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We report a juvenile patient with dermatitis herpetiformis, growth retardation and delayed onset of puberty. All symptoms reversed on gluten withdrawal and drug therapy was not required. It is suggested that dermatitis herpetiformis in this patient is the result of long-standing coeliac disease. [ABSTRACT FROM AUTHOR]

Background: In the Western world, it is widely accepted as natural - and seen almost as a law of nature - that mankind is divided into two sexes or genders - males and females. In many cultures and societies, however, more than two sex and/or gender categories are recognized, which in some instances refer to the biological sex and in others to gender roles and social status., Aims: To give an intercultural comparison of various ways of dealing with gender variance., Methods: In the following paper, we review the anthropological literature during the last 100 years describing individuals who live neither as men nor women in various non-Western cultures., Results: Only rarely, these individuals suffer from disorders of sex development in the modern medical or biological definition: in many if not all societies there have been individuals who are not covered by the gender category of male and female., Conclusion: There thus appears to be a cultural need for people with a special neither-male-nor-female status, which might be classified as 'gender variance'., ((c) 2008 S. Karger AG, Basel)

Background: Deletions and mutations in the NSD1 gene are the major cause of Sotos syndrome. We wanted to evaluate the genotype-phenotype correlation in patients suspected of having Sotos syndrome and determine the best discriminating parameters for the presence of a NSD1 gene alteration., Methods: Mutation and fluorescence in situ hybridization analysis was performed on blood samples of 59 patients who were clinically scored into 3 groups. Clinical data were compared between patients with and without NSD1 alterations. With logistic regression analysis the best combination of predictive variables was obtained., Results: In the groups of typical, dubious and atypical Sotos syndrome, 81, 36 and 0% of the patients, respectively, showed NSD1 gene alterations. Four deletions were detected. In 23 patients (2 families) 19 mutations were detected (1 splicing defect, 3 non-sense, 7 frameshift and 8 missense mutations). The best predictive parameters for a NSD1 gene alteration were frontal bossing, down-slanted palpebral fissures, pointed chin and overgrowth. Higher incidences of feeding problems and cardiac anomalies were found. The parameters, delayed development and advanced bone age, did not differ between the 2 subgroups., Conclusions: In our patients suspected of having Sotos syndrome, facial features and overgrowth were highly predictive of a NSD1 gene aberration, whereas developmental delay and advanced bone age were not., (Copyright (c) 2004 S. Karger AG, Basel.)

We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease.

The appearance of the external genitalia is the major determinant of the social sex, which is announced at or shortly after birth. In the absence of normal development of the external genitalia, definitive gender assignment and its announcement have to be postponed. While over the past 20 years the pathogenesis of most disorders causing abnormal development of the genitalia have been elucidated, our knowledge regarding the impact of these defects upon the psychosexual development is rather rudimentary. This information, however, is needed not only to establish criteria for correct sex assignment but also to design relevant outcome studies. Culture is an important part of the context in which decisions are made on sex assignment of patients with abnormalities of the external genitalia. Cultural differences in dealing with intersexuality and intersex individuals not only influences the patient's own psychosexual development but also medical decisions regarding sex assignment and consecutive management. There is evidence that attitudes concerning gender and sexuality, including the acceptance of intersexuality, differ significantly between various cultures. Thus cross-cultural studies might allow a new approach in dealing with intersexed persons, their families, and their social background, a most important aspect considering the recent discussions and criticisms of patients and individuals affected with intersex disorders.

In transient pseudohypoaldosteronism (TPHA), renal tubular resistance to aldosterone is thought to be secondary to renal disease. We report a case of TPHA caused by posterior urethral valves associated with urinary tract infection and review 62 cases previously reported. The infant presented with unspecific signs of vomiting and dehydration, so that pyloric stenosis was first suspected. Laboratory data and retroperitoneal sonography led to the diagnosis TPHA. This case illustrates that urine culture and renal ultrasonography should be performed in any infant with electrolyte disturbances to exclude infection or obstructive uropathy.

We describe a 2-month-old boy with penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, developmental retardation, and a subtelomeric deletion of chromosome 13q. His phenotype with anogenital malformations and characteristic facies closely resembled two unrelated patients with minute deletions of chromosome 13q who we reported earlier. In addition, he had unilateral renal agenesis. We propose that these patients represent a clinically recognizable, novel chromosomal microdeletion syndrome. The findings indicate the presence of a major gene(s) on chromosome 13q33.2qter that regulate(s) the migration and development of ano-reno-genital cells and organs. We speculate that mutations of this developmental gene(s) may also result in more frequent congenital malformations (isolated hypospadias, uterus bicornis, unilateral renal agenesis). Additional studies are needed to further delineate the genetic defect.

Background/aim of Study: Persistent hyperinsulinaemic hypoglycaemia is a rare metabolic disorder of glucose regulation. It is however the most common cause of persistent hypoglycaemia in the neonatal period. Various drugs have been used with generally poor results, but diazoxide and a long-acting somatostatin analogue, octreotide, have been found to be rather successful. When medical therapy fails, early pancreatectomy is recommended to maintain euglycaemia. Since pancreatectomy seems to carry the long-term risk of diabetes mellitus, some authors recommend long-term medical therapy as an alternative to surgery. The outcome of treatment seems to correlate with neurological status prior to surgery. Even in early recognised and treated patients, publications suggest that a subtle neurological deficit may be present despite apparently normal intelligence. In view of the varying recommendations on treatment and the variations in outcome, we reviewed our experience over a period of three years (1992-1995) to determine whether we could formulate a rational approach to the management., Methods: From our records, we identified 8 children who fullfilled the criteria for the diagnosis of persistent hyperinsulinaemic hypoglycaemia of infancy and retrospectively reviewed their documents. We also included 2 more who presented to us during the study period., Results: Two out of the 10 were born premature and four were considered large for gestational age, mean birth weight was 3679 gms (range 2580-4400 gms). All except three were symptomatic by day two of life. All except one were given hydrocortisone prior to transfer to our care at a mean age of 22 days (range 8-52 days). Our regime included a trial of diazoxide and octreotide. Near total pancreatectomy was performed in nine patients, seven following a short trial of octreotide. Our two most recent cases were given a longer trial of medical therapy of 9 and 6 months respectively prior to pancreatectomy. Our two early cases in the series had recurrence of hypoglycaemia within a week post-pancreatectomy. One still needed insulin therapy 5 months post-surgery. Seven were available for outcome assessment; while longitudinal growth is normal in all, three were developmentally delayed., Conclusion: Based on our experience with short and prolonged course of somatostation analogue, we conclude that early pancreatectomy should be performed on those with inadequate maintenance of euglycaemia while prolonged course of medical therapy is feasible only in selected cases.

Earlier observations on impaired in vitro effects of aldosterone on lymphocytic sodium and potassium pointed to the involvement of a defective nongenomic rather than genomic effector in pseudohypoaldosteronism. In this study, we investigated nongenomic aldosterone action in five patients with pseudohypoaldosteronism with regard to a rapid increase of free intracellular calcium [Ca2+]i in cultured nasal epithelial cells, assumably reflecting calcium influx through calcium channels. Patients were defined by episodes of salt loss despite high plasma aldosterone and renin levels. Four unaffected members of the families and four independent subjects served as controls. Considering an aldosterone-induced increase of [Ca2+]i by at least 10 nm as positive response, only 12% of cells from patients were responsive compared with 25% in normal subjects (P < 0.05). In terms of absolute changes, mean increase of [Ca2+]i was 1.6 +/- 1.1 nm in the patients (range-1-4) and 9.5 +/- 2.7 nm (P < 0.025) in the controls (range 1-25). Basal [Ca2+]i was not different between both groups (167 +/- 5 vs. 169 +/- 8 nm, mean +/- SE). These findings show an impaired nongenomic mineralocorticoid effector in patients with pseudohypoaldosteronism, which is in line with a defective sodium channel as shown recently by molecular cloning, and also with the fact that the classical, genomic intracellular receptor is structurally normal in these patients.

Familial persistent hyperinsulinemic hypoglycemia of infancy is a disorder of glucose homeostasis and is characterized by unregulated insulin secretion and profound hypoglycemia. Loss-of-function mutations in the second nucleotide-binding fold of the sulfonylurea receptor, a subunit of the pancreatic-islet beta-cell ATP-dependent potassium channel, has been demonstrated to be causative for persistent hyperinsulinemic hypoglycemia of infancy. We now describe three additional mutations in the first nucleotide-binding fold of the sulfonylurea-receptor gene. One point mutation disrupts the highly conserved Walker A motif of the first nucleotide-binding-fold region. The other two mutations occur in noncoding sequences required for RNA processing and are predicted to disrupt the normal splicing pathway of the sulfonylurea-receptor mRNA precursor. These data suggest that both nucleotide-binding-fold regions of the sulfonylurea receptor are required for normal regulation of beta-cell ATP-dependent potassium channel activity and insulin secretion.

We have previously demonstrated a deficiency of mineralocorticoid receptors in pseudohypoaldosteronism, by radioreceptorassay. We now report findings with an antireceptor antibody derived from the immunogenic region of the receptor. Lymphocytes from normal controls and from two cases of pseudohypoaldosteronism previously shown to lack receptor binding were tested. After the plasma membrane of lymphocytes was permeabilized with methanol the cells were incubated with a 1:200 dilution of antibody followed by fluorescent antirabbit immunoglobulin mouse serum. After washing fluorescence was detected by microscopy and cytofluorimetry in both controls and patients with pseudohypoaldosteronism. Recent studies on mineralocorticoid receptor cDNA in pseudohypoaldosteronism have not established a mutation in the sequence. We thus suggest that the pathogenesis of pseudohypoaldosteronism is not related to an abnormality of the receptor but rather due to intracellular factor(s) which can block the binding of aldosterone to its receptor.

Pseudohypoaldosteronism is thought to be a rare salt-losing disorder, caused by resistance to the action of aldosterone. Defective aldosterone receptor binding is present in familial as well as sporadic cases and it has been suggested that the pathogenesis is due to a defect in the aldosterone receptor system. To date, however, molecular genetic analysis has been unable to identify a mutation in the aldosterone receptor gene itself. We have reviewed the findings in patients with pseudohypoaldosteronism, for clues which might enable us to identify the underlying pathogenesis. Although aldosterone receptor binding is regularly decreased or absent in monocytes of patients with pseudohypoaldosteronism, in some patients receptor protein can be detected with a fluorescence-labeled antibody. Receptor protein was detected in patients from familial autosomal dominant families and in sporadic cases, but was undetectable in two patients with the familial recessive form. To further elucidate the pattern of inheritance we studied the response of the renin-angiotensin-aldosterone system to the stimulation by sodium depletion in the familial autosomal dominant form and in two families with sporadic cases. In both "sporadic" families investigated, one parent and one sibling had an exaggerated response of renin and aldosterone to sodium depletion indicating a defect of sodium conservation apparent only during stress, leading to reclassification as familial cases. No additional family member in the "classical" autosomal dominant families responded abnormally to sodium depletion. These findings indicate that pseudohypoaldosteronism is unusually heterogeneous in its clinical, biochemical, and genetic presentations and findings and suggest that its pathogenesis is heterogeneous as well.

The genetics of human sex determination is considered in view of the various disorders of gonad development. The Y chromosome plays an important role in the induction of sex determination by encoding the testis-determining factor (TDF). However, not all deviations in regular development can be explained by mutations of the TDF as unique factor. Therefore, it is necessary to postulate other mutations in still unknown genes of the cascade for male-specific determination as well as the requirement of an ovary-determining factor for regular female development.

A 20-year old woman, who underwent an intersex operation during infancy, was presented for evaluation of the gonads because of suspected true hermaphroditism. The phenotype was female with regular menstruations. Examination revealed an ovarian tumour of 8 cm on the left side and a normal right ovary. During the operation, the tumour was revealed as an endometriosis cyst, which could be excised whilst preserving the ovarian tissue. The right gonad was an ovotestis. The testicular part was removed because of a 4% risk of malignancy. The different combinations of ovary/testis and ovotestis are described. Diagnosis and therapy of true hermaphroditism should be performed as early as possible to obtain an adequate gonadal function and an undisturbed psychosexual development.

Recently, the gene for the determination of maleness has been identified in the sex-determining region on the short arm of the Y chromosome (SRY) between the Y-chromosomal pseudoautosomal boundary (PABY) and the ZFY gene locus. Experiments with transgenic mice confirmed that SRY is a part of the testis-determining factor (TDF). We describe a sporadic case of a patient with intersexual genitalia and the histological finding of ovotestes in the gonad, which resembles the mixed type of gonadal tissue without primordial follicle structures. The karyotype of the patient was 46,XY. By PCR amplification, we tested for the presence of PABY, SRY, and ZFY by using DNA isolated from peripheral blood leukocytes and for the presence of SRY by using DNA obtained from histological gonadal slices. The SRY products of both DNA preparations were further analyzed by direct sequencing. All three parts of the sex-determining region of the Y chromosome could be amplified from leukocytic DNA. The patient's and the father's SRY sequences were identical with the published sequence. In the SRY PCR product of gonadal DNA, the wild-type and two point mutations were present in the patient's sequence, simulating a heterozygous state of a Y-chromosomal gene: one of the mutations was silent, while the other encoded for a nonconservative amino acid substitution from leucine to histidine. Subcloning procedures showed that the two point mutations always occurred together. The origin of the patient's intersexuality is a postzygotic mutation of the SRY occurring in part of the gonadal tissue. This event caused the loss of the testis-determining function in affected cells.

We report on a 2-year old boy with the characteristic features of Di George syndrome. The diagnosis was confirmed by history, biochemical, immunologic and radiologic findings. After physical exercise he developed an unilateral epiphysiolysis capitis femoris, rarely seen in this age and not known to be a complication of hypoparathyroidism.

Pseudohypoaldosteronism is a rare inherited disease characterized by renal salt loss, hyperkalemia and metabolic acidosis despite highly elevated aldosterone values. We previously reported absent or reduced numbers of mineralocorticoid receptors in mononuclear leukocytes and defective effector mechanism as shown by no response in vitro to the incubation of aldosterone in terms of intracellular electrolyte content. We have studied the inheritance of this disorder in ten families and found two different kinds of inheritance: autosomal recessive--often in interrelated families--and autosomal dominant in unrelated families. Parallel studies in the families with the autosomal dominant form of inheritance demonstrated in addition that the effector mechanism of aldosterone is impaired in vitro both in the affected patients and in the carrier relatives characterized by a low number of mineralocorticoid receptors.

Testosterone and androstenedione were measured in testicular and epididymal tissue of 37 previously healthy infants between 1 and 24 months of age who died suddenly. In half of the patients elevated plasma levels of cortisol and androstenedione suggested preterminal stress. Plasma testosterone levels, however, did not differ from those in healthy infants. Testicular testosterone concentrations were maximal in boys from 1-3 months of age (median, 36.6 ng/g; range, 7-380 ng/g) with peak values similar to those found in pubertal or even adult testes. Thereafter testicular testosterone concentrations decreased and after the age of 6 months all values were below 12.5 ng/g, which corresponds to the low normal range of older prepubertal boys. Plasma testosterone and testicular testosterone correlated significantly (P less than 0.001). On average the testicular concentrations were 36.4 times higher than the corresponding plasma concentrations. Testicular androstenedione was low but correlated significantly with testicular testosterone (P less than 0.001). Epididymal testosterone concentrations were surprisingly high (1-3 months: median, 10.3 ng/g; range, 4-42.7 ng/g) and averaged 30% of the testicular testosterone concentration. Thus, epididymal testosterone concentrations were significantly higher than the circulating plasma testosterone levels, indicating the capacity of the infant epididymis to accumulate androgens. These findings suggest that high local testosterone concentrations during early infancy are important not only for the testis itself but particularly for the developing epididymis.

The characteristic excess production of androgens in the cortisol 21-hydroxylase defect is generally considered to be secondary to ACTH stimulation of alternate pathways. Whenever a morphological examination of the adrenals has been possible in this disorder, adrenocortical hyperplasia was a constant finding. The availability of methods for the prenatal diagnosis of the 21-hydroxylase defect has made it possible to examine some of the manifestations of this disorder during fetal life. We studied a severely virilized 20-week-old aborted female fetus with the 21-hydroxylase defect whose adrenals were neither grossly enlarged nor microscopically hyperplastic. In a pregnancy at risk for congenital adrenal hyperplasia due to a 21-hydroxylase deficiency, amniocentesis was performed in the 18th week of gestation. The 21-hydroxylase defect was established by HLA typing and highly elevated levels of 17-hydroxyprogesterone, testosterone, and androstendione in amniotic fluid. After counselling, the parents, who already had a girl with the salt-wasting form of 21-hydroxylase deficiency, wished termination of the pregnancy. The aborted 20-week-old fetus was within the normal range for gestational age in weight and height. The external genitalia were ambiguous and extremely virilized, with an enlarged clitoris and fused labioscrotal folds. A urogenital sinus opened at the base of the clitoris. The internal organs were female, with a normal uterus and ovaries. Both adrenals were normal in size and weight for their gestational age. Histological examination of the adrenals revealed no abnormalities, and no hyperplasia was detectable. Thus, the adrenals in the 21-hydroxylase defect during fetal life secrete excessive amounts of androgens and cause virilization in the absence of adrenocortical hyperplasia.

Conjugated and free urinary oestrone and oestradiol-17 beta were determined by radioimmunoassay in 98 urine samples of 44 normal male and female infants ranging from 7 days to 2 years of age. Both sexes excreted significantly more oestrone and oestradiol-17 beta during the first 3 months of life compared to the end of the first year. Values peaked at the beginning of the second month. During the first 7 months of life, female infants excreted significantly more conjugated oestradiol-17 beta than oestrone, whereas male infants consistently excreted equal amounts of conjugated oestradiol-17 beta and oestrone. However, both sexes excreted significantly more free unconjugated oestrone than oestradiol-17 beta during the same period.

In-vitro effects of aldosterone on intracellular sodium and potassium concentrations have been described for normal human mononuclear leucocytes (HML). After incubation for 1 h at 37 degrees C, intracellular sodium and potassium in HML are significantly higher in the presence of 1.4 nM aldosterone than after incubation without aldosterone. As published earlier, these effects were absent in patients with pseudohypoaldosteronism. In the present paper, the families of seven patients with pseudohypoaldosteronism (index cases) were studied. In the first family, two siblings were affected by the disease and had a reduced number of mineralocorticoid (MC) receptors on HML. Intracellular sodium and potassium in HML from these patients did not show a response to 1.4 nM aldosterone. The parents, who were first cousins, had no history of disease and normal receptor data, but in the mother, the response of HML electrolytes to aldosterone was abnormal. In the second family, the mother of a child with pseudohypoaldosteronism, the mother's sister, and her son, had low numbers of MC receptors. Only the aunt of the index case had an uncertain history of the disease. The MC effector mechanism was abnormal in both children and both mothers studied. In a third family, the effector defect was present only in HML of the father. In three further families the abnormality of the effector mechanism was detected in HML of the patient's mother. These data suggest an autosomal dominant inheritance of pseudohypoaldosteronism with variable expression of the gene.(ABSTRACT TRUNCATED AT 250 WORDS)