Androgen Receptor CAG Repeat Length in Relation to Phenotype Among Females with Nonclassical 21-Hydroxylase Deficiency.

Nonclassical 21-hydroxylase deficiency (NC21OHD) manifests with various degrees of post natal virilization. The length of CAG repeats of the androgen receptor gene (AR) is inversely correlated to activity of the human androgen receptor (AR) and affects phenotype of several androgen-dependent disorders. The aim of the study was to investigate the associations between CAG repeat length and the phenotype of females with NC21OHD. CAG repeat length and AR inactivation were assessed in females with NC21OHD, and related to their clinical presentation. CAG repeat length and AR inactivation were assessed in 119 females with NC21OHD. Biallelic mean (BAM) of the CAG repeat length and the weighted BAM (WBAM) were related to various clinical parameters. Age at diagnosis and age of menarche positively correlated with BAM (r=0.22, p=0.02, and r=0.23, p=0.01, respectively). A shorter (<25) BAM was associated with younger age at diagnosis (14.8 vs. 21.4 years, p<0.01), at adrenarche (8.1 vs. 10.2 years, p<0.01) and gonadarche (9.9 vs. 11.2 years, p<0.01), and higher corrected height standard deviation score at diagnosis (0.77 vs. 0.15, p=0.01). Precocious pubarche and precocious puberty were more frequent in these with the shorter BAM. Results of WBAM were similar. The CAG repeat length of the AR gene contributes to the clinical diversity of the phenotype in females with NC21OHD.

Concurrent nonfunctioning parathyroid carcinoma and parathyroid adenoma.

Parathyroid carcinoma is a rare etiology of primary hyperparathyroidism characterized by severe clinical symptoms of hypercalcemia and markedly elevated serum parathormone levels. Nonfunctioning parathyroid carcinoma is an inactive form of the disease. There are less than 30 reports of nonfunctioning parathyroid carcinoma in the English literature and the association with parathyroid adenoma has not been described. This report describes a patient with concurrent nonfunctioning parathyroid carcinoma and a functioning parathyroid adenoma.

Increased salt appetite in patients with congenital adrenal hyperplasia 21-hydroxylase deficiency.

Salt appetite was investigated in 14 patients with congenital adrenal hyperplasia of the salt-wasting form (SW group), 12 patients with the simple virilized form who are not salt losing, and 18 healthy siblings. Salt appetite was evaluated by questionnaire, preference tests, and dietary analyses. The findings showed that SW who were not therapeutically normalized showed increased salt appetite but no change in sweet preference. Their salt appetite correlated with symptoms of salt wasting, namely, plasma renin activity, plasma K(+), and urine Na(+) and (inversely) with blood pressure. Sensitivity to the taste of NaCl was not altered. Factor analyses of a larger group confirmed the distinction between salt appetite and sweet preference, but intake of dietary Na(+) and sweet carbohydrates and intake of salty and sweet snacks did not reflect distinct salt or sweet preferences. We confirm that putative perinatal dehydration, due to maternal nausea and vomiting during pregnancy, childhood vomiting, and diarrhea with occasional saline infusion, was related to increased salt appetite in adolescence. The findings suggest that salt appetite in humans is determined by interdependent, innate, physiological, and acquired attributes. Salt appetite in SW patients is an adaptive response mediated by the renin-angiotensin system, an innate predisposition to acquire salt preference (in anticipation of both sodium loss and its consequence), and imprinting by perinatal hyponatremic occurrences. Our findings contribute to understanding human salt intake, provide insight into the motivation for salt in patients with congenital adrenal hyperplasia 21-OH deficiency, and may point the way to improvements in therapeutic compliance in these patients.

Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.

Laparoscopic subtotal hysterectomy and bilateral adnexectomy in a child with congenital adrenal hyperplasia.

OBJECTIVE: To report the results of a subtotal hysterectomy and bilateral adnexectomy in a child with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. DESIGN: Case report. SETTING: Gynecology department, Afula, Israel. PATIENT(S): An 11-year-old child with a female genotype and saltwasting type congenital adrenal hyperplasia who was being raised as a boy. INTERVENTION(S): Laparoscopic subtotal hysterectomy and bilateral salpingo-oophorectomy were performed. MAIN OUTCOME MEASURE(S): Surgical efficiency, operating time, recovery, and aesthetic result. RESULT(S): The procedure was performed without complications in 26 minutes, and the child was dismissed the following day. Three 5-mL abdominal incisions were required. CONCLUSION(S): Laparoscopic subtotal hysterectomy and bilateral adnexectomy can be safely performed in children and is the procedure of choice in the rare cases in which it is indicated.

Comparison of the incidence of cholesteatoma surgery before and after using ventilation tubes for secretory otitis media.

Inserting ventilation tubes has become, probably, the most common surgical operation performed on children in the free world. In our study, we attempted to examine whether the widely used procedure of inserting ventilation tubes in children with secretory otitis media is indeed justified in the long term. For this purpose, we have studied the influence of the procedure on the formation of cholesteatoma by comparing the incidence of cholesteatoma surgery before and after using ventilation tubes in our department. The data were divided into two periods. The first period included the number of operations in the 10 years (1961-1970) before ventilation tubes were used as a routine treatment for secretory otitis media in our department. The second period included the number of operations in the last 10 years (1989-1998) following the usage of ventilation tubes over 30 years. We found that the number of cholesteatoma operations has decreased, from 413 operations in the 10 years before ventilation tubes were used to 228 operations over the last 10 years. The number of operations per 10000 of the entire population has decreased from 20 operations to 6.6 operations after using ventilation tubes (P=0.0000001). We have shown that the incidence of surgery for cholesteatoma has been declining. Having analyzed the options that might cause this decline, we believe that using ventilation tubes in secretory otitis media might help to reduce the incidence of cholesteatoma surgery in the long term.

Isolated extramedullary plasmacytoma of the true vocal fold.

We report a rare case of isolated extramedullary plasmacytoma (EMP) of the right true vocal fold in a 38-year-old male with a one-year history of hoarseness. Immunohistochemical staining of plasma cells in the tumour, showed over 90 per cent of them to be positive for kappa light chains. After two attempts at local surgical excision and recurrence within 10 months, the tumour was irradiated. Only seven reported cases of isolated EMP of the true vocal fold are reported in the literature. The therapeutic options are discussed.

Comparison between four immunoassays for growth hormone (GH) measurement as guides to clinical decisions following GH provocative tests.

OBJECTIVE: To compare four assays for the measurement of GH following provocative tests and to assess the projected clinical decisions, which would have been based on their respective results. DESIGN: Multiple assays of serum samples obtained during provocative tests for GH response. SUBJECTS: Forty-seven children with short stature, who underwent clinical evaluation and GH provocative tests. METHODS: All samples were measured by the immunoassay Sorin-RIA (A), which is routinely used in our laboratory. Basal and peak samples were analyzed by three other immunoassays: Sorin-IRMA (B), DPC-RIA (C) and Wallac-DELFIA (D). Results were classified as low, partial and normal GH response, corresponding to <10, 10-17.9 and >18 microIU/ml peak serum GH levels. RESULTS: High correlation was found between individual results by the four kits (r=0.92-0.94). However, the mean peak GH values were significantly different (p<0.0001). Further analysis using paired t-test has shown highly significant differences between the assays (p<0.0001) apart from assays A and B that were not significantly different. Clinical grouping by the four tests was profoundly different: by assay A, 14.9% were judged low response and 57.4% normal; by assay D, 36.2% were low and only 21.3% normal. Kappa statistics measurement demonstrated poor agreement between assays A and D and between B and D. CONCLUSION: As the criteria for the diagnosis of GH deficiency and the indications for GH therapy are based on laboratory GH results, more must be done to ensure uniformity and comparability of the GH assays.

Effects of delaying puberty on bone mineralization in female rats.

The effect of delaying puberty on bone mineralization was studied using female rats as a model. Repeated injections of gonadotrophin-releasing hormone antagonist (GnRHa) were used to suppress the onset of puberty from the age of 6-10 weeks. A group of control female rats was given aqueous solution injections at the same age and for the same duration. The effect of delaying puberty on bone mineralization was examined using dual energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (QCT), both methods being adapted for small animals. Bone mineral parameters were measured at baseline and at the ages of 10, 17 and 24 weeks in total body, femur and spine. Compared to controls, bone mineral content (BMC) and bone mineral density (BMD), as measured by DXA, were significantly decreased in GnRHa-treated rats in total body and femur at 10 and 24 weeks of age (P < 0.05). The results were even more significant after adjusting for weight. After this adjustment, spine BMC and BMD at 10, 17 and 24 weeks were significantly lower in the treatment group (P < 0.05). Trabecular BMD at the distal femur in the GnRHa treated group as measured by peripheral QCT was significantly lower (P < 0.05). However, cortical bone in the mid-femur had higher BMD, concurrent with lower cortical thickness in the treatment group. In conclusion, a delay in the onset of sexual maturation may cause prolonged, possibly irreversible defect in bone mineralization.

Duration of antibacterial effectiveness of gentamicin ear drops in external otitis.

The recommendation of Anderson and Steele, for the use of ear drops four times a day, has not been changed since 1948. In order to re-evaluate the frequency of using ear drops, we examined the duration of the effectiveness of the antibacterial activity of gentamicin ear drops in external otitis. Seventeen patients (25 ears) with external otitis were studied. We took 18 samples from each ear at 0, 1, 2, 3, 6, 8, 10, 12 and 14 hours and measured the concentration of gentamicin on the wick and in the ear canal. We found that the concentration of gentamicin began to decrease only after 12 hours and a more significant decrease was detected after 14 hours of treatment. We have shown that the antibiotic used on the wick is effective for 12 hours. In conclusion, we recommend using ear drops twice a day on a wick as routine therapy for external otitis.

Fetal pituitary negative feedback at early gestational age.

We describe an early prenatal diagnosis and the successful treatment of fetal Graves' disease from transplacental transfer of maternal thyroid stimulating autoantibodies (TSAb). The diagnosis of fetal thyrotoxicosis was made by umbilical cord sampling (UBS) at 20 weeks gestation, based on suppressed TSH with elevated FT4 levels. Therapy with propylthiouracil (PTU) improved fetal thyroid function tests as well as the clinical signs of fetal Graves' disease. Three more UBS were conducted before delivery indicating persisting mild fetal hyperthyroidism. Undetectable concentrations of thyrotrophin in fetal serum in the presence of markedly elevated FT4, suggests pituitary negative feedback at as early as 20 weeks gestation. Amniotic fluid thyrotrophin levels were measured at 20,24 and 26 weeks and were shown to correlate better with (elevated) maternal rather than (suppressed) fetal TSH values; therefore, we believe that amniotic fluid thyrotrophin measurement is unreliable for prediction of fetal thyroid status. Our observation is the first documentation of an intact feedback mechanism so early in fetal development and it suggests that pituitary maturation occurs earlier than previously believed.

Juvenile Behçet's disease in Israel. The Pediatric Rheumatology Study Group of Israel.

OBJECTIVE: Behçet's disease (BD) is a vasculitis mainly observed in young adult males. Juvenile BD is rare and only small series of pediatric cases have been reported. The objective of this study was to define the epidemiology and clinical features of BD among Israeli children. METHODS: A questionnaire was sent to 8 pediatric rheumatology units in Israel and 30 cases of BD diagnosed before the age of 16 years were identified. RESULTS: Fifteen patients fulfilled the International Study Group Criteria for BD, while 15 had an incomplete form of BD. Among the patients with complete BD, stomatitis and skin involvement were the most common manifestations. Other symptoms included genital ulcers, uveitis, CNS involvement, arthritis, and gastrointestinal involvement. A positive family history was elicited in 3 patients. HLA B5 was found in 7 of 12 patients (58%). The 15 patients with incomplete BD all had recurrent stomatitis; other manifestations included uveitis, arthritis, and genital ulcers. HLA B5 was found in 94% of this group. CONCLUSION: Juvenile BD in Israel is not uncommon, and is frequently associated with HLA B5 positivity. This could indicate a genetic susceptibility in our region. Half of the patients in our series had an incomplete form of BD, which may represent a less severe variant of the disease. In any case, careful follow-up is required, since their condition could eventually evolve into complete BD.

The risk of postoperative haemorrhage in tonsillectomy as an outpatient procedure in children.

The safety of performing tonsillectomy as an outpatient procedure is still questionable. This study determined whether there was an increased risk of postoperative bleeding by performing tonsillectomy as an outpatient procedure. A six years' retrospective chart review was made of 363 children who underwent tonsillectomy. Out of 363 children, 43 had been selected as an inpatient group before the operation, 264 patients were discharged home 6 h after the operation and were the outpatient group, and 56 children had to be kept overnight because of complications that had occurred. We compared the haemorrhage rate in the outpatient and the inpatient groups. We found no increase in the postoperative haemorrhage rate in the outpatient group. No statistically significant correlations were found between the children's ages, indication for surgery, type of operation or intra-operative complications and the risk of postoperative haemorrhage. Only children who had haemorrhage in the recovery room were identified as a high risk subgroup for recurrent bleeding. On the basis of our findings we believe that tonsillectomy can be performed as an outpatient procedure regardless of age, indication for surgery, or type of procedure, as long as good recovery room supervision exists for 4 to 6 h.

Safety of topical ear drops containing ototoxic antibiotics.

OBJECTIVE: Topical application of ear drops containing ototoxic antibiotics is commonly used for treatment of middle ear diseases. Because of their ototoxic potential, we evaluated the safety of these ear drops in clinical use. METHODS: The study included 446 children who underwent myringotomy and the insertion of tympanostomy tubes. Three hundred and fifty-eight received preventive treatment after the operation with polymyxin B-neomycin-dexamethasone ear drops for 2 weeks; 88 did not receive any ear drops. Audiometric tests were performed before the operation and up to 3 months following it. RESULTS: All 446 children had a normal sensorineural hearing threshold before and after the operation. There was no sensorineural hearing loss in the group that was treated with ear drops. CONCLUSIONS: Our experience leads us to believe that topical ear drops containing ototoxic antibiotics are clinically safe to use for a short period of time.

Hemifacial spasm associated with external carotid artery compression of the facial nerve.

We report a unique case of hemifacial spasm due to compression of the facial nerve by the main trunk of the external carotid artery within the parotid space. Decompression of the facial nerve as well as partial section of the proximal trunk of the nerve, caused the hemifacial spasm to disappear. Our case gives support to the theory that hemifacial spasm can be caused by pressure on the facial nerve along all its course and not only in its intra-cranial portion.

Growth hormone therapy in Silver Russell syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW).

UNLABELLED: Data were analysed on 33 children (22 males) with Silver Russell syndrome treated with growth hormone for periods up to 5 years. Baseline data (medians) at commencement of growth hormone (GH) therapy were age 6.7 years, bone age delay 1.7 years, height standard deviation score (SDS)-3.2, weight SDS -3.1, and growth velocity 5.7 cm/ year. All were prepubertal. Median birth weight SDS for gestational age was -3.2. GH was commenced at 14 IU/m2 per week and subsequently adjusted according to response. Growth velocity and growth velocity SDS for chronological age (CA) improved over baseline and gains in height SDS for CA were 1.0, 1.5 and 1.8 SD over 3, 4 and 5 years respectively (P < 0.001). No significant increase in height SDS for bone age was observed. Increased GH doses were required after the 1st year to maintain growth rates. Mean bone age advancement was 3.1 years after 3 years of treatment, and 6.0 years after 5 years treatment. Younger age was a predictor of the growth response over the 1st year. Predictors of response after 3 years were catch up growth, low weight SDS at birth and low height SDS for CA. Age at onset of puberty was normal, but height at onset of puberty was lower than normal means. CONCLUSION: We have demonstrated significant improvement in growth in Silver Russell syndrome after 3 years of GH therapy, however data on estimated mature height and final height are insufficient to conclude final outcomes. Further follow up is required to assess the long-term benefit.

A comparison of partial inferior turbinectomy and cryosurgery for hypertrophic inferior turbinates.

A variety of surgical procedures are performed for treatment of hypertrophic inferior turbinates, but there is no completely effective therapy. We evaluated subjectively and objectively 52 patients who underwent one of two procedures: partial inferior turbinectomy (PIT) or cryosurgery of the inferior turbinates (CS). The results of PIT showed good functional results in 77 per cent of cases for long-term effectiveness. The results of CS showed that effectiveness was reduced from a 62 per cent success rate after one year to 35 per cent later, but CS was a simple procedure which was performed on an outpatient basis with no post-operative morbidity.

Comparison of the proteins of middle ear effusion with human mast cell proteins.

In order to clarify the role of mast cells in the aetiology of secretory otitis media (SOM), we compared the protein components of middle ear effusion (MEE) with human mast cells using acrylamide gradient gel electrophoresis and electrofocusing methods. This first direct comparison between the proteins of MEE and human mast cells has been made possible by a method developed in our laboratory for cultivation of human mast cells in tissue culture. On electrophoresis, we found that out of 12 bands of MEE proteins that were different from the serum, seven (58 per cent) had a similar electrophoretic migration rate (Rx) to mast cells. On electrofocusing, three of the four bands of MEE had a similar Rx to the mast cells. We have shown that proteins of mast cells and MEE had similar Rxs. Therefore, our study supports previous studies which suggests that mast cells play an important role in the aetiology of SOM.