Oligogenic Inheritance of Monoallelic TRIP11, FKBP10, NEK1, TBX5, and NBAS Variants Leading to a Phenotype Similar to Odontochondrodysplasia.

Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes that are presently known to cause monogenic skeletal diseases. Here, we describe an 11-year-old Finnish girl, born to unrelated healthy parents, who had severe short stature and a phenotype similar to odontochondrodysplasia (ODCD), a monogenic skeletal dysplasia caused by biallelic TRIP11 variants. The family had previously lost a fetus due to severe skeletal dysplasia. Exome sequencing and bioinformatic analysis revealed an oligogenic inheritance of a heterozygous nonsense mutation in TRIP11 and four likely pathogenic missense variants in FKBP10, TBX5, NEK1, and NBAS in the index patient. Interestingly, all these genes except TBX5 are known to cause skeletal dysplasia in an autosomal recessive manner. In contrast, the fetus was found homozygous for the TRIP11 mutation, and achondrogenesis type IA diagnosis was, thus, molecularly confirmed, indicating two different skeletal dysplasia forms in the family. To the best of our knowledge, this is the first report of an oligogenic inheritance model of a skeletal dysplasia in a Finnish family. Our findings may have implications for genetic counseling and for understanding the yet unsolved cases of rare skeletal dysplasias.

Acquired cryptorchidism is frequent in infancy and childhood.

Accurate prevalence data for acquired cryptorchidism are currently sparse and systematic prospective studies have not yet been reported. Our aim was to determine the prevalence of testicular ascent in childhood. In a prospective longitudinal population-based child cohort from Copenhagen, Denmark (1997-2007), testicular position was examined according to a standardised protocol in a total of 1072 boys, at birth (n = 1051), at 3 months (n = 983), 18 months (n = 888), 36 months (n = 790) and again once between 4 1/2 and 10 years of age (n = 509). Ascensus testis was defined as ascent of the testis into a cryptorchid position after normal scrotal position at birth. A congenital cryptorchid testis with spontaneous postnatal descent followed by recurrence of cryptorchidism was named recurrent cryptorchidism. Ascensus testis occurred in 0.2%, 0.6% and 0.6% of boys at 3, 18 and 36 months of age respectively. When including recurrent cryptorchidism the prevalence was 0.2%, 1.2% and 0.8% respectively. Ascensus testis accounts for 58% of all cases of cryptorchidism (congenital and acquired) at 18 months, 71% at 36 months and thereafter 69%. Ascensus testis accounts for more than half of cryptorchid testes seen in childhood and occurs in both previously scrotal and cryptorchid testes. We therefore recommend that all boys should have testis position checked regularly during childhood, at least up to 3 years of age.

Mild gestational diabetes as a risk factor for congenital cryptorchidism.

CONTEXT: Cryptorchidism is the most common malformation in newborn boys. Maternal diabetes has previously been suggested to be a risk factor for this disorder in one epidemiological study. OBJECTIVE: Evaluation of the prevalence of maternal glucose metabolism disorders during pregnancy in newborn boys having normal testicular descent or congenital cryptorchidism. DESIGN: Postnatal analysis of maternal history concerning glucose metabolism abnormalities during pregnancy among cryptorchid and healthy Finnish boys. SETTING AND PARTICIPANTS: The material of this case-control study comprises 1163 boys with normal testicular descent at birth and 125 boys with congenital cryptorchidism. All these singleton Finnish boys were born in Turku University Central Hospital (1997-2001) and were examined at birth and/or at the expected date of delivery. MAIN OUTCOME MEASURES: Information about maternal diabetes diagnosis and abnormality of the result of a 2-h 75-g oral glucose tolerance test during pregnancy were obtained from the hospital records after delivery. RESULTS: After adjustment for possible confounding factors, i.e. maternal smoking during pregnancy, maternal age at delivery, and risk factors of cryptorchidism, e.g. prematurity and weight for gestational age, abnormal maternal glucose metabolism was significantly more common in the group of cryptorchid boys [diet-treated gestational diabetes, P = 0.0001; odds ratio, 3.98 (95% confidence interval, 1.97-8.05); diet-treated gestational diabetes or only an abnormal result in oral glucose tolerance test, P = 0.0016; odds ratio, 2.44 (95% confidence interval, 1.40-4.25)] when compared with boys with normal testicular descent. CONCLUSIONS: Mildly abnormal glucose metabolism during pregnancy was associated with an increased risk for congenital cryptorchidism. The mechanism remains to be elucidated.

Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys.

CONTEXT: Recent studies showed that male reproductive health problems, such as cryptorchidism, hypospadias, testicular cancer, and low sperm quality, are more prevalent in Denmark than in Finland. OBJECTIVES: We hypothesized that, if fetal testicular dysgenesis contributed to these observations, differences in gonadal development and the hypothalamus-pituitary-testis axis would already be detectable perinatally. Thus, we investigated healthy newborn boys in both countries. DESIGN: This was a prospective, longitudinal population-based study. SETTING: Two primary obstetric centers were included at the University Hospitals of Copenhagen, Denmark, and Turku, Finland. PARTICIPANTS: The participants of the study included 633 Danish and 1044 Finnish boys, born at term with appropriate weight for gestational age. INTERVENTIONS: Ultrasound determination of testis size at 0, 3, and 18 months and blood sampling (n = 727) at 3 months were analyzed. MAIN OUTCOME MEASURES: Testicular volume and reproductive hormones were measured. RESULTS: Testis volume was significantly higher at all ages in Finnish than in Danish boys (medians, 98 vs. 95, 185 vs. 119, and 188 vs. 136 mm(3), respectively; P < 0.00001). Testis growth from birth to 3 months was larger in Finnish than in Danish boys (mean, 75 vs. 26 mm(3); P < 0.0001). Serum hormone levels were higher in Finnish than Danish boys for inhibin B (median, 456 vs. 385 pg/ml; P < 0.0001), FSH (1.33 vs. 1.21 IU/liter; P < 0.036), and SHBG (143 vs. 136 nmol/liter; P < 0.022). Inhibin B was significantly positively correlated to testicular volume (r = 0.25; P < 0.006). CONCLUSIONS: The larger testes and higher inhibin B levels most likely represent a bigger volume of seminiferous tubules in Finnish compared with Danish boys. Although this phenomenon may be attributable to a genetic difference between the two countries, it may also reflect environmental factors influencing testicular development.