RESUMO
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.
Assuntos
Acromegalia , Gigantismo , Adulto , Feminino , Masculino , Humanos , Acromegalia/complicações , Acromegalia/epidemiologia , Gigantismo/etiologia , Osteogênese , PaisRESUMO
OBJECTIVES: 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. CASE PRESENTATION: 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. CONCLUSIONS: The rare co-occurrence of an AIP mutation and a MEN 1 variant of uncertain significance was demonstrated in this patient.
Assuntos
Gigantismo , Hormônio do Crescimento Humano , Neoplasia Endócrina Múltipla Tipo 1 , Neoplasias Hipofisárias , Adolescente , Feminino , Humanos , Mutação em Linhagem Germinativa , Gigantismo/etiologia , Hormônio do Crescimento/genética , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento Humano/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/complicações , ProlactinaRESUMO
Introduction: Acromegaly and gigantism entail increased morbidity and mortality if left untreated, due to the systemic effects of chronic GH and IGF-1 excess. Guidelines for the diagnosis and treatment of patients with GH excess are well established; however, the presentation, clinical behavior and response to treatment greatly vary among patients. Numerous markers of disease behavior are routinely used in medical practice, but additional biomarkers have been recently identified as a result of basic and clinical research studies.Areas covered: This review focuses on genetic, molecular and genomic features of patients with GH excess that have recently been linked to disease progression and response to treatment. A PubMed search was conducted to identify markers of disease behavior in acromegaly and gigantism. Markers already considered as part of routine studies in clinical care guidelines were excluded. Literature search was expanded for each marker identified. Novel markers not included or only partially covered in previously published reviews on the subject were prioritized.Expert opinion: Recognizing the most relevant markers of disease behavior may help the medical team tailoring the strategies for approaching each case of acromegaly and gigantism. This customized plan should make the evaluation, treatment and follow up process more efficient, greatly improving the patients' outcomes.
Assuntos
Acromegalia/diagnóstico , Gigantismo/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Acromegalia/etiologia , Biomarcadores , Gigantismo/etiologia , HumanosRESUMO
Gigantism (early-onset acromegaly) is a rare pediatric disorder caused by a growth hormone (GH)-secreting pituitary adenoma. Approximately 50% patients of gigantism have a germline mutation, most commonly an inactivating mutation in the aryl-hydrocarbon interacting receptor protein (AIP) gene on chromosome 11q13.2. We present an 11-year-old male patient with a GH-secreting pituitary macroadenoma who presented with excessive growth spurts, behavioral changes, and frontal headaches. He was successfully treated with an endoscopic endonasal gross total resection and subsequently demonstrated biochemical cure. Whole-exome sequencing showed a heterozygous germline mutation in the AIP gene suggesting pituitary adenoma predisposition. Analysis of the tumor tissue revealed a large-scale deletion on chromosome 11 overlapping with AIP leading to bi-allelic AIP loss. Coincident germline and somatic AIP mutations were likely causal in formation of a GH-secreting adenoma with an aggressive phenotype. This case exemplifies the need for early diagnosis and curative surgery in the management of AIP-mutated pituitary adenomas.
Assuntos
Mutação em Linhagem Germinativa , Gigantismo/etiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hipofisárias/patologia , Criança , Cromossomos Humanos Par 11/genética , Gigantismo/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Heterozigoto , Humanos , Masculino , Fenótipo , Neoplasias Hipofisárias/genética , Deleção de SequênciaRESUMO
INTRODUCTION: Pituitary gigantism is a rare but significant paediatric condition with complexities surrounding diagnosis and management. Transsphenoidal surgery (TSS) is the treatment of choice; however, medical treatment is often considered as adjuvant therapy. CASE: A 10½ -year-old boy presented with tall stature and a height velocity of 11 cm/year. His height was 178.7 cm (+5.8 SD above mean) and insulin-like growth factor-1 (IGF-1) was elevated. An oral glucose tolerance test demonstrated non-suppression of growth hormone (GH). Initial contrast MRI was inconclusive, but C-11 methionine functional positron emission tomography CT identified a 6 mm pituitary microadenoma. A multidisciplinary team clinic held with the family allowed discussion about medical and surgical treatment options. Due to a number of factors including the patient's young age, prepubertal status, a wish to allow him to settle into his new high school and his desire to reach a final height taller than his father's height, it was decided to try medical therapy first with a somatostatin analogue. Pubertal induction was also commenced and bilateral epiphysiodesis surgery performed. Initial response to octreotide was positive; however, 4 months into therapy his IGF-1 was climbing and a repeat GH profile was not fully suppressed. The patient therefore proceeded to have successful TSS excision of the adenoma. CONCLUSION: Rare cases such as this require sharing of knowledge and expertise, so the best possible care is offered. It is often necessary to work across sites and disciplines. Each case requires an individual approach tailored to the patient and their family.
Assuntos
Adenoma/complicações , Adenoma/diagnóstico , Gigantismo/diagnóstico , Gigantismo/etiologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Adenoma/terapia , Criança , Gigantismo/terapia , Humanos , Masculino , Neoplasias Hipofisárias/terapiaRESUMO
BACKGROUND: Familial glucocorticoid deficiency is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Most patients are diagnosed following episodes of hypoglycemia or convulsion. We report the case of an infant with familial glucocorticoid deficiency who presented with hyperpigmentation, gigantism, and motor developmental delay without documented hypoglycemia, convulsion, or circulatory collapse. CASE PRESENTATION: A 10-month-old Sri Lankan Sinhalese baby boy born to consanguineous parents presented with generalized hyperpigmentation and overgrowth since birth. He had marginal gross motor developmental delay. His weight, length, and head circumference were above normal range for his age. Investigations revealed low serum cortisol and high adrenocorticotrophic hormone levels with no cortisol response following adrenocorticotropin stimulation. Serum electrolytes and aldosterone levels were normal. A diagnosis of familial glucocorticoid deficiency was made based on isolated glucocorticoid deficiency, hyperpigmentation, and tall stature. CONCLUSIONS: This case report highlights that glucocorticoid deficiency can present without documented hypoglycemia and circulatory collapse and a high degree of suspicion is needed in diagnosis.
Assuntos
Insuficiência Adrenal/congênito , Insuficiência Adrenal/diagnóstico , Deficiências do Desenvolvimento/etiologia , Gigantismo/etiologia , Hiperpigmentação/etiologia , Humanos , Lactente , MasculinoRESUMO
CONTEXT: X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs. CASE DESCRIPTION: The patient's mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For more than 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During preconception planning, X-LAG was diagnosed: single-nucleotide polymorphism microarray showed chromosome Xq26.3 microduplication. After conception, single-nucleotide polymorphism microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother's pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and pituitary-specific transcription factor-1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and octamer-binding transcription factor 4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index, 5.6% in the mother and 8.5% in the infant, the highest reported in X-LAG. CONCLUSIONS: This is a prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.
Assuntos
Acromegalia/diagnóstico , Adenoma/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Gigantismo/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Diagnóstico Pré-Natal , Acromegalia/etiologia , Acromegalia/patologia , Adenoma/complicações , Adenoma/patologia , Adulto , Feminino , Gigantismo/etiologia , Gigantismo/patologia , Humanos , Lactente , Masculino , Relações Mãe-Filho , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/patologia , Gravidez , Resultado da GravidezRESUMO
In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.
Assuntos
Adenoma/complicações , Predisposição Genética para Doença/epidemiologia , Gigantismo/etiologia , Fator de Crescimento Insulin-Like I/genética , Neoplasias Hipofisárias/complicações , Acromegalia/etiologia , Acromegalia/genética , Acromegalia/terapia , Adenoma/diagnóstico , Adenoma/genética , Diagnóstico Precoce , Gigantismo/genética , Gigantismo/terapia , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Mutação , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Prognóstico , Medição de Risco , Fatores SexuaisRESUMO
Craniofacial fibrous dysplasia, characteristic of McCune-Albright syndrome (MAS), is usually present in patients with MAS-related acromegaly. We report here the first case of a patient with an undiagnosed MAS presenting with an acute hydrocephalus. A 21-year-old male with gigantism and craniofacial fibrous dysplasia consulted for rapidly progressive headache. An acute obstructive hydrocephalus due to a 39 × 35-mm cystic lesion in the third ventricle was discovered and operated, obtaining hydrocephalus resolution. Pathology described a colloid cyst material and a growth hormone-secreting pituitary adenoma. Genetic study revealed the mosaic GNAS R201H mutation in the pituitary tissue, confirming a MAS diagnosis. Adequate hormonal control was achieved postoperatively. Our results suggest that long-term untreated growth hormone excess in patients with MAS-related craniofacial fibrous dysplasia might end compromising cerebrospinal fluid flow. A prompt diagnosis and coordinated multidisciplinary treatment may help to avoid long-term deleterious impact of hyperfunctioning endocrinopathies in these patients.
Assuntos
Diagnóstico Tardio , Ossos Faciais/patologia , Displasia Fibrosa Poliostótica/diagnóstico , Gigantismo/etiologia , Cefaleia/etiologia , Hidrocefalia/etiologia , Crânio/patologia , Displasia Fibrosa Poliostótica/complicações , Displasia Fibrosa Poliostótica/patologia , Humanos , Masculino , Adulto JovemRESUMO
Tall stature is not a common motive for medical consultation, even though by definition 2.5 % of children in the general population are concerned. It is usually defined as height greater than+2 standard deviations (SD) using the appropriate growth chart for age and gender, or a difference greater than +2 SD between actual height and target height. With a patient presenting tall stature, the physician has to determine whether it is a benign feature or a disease. Indeed, making the diagnosis is essential for hormonal disease or genetic overgrowth syndromes. The past medical history including parents' height, prenatal and birth data, physical examination along with anthropometry (height, weight, head circumference, body mass index), and growth chart evaluation with the detailed growth pattern are generally sufficient to make the diagnosis such as familial tall stature, obesity, or early puberty. Bone age estimation may be helpful for some specific etiologies and is also necessary to help predict final adult height. After exclusion of common causes, further investigation is required. Sudden growth acceleration often reveals endocrine pathology such as early puberty, hyperthyroidism, or acrogigantism. Tall stature accompanied by dysmorphic features, congenital malformations, developmental delay, or a family medical history may be related to genetic disorders such as Marfan, Sotos, or Wiedemann-Beckwith syndromes. We relate here the most frequent etiologies of overgrowth syndromes.
Assuntos
Gigantismo/diagnóstico , Gigantismo/etiologia , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/etiologia , Adolescente , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Insulin-mediated pseudoacromegaly is a rarely described pediatric phenotype. We present two patients displaying excessive growth associated with marked acanthosis nigricans, hyperinsulinemia and metabolic dysregulation. CASE PRESENTATION: Both patients, of First Nations descent, presented with excessive growth - patient one at 3.92 years (height z-score +3.75) and patient two at 9.0 years (height z-score 5.15). Insulin-like growth factor-1 (IGF-1) levels were normal with appropriate growth hormone suppression, yet marked hyperinsulinemia. Prepubescent growth velocities exceeded 9 cm/year, resulting in final adult height predictions exceeding 3 standard deviations (SDs) of predicted. Clinical courses were complicated by type 2 diabetes, marked acanthosis nigricans and long-standing psychosocial distress. CONCLUSIONS: Pediatric patients with insulin-mediated pseudoacromegaly are at risk of significant physical, metabolic and psychosocial comorbidities. Unlike adults, the implications in childhood prompt consideration for therapies to decelerate linear growth and avert progression to metabolic dysregulation. Increased recognition of this condition may improve pathophysiological understanding, diagnostic criteria and therapeutic options.
Assuntos
Acantose Nigricans/etiologia , Acromegalia/diagnóstico , Gigantismo/etiologia , Hiperinsulinismo/etiologia , Estresse Psicológico/etiologia , Acantose Nigricans/diagnóstico , Acromegalia/fisiopatologia , Acromegalia/psicologia , Acromegalia/terapia , Criança , Terapia Combinada , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiologia , Diagnóstico Diferencial , Feminino , Gigantismo/diagnóstico , Hospitais Universitários , Humanos , Hiperinsulinismo/diagnóstico , Indígenas Norte-Americanos , Lactente , Resistência à Insulina , Masculino , Obesidade Infantil/diagnóstico , Obesidade Infantil/etiologia , Encaminhamento e Consulta , Saskatchewan , Isolamento Social , Estresse Psicológico/diagnóstico , Resultado do TratamentoRESUMO
Tall stature is statistically defined as a height standard deviation score (SDS) above 2 for a given age, sex and population group. The most common cause of tall stature is constitutional (often familial) tall stature. However, underlying endocrine or genetic disorders must be considered as some of them may require specific treatment or management. In constitutional tall stature, healthy children are referred to discuss treatment aiming at reducing adult height. The indications of treatment are rare and usually discussed in girls with extremely tall stature (height SDS>4, corresponding to 185cm in girls). The treatment options for tall children are limited and concerns have been raised about their long-term safety. Indeed, recent studies have suggested that high-dose estrogens in adolescent girls may be associated with an increased risk of infertility, as well as increased risk of cancer. Surgical epiphysiodesis has also been reported to reduce adult height but this invasive procedure in healthy children can be questionable and further data on its safety profile are required.
Assuntos
Estatura , Gigantismo/terapia , Adolescente , Idade de Início , Criança , Gigantismo/etiologia , Gigantismo/cirurgia , Transtornos do Crescimento , Humanos , Procedimentos OrtopédicosAssuntos
Estatura , Congressos como Assunto/organização & administração , Nanismo , Gigantismo , Acromegalia/etiologia , Acromegalia/terapia , Congressos como Assunto/normas , Nanismo/etiologia , Nanismo/terapia , Feminino , Gigantismo/etiologia , Gigantismo/terapia , História do Século XIX , História do Século XX , História do Século XXI , Humanos , MasculinoRESUMO
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.
Assuntos
Adenoma/complicações , Desenvolvimento do Adolescente , Estatura , Gigantismo/etiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Síndrome de Turner/complicações , Adenoma/sangue , Adenoma/fisiopatologia , Adenoma/cirurgia , Adolescente , Amenorreia/etiologia , Amenorreia/fisiopatologia , Biomarcadores/sangue , Feminino , Gigantismo/sangue , Gigantismo/fisiopatologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/fisiopatologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Imageamento por Ressonância Magnética , Mosaicismo , Puberdade Tardia/etiologia , Puberdade Tardia/fisiopatologia , Resultado do Tratamento , Síndrome de Turner/tratamento farmacológico , Síndrome de Turner/genética , Síndrome de Turner/fisiopatologiaRESUMO
Thyrotropin (TSH)-secreting pituitary adenomas are exceedingly rare at the pediatric age and no cases of co-secretion with other pituitary hormones in these tumors have been described in this age range. We present a case of a monomorphous plurihormonal pituitary adenoma that co-secreted TSH and GH in a pediatric patient. A 13-year-old male presented with increasing height velocity (17.75 cm/year, 9.55SD), weight loss, and visual impairment. Initial biochemical evaluations revealed secondary hyperthyroidism. A giant pituitary tumor compressing the surrounding structures was detected by magnetic resonance, and a transsphenoidal surgery was initially performed. Pathological examinations revealed an atypical, monomorphous plurihormonal Pit-1 lineage tumor with mixed features of silent subtype 3 adenoma and acidophil stem cell adenoma. In the postoperative period, secondary hyperthyroidism recurred with high levels of both GH and IGF1. In addition, due to tumor re-growth, a multimodality treatment plan was undertaken including surgery, somatostatin analogs, and radiotherapy. We report the first pediatric case of a plurihormonal TSH- and GH-secreting pituitary adenoma, further expanding the clinical manifestations of pediatric pituitary tumors. Comprehensive pathological evaluation and close follow-up surveillance are crucial to the prompt delivery of the best therapeutic options in the context of this particularly aggressive pituitary tumor.
Assuntos
Adenoma/patologia , Gigantismo/etiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Tireotropina/metabolismo , Adenoma/complicações , Adenoma/metabolismo , Adolescente , Biomarcadores Tumorais/análise , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Hipertireoidismo/etiologia , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de Transmissão , Recidiva Local de Neoplasia/patologia , Fator de Transcrição Pit-1/metabolismoRESUMO
Acromegaly and pituitary gigantism are very rare conditions resulting from excessive secretion of growth hormone (GH), usually by a pituitary adenoma. Pituitary gigantism occurs when GH excess overlaps with the period of rapid linear growth during childhood and adolescence. Until recently, its etiology and clinical characteristics have been poorly understood. Genetic and genomic causes have been identified in recent years that explain about half of cases of pituitary gigantism. We describe these recent discoveries and focus on some important settings in which gigantism can occur, including familial isolated pituitary adenomas (FIPA) and the newly described X-linked acrogigantism (X-LAG) syndrome.
Assuntos
Gigantismo/diagnóstico , Gigantismo/etiologia , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos X , Feminino , Displasia Fibrosa Poliostótica , Predisposição Genética para Doença , Gigantismo/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Hormônio do Crescimento Humano/metabolismo , Humanos , Imageamento por Ressonância Magnética , Neoplasia Endócrina Múltipla Tipo 1 , Mutação , Neoplasias Hipofisárias/metabolismo , SíndromeRESUMO
Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day â¼105 Bos taurus indicus × Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared with controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between body weight and the number of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only was there loss of allele-specific expression of imprinted genes in LOS, but also differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovines and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multilocus LOI syndrome, as is BWS.
Assuntos
Bovinos/genética , Feto/anormalidades , Impressão Genômica , Técnicas de Reprodução Assistida/veterinária , Alelos , Animais , Síndrome de Beckwith-Wiedemann/embriologia , Síndrome de Beckwith-Wiedemann/etiologia , Síndrome de Beckwith-Wiedemann/genética , Bovinos/embriologia , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Gigantismo/embriologia , Gigantismo/etiologia , Gigantismo/genética , Humanos , Masculino , Camundongos , Polimorfismo de Nucleotídeo Único , Técnicas de Reprodução Assistida/efeitos adversos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA , SíndromeAssuntos
Estatura , Gigantismo/etiologia , Diagnóstico Diferencial , Gigantismo/diagnóstico , HumanosRESUMO
PURPOSE: Acromegaly usually occurs as a sporadic disease, but it may be a part of familial pituitary tumor syndromes in rare cases. Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been associated with a predisposition to familial isolated pituitary adenoma. The aim of the present study was to evaluate the AIP gene in a patient with gigantism and in her relatives. METHODS: Direct sequencing of AIP gene was performed in fourteen members of the family, spanning among three generations. RESULTS: The index case was an 18-year-old woman with gigantism due to an invasive GH-secreting pituitary adenoma and a concomitant tall-cell variant of papillary thyroid carcinoma. A novel germline mutation in the AIP gene (c.685C>T, p.Q229X) was identified in the proband and in two members of her family, who did not present clinical features of acromegaly or other pituitary disorders. Eleven subjects had no mutation in the AIP gene. Two members of the family with clinical features of acromegaly refused either the genetic or the biochemical evaluation. The Q229X mutation was predicted to generate a truncated AIP protein, lacking the last two tetratricopeptide repeat domains and the final C-terminal α-7 helix. CONCLUSIONS: We identified a new AIP germline mutation predicted to produce a truncated AIP protein, lacking its biological properties due to the disruption of the C-terminus binding sites for both the chaperones and the client proteins of AIP.
Assuntos
Carcinoma/genética , Mutação em Linhagem Germinativa/genética , Gigantismo/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Carcinoma/complicações , Carcinoma Papilar , Feminino , Gigantismo/etiologia , Humanos , Itália , Linhagem , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/complicaçõesRESUMO
Prosthetic arteriovenous grafts (AVGs) are associated with greater morbidity than autogenous arteriovenous fistulas (AVFs), but their use is indicated when AVF formation is not possible. This report adds to the literature a case of lower limb gigantism, painful varicosities, and lymphedema following long-term use of AVG in the upper thigh. The patient's past medical history included renal transplantation on the same side well before the AVG was inserted and right leg deep vein thrombosis. Suspicion of AVG thrombosis was excluded by Doppler ultrasound, which demonstrated an access flow of 1700 mL/min. A computed tomography (CT) scan of the abdomen and pelvis did not identify the cause of her symptoms. Whereas functional incompetence of the iliac vein valve might be responsible for the varicosities, the extent of hypertrophy in this case raises the suspicion of lymphatic blockage possibly secondary to groin dissection undertaken at the time of graft insertion, in addition to the previous dissection at the time of transplantation. This case highlights the need for minimal groin dissection during AVG insertion, particularly in patients with a history of previous abdominopelvic surgery.