Cryptorchidism In Males Research Articles

The fate of germ cells in cryptorchid testis.

Cryptorchidism in males constitutes a notable risk factor for both infertility and testicular cancer. Infertility in adulthood is closely linked to the germ cell status in childhood. Furthermore, the significance of germ cell status is important as more than 95% of all reported testicular malignancies are germ cell tumors. The review aims to elucidate the pathogenesis of germ cells in cryptorchid testes concerning their association with infertility and testicular malignancies. Impaired germ cell numbers are evident in cryptorchid testes even during antenatal and neonatal stages. In cryptorchidism there is a rapid decline in germ cell number within the first year of life, partially attributed to physiologic gonocyte apoptosis. Additionally, germ cells fail to differentiate normally during mini-puberty leading to reduced germ cell proliferation and delayed clearance of gonocytes from the seminiferous epithelium. Absence of germ cells in testicular biopsies occurs already 10 months of age and germ cell deterioration progressively worsens with approximately 50% of persisting cryptorchid testes lacking germ cells during puberty. The deficient germ cell maturation and proliferation leads to later infertility. Elevated temperature in the cryptorchid testes and also hormonal deficiency contribute to this phenomenon. Germ cell neoplasia in situ (GCNIS) originating during fetal development may manifest in rare cases associated with disorders of sexual development, chromosomal abnormalities in boys, specific syndromes, and teratomas that include cryptorchidism. In adults, the presence of GCNIS predominantly represents a new histology pattern before invasive germ cell cancer is demonstrated and is neither congenital nor related to abnormal gonocyte transformation.

Association between lower limb spasticity and cryptorchidism in males with cerebral palsy.

To explore the association between presence and severity of lower limb spasticity (LLS) and risk of orchidopexy for cryptorchidism among people with cerebral palsy (CP) and to further define the cremasteric muscle spasticity theory. We queried the Pediatric Health Information System database for male patients with CP, stratified patients into those with/without LLS, and compared groups for orchidopexy occurrence. Comparative statistics were performed using χ2 and Mann-Whitney U tests for categorical and continuous variables respectively. The association between orchidopexy and spasticity type was investigated using logistic regression. In total, 44 561 males with CP were identified. Of these, 1.6% underwent orchidopexy (median age: 7 years 8 months [interquartile range: 4 years 6 months-11 years 4 months]). LLS presence was significantly associated with higher orchidopexy rate compared to spasticity absence (odds ratio [OR] = 1.33 [1.10-1.59], p = 0.003). Among 7134 patients with LLS, intervention was significantly associated with higher orchidopexy rate (injection procedures: OR = 2.47 [2.27-6.39], p = 0.034; surgical procedure: OR = 2.60 [1.22-6.76], p = 0.026). LLS groin proximity was significantly associated with higher orchidopexy rate (OR = 2.52 [1.42-4.96], p = 0.003). A strong association exists between LLS presence and severity and orchidopexy risk among people with CP. These findings support a cremasteric spasticity hypothesis as an important factor of cryptorchidism in CP. Providers should continue to examine for cryptorchidism in males with CP as they age. Lower limb spasticity (LLS) is associated with higher orchidopexy rate in cerebral palsy. Orchidopexy rate was higher in more severe LLS. Orchidopexy rate was higher in more proximal LLS.

Hormonal therapy is effective and safe for cryptorchidism caused by idiopathic hypogonadotropic hypogonadism in adult males.

Hormonal therapy is a reasonable treatment for cryptorchidism caused by idiopathic hypogonadotropic hypogonadism (IHH). However, the clinical evidence on whether it is effective and safe for the treatment of cryptorchidism caused by IHH is lacking. To evaluate the effect of hormonal therapy in testicular descent, puberty development, and spermatogenesis in adult males with cryptorchidism caused by IHH. This retrospective study included 51 patients with cryptorchidism caused by IHH from the Andrology Clinic of University affiliated teaching hospital. Patients were divided into two groups: group A patients received hormonal therapy; group B patients received surgical treatment for cryptorchidism followed by hormonal therapy. The rate of successful testicular descent following hormonal therapy (19/32 in group A) or surgical treatment (11/19 in group B) shows no statistically significant difference. There was also no statistically significant difference in penile length, Tanner stage of pubic hair, testicular volume, and success rate of spermatogenesis between the two groups. Testicular atrophy was seen in a single patient in group B. Hormone therapy in adult males with cryptorchidism caused by IHH is effective and safe regarding testicular descent, puberty development, and spermatogenesis. This study provides new insight into the treatment of cryptorchidism caused by IHH and highlights that hormonal therapy could be an effective, safe, and economic treatment option for cryptorchidism in males caused by IHH.

Effects of Elevated Maternal Adiposity on Offspring Reproductive Health: A Perspective From Epidemiologic Studies.

One in seven couples in developed countries suffers from infertility. Maternal overweight or obesity have detrimental and lasting effects on offspring cardiometabolic health, and although substantially more data are needed, hormonal imbalances in utero resulting from excessive maternal adiposity could also disrupt reproductive programming and affect the future reproductive health of offspring. Therefore, this mini-review evaluates the human epidemiologic evidence that maternal overweight/obesity could be associated with poor reproductive health outcomes in offspring. We searched PubMed for relevant studies using terms such as "maternal obesity" and "reproductive development." While the human epidemiologic literature is limited, studies have thus far observed that maternal obesity is associated with disrupted external genital development and several other markers of reproductive health across the lifespan. Specifically, maternal obesity is associated with higher risks of hypospadias and cryptorchidism in males and disrupted anogenital distance both in males and females. Maternal obesity has also been linked to earlier age at menarche in daughters, and precocious puberty in both sons and daughters. Finally, daughters of women with overweight or obesity have higher risks of developing polycystic ovarian syndrome, which has implications for fertility. This body of research suggests that in utero exposure to maternal obesity could disrupt reproductive system development, but substantially more evidence is needed, as almost no human epidemiologic studies have evaluated the long-term consequences of maternal obesity with regard to offspring fertility/fecundity.

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

BackgroundPathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement.ResultsIn this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient’s lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation.ConclusionsAn extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.

Renal complication due to prune belly syndrome: A case report

Introduction: Prune belly syndrome (PBS) is a congenital disorder characterized by injury or hypoplasia of the abdominal wall musculature, severe urinary tract abnormalities, and bilateral cryptorchidism in males. It has an estimated incidence of 1 in 40,000 live births. Life exp

126: Prader-Willi syndrome: fetal phenotype can lead to prenatal diagnosis

Prader-Willi syndrome (PWS) is a severe neurogenetic disorder characterized by morbid obesity, mental retardation and severe behavioral disorders. PWS can be diagnosed by methylation analysis during invasive prenatal diagnosis procedures, however, prenatal diagnosis is rare. We aimed to characterize PWS fetal phenotype, in order to offer the possibility of prenatal diagnosis. All 99 PWS patients treated at the Israel National Multidisciplinary PWS clinic under the age of 10 years were studied. Clinical features of PWS pregnancies were reported by the mothers. Medical records including ultrasound reports, obstetric records, and genetic results were collected. Results were compared both to normal PWS sibling's pregnancies (n=70) and to the Israeli general population. PWS pregnancies were complicated by higher rates of decreased fetal movements (DFM), small for gestational age (SGA), polyhydramnios, breech presentation and cryptorchidism in males (80.4%, 56.6%, 37.4%, 36.4%, 88% respectively, (Table 1). A combination of 2,3 and 4 features was found in 35,34,15% respectively. In 52% of PWS pregnancies at least 3 features were found and in 87% at least two. High rates of asymmetric fetal growth during the 3rd trimester with increased head to abdominal circumference (HC/AC) ratio were found (38%). When evaluating AC as a marker of asymmetric growth, in 64% of the pregnancies the AC was < 10th% and in 32% < 3rd%. The most common feature accompanying abnormal HC/AC ratio or AC< 5th% was DFM. Doppler studies were mostly normal (84.4%) (Table 2). Amniocentesis was performed in 17 cases (17.2%). Methylation test was not offered and the diagnosis of PWS was missed. We describe distinct prenatal phenotype in PWS. A combination of asymmetric fetal growth with normal Doppler studies and DFM, specifically if accompanied with polyhydramnios/ breech presentation or cryptorchidism. Such phenotype should alert obstetricians to consider the possibility of PWS and perform the diagnostic methylation test when amniocentesis is pursued.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Relationship between phenotype and genotype of 102 Chinese newborns with Prader–Willi syndrome

High rates of misdiagnosis and delayed intervention in neonatal PWS are leading to poor prognoses. To determine the clinical and image characteristics of newborns with Prader-Willi syndrome (PWS). A total of 102 cases of newborns definitively diagnosed with PWS at the Children's Hospital of Fudan University from 02/2014 to 12/2017 were retrospectively analyzed. We analyzed the modulated voxel-based morphology (VBM) of gray matter in PWS by T2 weighted imaging. Of 102 cases, 75 (73.5%) have paternal deletion of 15q11.2-q13, whereas 27 (26.5%) have maternal uniparental disomy (UPD). Of the 75 deletion cases, 75 (100%) week crying, 71 (94.7%) hypotonia, 70 (93.3%) poor feeding, 46 (61.3%) hypopigmentation, 43 (57.3%) male cryptorchidism, 10 (13.3%) female labia minora, 48 (64%) characteristic facial features. Of 27 UPD cases, 27 (100%) week crying and hypotonia, 25 (92.6%) hypophagia, 20 (74.1%) male cryptorchidism, 1 (3.7%) female labia minora, 19 (70.4%) characteristic facial features, 12 (44.4%) hypopigmentation. The modulated VBM analysis shows that the middle frontal gyrus, orbitofrontal cortex (middle), and inferior frontal gyrus are the most variable brain regions that determine the endo-phenotype difference between the two genotypes. Hypotonia, hypophagia, and maldevelopment of sexual organs are general characteristics of newborns with PWS in Chinese population. In UPD cases, the proportions of premature newborns, elderly parturient women and congenital malformations were higher than for paternal deletion cases. The differences in the gray matter volume of these three regions between the two genotypes may explain the differences in maladaptive behaviors and emotions.

Rare copy number variants identified in prune belly syndrome

Prune belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a rare congenital disorder characterized by absence or hypoplasia of the abdominal wall musculature, urinary tract anomalies, and cryptorchidism in males. The etiology of PBS is largely unresolved, but genetic factors are implicated given its recurrence in families. We examined cases of PBS to identify novel pathogenic copy number variants (CNVs). A total of 34 cases (30 males and 4 females) with PBS identified from all live births in New York State (1998–2005) were genotyped using Illumina HumanOmni2.5 microarrays. CNVs were prioritized if they were absent from in-house controls, encompassed ≥10 consecutive probes, were ≥20 Kb in size, had ≤20% overlap with common variants in population reference controls, and had ≤20% overlap with any variant previously detected in other birth defect phenotypes screened in our laboratory. We identified 17 candidate autosomal CNVs; 10 cases each had one CNV and four cases each had two CNVs. The CNVs included a 158 Kb duplication at 4q22 that overlaps the BMPR1B gene; duplications of different sizes carried by two cases in the intron of STIM1 gene; a 67 Kb duplication 202 Kb downstream of the NOG gene, and a 1.34 Mb deletion including the MYOCD gene. The identified rare CNVs spanned genes involved in mesodermal, muscle, and urinary tract development and differentiation, which might help in elucidating the genetic contribution to PBS. We did not have parental DNA and cannot identify whether these CNVs were de novo or inherited. Further research on these CNVs, particularly BMP signaling is warranted to elucidate the pathogenesis of PBS.

Clinical and molecular analysis of Noonan syndrome in Indonesia: a case report

Noonan syndrome (NS; OMIM#163950) is a relatively common autosomal dominant disorder with a worldwide prevalence of approximately 1:1,000 to 1:2,500. The syndrome is characterized by distinctive facial features, congenital heart defects (CHD), and short stature. Distinctive facial features consist of a broad and high forehead, hypertelorism, downslanting palpebral fissures, a high arched palate, low set and posteriorly rotated ears with a thick helix, and a short neck with excess nuchal skin and low posterior hairline. Additional relatively frequent features include chest deformities, cryptorchidism in males, mild intellectual disability, and bleeding diathesis.1,2In 2001, missense mutations in

Clinical and molecular analysis of Noonan syndrome in Indonesia: a case report

Noonan syndrome (NS; OMIM#163950) is a relatively common autosomal dominant disorder with a worldwide prevalence of approximately 1:1,000 to 1:2,500. The syndrome is characterized by distinctive facial features, congenital heart defects (CHD), and short stature. Distinctive facial features consist of a broad and high forehead, hypertelorism, downslanting palpebral fissures, a high arched palate, low set and posteriorly rotated ears with a thick helix, and a short neck with excess nuchal skin and low posterior hairline. Additional relatively frequent features include chest deformities, cryptorchidism in males, mild intellectual disability, and bleeding diathesis.1,2In 2001, missense mutations in

Influence of inbreeding on the incidence of cryptorchidism in males of Lowland-line bison

The aim of this study was to find whether the coefficient of inbreeding is correlated with the incidence of cryptorchidism in the Białowieża line of bison. Our study included 605 male European bison Bison bonasus (L.) born between 1971 and 2015 in the Białowieża Forest. The animals were free-ranging as well as from captive breeding programs. Among the animals culled, there were 144 European bison calves. The calves were not considered in the research, because the descending of the testes in European bison may not occur until a year after birth. The study period, from 1966 to 2015, was divided into 5 decades. The number of male European bison born in each decade was recorded, as well as the number of cryptorchidism cases identified through necropsy in these animals. The percentage of incidence of cryptorchidism among them was calculated for every decade. Subsequently, the Pearson correlation coefficient was calculated between the number of cryptorchidism cases and the coefficient of inbreeding. In 461 male European bison older than 1 year, there were 18 cases of cryptorchidism. In the animals born in the first decade, two autopsical cases of cryptorchidism (0.045%) were recorded, and 4 cases of cryptorchidism (0.03%) were found in the animals from the second decade. Among the bison born in the third decade, there were no cases of cryptorchidism. In the fourth decade, 7 cases of cryptorchidism (0.071%) were diagnosed, and among the bison born during the fifth decade, there were 5 cases (0.111%). The Pearson correlation coefficient suggests that, as the value of the coefficient of inbreeding rises, there is an increase in cryptorchidism cases in male European bison.

Characterization of core clinical phenotypes associated with recurrent proximal 15q25.2 microdeletions

A recurrent proximal microdeletion at 15q25.2 with an approximate 1.5 megabase smallest region of overlap has recently been reported in seven patients and is proposed to be associated with congenital diaphragmatic hernia (CDH), mild to moderate cognitive deficit, and/or features consistent with Diamond-Blackfan anemia. We report on four further patients and define the core phenotypic features of individuals with this microdeletion to include mild to moderate developmental delay or intellectual disability, postnatal short stature, anemia, and cryptorchidism in males. CDH and structural organ malformations appear to be less frequent associations, as is venous thrombosis. There is no consistent facial dysmorphism. Features novel to our patient group include dextrocardia, obstructive sleep apnea, and cleft lip.

Paediatric germ cell tumours and congenital abnormalities: a Children's Oncology Group study

Methods:Maternally reported congenital abnormalities (CAs) were examined in a case–control study of 278 cases of paediatric germ cell tumours (GCTs) and 423 controls.Results and conclusionsGerm cell tumours were significantly associated with cryptorchidism in males (OR=10.8, 95% CI: 2.1–55.1), but not with any other specific CA in either sex.

Mutación en el gen SOS1 como nueva causa de síndrome de Noonan

Noonan syndrome, characterized by short stature, facial anomalies, heart disease and cryptorchidism in males, is an autosomal dominant, genetically heterogeneous disease. Approximately 50 % of Noonan syndrome cases are caused by gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase (SHP2) and 5 % are caused by KRAS mutations. Recently, a new mutation in SOS1 gene has been identified in approximately 20 % of cases of Noonan syndrome without PTPN11 mutation. That difference in genotype has a relationship with phenotype that we must investigate. We report a case of Noonan syndrome due to an SOS1 mutation; we describe his phenotype and subsequent outcome.

An updated review of environmental estrogen and androgen mimics and antagonists

For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Man-made compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate flasks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 μg of bisphenol-A were retrieved from saliva collected during the first hour after polymerization. Other xenoestrogens recently identified among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male fish were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identified antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors.

Assays to measure estrogen and androgen agonists and antagonists.

Substantial evidence has surfaced on the hormone-like effects of many xenobiotics in fish, wildlife and humans (Colborn et al., 1993). The endocrine and reproductive effects of xenobiotics are believed to be due to their 1) mimicking the effects of endogenous hormones such as estrogens and androgens, 2) antagonizing the effects of normal, endogenous hormones, 3) altering the pattern of synthesis and metabolism of natural hormones, and 4) modifying the hormone receptor levels. Estrogen mimics (xenoestrogens) are among the environmental chemicals found to cause reproductive impairment in wildlife and humans. All of these compounds were found to be estrogenic long after they had been released into the environment. A single causal agent can be identified in cases in which humans have had occupational exposures, whereas in cases where wildlife have shown signs of reproductive damage the exposure is usually a combination of endocrine disruptors that may have acted cumulatively. It has been hypothesized that environmental estrogens may play a role in the decrease of human semen quantity and quality of human semen during the last 50 years. They may also be partly responsible for the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. Testing this hypothesis will require: 1) the identification of xenoestrogens among the chemicals present in the environment, 2) the development of a methodology to assess the interactions among mixtures of xenoestrogens to which humans are exposed, and 3) the discovery of markers of estrogen exposure. The development of fast and sensitive bioassays is central to the achievement of these three goals.

Lateral meningocele syndrome: Three new patients and review of the literature

One female and two male patients with multiple lateral meningoceles are presented. They do not have neurofibromatosis or Marfan syndrome and share findings with the two previously described patients with multiple lateral meningoceles. The original report by Lehman et al. [1977: J Pediatr 90:49-54] was titled "familial osteosclerosis," because osteosclerosis was present in the proposita and her mother; the patient described by Philip et al. [1995: Clin Dysmorphol 4:347-351] also had increased bone density of the skull base and the sutures. Thickened calvaria were present in one of our patients; two had a prominent metopic suture. Other shared findings include multiple lateral meningoceles, Wormian bones, malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and cryptorchidism in males. In addition, our patients showed ligamentous laxity, keloid formation, hypotonia, and developmental delay. A short umbilical cord was noted in two patients. One had a hypoplastic posterior arch of the atlas and an enlarged sella, as reported by Lehman et al. [1977]. Our patients appear to have the same syndrome as previously reported. We suggest it be called "lateral meningocele syndrome," because of this unique finding.

The Noonan syndrome/cherubism association

Noonan syndrome is characterized by short stature, unusual facies, congenital heart disease, chest deformity, mild mental retardation, and cryptorchidism in males. It may be sporadic or inherited as an autosomal dominant trait and occurs between 1 in 1000 and in 1 2500 live births. Cherubism is a giant cell lesion of the jaws thought to be transmitted as an autosomal dominant trait. It is usually recognized by age 7 years, follows a variable course, and is not known to be related to other genetic disorders. We herein report on four patients with Noonan syndrome, all of whom had cherubism. Two other probable cases are cited in the literature for a total of six known cases.

Adults with Prader-Willi syndrome: a survey of 232 cases.

Older individuals with Prader-Willi syndrome have rarely been documented. This report describes the physical characteristics, health problems, cognition, psychosocial adjustment and impact on the family of 232 adults with the syndrome, ranging in age from 16 to 64 years. The sample showed that Prader-Willi syndrome occurs with equal frequency in both sexes. Most were short, overweight, cognitively impaired, emotionally labile, had poor gross motor skills and were always hungry. Males were taller and heavier than females, and both sexes were far shorter and heavier than US norms. Micropenis and cryptorchidism in males and primary amenorrhea, late menarche and irregular menstrual cycles in females indicated hypogenitalism in both sexes. Of 106 with chromosome analysis, 54 had an abnormality on chromosome 15, primarily a deletion; the others had normal chromosomes.