Prolactin secretion in patients with idiopathic diabetes insipidus.

It has been demonstrated that hyperprolactinemia is sometimes present even in patients with idiopathic diabetes insipidus (DI). In this study, we examined the responses of serum prolactin (PRL) to hypertonic saline infusion and TRH injection in 11 patients with idiopathic DI diagnosed by clinical examinations. Serum sodium in these patients (147.5 +/- 3.2 mEq/L) was significantly higher at baseline than in normal subjects (139.7 +/- 2.4 mEq/L). The plasma arginine vasopressin (AVP) level was significantly lower in DI (0.42 +/- 0.24 pg/ml) at baseline than in normal subjects (2.53 +/- 1.03 pg/ml). However, the serum PRL level in both groups did not differ significantly except in one patient with idiopathic DI (35.6 ng/ml). There was no significant correlation between the basal serum sodium and basal serum PRL in either group. After an infusion of hypertonic saline, the serum sodium level gradually increased to 155.6 +/- 3.4 mEq/L in DI and to 146.5 +/- 4.3 mEq/L in the normal subjects. However, this increase did not affect PRL secretion in either group. PRL response to TRH was essentially normal in all patients with idiopathic DI. These results indicate that the secretion of PRL is not generally affected by chronic mild hypernatremic hypovolemia in the patients with idiopathic DI.     

Baroreceptor-mediated suppression of osmotically stimulated vasopressin in normal humans

Increases in central venous pressure and arterial pressure have been reported to have variable effects on normal arginine vasopressin (AVP) levels in healthy humans. To test the hypothesis that baroreceptor suppression of AVP secretion might be more likely if AVP were subjected to a prior osmotic stimulus, we investigated the response of plasma AVP to increased central venous pressure and mean arterial pressure after hypertonic saline in six normal volunteers. Plasma AVP, serum osmolality, heart rate, central venous pressure, mean arterial pressure, and pulse pressure were assessed before and after a 0.06 ml.kg-1.min-1-infusion of 5% saline give over 90 min and then after 10 min of 30 degrees head-down tilt and 10 min of head-down tilt plus lower-body positive pressure. Hypertonic saline increased plasma AVP. After head-down tilt, which did not change heart rate, pulse pressure, or mean arterial pressure but did increase central venous pressure, plasma AVP fell. Heart rate, pulse pressure, and central venous pressure were unchanged from head-down tilt values during lower-body positive pressure, whereas mean arterial pressure increased. Plasma AVP during lower-body positive pressure was not different from that during tilt. Osmolality increased during the saline infusion but was stable throughout the remainder of the study. These data therefore suggest that an osmotically stimulated plasma AVP level can be suppressed by baroreflex activation. Either the low-pressure cardiopulmonary receptors (subjected to a rise in central venous pressure during head-down tilt) or the sinoaortic baroreceptors (subjected to hydrostatic effects during head-down tilt) could have been responsible for the suppression of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potent stimuli for vasopressin release,hypertonic saline and hemorrhage,cause antipyresis in the rat

Two potent stimuli for AVP release into the blood, hemorrhage and hypertonic saline, were evaluated for their antipyretic effects in the rat. Hemorrhage of 20% of estimated blood volume reduced brain temperature of febrile but not afebrile rats confirming earlier research in the sheep. Hypertonic saline was also antipyretic in the rat. Hypertonic urea was somewhat less antipyretic whereas hypertonic glucose had no effect on febrile temperatures. AVP release into the peripheral circulation showed the relationship saline > urea > glucose and parallelled the antipyretic effectiveness of these solutes. The antipyresis caused by hypertonic saline was not significantly different in rats passively immunized intravenously with AVP antiserum than in rats which received hypertonic saline alone. These results provide indirect evidence that endogenous AVP is released in the brain following hemorrhage or hypertonic challenge and that this endogenous AVP can affect central febrile pathways.     

Aminergic control of vasopressin secretion in the conscious rat.

The influence of aminergic pathways on basal and stimulated vasopressin (AVP) release was studied in conscious rats, the stimulus for hormone release being an intracerebroventricular (ICV) injection of 5 microliters 0.85M sodium chloride. The animals were treated with either phenoxybenzamine, propranolol or haloperidol prior to administration of the central hypertonic stimulus. Phenoxybenzamine elevated basal plasma vasopressin concentrations, while propranolol and haloperidol had no effect. The secretion of AVP in response to the hypertonic stimulus was potentiated by phenoxybenzamine and haloperidol, but the effect of propranolol was equivocal. The antagonists had no effect on basal arterial pressure at the time of hypertonic saline administration or the pressor response to ICV sodium chloride.     

A new missense mutation of the vasopressin-neurophysin II gene in a family with neurohypophyseal diabetes insipidus

OBJECTIVE: Autosomal dominant familial neurohypophyseal diabetes insipidus is a rare disorder characterized by polydipsia and polyuria. We present the results of the molecular analysis of the AVP-NPII gene of a German kindred. METHODS: All three exons of the gene were amplified by polymerase chain reaction and sequenced. RESULTS: In 7 affected individuals a new missense mutation (1770G > T) in exon 2 was found predicting a cysteine to phenylalanine substitution at codon 58 in the neurophysin II domain (NPII). CONCLUSION: As a result of this mutation a cysteine residue is exchanged, which is involved in a disulfide bond with cysteine 44 of the NPII moiety, hypothesizing that the resulting misfolded protein may lead to chronic neurotoxicity by accumulation of these products in the endoplasmatic reticulum.     

Presymptomatic direct detection of adenomatous polyposis coli (APC) gene mutations in familial adenomatous polyposis

The recent identification of the familial adenomatous polyposis (FAP) gene (designated as APC) enables conclusive genetic testing of at-risk family members for the specific mutation in families in which the germline gene mutation has been characterized. Presymptomatic molecular diagnosis of FAP was performed by direct direction of mutations in lymphocyte DNA in four families. Each of the families has a different mutation of the APC gene. Twenty-seven offspring of affected individuals (a priori risk of 50%) were tested. Ten of the 27 had already developed clinical features of FAP. Of the remaining seventeen, two had had a negative colon exam at an early age, and nine had never had colon exams (mean age, 12.1±3.1 SD years). Six children from this group (54%) were found to carry their affected parent's mutation. No change in the conventional FAP colon screening regimen is recommended for these children. In contrast, when direct tests indicate that an individual does not have the FAP mutation, we recommended that screening be decreased. Reduction of uncertainty for at-risk FAP family members is an important benefit of genetic testing.     

A novel arginine vasopressin-neurophysin II mutation causes autosomal dominant neurohypophyseal diabetes insipidus and morphologic pituitary changes

To determine the genetic basis of autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) in a Cypriot family, we ascertained and studied a large, four-generation kindred in which all participating family members had arginine vasopressin-neurophysin II (AVP-NP-II) gene analyses done. A G to A transition was found by DNA sequence analysis at position 1773 (G1773A) of the AVP-NPII gene which is predicted to encode a substitution of tyrosine for cysteine in codon 59 (CYS59TYR). The mutation was confirmed by restriction endonuclease analysis of PCR amplification products that contain the corresponding segment of the AVP-NPII gene. To clarify the morphologic status of the pituitaries of family members, 12 affected and 3 nonaffected members had magnetic resonance imaging (MRI) studies. The bright spot of the posterior pituitary lobe was completely absent in 75% and faintly identified in 25% of the affected members who were examined with MRI. We conclude that (1) a novel G1773A transition in exon 2 of the AVP-NPII gene causes ADNDI in the large Cypriot kindred studied, (2) this mutation is predicted to encode a CYS59TYR substitution in NPII, and (3) MRI studies of the posterior pituitary lobes of affected family members show either a decreased intensity or a complete absence of the bright spot in all cases studied.     

A Recurrent PDGFRB Mutation Causes Familial Infantile Myofibromatosis

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.     

Osmotic threshold and sensitivity for vasopressin release and fos expression by hypertonic NaCl in ovine fetus

In adults, hyperosmolality stimulates central osmoreceptors, resulting in arginine vasopressin (AVP) secretion. Near-term fetal sheep have also developed mechanisms to respond to intravascular hypertonicity with stimulation of in utero AVP release. However, prior studies demonstrating fetal AVP secretion have utilized plasma tonicity changes greater than those required for adult osmotically induced AVP stimulation. We sought to examine near-term fetal plasma osmolality threshold and sensitivity for stimulation of AVP secretion and to correlate plasma hormone levels with central neuronal responsiveness. Chronically instrumented ovine fetuses (130 +/- 2 days) and maternal ewes simultaneously received either isotonic or hypertonic intravascular NaCl infusions. Maternal and fetal plasma AVP and angiotensin II (ANG II) levels were examined at progressively increasing levels of plasma hypertonicity. Intravenous hypertonic NaCl gradually elevated plasma osmolality and sodium levels. Both maternal and fetal plasma AVP increased during hypertonicity, whereas ANG II levels were not changed. Maternal AVP levels significantly increased with a 3% increase in plasma osmolality, whereas fetal plasma AVP significantly increased only at higher plasma osmolality levels (over 6%). Thus the slope of the regression of AVP vs. osmolality was greater for ewes than for fetuses (0.232 vs. 0.064), despite similar maternal and fetal plasma osmolality thresholds for AVP secretion (302 vs. 304 mosmol/kg). Hyperosmolality induced Fos immunoreactivity (FOS-ir) in the circumventricular organs of the fetal brain. FOS-ir was also demonstrated in the fetal supraoptic and paraventricular nuclei (SON and PVN), and double labeling demonstrated that AVP-containing neurons in the SON and PVN expressed Fos in response to intravenous NaCl. These results demonstrate that, in the ovine fetus at 130 days of gestation, neuroendocrine responses to cellular dehydration are functional, although they evidence a relatively reduced sensitivity for AVP secretion compared with the adult.     

The Clinical Physiology of Water Metabolism: Part III: The Water Depletion (Hyperosmolar) and Water Excess (Hyposmolar) Syndromes

Hyperosmolality occurs when there are defects in the two major homeostatic mechanisms required for water balance—thirst and arginine vasopressin (AVP) release. In this situation hypotonic fluids are lost in substantial quantities causing depletion of both intracellular and extracellular fluid compartments. Patients with essential hypernatremia have defective osmotically stimulated AVP release and thirst but may have intact mechanisms for AVP release following hypovolemia. Hyperosmolality can also be seen in circumstances in which impermeable solutes are present in excessive quantities in extracellular fluid. Under these conditions there is cellular dehydration and the serum sodium may actually be reduced by water drawn out of cells along an osmotic gradient.Hyposmolality and hyponatremia may be seen in a variety of clinical conditions. Salt depletion, states in which edema occurs and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may all produce severe dilution of body fluids resulting in serious neurologic disturbances. The differential diagnosis of these states is greatly facilitated by careful clinical assessment of extracellular fluid volume and by determination of urine sodium concentration. Treatment of the hyposmolar syndromes is contingent on the pathophysiology of the underlying disorder; hyponatremia due to salt depletion is treated with infusions of isotonic saline whereas mild hyponatremia in cirrhosis and ascites is best treated with water restriction. Severe symptomatic hyponatremia due to SIADH is treated with hypertonic saline therapy, sometimes in association with intravenous administration of furosemide. Less severe, chronic cases may be treated with dichlormethyltetracycline which blocks the action of AVP on the collecting duct.     

Increased arginine-vasopressin response to hypertonic stimulation and upright posture in idiopathic hyperprolactinemia

To evaluate the possible influence of idiopathic hyperprolactinemia on the arginine-vasopressin (AVP) response to osmotic and pressure-volumetric stimuli, 14 idiopathic hyperprolactinemic women and 13 normoprolactinemic women were studied during a hypertonic saline infusion test (0.51M NaCl infusion for 2h) and an orthostatic test (standing upright and maintaining an orthostatic position for 20min). In both experimental conditions, the AVP response was significantly higher in women with idiopathic hyperprolactinemia than in normal normoprolactinemic women. These results indicate that in women hyperprolactinemia influences the AVP response to hyperosmotic and hypovolemic stimuli.     

Genotype-phenotype correlations in attenuated adenomatous polyposis coli.

Germ-line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli (AAPC), a variant of familial adenomatous polyposis (FAP). AAPC is recognized by the occurrence of <100 colonic adenomas and a later onset of colorectal cancer (age >40 years). The aim of this study was to assess genotype-phenotype correlations in AAPC families. By protein-truncation test (PTT) assay, the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds, and their phenotypic differences were examined. Five novel germ-line APC mutations were identified in seven kindreds. Mutations were located in three different regions of the APC gene: (1) at the 5' end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3' distal end of the gene. Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1, and upper-gastrointestinal manifestations were more severe in them. In individuals with mutations in either region 2 or region 3, the average number of adenomas tended to be lower than those in individuals with mutations in region 1, although age at diagnosis was similar. In all AAPC kindreds, a predominance of right-sided colorectal adenomas and rectal polyp sparing was observed. No desmoid tumors were found in these kindreds. Our data suggest that, in AAPC families, the location of the APC mutation may partially predict specific phenotypic expression. This should help in the design of tailored clinical-management protocols in this subset of FAP patients.     

Clinical,histopathologic, and genetic investigation in two large families with dentinogenesis imperfecta type II

Dentinogenesis imperfecta (DI) type II, an inherited disorder affecting dentin, has been linked to mutations in the dentin sialophosphoprotein (DSPP) gene on chromosome 4q21. The gene product is cleaved into two dentin-specific matrix proteins, dentin sialoprotein (DSP) and dentin phosphoprotein. The aim of this investigation was to study genotypes and phenotypes in two affected families with special reference to clinical, radiographic, and histopathologic manifestations. Seven affected members of Family A and five of Family B were documented clinically and radiographically; 14 and 10 teeth, respectively, were available for histopathologic investigation and prepared for ground sections, which were assessed semiquantitatively for dysplastic manifestations in the dentin according to the scoring system, dysplastic dentin score (DDS). Venous blood samples were collected from six affected and ten unaffected members of Family A, and from eight affected and six unaffected members of Family B. Genomic DNA was extracted and used for sequence analyses. The two families presented with different missense mutations. An Arg68Trp missense mutation in the DSP part of the gene was revealed in all six analyzed affected individuals in Family A. This mutation was not present in any of the ten healthy members. In Family B, an Ala15Val missense mutation involving the last residue of the signal peptide was found in all eight affected but in none of the six healthy members. The clinical and radiographic disturbances and DDS were more severe in Family B. The data indicate the presence of a genotype-phenotype correlation in DI type II.     

Lesion of central part of the dorsomedial nucleus alters vasopressin but not corticotropin releasing hormone mRNA levels in rat hypothalamic paraventricular nucleus

Functional significance of neural projections from the hypothalamic dorsomedial nucleus (DMN) to the paraventricular nucleus (PVN) was investigated using surgical lesion of the central part of the DMN. Under basal conditions, DMN lesion resulted in a decrease in magnocellular vasopressin (AVP) mRNA levels in the PVN, rise in pituitary proopiomelancortin (POMC) mRNA concentrations and elevated plasma corticosterone levels. Corticotropin-releasing hormone (CRH) mRNA levels remained unaffected. In sham operated animals, osmotic stress induced by hypertonic saline injection failed to modify AVP mRNA, but increased CRH and POMC mRNA levels and peripheral hormone release. The rise in CRH mRNA levels after osmotic stress was potentiated in DMN lesioned animals. Thus, the DMN participates in the control of hypothalamic peptide gene expression and pituitary adrenocorticotropic function.     

Two families with hereditary diabetes insipidus not due to osmoreceptor failure.

Two families with hereditary central diabetes insipidus (CDI) are reported. The pedigree in both families shows an autosomal dominant trait. The plasma arginine-8-vasopressin (AVP) determined by radioimmunoassay was markedly lower in these CDI patients than in healthy controls; the difference being even more pronounced after a hyperosmotic challenge. Since in the present study histamine also failed to increase the plasma AVP concentration, the authors consider it unlikely that an osmoreceptor failure would be implicated in the pathogenesis of CDI in these cases. The AVP concentration of the lumbar cerebrospinal fluid was also measured in two members of one of the families: the level found at the lower normal range indicates that some AVP secretion has been maintained in the extrahypothalamic vasopressinergic system of these patients.     

High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families.

A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been localized at 4q35. Subsequently, it was found that probe p13E-11 detects a polymorphic EcoRI fragment, usually > 28 kb, in normal individuals, whereas in sporadic and familial FSHD cases, an EcoRI fragment, usually < 28 kb, was found. Although these findings have been amply confirmed, several aspects are as yet either controversial or unsolved. In the present investigation, 34 Brazilian FSHD families were studied at the clinical and the molecular level for the following purposes: to assess the frequency of new mutations and their effect on estimates of biological fitness, to characterize FSHD-associated EcoRI fragments detected with probe p13E-11 in familial--as compared with isolated--FSHD cases, and to assess whether anticipation occurs in multigenerational families. Results from our study suggest that new mutations are apparently frequent for FSHD and may account for at least one-third of the cases, that somatic mosaicism may not be rare, and that biological fitness appeared to be reduced in FSHD, ranging from 0.6 to 0.82 by different estimates, with no difference in sexes. Interestingly, the size of the new EcoRI fragment is apparently smaller in more severely affected isolated patients. Moreover, the age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggests that anticipation occurs for FSHD in the majority of the families.     

Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients.

This paper presents the analysis of familial cancer data collected in a hospital-based study of 159 childhood soft-tissue-sarcoma patients. Two different statistical models detected excess aggregation of cancer, which could be explained by a rare dominant gene. For each kindred, we estimated the probability of the observed cancer distribution under the dominant-gene model and identified 12 families that are the most likely to be segregating the gene. Two of those families have confirmed germ-line mutations in the p53 tumor-suppressor gene. The relative risk of affection for children who are gene carriers was estimated to be 100 times the background rate. Females were found to have a slightly higher age-specific penetrance, but maternal and paternal lineages made equal contributions to the evidence in favor of the dominant gene. The proband's histology, ethnicity, and age at diagnosis were evaluated to determine whether any of these altered the probability of affection in family members. Only embryonal rhabdomyosarcoma was found to be a significant covariate under the dominant-gene model. While molecular genetic studies of familial cancer will eventually provide answers to the questions of genetic heterogeneity, age- and site-specific penetrance, mutation rates, and gene frequency, information from statistical models is useful for setting priorities and defining hypotheses.