Loss of function of FIGNL1, a DNA damage response gene, causes human ovarian dysgenesis.

Ovarian dysgenesis (OD), an XX disorder of sex development, presents with primary amenorrhea, hypergonadotrophic hypogonadism, and infertility. In an Ashkenazi Jewish patient with OD, whole exome sequencing identified compound heterozygous frameshifts in FIGNL1, a DNA damage response (DDR) gene: c.189del and c.1519_1523del. Chromosomal breakage was significantly increased in patient cells, both spontaneously, and following mitomycin C exposure. Transfection of DYK-tagged FIGNL1 constructs in HEK293 cells showed no detectable protein in FIGNL1c.189del and truncation with reduced expression in FIGNL1c.1519_1523del (64% of wild-type [WT], P = .003). FIGNL1 forms nuclear foci increased by phleomycin treatment (20.6 ± 1.6 vs 14.8 ± 2.4, P = .02). However, mutant constructs showed reduced DYK-FIGNL1 foci formation in non-treated cells (0.8 ± 0.9 and 5.6 ± 1.5 vs 14.8 ± 2.4 in DYK-FIGNL1WT, P < .001) and no increase with phleomycin treatment. In conclusion, FIGNL1 loss of function is a newly characterized OD gene, highlighting the DDR pathway's role in ovarian development and maintenance and suggesting chromosomal breakage as an assessment tool in XX-DSD patients.

Are current cut-off values of 11-DOC in children useful for assessing suspected nonclassical congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency?

OBJECTIVE: A nonclassic form of 11ß-hydroxylase deficiency (NC11ß-OHD) has been reported to cause mild androgen excess symptoms. Currently, the gold standard for biochemical diagnosis is elevated 11-deoxycortisol (11-DOC) levels after corticotropin stimulation test (ACTHstimT). However, there are no clear 11-DOC level cutoffs. One of the accepted references for 11-DOC levels for the paediatric population was published in 1991 by Lashansky et al. AIM: To determine the correlation between 11-DOC levels measured during ACTHstimT and clinical symptoms attributed to NC11ß-OHD. DESIGN: A retrospective study including all paediatric patients who underwent ACTHstimT at Shamir Medical Center between 2007 and 2015. Clinical data were collected from the patients' medical files. Outcome measures included the number of patients with hyperandrogenism signs and predefined elevated 11-DOC cut-off levels according to Lashansky for sex and age, and according to commercial kit cut-offs. RESULTS: Data were complete at presentation for 136 patients. Long-term clinical data were documented for 98 patients, mean follow-up duration of 3.1 years (1.37-5.09). There was no statistically significant difference in the number of cases with elevated 11-DOC according to both cut-offs and early puberty, premature adrenarche nor acne. Follow-up data demonstrated no statistically significant difference in the number of cases with elevated 11-DOC levels among patients with compromised final adult height, polycystic ovarian syndrome or hyperandrogenism. CONCLUSIONS: Basal and corticotropin stimulated 11-DOC levels were not significantly elevated above the 1.5 times cut-offs according to paediatric-specific norms or the commercial assay in paediatric individuals with possible clinical suspicion of NC11ß-OHD.

Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents.

PURPOSE: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old. METHODS: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded. RESULTS: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years. CONCLUSIONS: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.

Consumption of soy-based infant formula is not associated with early onset of puberty.

PURPOSE: The use of soy products is common in young children with cow milk allergy (CMA). The aim was to examine prospectively the association between infantile consumption of soy-based formula, growth parameters and early pubertal signs, in comparison to cow milk-based formula. METHODS: A nested case-control study was conducted, selected from a cohort of infants prospectively followed from birth until the age of 3 years for eating habits and the development of IgE-mediated CMA. Infants who consumed only soy-based formula were included in the soy group. The control group was randomly selected from those without IgE-CMA and not receiving soy formula. Study participants were reevaluated between ages 7.8 and 10.5 years by an interview, nutritional intake by 3 days diaries, and height, weight, and pubertal signs by physical examination. RESULTS: The soy-fed group included 29 participants (17 males), median age 8.92 years IQR (8.21, 9.42). The control group included 60 participants (27 males), median age 8.99 years IQR (8.35, 9.42). The groups had comparable height and BMI z scores (- 0.17 ± 1.08 versus - 0.16 ± 1.01, p = 0.96, and 0.67 ± 1.01 versus 0.53 ± 1.02, p = 0.56, for soy and control groups, respectively). Four (three males and one female) from the soy-group (13.8%) and eight females from the control-group (13.3%) had early pubertal signs (p = 0.95). No association was detected between puberty and infantile nutrition, after controlling for BMI and family data. No association with puberty or differences between groups were found in current daily consumption of soy, micronutrients, energy, carbohydrates, fat, and protein. CONCLUSIONS: This is the first prospective, physical examination-based study, demonstrating no association between infantile soy-based formula consumption and growth and puberty parameters.

Bone Age Assessments by Quantitative Ultrasound (SonicBone) and Hand X-ray Based Methods are Comparable.

BACKGROUND: Bone maturation is currently assessed by subjective and automated radiography. OBJECTIVES: To evaluate the concordance and reproducibility of a quantitative ultrasound (QUS) based device versus X-ray based methods. METHODS: The study population comprised 150 children, 76 males, 4-17 years of age. X-ray scans were evaluated according to wrist, carpal and phalanx areas for bone age. QUS was performed by the the BAUS™ device (SonicBone, Rishon Lezion, Israel), using speed-of-sound (SOS) and distance attenuation factor (ATN) in similar areas. Data from 100 subjects were used to establish the device conversion equation, and 50 measurements were assigned to assess inter-modality agreement. RESULTS: BAUS showed high repeatability performance, 0.73% relative standard deviation for SOS and 3.5% for ATN. R2 for the conversion equation, including gender, SOS, and ATN, was 0.80 for all methods (P < 0.001). There was no significant bias in bone age assessments. CONCLUSIONS: Bone age assessment by SonicBone is comparable to the assessment by X-ray based methods.