Simpson-Golabi-Behmel syndrome in a 39-year-old male patient with suspected acromegaly-A case study.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare genetic condition and is inherited in an X-linked recessive manner. The disease is caused by a change in the nucleotide sequence of an X-linked gene encoding glypican 3, a protein belonging to the heparan-sulfate membrane proteoglycan family. SGBS case studies are almost entirely restricted to the pediatric population. Scarce literature describing SGBS course in adults may be due to both the high mortality of SGBS patients in childhood and low rate of SGBS diagnosis in adults. We present a case of a 39-year-old man with an initial diagnosis of acromegaly. Genetic tests revealed a hitherto unreported deletion in the GPC3 gene. SGBS manifestations in our patient included tall stature, dysmorphic features, and central nervous system (CNS) anatomical pathology. MRI of the head visualized abnormalities of median line structures, a feature consistent with SGBS: an unclosed craniopharyngeal canal, a sellar-suprasellar cyst, dysmorphic pituitary gland, and a cyst of the septum pellucidum. Moreover, cardiomyopathy complicated by life-threatening paroxysmal ventricular tachycardia was diagnosed. Although various cardiac anomalies are often found in SGBS, their pathogenesis is unclear and may be multifactorial. We believe that the presented case contributes to a better understanding of SGBS and may help clinicians in introducing prophylaxis and treatment for its comorbidities.

Simpson-Golabi-Behmel syndrome with 46,XY disorders of sex development: A case report.

We present a case of a Chinese child with X-linked Simpson-Golabi-Behmel syndrome (SGBS). To the best of our knowledge, this is the first report of 46,XY disorders of sex development (ambiguous genitalia, cryptorchidism, and uterus in the pelvis) in surviving SGBS patients. Other external anomalies included characteristic facial anomalies, overgrowth, macrocephaly, organomegaly, pectus excavatum, and cryptorchidism. It could be that the GPC3 gene mutation caused Leydig cell dysfunction in our patient. Disorders of sex development can be included as part of the clinical spectrum of SGBS.

Molecular analysis of a novel intragenic deletion in GPC3 in three cousins with Simpson-Golabi-Behmel syndrome.

Simpson-Golabi-Behmel syndrome (SGBS) is characterized by multiple congenital abnormalities, pre/postnatal overgrowth, distinctive craniofacial features intellectual disability (ID) of variable degree, and an increased risk for embryonal tumors. SGBS is X-linked recessive and caused by deletions, duplications, and point mutations in GPC3, encoding a membrane associated cell surface heparan sulfate proteoglycan named glypican 3. GPC3 plays essential roles in the regulation of cell growth signaling and cell division. Here, we report on a family with three affected cousins who show variable clinical signs of SGBS and ID. Initial microarray-CGH revealed a deletion of approximately 30-50 kb that includes at least one exon of GPC3. By subsequent Sanger sequencing of genomic DNA we could map the chromosomal break points to define a deletion size of 43,617 bp including exons 5 and 6 of the GPC3 gene. RT-PCR analysis on RNA derived from whole blood could further confirm the deletion of both exons on transcript level. This loss of two exons results in a frameshift and a premature stop of translation. Based on our results we have established a breakpoint spanning PCR that could identify the mutation in the mothers and grandmother of the patients. Thus, we provided a molecular test that allows accurate genetic counselling and prenatal diagnosis for this family.

Calcium-dependent release of adipocyte fatty acid binding protein from human adipocytes.

BACKGROUND: Fatty acid binding protein 4 (FABP4) is a predominantly cytosolic protein of the adipocytes, but also abundantly present in human plasma; its plasma concentrations were linked to obesity and metabolic syndrome. Recent studies have suggested a direct extracellular effect of FABP4 in the regulation of glucose metabolism and heart function independently of its effect as a carrier protein. Interestingly, FABP4 has no secretory signal sequence; hence, the mechanisms how FABP4 is released from adipocytes are unclear. METHODS AND RESULTS: In this study we investigated the mechanisms for FABP4 secretion from human adipocytes by using isolated primary pre-adipocytes (PAs) and the human adipocyte cell strain Simpson-Golabi-Behmel syndrome. In undifferentiated PAs, FABP4 expression was barely detectable and increased continuously during differentiation. The increase in FABP4 mRNA expression was accompanied by high levels of FABP4 secretion. In differentiated human adipocytes, FABP4 secretion was not abolished by blocking the Golgi-dependent secretory pathway in vitro, supporting a non-classical secretion mechanism for FABP4. However, raising intracellular Ca(2+) levels enhanced FABP4 secretion in a concentration-dependent manner. CONCLUSION: This study shows that FABP4 is actively released from human adipocytes in vitro via a non-classical, calcium-dependent mechanism.

Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer.

UNLABELLED: Persistently high levels of growth hormone (GH) can cause liver cancer. GH activates multiple signal-transduction pathways, among them janus kinase (JAK) 2-signal transducer and activator of transcription (STAT) 5 (signal transducer and activator of transcription 5). Both hyperactivation and deletion of STAT5 in hepatocytes have been implicated in the development of hepatocellular carcinoma (HCC); nevertheless, the role of STAT5 in the development of HCC as a result of high GH levels remains enigmatic. Thus, we crossed a mouse model of gigantism and inflammatory liver cancer caused by hyperactivated GH signaling (GH(tg) ) to mice with hepatic deletion of STAT5 (STAT5(Δhep) ). Unlike GH(tg) mice, GH(tg) STAT5(Δhep) animals did not display gigantism. Moreover, the premature mortality, which was associated with chronic inflammation, as well as the pathologic alterations of hepatocytes observed in GH(tg) mice, were not observed in GH(tg) animals lacking STAT5. Strikingly, loss of hepatic STAT5 proteins led to enhanced HCC development in GH(tg) mice. Despite reduced chronic inflammation, GH(tg) STAT5(Δhep) mice displayed earlier and more advanced HCC than GH(tg) animals. This may be attributed to the combination of increased peripheral lipolysis, hepatic lipid synthesis, loss of hepatoprotective mediators accompanied by aberrant activation of tumor-promoting c-JUN and STAT3 signaling cascades, and accumulation of DNA damage secondary to loss of cell-cycle control. Thus, HCC was never observed in STAT5(Δhep) mice. CONCLUSION: As a result of their hepatoprotective functions, STAT5 proteins prevent progressive fatty liver disease and the formation of aggressive HCC in the setting of hyperactivated GH signaling. At the same time, they play a key role in controlling systemic inflammation and regulating organ and body size.

A patient with a unique frameshift mutation in GPC3, causing Simpson-Golabi-Behmel syndrome, presenting with craniosynostosis, penoscrotal hypospadias, and a large prostatic utricle.

We present a Hispanic male with the clinical and molecular diagnosis of Simpson-Golabi-Behmel syndrome (SGBS). The patient was born with multiple anomalies not entirely typical of SGBS patients, including penoscrotal hypospadias, a large prostatic utricle, and left coronal craniosynostosis. In addition, he demonstrated endocrine anomalies including a low random cortisol level suspicious for adrenal insufficiency and low testosterone level. To our knowledge, this is the first report of a prostatic utricle in SGBS and the second report of craniosynostosis. The unique disease-causing mutation likely arose de novo in the mother. It is a deletion-insertion that leads to a frameshift at the p.p. S359 [corrected] residue of GPC3 and a premature stop codon after five more amino acids. p. S359 [corrected] is the same residue that is normally cleaved by the Furin convertase, although the significance of this novel mutation with respect to the patient's multiple anomalies is unknown. We present this case as the perinatal course of a patient with unique features of SGBS and a confirmed molecular diagnosis.

Skeletal advance and arrest in giant non-metamorphosing African clawed frog tadpoles (Xenopus laevis: Daudin).

This study examines the skeletons of giant non-metamorphosing (GNM) Xenopus laevis tadpoles, which arrest their development indefinitely before metamorphosis, and grow to excessively large sizes in the absence of detectable thyroid glands. Cartilage growth is isometric; however, chondrocyte size is smaller in GNM tadpoles than in controls. Most cartilages stain weakly with alcian blue, and several cartilages are calcified (unlike controls). However, cartilages subjacent to periosteum-derived bone retain strong affinities for alcian blue, indicating a role for periosteum-derived bone in the retention of glycosaminoglycans during protracted larval growth. Bone formation in the head, limb, and axial skeletons is advanced in comparison with stage-matched controls, but arrests at various mid-metamorphic states. Both dermal and periosteum-derived bones grow to disproportionately large sizes in comparison to controls. Additionally, mature monocuspid teeth form in several GNM tadpoles. Advances in skeletal development are attributable to the old ages and large sizes of these tadpoles, and reveal unexpected developmental potentials of the pre-metamorphic skeleton.

Gigantism and comparative life-history parameters of tyrannosaurid dinosaurs.

How evolutionary changes in body size are brought about by variance in developmental timing and/or growth rates (also known as heterochrony) is a topic of considerable interest in evolutionary biology. In particular, extreme size change leading to gigantism occurred within the dinosaurs on multiple occasions. Whether this change was brought about by accelerated growth, delayed maturity or a combination of both processes is unknown. A better understanding of relationships between non-avian dinosaur groups and the newfound capacity to reconstruct their growth curves make it possible to address these questions quantitatively. Here we study growth patterns within the Tyrannosauridae, the best known group of large carnivorous dinosaurs, and determine the developmental means by which Tyrannosaurus rex, weighing 5,000 kg and more, grew to be one of the most enormous terrestrial carnivorous animals ever. T. rex had a maximal growth rate of 2.1 kg d(-1), reached skeletal maturity in two decades and lived for up to 28 years. T. rex's great stature was primarily attained by accelerating growth rates beyond that of its closest relatives.

Intraspecific competition and high food availability are associated with insular gigantism in a lizard.

Resource availability, competition, and predation commonly drive body size evolution. We assess the impact of high food availability and the consequent increased intraspecific competition, as expressed by tail injuries and cannibalism, on body size in Skyros wall lizards (Podarcis gaigeae). Lizard populations on islets surrounding Skyros (Aegean Sea) all have fewer predators and competitors than on Skyros but differ in the numbers of nesting seabirds. We predicted the following: (1) the presence of breeding seabirds (providing nutrients) will increase lizard population densities; (2) dense lizard populations will experience stronger intraspecific competition; and (3) such aggression, will be associated with larger average body size. We found a positive correlation between seabird and lizard densities. Cannibalism and tail injuries were considerably higher in dense populations. Increases in cannibalism and tail loss were associated with large body sizes. Adult cannibalism on juveniles may select for rapid growth, fuelled by high food abundance, setting thus the stage for the evolution of gigantism.

CUGC for Simpson-Golabi-Behmel syndrome (SGBS).

NAME OF THE DISEASE (SYNONYMS): Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870. NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME SEGMENTS: GPC3. OMIM# OF THE GENE(S): 300037. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the GPC3 gene(s) in ⊠ diagnostic, ☐ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant.

CONTEXT: Treatment of pituitary gigantism is complex and the results are usually unsatisfactory. OBJECTIVE: The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a GH receptor antagonist, pegvisomant. DESIGN: This was a descriptive case series of up to 3.5 yr duration. SETTING: The study was conducted at a university hospital. PATIENTS: Patients included three children (one female, two males) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery, somatostatin analog, and dopamine agonist. INTERVENTION: The intervention was administration of pegvisomant. MAIN OUTCOME MEASURES: Plasma IGF-I and growth velocity were measured. RESULTS: In all three children, pegvisomant rapidly decreased plasma IGF-I concentrations. Growth velocity declined to subnormal or normal values. Statural growth fell into lower growth percentiles and acromegalic features resolved. Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog. CONCLUSIONS: Pegvisomant may be an effective modality for the therapy of pituitary gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular surveillance of tumor size is mandatory.

Excessive growth.

Tall stature and excessive growth syndrome are a relatively rare concern in pediatric practice. Nevertheless, it is important to identify abnormal accelerated growth patterns in children, which may be the clue in the diagnosis of an underlying disorder. We present a case of pituitary gigantism in a 2 1/2-year-old child and discuss the signs, symptoms, laboratory findings, and the treatment. Brief discussions on the differential diagnosis of excessive growth/tall stature have been outlined. Pituitary gigantism is very rare in the pediatrics age group; however, it is extremely rare in a child that is less than 3 years of age. The nature of pituitary adenoma and treatment options in children with this condition have also been discussed.

[Physical development of the teenagers who were exposed to radiation in utero after the accident on the Chernobyl Nuclear Power Plant].

Some features of physical development of teenagers exposed to radiation during utero development are revealed. These teenagers have been found to have more often, than in the control group disorders connected with harmonicity of physical development. Thus in the group of teenagers who have been exposed to acute radiation in utero period of their development prevails tall young men and girls while among the teenagers who have been born in 1986 and stayed living in the polluted territories low growth, subnanysm and nanysm is more often observed.

An Adolescent with Progressive Enlargement of Digits: Case report and proposed diagnostic criteria for macrodystrophia lipomatosa.

Macrodystrophia lipomatosa (ML) is a rare congenital non-hereditary condition caused by an increase in all mesenchymal elements. We report a 14-year-old girl who presented to the Medical Outpatient Department, Kunhitharuvai Memorial Charitable Trust Medical College, Kozhikode, India, in 2017 with progressive enlargement of digits. An X-ray and T1-weighted magnetic resonance imaging scan showed enlargement of the phalanges of the middle and index finger of the left hand with an overgrowth of soft tissues. The patient was subsequently diagnosed with ML. As the condition is benign and usually asymptomatic, no medical treatment was deemed necessary. This report describes a case of ML and proposes a set of diagnostic criteria to aid clinicians in the differential diagnosis of the condition.

McCune-Albright syndrome: clinical picture and natural history in children and adolescents.

The classical triad of McCune-Albright syndrome (MAS) consists of polyostotic fibrous dysplasia (FD), skin hyperpigmentation (café-au-lait spots), and endocrine dysfunction, frequently seen in females as precocious puberty. Patients with MAS display mosaicism of activating somatic mutations of the alpha-subunit of Gs. Thus, the clinical presentation of each individual is dependent on the particular distribution of affected cells, causing a broad spectrum of endocrine and non-endocrine manifestations. Typical endocrinopathies are precocious puberty, hyperthyroidism, growth hormone excess, hyperprolactemia, and hypercortisolism. The onset of these manifestations is usually during infancy and childhood. Since specific treatment is required, the prognosis depends on the severity of each individual endocrine manifestation. Additionally, there are non-endocrine manifestations, such as fibrous dysplasia of bone (FD), renal phosphate wasting, and skin hyperpigmentation, i.e. café-au-lait spots. FD, mostly polyostotic, causes fractures needing surgical and orthopedic treatment. Since previous studies have suggested the overall prognosis of patients with McCune-Albright syndrome to be non-fatal, recent data have drawn our attention to non-endocrine affections, including hepatobiliary dysfunction and cardiac disease, which are probably an important risk factor for early death. In summary, the clinical picture in MAS is related to its mosaic nature, i.e. any cell, tissue and organ in any site of the body could be affected to varying degrees, ranging from one or two mild clinical signs with excellent long-term prognosis to a severe life-threatening multiorgan disease.

Coexisting diseases modifying each other's presentation - lack of growth failure in Turner syndrome due to the associated pituitary gigantism.

Introduction: Turner syndrome presents with one of the most frequent chromosomal aberrations in female, typically presented with growth retardation, ovarian insufficiency, facial dysmorphism, and numerous other somatic stigmata. Gigantism is an extremely rare condition resulting from an excessive growth hormone (GH) secretion that occurs during childhood before the fusion of epiphyseal growth plates. The major clinical feature of gigantism is growth acceleration, although these patients also suffer from hypogonadism and soft tissue hypertrophy. Case report: We presented a girl with mosaic Turner syndrome, delayed puberty and normal linear growth for the sex and age, due to the simultaneous GH hypersecretion by pituitary tumor. In the presented case all the typical phenotypic stigmata related to Turner syndrome were missing. Due to excessive pituitary GH secretion during the period while the epiphyseal growth plates of the long bones are still open, characteristic stagnation in longitudinal growth has not been demonstrated. The patient presented with delayed puberty and primary amenorrhea along with a sudden appearance of clinical signs of hypersomatotropinism, which were the reasons for seeking medical help at the age of 16. Conclusion: Physical examination of children presenting with delayed puberty but without growth arrest must include an overall hormonal and genetic testing even in the cases when typical clinical presentations of genetic disorder are absent. To the best of our knowledge, this is the first reported case of simultaneous presence of Turner syndrome and gigantism in the literature.