACT FROM AUTHOR]

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (

Abstract Background Cetaceans (whales, porpoises, and dolphins) are a lineage of aquatic mammals from which some species became giants. Only recently, gigantism has been investigated from the molecular point of view. Studies focused mainly on coding regions, and no data on the influence of regulatory regions on gigantism in this group was available. Accordingly, we investigated the molecular evolution of non-coding regulatory regions of genes already described in the literature for association with size in mammals, focusing mainly on the promoter regions. For this, we used Ciiider and phyloP tools. Ciiider identifies significantly enriched transcription factor binding sites, and phyloP estimates the molecular evolution rate of the promoter. Results We found evidence of enrichment of transcription binding factors related to large body size, with distinct patterns between giant and non-giant cetaceans in the IGFBP7 and NCAPG promoters, in which repressive agents are present in small cetaceans and those that stimulate transcription, in giant cetaceans. In addition, we found evidence of acceleration in the IGF2, IGFBP2, IGFBP7, and ZFAT promoters. Conclusion Our results indicate that regulatory regions may also influence cetaceans’ body size, providing candidate genes for future research to understand the molecular basis of the largest living animals.

Macrodystrophia Lipomatosis (MDL) is a rare congenital, non-hereditary, and benign form of gigantism characterised by the overgrowth of adipose tissue in a specific area of the body, usually affecting the hand or foot in the distribution of the median and plantar nerves, respectively. Here, the authors present a case of a 21-year-old male patient, who presented to the Surgical Outpatient Department (OPD) with the gradual, progressive enlargement of the left index finger and thumb over the last six months, experiencing difficulty in holding objects and maintaining grip. This case highlights the importance of radiological imaging in diagnosis and treatment planning. Macrodystrophia lipomatosis should be considered as a differential diagnosis for hypertrophic digits, even in adult patients.

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.

Whales are an extraordinary study group for questions about ecology and evolution because their combinations of extreme body sizes and unique foraging strategies are unparalleled among animals. From a terrestrial ancestry, whales evolved specialized oceanic foraging mechanisms that characterize the two main groups of living cetaceans: echolocation by toothed whales and bulk filter feeding by baleen whales. In toothed whales, lineage-specific increases in body size, enhanced diving capacity, and echolocation enable them to hunt the most abundant prey on the planet: deep-sea fish and cephalopods. Even greater body size increases, along with filter feeding and fasting capacity, permit large baleen whales to migrate long distances and exploit epipelagic patches of schooling prey, such as krill or fish, which are highly abundant but ephemeral. For both groups, prey abundance and distribution limit foraging performance, yielding divergent energetic niches that have shaped their convergent evolution to gigantism. [ABSTRACT FROM AUTHOR]

Pterygotid eurypterids (Chelicerata) were all regarded as active apex nektonic predators, particularly in the Silurian. The chelicerae and lateral eyes of Acutiramus cummingsi were then interpreted as being inconsistent with a predatory lifestyle. Jaekelopterus, Pterygotus and Erettopterus were interpreted as having more acute vision than Acutiramus, but their chelicerae implied they had different ecologies, with not all taxa as top predators. The chelicerae of Acutiramus are here interpreted as being much more robust than was previously assumed, and their eyes as adapted to hunting at depth, at night or in murky water, so neither precludes a predatory lifestyle. Previous models of the mode of life of pterygotid eurypterids are assessed, based on a review of their trace fossils, functional morphology and a new analysis of their biotic associations. All pterygotid taxa are here interpreted as slow swimming vagrant and ambush predators, using their chelicerae to rapidly capture prey, and their more robust coxal gnathobases and metastoma to process it. Slimonia, and Acutiramus with more gracile cutting chelicerae, tend to associate with, and likely specialised on, lightly-armoured phyllocarid crustaceans. Erettopterus and Pterygotus, with more robust chelicerae, tend to associate with more heavily armoured thelodonts and osteostracans, respectively. Jaekelopterus tend to associate with osteicthyans, placoderms and pteraspids. Praedichnia (predation traces) on the pteraspids Lechriaspis and Larnovaspis, eurypterids Eurypterus and Acutiramus and trilobite Spinisscutellum, and their coprolites, provide further evidence for such predatory interactions. The cheliceral morphology, visual acuity, associations and fossil record all support the hypothesis that Acutiramus is actually more basal to Jaekelopterus and Pterygotus, the largest ever arthropods, with Jaekelopterus now estimated at 2.59 m long. [ABSTRACT FROM AUTHOR]

A new periotic (MuMAB 240508) is described from the Tortonian of the Stirone River, Northern Italy. The new specimen is described and compared to all the known periotics of extant and extinct balaenopterid species. The new specimen shows balaenopterid characters, including the triangular anterior process, the transverse and anteroposterior elongations of the pars cochlearis, as well as in the arrangement of the endocranial foramina of the periotic. The presence of a medial promontorial groove, a lack of separation between the round window and the perilymphatic foramen together with the presence of a protruding set of medial crests suggest that this periotic may belong to an archaic and undescribed balaenopterid species. A phylogenetic analysis was performed to understand the relationships of this specimen within the broader context of balaenopterid phylogeny; this analysis showed that MuMAB 240508 belongs to a basal balaenopterid taxon that is the sister group to all the other Balaenopteridae with the exception of 'Balaenoptera' ryani. An ordinary least squares regression analysis showed that a relationship exists linking the length of the anterior process of the periotic and the total body length in Balaenopteridae. By means of such a relationship, the total body length of the individual to which MuMAB 240508 belonged to was reconstructed and resulted in c. 14.4 m. This individual was longer than all the other contemporaneous balaenopterid mysticetes confiming the hypothesis that the origin of large size occurred in this family earlier than previously thought. [ABSTRACT FROM AUTHOR]

Purpose: We present a historical overview on neuropathic ulcers in patients with acromegalic gigantism. Materials and methods: The case histories of 6 famous patients with acromegalic gigantism and living in the twentieth century were analyzed. The combined final height and maximum weight of these giants were: 272 cm. & 215.9 kg., 218.4 cm. & 125 kg., 242 cm. & 165 kg., 220.5 cm. & 135 kg., 235 cm. & 136 kg. and 224.8 cm. & 174 kg. Conclusions: Neuropathic foot ulcers leading to hospital admissions and surgical and medical interventions were reported in 6 patients with acromegalic gigantism. These ulcers significantly impaired the daily activities of these individuals. Neuropathies of the sural nerve in patients with acromegalic gigantism can lead to hypoesthesia and hypoalgesia of the lower legs and feet. Potential contributing factors for the development of neuropathic ulcers of the feet in patients with acromegalic gigantism and neuropathy might be leg and foot deformities, muscle weakness and poor quality footwear. Diabetes mellitus, or impaired glucose intolerance does not necessarily seem to play a role. [ABSTRACT FROM AUTHOR]

Using a dynamic optimisation model for juvenile fish in stochastic food environments, we investigate optimal hormonal regulation, energy allocation and foraging behaviour of a growing host infected by a parasite that only incurs an energetic cost. We find it optimal for the infected host to have higher levels of orexin, growth and thyroid hormones, resulting in higher activity levels, increased foraging and faster growth. This growth strategy thus displays several of the fingerprints often associated with parasite manipulation: higher levels of metabolic hormones, faster growth, higher allocation to reserves (i.e. parasite‐induced gigantism), higher risk‐taking and eventually higher predation rate. However, there is no route for manipulation in our model, so these changes reflect adaptive host compensatory responses. Interestingly, several of these changes also increase the fitness of the parasite. Our results call for caution when interpreting observations of gigantism or risky host behaviours as parasite manipulation without further testing. [ABSTRACT FROM AUTHOR]

Aim: The 'island rule' postulates that on islands large continental animals become smaller, and small continental animals become larger. Its generality has been supported by some studies but contested by others. Bats are cosmopolitan and speciose mammals thus are ideal to test ecogeographic patterns. Based on three functionally distinct measures of body size, I compare mainland and island variation in bats at the order to subspecies level. Location: Globally. Taxon: Chiroptera. Methods: I compiled information from literature on the skull length, forearm length, and body mass of 251 bat species in 840 locations. For conspecific bats from different locations, I calculated size divergences, and categorized them as within‐mainland (M–M), mainland‐to‐island (M–I), or island‐to‐island (I–I). I used a modified size ratio to quantify divergences, analysis of variance, non‐parametric tests, and effect sizes to complement statistical significances. Results: On islands, cranial size increases, wing length becomes more uniform, and body mass decreases more often than not. The first trend would support the island rule, but had a small effect size. Families differ considerably in how they vary geographically. Species are ranked very differently based on functionally distinct size measures. Divergences are uniform across M–M, M–I, and I–I ranges, and large between bats of different subspecies. Main Conclusions: Likely owing to limitations imposed by flight and echolocation, bats do not follow the island rule. The absence of correlation between how bats are ranked based on them indicates that functionally distinct size measures are not necessarily coadaptive. High vagilities may lead to low local differentiation, but interfamilial variation shows this differentiation to also depend on other factors. Body sizes converge to species‐specific optima, not to supraspecific optima as predicted by theoretical studies. Size differences are reflected in taxonomy more often if observed across M–I ranges. [ABSTRACT FROM AUTHOR]

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function. [ABSTRACT FROM AUTHOR]

X-linked acrogigantism (X-LAG) is characterized by extreme tall stature from early childhood resulting from duplication of the GPR101 gene, in turn resulting in GH excess. Most cases present with pituitary tumors secreting GH and prolactin. Diffuse pituitary hyperplasia is uncommon and normal prolactin is rare. We present a girl with tall stature from 3 years of age; her height was +4.25 SD score at 5 years, with no signs of syndromic disease. She had significant GH excess, serum IGF-1 4 times the upper limit of normal and normal circulating GHRH, with normal pituitary magnetic resonance imaging over 13 years. No abnormalities were found in either the AIP or MEN1 genes. Treatment with somatostatin analogues and dopamine agonists showed minimal therapeutic benefit, but significant side effects. She tested positive for duplication of GPR101 6 years after the initial diagnosis. She was then initiated on pegvisomant aged 12 years, achieving prompt IGF-1 normalization and growth cessation. Aged 16.5 years, she showed escape from IGF-1 control, and height velocity increased, but this responded well to a dose increase in pegvisomant, with reassuring long-term pediatric safety over 7 years. Her final height is +2.9 SD score. Currently, life-long pegvisomant treatment is planned with genetic counselling regarding future offspring. [ABSTRACT FROM AUTHOR]

Since the publication of an apparently gigantic sauropod vertebra from the Late Jurassic of western North America in the late 1800s, the possibility that land animals grew to be as massive as the greatest whales has been a matter of discussion. The recent clarification of the phylogenetic and anatomical identity of a bone from the Late Cretaceous of India, also suggests the existence of a sauropod of such cetacean like bulk, possibly in the range of 110-170 tonnes, although with a more probable mass in the area of 110-130 tonnes. Recent re-estimates of the specific gravities of sauropods are used to recalculate the masses of the largest sauropods. Also, linear equations were developed to predict the total length of the femur of Bruhathkayosaurus from different osteological variables. It was found that femur length to tibia length scales with negative allometry in sauropods, and therefore, estimating the body mass from the tibia length of Bruhathkayosaurus may overestimate its mass. Potential reasons for the apparent ability of land animal groups - sauropods especially - to be at least as massive as creatures of the seas, and for longer spans of geological time, are tentatively suggested. [ABSTRACT FROM AUTHOR]

Acromegaly/giantism results from the chronic excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), in more than 96% of cases, due to a GH-secreting pituitary adenoma. Primary treatment of choice is transsphenoidal resection of the adenoma. More than 30% to 40% of operated cases require adjunctive forms of treatment, be it pharmacological or radiotherapeutical. The multimodal treatment of acromegaly has resulted in substantial improvements in the quality of life and life expectancy of these patients. We herein present the complex case of a patient with acromegaly due to a mammosomatotrope adenoma, with a germ-line AIP (aryl hydrocarbon receptor–interacting protein) mutation, who had a chronic and protracted course of more than 15 years during which he was treated with surgery, somatostatin receptor ligands, dopamine agonist, and the GH receptor antagonist pegvisomant. At one point, he was able to come off medications and was even found to be transiently GH-deficient, only to develop acromegaly again after a couple of years. [ABSTRACT FROM AUTHOR]

GH-secreting pituitary adenomas can cause gigantism or acromegaly, determined by onset before or after epiphyseal fusion of the distal ends of the radius and ulna. Overlapping phenotypes can occur when the condition presents peripubertally. Gigantism is associated with identifiable hereditary causes and genetic mutations in almost 50% of cases; genetic testing should be considered in patients with gigantism and early-onset acromegaly, especially (but not only) when pituitary tumors have aggressive features and/or are refractory to standard treatments. Here, we present a case of a young adult with a giant somatotroph adenoma resistant to multiple treatment modalities and negative for mutations in AIP , which encodes aryl hydrocarbon receptor-interacting protein. [ABSTRACT FROM AUTHOR]

Large-winged blattoids of the Middle to Late Pennsylvanian reveal a striking appearance, diversification, and decline in the fossil record. Among them, the families Necymylacridae Durden, 1969, and Gyroblattidae Durden, 1969, as well as the mylacrid genus Opsiomylacris exhibit, the largest pre-Cenozoic blattoids with forewing lengths up to 7.5 cm. As finds from coal-bearing sedimentary basins in Europe, North Africa, and North America indicate, these giant insects started to spread around the Bashkirian–Moscovian transition and experienced a diversification in late Moscovian and Kasimovian times, until they disappeared in the middle Gzhelian. Whereas necymylacrids are only patchily reported and still lack distributional patterns, we disclose the occurrence and particular habitat preference of gyroblattids. Although appearing first in some vast North American basins, they became successively widespread only in small-sized basins of the European Variscan interior. Frequently found associated with enigmatic gymnosperms, they may have lived in well-drained hinterland areas from where they immigrated into the ever-wet basin centers only with increasing seasonality. Gyroblattids apparently followed meso- to xerophilous plants and likely colonized spaces offering a broader spectrum of edaphic conditions that resulted from the closeness of erosional and depositional areas. The presented analysis and revision of all gyroblattids aim to facilitate future more realistic biodiversity estimations based on fossil taxa. [ABSTRACT FROM AUTHOR]

Abstract Using a dynamic optimisation model for juvenile fish in stochastic food environments, we investigate optimal hormonal regulation, energy allocation and foraging behaviour of a growing host infected by a parasite that only incurs an energetic cost. We find it optimal for the infected host to have higher levels of orexin, growth and thyroid hormones, resulting in higher activity levels, increased foraging and faster growth. This growth strategy thus displays several of the fingerprints often associated with parasite manipulation: higher levels of metabolic hormones, faster growth, higher allocation to reserves (i.e. parasite‐induced gigantism), higher risk‐taking and eventually higher predation rate. However, there is no route for manipulation in our model, so these changes reflect adaptive host compensatory responses. Interestingly, several of these changes also increase the fitness of the parasite. Our results call for caution when interpreting observations of gigantism or risky host behaviours as parasite manipulation without further testing.

IntroductionPituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.MethodsFollowing the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.ResultsIn germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction.ConclusionThe identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Pituitary gigantism is a rare condition and it often has an identifiable genetic cause. In this article we report a case of a young girl with pituitary gigantism and two genetic changes. A 15-year-old girl with primary amenorrhea was diagnosed with a growth hormone (GH) and prolactin (PRL)-producing tumor, needing surgery and medical treatment with octreotide in order to achieve disease control. The co-occurrence of an AIP mutation and a MEN1 variant of uncertain significance was demonstrated in this patient. The germline mutation involving AIP was inherited from her father who at the age of 55 was unaffected and the MEN1 variant was a de novo duplication of the region 11q13.1. The latter variant, not previously reported, is unlikely to be pathogenic. Nonetheless, screening for other components of multiple endocrine neoplasia type 1 (MEN1) was performed and proved negative. The rare co-occurrence of an AIP mutation and a MEN 1 variant of uncertain significance was demonstrated in this patient. [ABSTRACT FROM AUTHOR]

Purpose: We present the results of transsphenoidal microsurgical treatment in 14 patients with gigantism. The influence on the prognosis of factors such as the tumor size and preoperative levels of GH and IGF-1 is also quantified. Materials and methods: The patients, operated between 1982 and 2004, were reviewed retrospectively in June 2022. All patients had complete endocrinological studies in the preoperative period and a postoperative control between 6 days and 3 weeks. Follow-up has been supported with annual check-ups between 3 and 31 years. We have compared the preoperative levels of GH and IGF-1 of these patients with the levels of a series of acromegalic patients operated on in the same Center. Results: In this series there were 4 women and 10 men. The age ranged between 14 and 21 years. In 6 patients, postoperative hormone levels achieved the disease control criteria (42.8%). The CT/MRI studies revealed the existence of invasive tumors in 10 of the patients (71.4%). Postoperative CT/MRI showed no tumor tissue in 3 patients but in 7 patients there were tumor remains. The remaining 4 patients had abnormal images although not considered as tumor. A statistical comparison of preoperative serum GH and IGF-1 levels in patients with gigantism and patients with acromegaly showed a significant elevation in the former. Conclusion: Pituitary adenomas that cause gigantism are generally large and invasive, which makes them difficult to cure. High preoperative levels of GH and IGF-1 are also factors that decrease remission. [ABSTRACT FROM AUTHOR]

The Neotropical family Hylodidae comprises 46 currently recognized rheophilic Torrent frog species, today classified in the genera Crossodactylus, Hylodes, Megaelosia, and Phantasmarana, all endemic to the Atlantic Forest. Megaelosia and Phantasmarana are distributed along the Serra do Mar and Serra da Mantiqueira mountain ranges, southeastern Brazil, and are the least speciose genera of the family, including all the mute giant hylodids. Megaelosia is a monotypic genus, whereas Phantasmarana comprises six currently recognized species: P. apuana, P. bocainensis, P. boticariana, P. jordanensis, P. lutzae, and P. massarti. Herein, we provide a taxonomic revision of these Giant Neotropical Torrent frogs, offering a comprehensively sampled species-level molecular phylogeny. By combining molecular and morphological data, we confirm that Megaelosia and Phantasmarana are valid genera. We provide diagnostic traits for both genera, redescribe the poorly known species P. jordanensis, and describe two new species from distinct localities at Parque Estadual da Serra do Mar, P. curucutuensis sp. nov. and P. tamuia sp. nov., presenting details of adult and larval morphology, and notes on their natural history and behaviour. We further discuss systematic and taxonomic concerns, and evolutionary processes related to distribution, body sizes, and communication in the family Hylodidae. [ABSTRACT FROM AUTHOR]

Background: Our objective was to describe the clinical course and treatment challenges in a very young patient with a pituitary adenoma due to a novel aryl hydrocarbon receptor–interacting protein (AIP) gene mutation, highlighting the limitations of somatostatin receptor immunohistochemistry to predict clinical responses to somatostatin analogs in acromegaly. Case Report: We report the case of a 7-year-old boy presenting with headache, visual field defects, and accelerated growth following failure to thrive. The laboratory results showed high insulin-like growth factor I (IGF-I) (standardised deviation scores ( +3.49) and prolactin levels (0.5 nmol/L), and magnetic resonance imaging identified a pituitary macroadenoma. Tumoral/hormonal control could not be achieved despite 3 neurosurgical procedures, each time with apparent total resection or with lanreotide or pasireotide. IGF-I levels decreased with the GH receptor antagonist pegvisomant. The loss of somatostatin receptor 5 was observed between the second and third tumor resection. In vitro, no effect on tumoral GH release by pasireotide (with/without cabergoline) was observed. Genetic analysis revealed a novel germline AIP mutation: p.Tyr202∗ (pathogenic; class 4). Discussion: In vitro response of tumor tissue to somatostatin may better predict tumoral in vivo responses of somatostatin analogs than somatostatin receptor immunohistochemistry. Conclusion: We identified a novel pathologic AIP mutation that was associated with incipient acrogigantism in an extremely young patient who had a complicated course of disease. Growth acceleration can be masked due to failure to thrive. Tumoral growth hormone release in vivo may be predicted with in vitro exposure to somatostatin receptor analogs, as it cannot be assumed that all AIP-mutated somatotropinomas respond well to pasireotide.