17ß-hydroxysteroid dehydrogenase type 3 deficiency: female sex assignment and follow-up.

BACKGROUND: Deficiency of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is a rare autosomal recessive 46,XY disorder of sex development (DSD). It is due to pathogenetic variants in the HSD17B3 gene. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Δ4-androstenedione (Δ4-A) to testosterone (T) in the fetal testis. Affected individuals are usually raised as females and diagnosis is made at puberty, when they show virilization. METHODS: A girl with a presumptive diagnosis of complete androgen insensitivity syndrome underwent endocrine and genetic assessment. Long-term follow-up was reported. RESULTS: The diagnosis of 17ß-HSD3 deficiency was made (stimulated T/Δ4-A ratio: 0.15; HSD17B3 gene analysis: c.277+4A>T in intron 3/c.640_645del (p.Glu214_Glu215del) in exon 9. After extensive information, parents decided to maintain female sex. Gonadal removal was performed and histological evaluation demonstrated deep fibrosis of testicular tissue. Follow-up till 8.5 years of age showed somatic and neuro-psychological development fitting with the female sex. CONCLUSIONS: Management of a child with the rare 17ß-HSD3 deficiency remains challenging. Any decision must be carefully evaluated with parents. Long-term follow-up must be warranted by a multidisciplinary DSD team to evaluate the adequacy of the choices made on quality of life in later life.

Observational retrospective study on acquired megalourethra after primary proximal hypospadias repair and its recurrence after tapering.

INTRODUCTION: Acquired megalourethra (AMU) after repair of proximal hypospadias can be a serious complication. An observational retrospective study of its incidence among different types of repair was performed. MATERIALS AND METHODS: Clinical charts of patients operated on for proximal hypospadias were reviewed. INCLUSION CRITERIA: all primary hypospadias operated in 1991-2004, with the meatus positioned in proximal penile, scrotal or perineal position. RESULTS: Of 770 hypospadias cases treated, 130 (16%) were proximal. Seventy-two patients (55%) were treated using preputial flaps: 36 with a tubularized preputial island flap (TIF) and 36 an onlay island flap (OIF). Fifty-eight patients (45%) underwent staged repairs: Belt-Fuquà (BF) in 18 and Bracka procedure in 40 cases. After a mean follow up of 16 years (range 6-19) the overall incidence of complications for each technique was: TIF 36%; OIF 33%; BF 25%; two-stage Bracka 7.5%. The most common complication encountered was neo-urethral fistula. AMU occurred in only 5 cases, none with associated distal urethral stenosis, all in the TIF and OIF groups, and all successfully treated by reduction re-do urethroplasty. CONCLUSION: A very small number of the patients operated using preputial island flaps techniques developed AMU. None of the staged repairs developed AMU, and this is the preferred choice in proximal hypospadias when the urethral plate requires division and/or substitution. All cases of AMU resolved after urethral tapering.

Molecular characterization of 6 unrelated Italian patients with 5alpha-reductase type 2 deficiency.

Steroid 5alpha-reductase (5alphaR) deficiency (OMIM number #264600) is a rare 46,XY disorder of sex differentiation caused by mutations in the 5alphaR type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during fetal development. We report on the analysis of the SRD5A2 gene in 6 unrelated 46,XY Italian patients with external genitalia morphology ranging from predominantly female to nearly completely male. Three subjects were seen and assessed at birth, 1 patient was referred to us before puberty, and 2 at postpubertal age. Six different causative mutations (5 missense and 1 nonsense) and a rare polymorphism were identified. Four patients presented homozygous single-base substitutions. These SRD5A2 mutations were located in exon 2 (variant Cys133Gly), exon 4 (Gly196Ser and Ala207Asp) and exon 5 (Tyr235Phe). A fifth subject was a compound heterozygote who carried a nonsense mutation in exon 1 (Trp53X) and a second SRD5A2 alteration in exon 5 (Tyr235Phe). The final patient presented a mutation in only 1 allele (Gly34Trp) together with the Ala49Thr variant. The molecular characterization of these patients made it possible to identify novel mutations and to confirm, before gender assignment or any surgical approach, the suspected 5alphaR deficiency in 2 newborns, 1 of whom had inconclusive hormonal data. 5alphaR deficiency in subjects without parental consanguinity and the presence of compound heterozygotic patients suggest that SRD5A2 mutations carrier frequency may be higher than previously thought.

[Initial experience of an alternative surgical strategy for stenosis post- urethroplasty using dorsal buccal mucosa graft]. / Estrategia quirúirgica alternativa en las estenosis posturetroplastia con técnica de colgajo prepucial tubulizado: experiencia inicial.

In the early '80s, tubularized preputial flap has been intensively used for proximal hypospadias. Even if not yet used today, there are a conspicuous number of patients treated in that time that today present with obstructive symptoms. In this paper, authors propose an initial experience of an alternative strategy to the complete re-do. Three patients (6, 9 and 27 years old) were diagnosed of stenosis at the junction of the tubularized preputial flap and the native urethra. Proximal and distal urethra was normal at the urethrogram in all cases. A augmentation was performed. One year follow up is free of obstructive symptoms and flowmetry is normal. The technique proposed seems to be the best balanced owing to a minimal invasivity and better results along time.

Hypospadias surgery: a 10-year review.

Hypospadias surgery is one of the most difficult areas in pediatric urology and has been characterized by constant evolution. Some of the surgical techniques proposed in the past are now considered inadequate because of an unacceptable complication rate or poor functional and aesthetic results. The key for assessing a surgical technique (or a particular aspect of it) is continuous evaluation through long-term patient follow-up. We present the medical records of 693 patients over 10 years, all operated on by the same surgeon (the first author), with a minimum of 12 months of follow-up. The overall complication rate was 6.49% (45 cases). The most frequent complication was urethral fistula, occurring in 28 patients (62%). Other complications were redo for penile deformity or meatal retraction (eight cases, 17%), megalourethra (five cases, 11%), meatal stenosis (two cases, 4%), and urethral stenosis (two cases, 4%). We have noticed an increased rate of complications in patients older than 12 months (18.7% vs. 3.4% in patients younger than 12 months) and in patients operated on at puberty or later (15%). We have seen no difference in the complication rate related to the type of hospitalisation (day surgery vs. traditional hospitalisation). Regarding the relationship between the type of complication and the type of defect, except for the constant presence of fistulae, a high incidence of megalourethra was seen in proximal defects treated with preputial graft. The sexual outcomes of 32 subjects are presented. Multiple factors influence the final result, but the most important factor is the surgeon's own experience. Knowledge of different techniques and delicate tissue handling are essential. Our experience shows that the ideal age for surgery is 8-12 months. Owing to a minimal emotional impact on the child and to a reasonable use of economical resources, we consider day surgery the ideal way to treat these patients whenever possible. Even in the absence of complications, follow-up must be continued at least until the end of puberty and, when possible, up to the patient's sexual debut. Adequate interviews with the patients (principally teenagers and young adults) are the best way to evaluate their need for psychological support.

Clinical management and molecular cytogenetic characterization in a 45,X/46,X,idic(Yp) patient with severe hypospadia.

Cryptorchidism and proximal hypospadia in a newborn are highly suspicious for an intersex disorder, and proper investigations should be planned immediately after birth. In some hypospadic patients, the presence of a palpable gonad in the scrotum may induce to assign the male sex, whereas the anatomy of internal and external genitalia could be extremely complex, requiring an accurate evaluation before any definitive attribution of gender. The authors present a case of an infant, referred to the hospital for surgical treatment of a proximal hypospadia, who showed ambiguous external genitalia, absence of the right gonad, a partially dysgenetic left testis, and presence of both müllerian and wolffian structures. Cytogenetic analysis detected a mosaicism with a cell line showing an isodicentric Yp chromosome and a second one, a 45, X chromosomal complement. Because the baby had been assigned previously to male gender, he underwent a staged masculinizing correction of the genital anomalies. The authors discuss the necessity of a careful evaluation of these patients at birth by a multispecialistic team, for appropriate sex assignment and for the assessment of the risk of neoplastic degeneration.

Functional outcome after pyeloplasty in children: impact of the cause of obstruction and of the mode of presentation.

OBJECTIVE: To compare functional outcome after pyeloplasty in two groups of patients affected by hydronephrosis, which had different modalities of diagnosis. The first, asymptomatic, detected by prenatal ultrasonography and the second referred later because of clinical symptoms. PATIENTS AND METHODS: 84 patients (54 prenatally detected and 30 symptomatic) among 339 observed with hydronephrosis, operated in a single centre for ureteropelvic junction obstruction, have been retrospectively studied. Seventeen cases with prenatal diagnosis had an early treatment and thirty-seven were operated on after an initial observation. Symptomatic cases were all operated on at diagnosis. Ultrasonographic and renographic assessment were made at diagnosis, before and after surgery. RESULTS: Renal function of prenatally detected cases was not influenced by early or delayed surgery. Insignificant functional loss was recorded among some cases operated after conservative management. Improvement in differential renal function (p<0.05) was recorded in symptomatic patients after pyeloplasty. A high percentage of obstructions secondary to lower polar crossing vessel were found among symptomatic cases (12 out of 30). Intrinsic obstructions were predominant among cases with in utero diagnosis (48 out of 54). Whenever the cause of obstruction is considered, postoperative functional improvement was limited to crossing vessels cases. CONCLUSIONS: Renal function among antenatally diagnosed obstructions is scarcely influenced by surgery; potential risk of further renal damage cannot be excluded when expectant management is decided. Later detected, symptomatic cases show a better functional response to surgery. This seems corresponding to distinct clinical entities based on different causes of hydronephrosis. A reversible renal damage seems to be associated to extrinsic obstructions from polar vessel, which are predominant among symptomatic, later detected cases. A congenital, irreversible loss of function accompanies intrinsic obstructions, typical of prenatally diagnosed cases.

Epithelial splenic cysts in children: surgical treatment by cyst-wall "peeling".

Primary splenic cysts are a rare finding. Some are large and require surgical removal. The epidermoid type has an epidermal lining, and prevention of recurrence is dependent on complete resection of the cyst wall, preserving the splenic tissue. Several open, laparoscopic, or percutaneous procedures have been proposed with or without splenic resection, but few give completely satisfactory results. Five consecutive splenic epithelial cysts in pediatric patients were treated by parenchyma-sparing complete removal of the cyst wall, which was gently peeled off the splenic tissue without major bleeding in all but one case. Long-term follow-up showed freedom from recurrence.

Role of tachykinins in the bronchoconstriction induced by HCl intraesophageal instillation in the rabbit.

Gastroesophageal acid reflux (GER) is a common disorder associated with the exacerbation of asthma. In this study we investigated the effects on the airways of intraoesophageal HCl instillation in the rabbit and the role of tachykinins in these effects. In anaesthetized New Zealand rabbits bronchopulmonary functions [total lung resistance (R(L)) and dynamic compliance (C(dyn))] were calculated before and after HCl intraoesophageal instillation. Infusion of HCl induced a significant bronchoconstriction (P < 0.05) in the terms of R(L) and C(dyn) changes, that were increased by phosphoramidon pre-treatment and reduced by capsaicin pre-treatment. Moreover, a pre-treatment with SR 48968, a tachykinin NK2 receptor antagonist, or SR 140333, a NK1 receptor antagonist, significantly inhibited the bronchoconstriction induced by intraoesophageal HCl infusion in terms of R(L) and C(dyn)changes. Finally, the HCl induced bronchoconstriction was unaffected by SR 142801, a tachykinin NK3 receptor antagonist. In conclusion these results suggest that bronchoconstriction induced by intraoesophageal HCl infusion is mainly dependent on the release of tachykinins and that both NK1 and NK2 tachykinin receptors are involved.

[The efficacy of surgical treatment of hypospadias: analysis of hospital data from Lazio region during the three year period (1996-8)]. / Efficacia del trattamento chirurgico per ipospadia: analisi dei dati delle dimissioni ospedaliere nel triennio 1996-98 nella Regione Lazio.

INTRODUCTION: The aim of this study is to assess effectiveness of surgical treatment for hypospadia in the Regione Lazio (Italy). Hospital discharge data concerning surgical repair of hypospadia between 1996-1998 were analysed in order to: 1. estimate the trend of demand for hypospadia treatment; 2. correlate clinical results with the type of Surgical Unit of admission (general pediatric, urological, plastic); 3. correlate surgical results with the workload of the Unit; 4. quantify the general risk of a secondary treatment. METHODS: The source of data was the Hospital Information System of the Regione Lazio. Cases have been grouped according to Health District, age at first operation, interval to re-hospitalization after the first treatment for hypospadia. RESULTS: Age at first operation progressively declined in the last years. The annual risk of readmission and reoperation after the first surgical treatment, calculated on a group of 521 cases in 1996, are respectively 6.6% and 5%. CONCLUSIONS: The demand for hypospadia surgery in children was, as expected, stable in the time. However, a tendency to an earlier correction has been observed, mainly in the first and second year of life. Nearly all (99%) of the surgery for hypospadia in the Regione Lazio is performed in four hospitals; one of them accounts for three quarters of the workload. During the observed period a progressive reduction of hospital stay was seen. In the hospital with the best results in term of surgical efficiency, a significant number of patients is treated on a Day Surgery basis. Institutions treating less than 50 cases per year show a significantly high rate of re-hospitalisation within 12 months.

The involvement of sensory neuropeptides in airway hyper-responsiveness in rabbits sensitized and challenged to Parietaria judaica.

BACKGROUND: C-fibres have received considerable attention in the context of airway hyper-responsiveness (AHR), in fact several lines of evidence suggest that tachykinins might be involved in the pathogenesis of AHR. OBJECTIVE: The aim of this study was to investigate the role of capsaicin-sensitive sensory C-fibres and tachykinins in rabbits sensitized to the major allergen of Parietaria judaica pollen (Par j1). METHODS: Airway responsiveness was determined by exposing sensitized rabbits to cumulative concentrations of aerosolized histamine before and after an allergic challenge and after a pre-treatment with either vehicle or capsaicin or tachykinin receptor antagonists. Bronchoalveolar lavage was performed following histamine challenge and total and differential cell counts were performed. RESULTS: In sensitized rabbits, an AHR to inhaled histamine was observed 24 h after a Par j1 challenge. Capsaicin pre-treatment inhibited the AHR achieved 24 h following antigen exposure (P < 0.01). Pre-treatment with the tachykinin NK2 receptor antagonist, SR 48968, significantly reduced the antigen-induced AHR (P < 0.05), while pre-treatment with tachykinin NK1 (SR 140333) and NK3 (SR 142801) receptor antagonists did not significantly modify it. Bronchoalveolar lavage fluid obtained from vehicle and capsaicin-treated rabbits challenged with Par j1 exhibited no significant differences in total and differential cell counts. CONCLUSIONS: Parietaria judaica-induced AHR in immunized rabbits was shown to be inhibited by pre-treatment with capsaicin, an effect that is not related to an action on the associated pulmonary infiltration of eosinophils. The involvement of NK2 receptor stimulation in this phenomenon also suggests that NK2 receptor antagonists may be useful for investigating mechanisms of bronchopulmonary alterations in asthmatic patients.

Endothelin-1 increases cholinergic nerve-mediated contraction of human bronchi via tachykinin synthesis induction.

1. In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse trachea and in human isolated airway preparations. 2. We investigated the role of secondary mediators in ET-1 induced potentiation of cholinergic nerve-mediated contraction in human bronchi, in particular the possible role of neuropeptides in this phenomenon. 3. Bronchial tissues after endothelin treatment were exposed to a standard electrical field stimulation (EFS) (30% of EFS 30 Hz)-induced contraction. In addition, in some experiments, preparations were treated with a tachykinin NK(2) receptor antagonist and subsequently exposed to the same protocol. HPLC and RIA were performed on organ bath fluid samples. Moreover, the human bronchi were used for the beta-PPT (preprotachykinin) mRNA extraction and semiquantitative reverse transcription polymerase chain reaction (RT - PCR), prior to and 30-40 min following ET-1 challenge. 4. The selective tachykinin NK(2) receptor antagonist, SR48968, was effective to reduce ET-1 potentiation of EFS mediated contraction. HPLC or RIA showed significant increased quantities of NKA in organ bath effluents after EFS stimulation in bronchi pretreated with ET-1. Finally, beta-PPT mRNA level after stimulation of bronchi with ET-1 was increased about 2 fold respect to control untreated bronchi. 5. In conclusion, this study demonstrated that, at least in part, the ET-1 potentiation of cholinergic nerve-mediated contraction is mediated by tachykinin release, suggesting that in addition to nerves, several type of cells, such as airway smooth muscle cell, may participate to neuropeptide production.

Progression of renal function in preterm neonates with gestational age < or = 32 weeks.

Serum creatinine (SeCr), creatinine clearance (CrCl), and fractional excretion of sodium (FeNa) were measured in 83 preterm neonates divided into four groups according to gestational age (GA). At birth, there were no differences in mean SeCr values in the four groups nor any significant correlation between initial values and GA. In all groups there was an initial SeCr increase; an inverse correlation between SeCr and GA was observed from the 3rd day of life to the 5th week (p<0.001). CrCl showed a positive correlation to GA from the first week onwards (p<0.001); in each group CrCl values correlated positively to days of life (p=0.0001). Rate of CrCl increase correlated positively to GA (p=0.0005). FeNa showed an inverse correlation to GA from the first week (p<0.001). In each group, the FeNa value correlated negatively to postnatal age (p<0.001) and the velocity of decrease was directly correlated to GA (p=0.0358). Our findings indicate that glomerular function shows a progression directly correlated to GA and postnatal age, while tubular function correlates inversely to the same parameters. The values reported could be useful for following renal function in very low birth weight infants.

The role of the renal resistive index ratio in diagnosing obstruction and in the follow-up of children with unilateral hydronephrosis.

OBJECTIVE: To assess the role of the renal resistive index ratio (RIR) in discriminating equivocal upper urinary tract dilatation in children, and thus in establishing the need for surgery, in comparison with traditional diagnostic tools. PATIENTS AND METHODS: The study comprised 40 children with unilateral hydronephrosis unrelated to vesico-ureteric reflux, posterior urethral valves, megaureter or a duplex system. In all patients one or more of the following 'indices of obstruction' were positive; an anteroposterior renal pelvic diameter of >20 mm, a half-time diuretic 'washout' (T/2) of > 20 min, a separate renal function of < 40%, and symptoms of obstruction (pain, sepsis). All these variables were measured on admission and after a mean (range) follow-up of 9 (2-24) months. After this period, all patients who were symptomatic or with two or more of the variables above the normal range were considered as obstructed and underwent a dismembered pyeloplasty. The variables were then re-assessed 6 months after surgery. The RIR was evaluated using duplex Doppler ultrasonography with a 3.5-5 MHz transducer, by the same operator. Differences between obstructive and unobstructive unilateral hydronephrosis were estimated from the mean values of the variables assessed and Student's t-test used to determine significant differences. The correlation between the T/2 and RIR before and after surgery was also evaluated. RESULTS: During follow-up the RIR was abnormal in 27 of 30 patients with hydronephrosis who were considered to be 'obstructed'. Twenty-three of these patients, selected for surgery, had a positive diuretic renogram; 11 had loss of differential renal function and 16 had recurrent clinical symptoms. There were significant differences in the mean RIR and T/2 between obstructed and unobstructed patients. Six months after dismembered pyeloplasty, the RIR returned to normal in all patients except three in whom it was previously > 1.1. The diuretic renogram, if initially showing pathology, always became normal. The RIR did not change in patients with an unchanged and severe loss of differential renal function before and after surgery. CONCLUSIONS: In this study the RIR was a good index of obstruction in children with unilateral hydronephrosis and it correlated well with the results of diuretic renography. The specificity of the RIR was reduced whenever there was severe renal damage.

[Treatment of bronchial asthma in chidren]. / Terapia dell'asma bronchiale in età pediatrica.

Asthma is a condition characterised by airways inflammation and bronchial hyperresponsiveness to specific and aspecific spasmogens associated with reversible airways obstruction. The bronchomotor tone is the result of an interaction between neurotransmitter release and local mediators. The efferent neurohumoral pathways to the muscular, vascular and glandular element include parasympathetic nerves, sympathetic nerves, and non-adrenergic non-cholinergic (NANC) neurotransmission. It is currently recognised that the alteration of these mechanisms can induce bronchial hyperresponsiveness that represents a characteristic feature of asthma. Asthma is common in children and its prevalence in this age group is increasing. The current therapy of asthma involves the use of anti-inflammatory drugs to control the underlying process (causal therapy) and the use of bronchodilators that provide rapid relief of bronchoconstriction (symptomatic therapy). The bronchodilators are represented by beta 2 adrenergic agonists, methylxanthines and anti-cholinergic drugs; the anti-inflammatory drugs are represented by corticosteroids, antileukotrienes and chromones. Other new therapies being studied include anti-immunoglobulin E, anti IL-5 agents, endothelin receptor antagonists, and others.

The role of minimal surgery with renal preservation in abnormal complete duplex systems.

Among 36 children, mostly less than 1 year of age, referred for a complete duplex-system anomaly, 18 were diagnosed before birth by obstetrical ultrasonography where a diagnosis of dilated upper urinary tract was the most frequent report; in the remaining cases urinary tract infection was the main presenting symptom. Five children had bilateral anomalies. Principal diagnoses associated with the complete duplex system were: 18 ureteroceles (UC) (11 extravesical [EUC] with bladder-neck or urethral extension, 7 intravesical [IUC]), 5 ectopic ureters without UC and 28 lower-polar vesicoureteral reflux (VUR) associated in 6 with upper polar VUR. The initial assessment was based on a voiding cystogram and radionuclide scan. Renal-polar function was severely impaired when major ureteral ectopia or severe primary reflux was present. Primary surgery was performed in 8 patients, demolitive in 4 (3 upper-polar nephrectomies, 1 nephrectomy) and reconstructive in 4 (duplex en-bloc reimplantation); staged management with minimal endoscopic incision was undertaken in 15 UCs (9 EUCs and 6 IUCs). Expectant management was elected in all cases of mild primary, single, or double VUR not associated with UC and was followed by spontaneous reduction in one-half of the cases. Secondary VUR complicated endoscopic incision in 2 of 6 IUCs and 5 of 9 EUCs; a certain degree of functional improvement after decompression could be observed in all IUCs versus only 2 EUCs. Twenty-one patients requested secondary surgery; 17 needed an open intravesical procedure for ureteral reimplantation, combined in 8 with UC excision and bladder-floor reconstruction and in 5 with upper-pole nephrectomy. A nephrectomy was required in 4 cases. All primary or secondary demolitive procedures involved 9 of 11 EUCs extravesical and 2 of 5 ectopic ureters. EUCs and ureteral ectopia were associated with severe renal-polar damage, and function was rarely affected by primary decompressive procedures even in prenatally detected, uninfected cases. Endoscopic incision of EUCs was frequently followed by secondary VUR, which made secondary intravesical operations more complex. For these reasons, primary elective resection of a dysplastic upper pole is preferable in most cases to temporary decompressive measures. Conservative surgery is always indicated in IUC, which may benefit from endoscopic decompression. Isolated VUR involving the lower pole of a completely duplicated system may respond to expectant management in a significant number of cases.

46,XX,der(2)t(2;10)(2pter-->2q37::10p13-->10pter)[127]/45,X,der(2)t(2;10) (2pter-->2q37::10p13-->10pter)[23]. Karyotype-phenotype correlation and genetic counselling in complex karyotypes.

We describe a female child with complex cytogenetic anomalies consisting in partial trisomy of the short arm of chromosome 10, terminal deletion of the long arm of chromosome 2 and--at the same time--a mosaicism for X monosomy. To our knowledge, this is the first case reported in which 10p trisomy is associated to a 2qter deletion. Due to the scarcity of cases reported with pure trisomy, it has not been possible to define the 10p+ syndrome precisely yet. Comparison of our proband's phenotype to both the 2q37 deletion and 10p trisomy showed more features described in 2q37- subjects than in 10p+ ones. We also discuss the difficulties of genetic counseling in children with complex aberrations.