Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.

Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.

Role of clean intermittent self catheterisation (CISC) in the prevention of recurrent urethral strictures after internal optical urethrotomy.

BACKGROUND: Urethral stricture is one of the oldest diseases Urethral dilatation Internal optical urethrotomy,were the only treatment. Clean Intermittent Self Catheterisation was introduced by Lapides has greatly decreased the recurrence of stricture. Objectives were to determine the role of Clean Intermittent Self Catheterisation (CISC) in the prevention of recurrence of urethral strictures after Internal Optical Urethrotomy and to study the frequency of any postoperative complications and tolerability for the patients associated with this procedure. METHODS: A randomised controlled study conducted in the department of urology and renal transplantation, Institute of Kidney Diseases Hayatabad Medical Complex, Peshawar from June 2007 to June 2010. Total of 60 patients with mean age 48 years (range 20-73) were selected and randomly divided into Treatment Group (30 patients) and Control Group (30 Patients). Eight "drop out" occurred in the treatment group and four "drop out" occurred in the controlled group. All the patients were treated with Internal Optical Urethrotomy using Sachse method followed by indwelling catheter for 5 days. The treatment group was then taught to perform Clean Intermittent Self Catheterisation by inserting a Classic Neleton Catheter (No. 16 or 18) twice a day for 1 week, then once a day for another 4 weeks and then once weekly continued for one year. All the patients were followed up regularly at 1 month intervals during the first 6 months and then every 2 months for the next 6 months. RESULTS: Total of 48 patients completed the study, 22 in the treatment group and 26 in the control group. Within the first year, 4 patients (22%) in the treatment group developed urethral stricture. In the control group, 12 patients (46%) developed urethral stricture within the first year, showing a significant difference (p < 0.01). In the treatment group four patients developed simple UTIs while in the control group three patients developed UTIs, one with concomitant epididymitis. No other complications were noted up to one year follow up. CONCLUSION: Clean Intermittent Self Catheterisation is a simple and effective way of reducing stricture recurrence after Internal Optical Urethrotomy and is associated with less morbidity and is cost effective. CISC is an important modality for maintaining the normal urethral calibre.

Complex genetics in idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) is an important human disease model. Investigations of the genetics of IHH have facilitated insights into critical pathways regulating sexual maturation and fertility. IHH has been traditionally considered a monogenic disorder. This model holds that a single gene defect is responsible for the disease in each patient. In the case of IHH, 30% of cases are explained by mutations in one of eleven genes. In recent years, several lines of evidence have challenged the monogenic paradigm in IHH. First, disease-associated mutations display striking incomplete penetrance and variable expressivity within and across IHH families. Second, each locus is responsible for only a small percentage of cases. Third, more than one disease-associated mutation seems to be segregating in some families with IHH, and their combined or separate presence in individuals accounts for the variability in disease severity. Finally, IHH is not strictly a congenital and life-long disorder; occasionally it manifests itself during adulthood (adult-onset IHH); in other cases, the disease is not permanent, as evidenced by normal activity of the hypothalamic-pituitary-gonadal axis after discontinuation of treatment in adulthood (IHH reversal). Together, these observations suggest that IHH is not strictly a monogenic mendelian disease, as previously thought. Rather, it is emerging as a digenic, and potentially oligogenic disease, in which hormonal and/or environmental factors may critically influence genetic predisposition and clinical course. Future investigations of IHH should characterize the extent of the involvement of multiple genes in disease pathogenesis, and elucidate the contributions of epigenetic factors.