Type 1 diabetes in Jewish Ethiopian immigrants in Israel: HLA class II immunogenetics and contribution of new environment.

The interrelationship between human leukocyte antigen immunogenetics and environmental factors and their contribution to the emergence of type 1 diabetes (T1D) were studied in Jewish immigrants from Ethiopia in Israel. This community displays high incidence of T1D, and is unique both by its ethnic segregation and its rapid exposure to a new environment after the immigration. The study population consisted of 152 Ethiopian Jews living in Israel, 33 with T1D and 119 unrelated controls. Human leukocyte antigen class II susceptible and protective alleles in the Jewish Ethiopian patients were similar to those in patients of other ethnic groups in Israel and in non-Jewish Ethiopian patients, with a few exceptions. Three haplotypes were markedly associated with diabetes in Jewish Ethiopian patients: DRB1*0301 DQA1*05 DQB1*02 (OR 4.4, p < 0.001); DRB1*0404 DQA1 03 DQB1*0302 (OR 19.2, p = 0.006), and DRB1*0405 DQA1*03 DQB1*0302 (OR 87.8, p < 0.001). The highly susceptible allele DRB1*0301 was more common in the general Ethiopian population (25.2%) than in all other ethnic groups in Israel, which may render this community prone to the disease. The age at onset of disease in patients with two susceptible haplotypes was negatively correlated with the duration of living in Israel (r = -0.621, p = 0.04). We concluded that ongoing exposure of genetically predisposed immigrants from Ethiopia to diabetogenic environmental factors eventually leads to a high incidence of overt diabetes in this ethnic group.

[Cyclic psychosis associated with the menstrual cycle].

Cyclic psychosis associated with the menstrual cycle is an uncommon disorder, not included under the accepted definitions of functional psychoses. We present three female adolescents who developed an acute psychosis a few days before menstruation, which resolved completely upon bleeding or several days later, only to reappear in the same form in subsequent cycles. The clinical presentation was not in line with that of the typical functional psychoses. An extensive medical work-up did not show any significant disturbances, with the exception of anovulatory cycles in one youngster. Psychotropic treatment had no effect on the course of the psychosis. Treatment with progesterone in the second half of the cycle in one case, and with a combined progesterone/estrogen contraceptive agent in another, resulted in full recovery within several cycles. The third girl showed a spontaneous remission within four cycles. Remission continued in all cases after discontinuation of the hormonal treatment, and with no need to reintroduce any psychotropic agent, for a period of 2-4 years. We discuss several possible etiologic mechanisms for cyclic psychosis associated with the menstrual cycle, including it being a cycloid non-specific affective disorder, and its association with a temporary functional hypothalamic-pituitary dysfunction, and with anovulation. We also discuss the role of psychotropic and hormonal treatment in this disorder.

An outbreak of echovirus 13 meningitis in central Israel.

Until recently, echovirus 13 has been a very rare cause of aseptic meningitis. We investigated an outbreak of echovirus 13 in central Israel during the summer of 2000 using a prospective case control study and a retrospective study. Echovirus 13 was isolated from 79 cerebrospinal fluid (CSF) specimens from different medical centres in central Israel. Patients' ages ranged from 10 days to 41 years (95% < 15 years, M/F ratio 62/38). A total of 128 patients with clinical aseptic meningitis were admitted to the Department of Pediatrics during the outbreak (aged 10 days to 18 years, mean 5.4 years), and 58 CSF samples were processed for viral cultures. Thirty of them did not grow any virus, 26 samples yielded echovirus 13, and 2 samples echovirus 7. The clinical features of patients with echovirus 13 in the CSF were similar to those in whom no virus was isolated or those infected with other enteroviral strains except for higher rate of fever on admission, and prolonged time with fever following the diagnosis in the echovirus 13 patients. CSF cell count varied from 4 to 2,333 cells/mm3 with polymorphonuclears (PMN) predominant in 90% of our patients. In a case-control study there was no significant difference between patients and matched controls with regard to parameters such as: day care attendance, recreation in summer camp, swimming pools and at the beach, and consumption of tap water. All the patients in our series recovered fully with no neurological abnormalities. The illness caused by echovirus 13 was benign and involved mainly patients younger than 15 year of age. Several features that characterized this outbreak include relatively high WBC in the blood and a minent CSF PMN response.

Growth hormone activates renin-aldosterone system in children with idiopathic short stature and in a pseudohypoaldosteronism patient with a mutation in epithelial sodium channel alpha subunit.

Growth hormone (GH) treatment causes salt and water retention, and this effect has been suggested to be mediated by activation of epithelial sodium channel (ENaC). Multi-system pseudohypoaldosteronism (PHA) is a salt wasting disease resulting from mutations in ENaC subunit genes. We examined effects of GH therapy for 12-21 months on the renin-angiotensin-aldosterone system (RAAS) in 12 children with idiopathic short stature (ISS) and a PHA patient with defective ENaC function and concomitant GH deficiency. On GH therapy (0.7 U/kg/week), plasma renin activity (PRA), serum aldosterone and insulin-like growth factor-I (IGF-I) levels were periodically determined every 1-3 months in all children. The PHA patient was studied for 6 yr during which time serum, urine, and sweat electrolytes and secretion rate were also examined before, on and off GH therapy. In the PHA patient, mean plasma aldosterone concentration, 7.7 nmol/l (278 ng/dl) before therapy (n=9) rose to 73 nmol/l (2650 ng/dl) 10 months after GH. PRA and IGF-I increased similarly, reaching a plateau between 8 and 12 months. Off GH, there was a decrease to pretreatment levels in 30 months. Aldosterone and PRA strongly correlated with IGF-I (r=0.66 and 0.67). GH therapy also improved the growth rate, and increased both sweat secretion rate and Na(+)/K(+) ratio. In children with ISS, aldosterone and IGF-I peaked 6-12 months after GH. Off GH their levels normalized in 3 months. These findings indicate that long-term GH activates the RAAS in both children with ISS and a PHA patient, and that this effect does not depend on a fully functional ENaC.

Relationship of etiology to treatment in congenital hypothyroidism.

We examined the patterns of TSH, T(4), and treatment schedules from diagnosis to 4 yr of age in 125 children (50 males anf 75 females) with congenital hypothyroidism (CH). Subjects were divided into 3 groups based on their thyroid scans: 1) athyreosis (n = 31), 2) dysgenesis (n = 54; 49 lingual and 5 hypoplastic), and 3) dyshormonogenesis (n = 40). Follow-up evaluation was carried out at 2-4 wk and 3, 6, 9, 12, 24, 36, and 48 months of age. Median gestational age, age at onset of therapy, and starting L-T(4) dose were similar in the three groups. In infants with athyreosis median screening TSH levels were higher (P < 0.02) and confirmatory T(4) levels were lower than in the other two groups (P < 0.01 vs. dysgenetic; P < 0.05 vs. dyshormonogenetic CH). During the first 6 months of therapy, mean TSH levels were highest in the athyrotic group, intermediate in the dysgenetic group, and lowest in the dyshormonogenetic group. In children with athyreosis, TSH levels normalized by 12 months of age. At 12 months dysgenetic patients had the highest TSH levels (P < 0.05). During the entire study period, TSH levels were lowest in patients with dyshormonogenesis (except at 48 months) and normalized earlier. Mean T(4) levels normalized by 2-4 weeks in all groups. At 3 and 6 months, the percentage of patients who required dose changes was highest in the athyrotic group, and at 12 months it was highest in the dysgenetic group. The athyrotic group received the highest dose of L-T(4), and dyshormonogenetic group received the lowest dose. We conclude that treatment and follow-up schedules for CH may differ in the three etiological categories based on the different hormonal patterns and responses to therapy. Children with athyreosis need close monitoring particularly early in life, whereas those with dysgenesis and dyshormonogenesis require more attention later in life.

Chronic urticaria in children: expanding the "autoimmune kaleidoscope".

Most cases of chronic urticaria (CU) are considered idiopathic. It has recently been accepted that autoimmunity plays a critical role in the pathogenesis of CU in some of these patients. Although urticaria is common in the pediatric population, the knowledge regarding CU-associated autoimmunity is very limited. We describe the association of CU with a wide spectrum of clinical and laboratory autoimmune disorders in 2 children and emphasize the concept that CU is another manifestation of the "autoimmune kaleidoscope."

The effect of endogenous dehydroepiandrosterone sulphate on antibody response to hepatitis B vaccine in neonates.

BACKGROUND: DHEAS, the most abundant steroid secreted by the adrenal cortex, is suggested to have an important role in the development of immune reaction by activating T cell function and increasing antibody response, and has been tried as a vaccine adjuvant in elderly people. OBJECTIVES: We examined the correlation between endogenous DHEAS and antibody response in the neonatal period by comparing the serum DHEAS levels with the amount of antibody response against hepatitis B vaccination in neonates. METHODS: Vaccine was administered to 12 healthy infants within 24 hours of birth (day 0), and blood specimens were obtained on days 0 and 30 for determination of anti-hepatitis B surface antibody concentration and DHEAS levels. RESULTS: DHEAS levels varied widely (range 0.38-3.70 micrograms/ml, mean +/- 1SD 2.14 +/- 0.98). While we could identify two groups of patients--those with high DHEAS levels (2.90 +/- 0.56) and those with lower levels (1.30 +/- 0.56)--there was no correlation between DHEAS levels and the antibody response to hepatitis B vaccine (r = -0.05). CONCLUSIONS: In neonates, antibody response to hepatitis B vaccine does not correlate with DHEAS serum levels. These results do not support the usage of DHEAS as a vaccine adjuvant in neonates.

Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism.

BACKGROUND: Active sodium absorption is the dominant mechanism of ion transport in airway epithelium, but its role in pulmonary physiology and airway host defense is unknown. To address this question, we studied the function of airway epithelial cells and determined the frequency of pulmonary symptoms in patients with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of-function mutations in the genes for the epithelial sodium channel. METHODS: In nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we tested for mutations in the genes for the epithelial sodium channel, estimated the rate of sodium transport in the airway, determined the volume and ion composition of airway surface liquid, reviewed clinical features, collected laboratory data pertinent to pulmonary function, and, in three adults, measured mucociliary clearance. RESULTS: The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value. The mean (+/-SE) mucociliary transport rate was higher in the 3 adult patients than in 12 normal subjects (2.0+/-0.7 vs. 0.5+/-0.3 percent per minute, P=0.009). Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than five years of age) had less frequent respiratory symptoms. CONCLUSIONS: Patients with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces; the result is an increased volume of liquid in the airways. These results demonstrate that sodium transport has a role in regulating the volume of liquid on airway surfaces.

Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit.

ENaC functions in the transport of sodium ions across epithelial cells and consequently regulates blood volume and pressure. ENaC complex includes at least three different subunits, alpha, beta, and gamma, which are developmentally regulated and differentially controlled by aldosterone. In this study, we determined the exon-intron organization of the beta ENaC subunit by sequencing genomic DNA from three subjects from three different ethnic groups. The results showed that the coding region of the human betaENaC gene (SCNN1B) extends from exon 2 to exon 13. No polymorphism was observed in the examined subjects, indicating strict conservation of the coding region sequence. The introns of beta subunit gene are located at exactly the same positions as in the alpha and gamma subunits, although these proteins share only 26-32% sequence identity. These results thus elucidate the gene structure of the beta subunit and indicate that exon-intron architecture of the three genes encoding the three subunits of ENaC have remained highly conserved despite the divergence of their sequences.

Pseudohypoaldosteronism due to renal and multisystem resistance to mineralocorticoids respond differently to carbenoxolone.

Type I pseudohypoaldosteronism (PHA) is a hereditary syndrome of salt wasting resulting from unresponsiveness to mineralocorticoids. PHA is manifested in two clinically and genetically distinct forms, affecting either only the kidney or multiple target organs of aldosterone. We examined the mineralocorticoid effect of carbenoxolone (CBX) in young PHA patients with either renal or multisystem resistance to aldosterone to find out whether CBX may help reduce the requirement for a high-salt diet. CBX did not show any significant salt-retaining effect in two patients with multiple PHA, and did not affect the renin-aldosterone system. In contrast, CBX significantly suppressed the renin-aldosterone system in a renal PHA patient for the whole duration of treatment, but without a long-term salt-retaining effect. On CBX treatment, urinary cortisone levels decreased and the cortisol:cortisone ratio increased, indicating that CBX inhibited 11beta-HSD activity that metabolizes cortisol to cortisone. The complete lack of effect of CBX on the renin-aldosterone system in multisystem PHA patients indicates that CBX does not exert an effect via mineralocorticoid (MR) or glucocorticoid receptors. Examination of the structure and expression of the MR gene by Southern blot analysis and polymerase chain reaction (PCR) showed no abnormality. Whereas multiple PHA results from a spectrum of mutations in the mineralocorticoid activated epithelial sodium channel subunits, the genetic basis of renal PHA is still unknown. The response to CBX suggests that there is at least a partly functional MR in renal PHA patients.

Severe pseudohypoaldosteronism in a pair of twins not associated with hydramnios.

A pair of non-identical twins with severe pseudohypoaldosteronism (PHA) were followed over a period of 4 years. The diagnosis was based on dehydration, hyponatremia, hyperkalemia, high urine sodium/potassium ratios, and high serum concentrations of aldosterone and renin. Sweat and saliva electrolyte concentrations were high, suggesting multifocal target-organ unresponsiveness to mineralocorticoids. No hydramnios was observed during pregnancy. Despite continuous treatment with sodium chloride and sodium bicarbonate (< or = 20 g/day) and cation exchange resin (Kayexalate, sodium polystyrene sulfonate, < or = 4 g/kg per day), the children had repeated episodes of dehydration, hyponatremia, and hyperkalemia. Growth velocity was normal in both twins. Catch-up growth was observed following infancy in the first twin. Normalization of plasma aldosterone, electrolytes, and renin concentrations was achieved at the age of 9 months.

Endogenous methemoglobinemia associated with diarrheal disease in infancy.

Infantile diarrhea is sometimes associated with methemoglobinemia. To determine the significance of intestinal bacterial infection or overgrowth and other predisposing factors in this entity, we evaluated prospectively 45 consecutive patients who were admitted for gastroenteritis and methemoglobinemia between March 1980 and September 1992. All the patients were younger than 3 months of age. In 95% of them, methemoglobinemia occurred between the ages of 15 days to 2 months. The peak mean methemoglobin concentration was 9.4% (range, 2.4-57%). Although stool cultures were positive in only 22% of the infants, the epidemiologic data strongly suggested a bacterial or viral etiology in our study population: for 12 years, there was a significant decrease in the annual incidence of methemoglobinemia associated with diarrhea in parallel to the decrease in infantile diarrhea due to known pathogens throughout the country in the same period. There was also a marked seasonal variation in the incidence of the disease, with two peaks in January and the summer months when viral and bacterial infections, respectively, are prevalent. Failure to thrive and low admission-weight percentiles were associated with methemoglobinemia in most of the patients and diarrhea lasting > or = 7 days in 22 (49%) patients. The blood pH and the degree of acidosis did not correlate with the severity of methemoglobinemia. All the patients were formula fed. In the etiology of methemoglobinemia in infants with enteritis, viral and bacterial pathogens appear to play an important role by altering intestinal flora. Breast feeding appears to protect against this entity.

Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1.

Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones. Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity. These findings demonstrate the molecular basis and explain the pathophysiology of this disease.

Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping.

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is a rare Mendelian disorder characterised by end-organ unresponsiveness to mineralocorticoids. Most steroid hormone insensitivity syndromes arise from mutations in the corresponding receptor, but available genetic evidence is against involvement of the mineralocorticoid receptor gene, MLR, in PHA1. A complete genome scan for PHA1 genes was undertaken using homozygosity mapping in 11 consanguineous families. Conclusive evidence of linkage with heterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. The two chromosomal regions harbour genes for subunits of the amiloride-sensitive epithelial sodium channel: SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Liddle's syndrome of hypertension and pseudoaldosteronism has been shown to arise from mutations in SCNN1B and SCNN1G. These results strongly suggest that PHA1 and Liddle's syndrome are allelic variants caused by mutations in genes encoding subunits of this sodium channel. These genes are of broad biological interest both in relation to sodium and water homeostasis in mammals and by virtue of their homology to the mec genes of Caenorhabditis elegans involved in mechanosensitivity and neuronal degeneration.

Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis.

Pseudohypoaldosteronism type 1 (PHA1) is an uncommon inherited disorder characterized by salt-wasting in infancy arising from target organ unresponsiveness to mineralocorticoids. Clinical expression of the disease varies from severely affected infants who may die to apparently asymptomatic individuals. Inheritance is Mendelian and may be either autosomal dominant or autosomal recessive. A defect in the mineralocorticoid receptor has been implicated as a likely cause of PHA1. The gene for human mineralocorticoid receptor (MLR) has been cloned and physically mapped to human chromosome 4q31.1-31.2. The etiological role of MLR in autosomal recessive PHA1 was investigated by performing linkage analysis between PHA1 and three simple sequence length polymorphisms (D4S192, D4S1548, and D4S413) on chromosome 4q in 10 consanguineous families. Linkage analysis was carried out assuming autosomal recessive inheritance with full penetrance and zero phenocopy rate using the MLINK program for two-point analysis and the HOMOZ program for multipoint analysis. Lod scores of less than -2 were obtained over the whole region from D4S192 to D4S413 encompassing MLR. This provdes evidence against MLR as the site of mutations causing PHA1 in the majority of autosomal recessive families.

Selective increases in adrenal steroidogenic capacity during acute respiratory disease in infants.

To examine steroidogenic responses of the different zones of the adrenal cortex to acute disease we determined the basal and adrenocorticotropin (ACTH)-stimulated levels of cortisol, dehydroepiandrosterone (DHEAS) and aldosterone in 16 infants aged 1-4 months with acute bronchiolitis. Fourteen of the infants were retested after recovery. During illness the mean basal levels of cortisol and DHEAS were twice as high as the levels after recovery (370 vs 180 nmol/l and 2.7 vs 1.3 mumol/l, respectively). The mean peak ACTH-stimulated levels of cortisol and DHEAS during illness were 1.5- and 2.5-fold higher, respectively, than the levels found after recovery. Although aldosterone secretion was stimulated > or = 3-fold by ACTH, illness was not associated with any change in aldosterone secretory capacity. The basal and stimulated levels of both cortisol and DHEAS during illness and after recovery were correlated significantly. Thus, the relative steroidogenic capacities for these two steroids were characteristic of the individual infant and showed constancy over a period of at least several weeks. While the levels of cortisol and aldosterone were not dependent on the age of the infants, both the basal and stimulated levels of DHEAS correlated strongly with age. We conclude that during acute disease the steroidogenic capacity selectively increases in the zones that secrete cortisol and DHEAS (only in infants < 3 months) but not in the zona glomerulosa that secretes aldosterone. The DHEAS response may be related to its putative effects to enhance immune responses.

Serious complications of routine ritual circumcision in a neonate: hydro-ureteronephrosis, amputation of glans penis, and hyponatraemia.

A 13-day-old infant developed bilateral hydroureteronephrosis, severe hyponatraemia, hyperkalaemia, and acidosis, as a result of urethral damage following circumcision. The hydroureteronephrosis and biochemical abnormalities normalized after resolution of the penile injury. Conclusion. Infants with urinary retention following circumcision may develop hydro-ureteronephrosis and electrolyte disturbances. An awareness of the potential dangers of circumcision may help to limit its complications.

Pseudohypoaldosteronism with increased sweat and saliva electrolyte values and frequent lower respiratory tract infections mimicking cystic fibrosis.

Four patients with severe pseudohypoaldosteronism caused by multiple end-organ resistance to aldosterone had frequently recurring lower respiratory tract infections and persistently elevated sweat and saliva electrolyte values. The increased saliva electrolyte values in these patients probably affect normal mucociliary function in the respiratory tract and facilitate the occurrence of frequent lower respiratory tract involvement. Patients with pseudohypoaldosteronism may require treatment similar to that for cystic fibrosis to prevent long-term respiratory complications.

The effect of carbenoxolone on the peripheral metabolism of cortisol in human patients.

Carbenoxolone in human patients induces a state that is similar to that seen in the syndrome of apparent mineralocorticoid excess. The mechanism in both the drug-induced and the naturally occurring disorder is thought to be the inhibition of a normal mechanism for preventing access of cortisol to the mineralocorticoid receptor, namely 11 beta-hydroxy dehydrogenation. We took the opportunity to study the effect of carbenoxolone on the peripheral metabolism of cortisol in the course of evaluating the drug's therapeutic effectiveness in pseudohypoaldosteronism. Carbenoxolone, at a dose that induces mineralocorticoid effects in patients with normally responsive mineralocorticoid receptor systems, did not lead to significant changes in the urinary cortisol: cortisone tetrahydrometabolite ratio. There was, however, a marked inhibition of ring A reduction of both cortisol and cortisone to tetrahydro metabolites. Urinary cortisol level was not significantly changed, but urinary cortisone level was decreased and the cortisol:cortisone ratio markedly increased. We conclude that the urinary cortisol:cortisone tetrahydrometabolite ratio is not necessarily a valid measure of effective inhibition of 11 beta-hydroxy dehydrogenation. A better measure of the inhibitory effect of carbenoxolone on 11 beta-hydroxy dehydrogenation is the urinary free cortisol:cortisone ratio.