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- Butwicka, Agnieszka, et al.
(författare)
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Hypospadias and increased risk for neurodevelopmental disorders
- 2014
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Ingår i: Journal of Child Psychology and Psychiatry. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-9630 .- 1469-7610.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hypospadias (aberrant opening of the urethra on the underside of the penis) occurs in 1 per 300 newborn boys. It has been previously unknown whether this common malformation is associated with increased psychiatric morbidity later in life. Studies of individuals with hypospadias also provide an opportunity to examine whether difference in androgen signaling is related to neurodevelopmental disorders. To elucidate the mechanisms behind a possible association, we also studied psychiatric outcomes among brothers of the hypospadias patients. METHODS: Registry study within a national cohort of all 9,262 males with hypospadias and their 4,936 healthy brothers born in Sweden between 1973 and 2009. Patients with hypospadias and their brothers were matched with controls by year of birth and county. The following outcomes were evaluated (1) any psychiatric (2) psychotic, (3) mood, (4) anxiety, (5) eating, and (6) personality disorders, (7) substance misuse, (8) attention-deficit hyperactivity disorder (ADHD), (9) autism spectrum disorders (ASD), (10) intellectual disability, and (11) other behavioral/emotional disorders with onset in childhood. RESULTS: Patients with hypospadias were more likely to be diagnosed with intellectual disability (OR 3.2; 95% CI 2.8-3.8), ASD (1.4; 1.2-1.7), ADHD (1.5; 1.3-1.9), and behavioral/emotional disorders (1.4; 1.2-1.6) compared with the controls. Brothers of patients with hypospadias had an increased risk of ASD (1.6; 1.3-2.1) and other behavioral/emotional disorders with onset in childhood (1.2; 0.9-1.5) in comparison to siblings of healthy individuals. A slightly higher, although not statistically significant, risk was found for intellectual disability (1.3; 1.0-1.9). No relation between other psychiatric diagnosis and hypospadias was found. CONCLUSIONS: This is the first study to identify an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD in their brothers, suggesting a common familial (genetic and/or environmental) liability.
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| 2. |
- Nordenvall, Anna Skarin, et al.
(författare)
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Hypospadias as a novel feature in spinal bulbar muscle atrophy
- 2016
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Ingår i: Journal of Neurology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0340-5354 .- 1432-1459.
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Tidskriftsartikel (refereegranskat)abstract
- Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repeat expansions in the androgen receptor (AR) gene. The SBMA phenotype consists of slowly progressive neuromuscular symptoms and undermasculinization features as the result of malfunction of the AR. The latter mainly includes gynecomastia and infertility. Hypospadias is also a feature of undermasculinization with an underdeveloped urethra and penis; it has not been described as part of the SBMA phenotype but has been suggested to be associated with a prolonged CAG repeat in the AR gene. This study includes the first epidemiologic description of the co-occurrence of hypospadias and SBMA in subjects and their male relatives in Swedish population-based health registers, as well as an additional clinical case. One boy with severe hypospadias was screened for mutations in the AR gene and was found to have 42 CAG repeats in it, which is in the full range of mutations causing SBMA later in life. We also detected a maximum of four cases displaying the combination of SBMA and hypospadias in our national register databases. This is the third case report with hypospadias in association with CAG repeat expansions in the AR gene in the full range known to cause SBMA later in life. Our findings suggest that hypospadias may be an under diagnosed feature of the SBMA phenotype and we propose that neurologists working with SBMA further investigate and report the true prevalence of hypospadias among patients with SBMA.
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| 3. |
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| 4. |
- Skarin Nordenvall, Anna
(författare)
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Register-based studies of hypospadias
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hypospadias is a common genital malformation ofcomplex origin. It is characterized by misplacement of the urethral orifice, proximal to the tip of the glans penis, and is most often accompanied by a cleaved prepuce and varying degrees of ventral penile curvature. The phenotype ranges from distal hypospadias, where the misplacement of the urethral orifice is small, to more proximal cases where the urethral orifice may be located in the perineum and lead to uncertain sex at birth. This thesis aims to elucidate aspects of the etiology, and increase the knowledge concerning the consequences of being born with hypospadias. All studies are based on information collected from national population-based Swedish registers, containing healthcare and demographic data. In Study I we investigated associated risk factors, in terms of parental and perinatal characteristics, and the prevalence of hypospadias. We found an increased prevalence of boys assigned with hypospadias during the late 20th century. Further, we found that boys born small for gestational age, as twins, as a result of ART, or by parents from greater Europe (excluding the Nordic countries) or Asia were at an increased risk of being registered with a diagnosis of hypospadias. The trend in prevalence was not attributable to temporal changes in the investigated risk factors. Study II highlighted the association between hypospadias and the neuromuscular disorder known as spinal-bulbar muscle atrophy (SBMA), for which the common denominator is a CAG repeat expansion in the androgen receptor (AR) gene. We described one clinical case; a boy born with proximal hypospadias who was found to have 42 CAG repeats in the AR gene, which is a mutation known to cause SBMA later in life. In Swedish health care registers we found four potential cases of SBMA and hypospadias in individuals and within families. In Study III we investigated socioeconomic outcomes in men born with hypospadias as a proxy of well-being in adulthood. We found that men born with hypospadias displayed a similar level of education and income, and were as likely to be married as non-affected men. Men with proximal hypospadias did, however, suffer a greater risk of receiving a disability pension. This risk may be due to the effect of unmeasured psychiatric comorbidity, conditions related to androgen deficiency, or hypospadias as a part of unrecognized syndromes. In Study IV we aimed to assess the fertility of adult men born with hypospadias. We found a lower probability of registered paternity among men with hypospadias; the association was most prominent in men with proximal hypospadias and of small magnitude in distal hypospadias. Men with hypospadias were more likely to being diagnosed with male infertility and of conceiving through ART. The overall results imply that fertility is impaired in men with distal and proximal hypospadias, probably as a result of anatomic features, gonadal dysfunction, psychological, or genetic factors.
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