Phenotypic expression of tissue mosaicism in a 45,X/46,X,dicY(q11.2) female.

We describe a girl who presented at the age of 11 years with short stature. She had female external genitalia and some clinical features of Turner syndrome. At laparotomy a uterus and Fallopian tubes and small gonad-like tissue masses in the region of the Fallopian fimbria were found. The tissue masses were removed and histological examination revealed no organized testicular or ovarian morphology. Remnants of Fallopian tubes, epididymis, and clusters of Leydig cells were seen but no Sertoli cells were found. Endocrine studies showed levels of sex hormones consistent with primary gonadal failure. G-banding analysis of 16 blood lymphocytes revealed the karyotype 46,X,dicY(q11.2) in all cells. Varying proportions of X and Y centromeres in blood lymphocytes, skin fibroblasts, and in the incompletely formed Wolffian and Müllerian duct derivatives were demonstrated by FISH. Molecular studies confirmed the absence of most of the long arm of the Y chromosome and an intact short arm. The SRY gene was shown to be present, but we presume that due to the mosaicism the dose was insufficient to allow normal testicular development.

Genotype-phenotype associations in non-classical steroid 21-hydroxylase deficiency.

OBJECTIVE: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin. DESIGN: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60min 17-hydroxyprogesterone (17-OHP), 45-386nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well. METHODS: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58-151nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. RESULTS: At diagnosis, group B tended to be younger (5. 8+/-3.0 vs 8.1+/-4.3 years, P=0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P=0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62nmol/l, P<0.01). Group B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/-2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P<0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P=0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. CONCLUSIONS: The findings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.

D-penicillamine-induced pancreatic islet autoantibody production is independent of the immunogenetic background: a lesson from patients with Wilson's disease.

D-penicillamine (d-PA) was reported to induce various immunological abnormalities including production of autoantibodies to insulin. These abnormalities were mainly described in patients with primary immunological disorders such as rheumatoid arthritis. In order to clarify whether d-PA-induced immune disorders are restricted to patients genetically prone to develop autoimmune diseases or to a direct drug effect, we tested for the presence of various autoantibodies and for molecular HLA typing in 17 patients with Wilson's disease treated with this drug. In 2/17 patients, low-titer (10 JDFU) circulating islet cell autoantibodies (ICA) were detected, while another patient was positive for the presence of insulin autoantibodies. None of the sera tested showed reactivity for glutamic acid decarboxylase or ICA512. Five of twelve patients were positive for anti-single-stranded DNA autoantibody. Molecular HLA typing of the autoantibody-positive subjects showed that they carry HLA haplotypes not associated with insulin-dependent diabetes. The insulin response to intravenous glucose tolerance test in two patients with autoantibodies was found to be normal. A second blood testing of the autoantibody-positive patients 5 months following initial evaluation revealed conversion to negativity in all three. Our results suggest that d-PA-induced autoantibodies in patients with Wilson's disease are independent of the immunogenetic background characteristics of diabetes.

Prolonged vaginal bleeding during central precocious puberty therapy with a long-acting gonadotropin-releasing hormone agonist.

OBJECTIVE: To describe our experiment with the treatment of GnRH-a in premenarchal girls with idiopathic central precocious puberty (CPP). PATIENTS AND METHODS: Twenty-eight girls, aged 6.5-11 years, with idiopathic central precocious puberty were treated every 28 days with an intramuscular depot gonadotropin releasing hormone agonist (GnRH-a) in an attempt to delay sexual maturation. RESULTS: Eight of the 28 (28.5%) developed vaginal bleeding after GnRH-a administration. Of these, prolonged vaginal bleeding of 11-13 days occurred in four girls, three recurrent episodes occurred in one during the second injection, and in one other girl the 4th episode occurred after 6 months of treatment. CONCLUSION: Uterine bleeding following GnRH-a treatment in premenarchal girls with CPP is common, and may be massive and recurrent, since most episodes resolved spontaneously and necessitated no further treatment, careful advice should be given to the girls and their families prior to treatment initiation, in an attempt to avoid unnecessary anxiety and achieve better compliance.

Syndrome of alopecia totalis and 17b-hydroxysteroid dehydrogenase deficiency.

A distinct and previously undescribed syndrome of alopecia totalis, ichthyosis, and male pseudohermaphroditism due to steroid 17b-hydroxysteroid dehydrogenase deficiency was observed in an Israeli-Arab newborn infant.

Increased prevalence of urinary tract infections and anomalies in infants with pyloric stenosis.

We performed a retrospective analysis of all patients admitted to our institution with a diagnosis of infantile hypertrophic pyloric stenosis (IHPS) during a 10-year period from 1985-95 in order to assess the possible association between IHPS and urinary tract infections (UTIs). All 285 patients with IHPS had radiological or ultrasonographic confirmation of that diagnosis and underwent the Ramstedt procedure. Those who continued to be symptomatic were evaluated for UTI by urine analysis and culture. Positive cases were further evaluated for urinary system anomalies. The male:female ratio of IHPS was 3.4:1. Concomitant UTI was diagnosed in 8 patients by suprapubic aspiration or bladder catheterization. The prevalence of UTI in this series was 2.8%, 20-fold higher than the expected prevalence. Three of the 8 patients with UTI (37.5%) had urinary tract anomalies. These findings suggest an association between IHPS and UTI. We recommend that all IHPS patients be evaluated for UTI and positive cases undergo further evaluation for urinary anomalies.

MODED: microcephaly-oculo-digito-esophageal-duodenal syndrome.

We report on 4 families with microcephaly, type A brachydactyly, variable learning disabilities, short stature, duodenal atresia, patent ductus arteriosus (PDA), hallux valgus, restricted elbow and finger movements, and amesophalangy and syndactyly of toes. Three previous families manifested all signs of the syndrome, and in another four reports the phenotype was incomplete. These cases are reviewed. Penetrance of digital and toe anomalies is almost complete and microcephaly is present in 78% of known cases. Short stature was present in 70% of our cases, but this is probably an overestimation. Esophageal and duodenal atresias were present in 25% of known cases. Correction for ascertainment bias gave a lower estimate of 16.6%. Learning disabilities were present in 31% of all patients. Longitudinal follow-up suggested that hypoplasia or absence of the diaphyseal ossification centers is the primary cause of the phalangeal changes. Observations in a 9-year-old girl, followed since age 3.3, suggest that the eventual absence of the middle phalanges of the toes may be caused by fusion.

Preoperative treatment of intractable hyperthyroidism with acute lithium administration.

We present a 15-year-old girl with an unusual clinical course of intractable thyrotoxicosis that was resistant to thiocarbamide therapy and propranolol. Although the latter beta-adrenergic blocking agent has been used as the sole drug in the preparation of thyrotoxicosis patients for thyroidectomy, it was unsatisfactory for control of our case. In contrast, the patient's clinical response to lithium carbonate 900-1500 mg/d for 10 days was very good and no side effects were observed. This demonstrates the importance of lithium as the drug of choice in thyrotoxic emergencies and uncontrolled preoperative patients when rapid and safe inhibition of thyroid hormone secretion is required.

A delayed starting schedule of oral contraception: the effect on the incidence of breakthrough bleeding and compliance in women.

OBJECTIVES: To assess the effect of oral contraception started on the first day of menses and the fifth day following its onset, on women's compliance and the incidence of early breakthrough bleeding. METHODS: Oral contraceptives (OCs) containing 30 micrograms ethinylestradiol and 75 micrograms gestodene were prescribed to 100 consecutive, healthy women for whom OCs were found to be the most suitable method of contraception. In the first 50 women, OCs were started on the first day of menses (day 1 group), while in the remaining 50 women, OCs were started on the fifth day after the onset of menses (day 5 group). RESULTS: The day 5 group had better compliance and a reduced incidence of breakthrough bleeding. No differences were observed between the two groups regarding age, parity and gravity. CONCLUSION: Starting an OC regimen should include initiation on the fifth day following the onset of menses. This regimen might increase patient compliance and lower the incidence of breakthrough bleeding.

Insulin-like growth factor-I and IGF binding protein-3 remain high after GnRH analogue therapy in girls with central precocious puberty.

OBJECTIVE: IGF-I rises in normal adolescence and in central precocious puberty (CPP), secondary to a rise in sex steroids and GH. The aim of this study was to examine changes in serum IGF-I and its major binding protein IGFBP-3 after pharmacological arrest of puberty. PATIENTS AND MEASUREMENTS: Ten girls diagnosed for CPP were evaluated before and during the first 3 months of GnRH analogue (GnRHa) therapy aimed at suppression of the gonadal axis. Serum IGF-I was measured by immunoradiometric assay (IRMA) and IGFBP-3 by both IRMA and Western ligand blotting (WLB). RESULTS: Serum IGF-I was markedly higher in patients with CPP as compared with age matched controls (48.8 +/- 6.5 vs 23.1 +/- 4.9 nmol/l, P < 0.01). While GnRHa therapy caused serum oestradiol levels to return to prepubertal levels in all 10 patients, serum IGF-I levels decreased only minimally after 1, 2 or 3 months of therapy (43.2 +/- 5.6, 42.3 +/- 6.4 and 44.1 +/- 7.2 nmol/l respectively). Serum IGFBP-3 levels as determined using IRMA were also higher in CPP compared with age matched controls (4.70 +/- 0.37 vs 3.71 +/- 0.42 mg/l, P < 0.01). These differences were also evident when measured by WLB. GnRHa therapy caused a small and insignificant decrease in serum IGFBP-3 levels after 1, 2 or 3 months of therapy (4.57 +/- 0.33, 4.48 +/- 0.4 and 4.42 +/- 0.3 mg/l respectively). CONCLUSIONS: The lack of suppression of both IGF-I and IGFBP-3, despite therapy which halts puberty and slows growth velocity, suggests that steroids may be involved in the induction of changes in the GH/IGF-I axis but not in their subsequent maintenance.

Normal diurnal variation in serum cortisol concentration in asthmatic children treated with inhaled budesonide.

BACKGROUND: Twenty-four-hour serum cortisol secretion is a sensitive parameter for the assessment of the pituitary-adrenal function of asthmatic children treated with inhaled corticosteroids. This study was undertaken to determine the effect of the long-term administration of inhaled budesonide on 24-hour cortisol production in young children with asthma. METHODS: We studied 11 children, aged 7 to 12 years, with severe perennial asthma. All had been receiving 100 micrograms of inhaled budesonide twice daily, administered with a spacer device, for 3 to 5 years. Serum cortisol concentration was measured at 8:00 A.M., 60 minutes after intravenous administration of 0.25 mg of corticotropin, and every 30 minutes for 24 hours in an open-design study. Urinary cortisol secretion was measured by 24-hour urine collection. All determinations were made with a radioimmunoassay kit. RESULTS: The individual morning serum cortisol concentration and the serum cortisol concentration at 60 minutes after corticotropin stimulation were within normal limits in all children. The 24-hour urinary cortisol excretion was also normal. The individual 24-hour serum cortisol concentration showed a normal pattern in all children, with no evidence of nocturnal suppression of serum cortisol concentration. CONCLUSION: Prolonged (3 to 5 years) administration of 200 micrograms/day of inhaled budesonide in young children with severe asthma does not impair pituitary-adrenal function, even according to the sensitive test for 24-hour serum cortisol secretion.

Evaluation of human chorionic gonadotropin stimulation tests in prepubertal and early pubertal boys.

We evaluated the diagnostic significance of single versus repeated human chorionic gonadotropin (hCG) stimulation of testicular steroidogenesis in 25 boys (10 prepubertal group A; 15 early pubertal, group B) with suspected hypogonadism. All subjects received a single injection of hCG (5000 U/1.7 m2) and 1 month later, three repeated injections of 1500 U, one each on alternate days. In 19 out of the 25 boys, testosterone increased normally in both tests: from 20 +/- 6 to 156 +/- 82 ng/dl and from 107 +/- 105 to 615 +/- 293 ng/dl, following a single hCG injection, and from 30 +/- 19 to 439 +/- 298 ng/dl and from 94 +/- 55 to 826 +/- 272 ng/dl, following repeated injections in groups A and B, respectively. The difference between the tests was significant (P < 0.01). Conclusion. Single hCG injection used as a screening test in the evaluation of hypogonadism is conclusive when positive. Only when the initial test is negative may a repeated test help establish the diagnosis.

Hyperprolactinemia after treatment of long-acting gonadotropin-releasing hormone analogue Decapeptyl in girls with central precocious puberty.

OBJECTIVE: To clarify the effects of prolonged treatment with long-acting GnRH analogue on serum PRL levels. DESIGN: Blood PRL levels were measured at 9 A.M. every 28 days for a period of 6 months. SETTING: Pediatric Endocrine Clinic, Hasharon Hospital, Petah Tiqva, Israel. PATIENTS: Thirteen girls with idiopathic central precocious puberty. RESULTS: Hyperprolactinemia developed in 5 of 13 girls after treatment with long-acting GnRH-a; mean blood PRL in all 13 girls rose significantly from 11.9 +/- 5.6 to 21.5 +/- 12.5 micrograms/L (mean +/- SD). CONCLUSIONS: The mechanism of hyperprolactinemia in our patients is unclear. It may have resulted from a decline in the release of the hypothalamic PRL inhibitory factor. Clinically, transient hyperprolactinemia during long-acting GnRH-a treatment for central precocious puberty also may reflect a constant depression of LH secretion.

Melkersson-Rosenthal syndrome.

Four patients with recurrent upper lip and facial swelling and lingua plicata together with peripheral facial nerve palsy involvement were diagnosed as having Melkersson-Rosenthal syndrome. Because of the rarity of this syndrome in children, we present the results of follow-up evaluations of our patients and review the literature.

Nonketotic hyperosmolar coma in children.

Nonketotic hyperosmolar diabetic coma is well known in adults, but infrequently reported in children. This syndrome is associated with a 20-70% mortality rate. We report the successful treatment of a 12.5 year old girl with a hyperglycemic (1,800 mg/dl glucose) nonketotic hyperosmolar diabetic coma and summarize the reported cases in the literature.

Swimming and grommets.

BACKGROUND: Traditionally, children with tympanostomy ventilating tubes, or grommets, were advised that water should not enter their ears in order to prevent ear infections. This group of children has been considered somewhat handicapped regarding swimming. We conducted a prospective study to determine if there is a relation between suppurative otitis media and surface swimming in children with grommets. METHODS: Forty-two children with tympanostomy ventilating tubes were included in this study. Of the 42 children, 22 were swimmers and 20 were nonswimmers, who served as the control group. The age range was 3 to 12 years, and there was no difference in the age distribution between the groups. Surface swimming was allowed without earplugs or a bathing cap, although it was mandatory to use polymyxin B-neomycin-hydrocortisone eardrops at bedtime on the day of swimming. No diving was allowed. RESULTS: Three of 22 swimmers and 2 of 20 nonswimmers developed otorrhea. In 4 of the 5 children, the otorrhea was followed by an upper respiratory tract infection. In all cases, a bacterial culture revealed Pseudomonas. The ear drainage was easily controlled with local otic treatment in all the patients. CONCLUSIONS: Taking into consideration the possible risks of infection and bearing in mind the value and joy of swimming to children and parents, families should be reassured that surface swimming does not increase the risk of infection in children with tympanostomy tubes.

Growth and pituitary-adrenal function in children with severe asthma treated with inhaled budesonide.

BACKGROUND: The increased use of inhaled corticosteroids in the management of asthma raises concern about the safety of these drugs in children. We sought to determine the safety of long-term administration of inhaled budesonide in young children with asthma. METHODS: We studied 15 children 2 to 7 years old who had severe perennial asthma. They inhaled 100 micrograms of budesonide twice daily for three to five years. Efficacy was assessed by serial evaluation of respiratory symptoms and the need for other medications, and safety by serial evaluation of height, height velocity, weight, bone age, and pituitary-adrenal function. RESULTS: The severity of asthma decreased within the first month after the initiation of therapy, as demonstrated by a 58 percent reduction in the number of days with symptoms of asthma and a 75 percent decrease in the use of bronchodilators. This improvement was maintained thereafter. The growth pattern of all patients, including their height, weight, and bone age, was normal (as compared with standard normal values) throughout the treatment period. Pituitary-adrenal function was not adversely affected by the treatment, as demonstrated by normal serum cortisol concentrations in the morning and 60 minutes after stimulation with corticotropin, normal 24-hour serum cortisol concentrations (mean [+/- SD] of samples collected at 30-minute intervals for 24 hours, 8.4 +/- 4.2 micrograms per deciliter [232 +/- 116 nmol per liter]), and normal urinary cortisol excretion (34 +/- 9 micrograms [95 +/- 25 nmol] per day). CONCLUSIONS: Prolonged administration of 200 micrograms of inhaled budesonide daily to young children with severe asthma does not impair growth or pituitary-adrenal function.

Váradi syndrome (OFD VI) or Opitz trigonocephaly syndrome: overlapping manifestations in two cousins.

We report on 2 cousins, offspring of consanguineous matings, with multiple congenital anomalies. Square face, frontal bossing with metopic ridge, small anteverted nose, flat nasal bridge, slanted palpebral fissures, and epicanthal folds contributed to an unusual appearance. Multiple bucco-alveolar frenula and notched inferior alveolar ridges were present at birth and one had a notched uvula and submucous cleft of the hard palate. Both had congenital heart anomalies, micropenis, and cryptorchidism. Persistence of Müllerian structures was documented at necropsy in one patient. The surviving patient was mentally retarded and had unilateral central hexadactyly and partial agenesis of the corpus callosum. Bulimia and episodic hyperthermia were attributed to hypothalamic dysfunction. Results of unstimulated endocrine studies and gonadotropin releasing hormone (GnRH), and human chorionic gonadotropin (HCG) stimulation tests were normal. The manifestations of the 2 patients overlap those reported in the OFD VI and Opitz trigonocephaly syndromes.