Neonatal features of the Prader-Willi syndrome; the case for making the diagnosis during the first week of life

Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition. Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire. Ninety patients (54 male: 36 female) were seen between 1991-2015, most with paternal deletion (n=56) or maternal isodisomy (n=26). Features included cryptorchidism in 94% males, preterm birth (26%), birthweight <2500g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) occurred in 82.5% patients compared with 4% healthy siblings. Of 35 children born since 1999, 23 were diagnosed clinically within 28 days while diagnosis in 12 was > 28 days: 1-12 months in 7; and 3.75-10.5 years in 5. Typical PWS features in these 12 infants included hypotonia (100%), feeding difficulties (75%), cryptorchidism (83% males) and reduced FM (66%). Causes other than PWS including neuromuscular disease were considered in nine patients. Neonatal hypotonia, reduced FM, feeding difficulties and cryptorchidism should immediately suggest PWS, yet late diagnosis continues in some cases. Awareness of the typical features of PWS in newborn units is required to allow prompt detection even in the presence of confounding factors such as prematurity

Hypogonadism in the Prader-Willi syndrome from birth to adulthood: a 28-year experience in a single centre

Background. Hypogonadism is a key feature of Prader–Willi syndrome (PWS) but clear strategies for hormone replacement are lacking. Objective. To evaluate the gonadal status and outcome in patients attending a Scottish PWS clinic from 1991 to 2019. Methods. In 93 (35F:56M) patients, median follow-up 11.2 years, gonadal and pubertal status were assessed clinically. Pelvic ultrasound findings and basal/stimulated gonadotrophins were compared with age-matched controls. Results. Females:of 22 patients aged > 11, 9 had reached B4–5, while 5 were still at B2–3, and 6 remained prepubertal. Eight patients experienced menarche aged 9.8–21.4 years, none with a normal cycle. Uterine length and ovarian volumes were normal but uterine configuration remained immature, with low follicular counts. Gonadotrophins were unremarkable, serum oestradiol 129 (70–520) pmol/L. Only 5 patients received oestrogen replacement. Males:fifty-four (96%) patients were cryptorchid (9 unilateral). Weekly hCG injections resulted in unilateral/bilateral descent in 2/1 of 25 patients. Of 37 boys aged > 11, 14 (9 with failed/untreated bilateral cryptorchidism) failed to progress beyond G1, 15 arrested at G2–3 (testes 3–10 mL), and 8 reached G4–5. Gonadotrophins were unremarkable except in boys at G2–5 in whom FSH was elevated: 12.3/27.3 vs 3.25/6.26 U/L in controls (P < 0.001). In males aged > 13, testosterone was 3.1 (0.5–8.4) nmol/L. Androgen therapy, given from 13.5 to 29.2 years, was stopped in 4/24 patients owing to behavioural problems. Conclusion. Despite invariable hypogonadism, few females and only half the males with PWS in this study received hormone replacement. Double-blind placebo-controlled crossover trials of sex steroids are required to address unproven behavioural concerns

Familial Multiplicity of Estrogen Insensitivity Associated with a Loss-of-Function ESR1 Mutation

International audienceContext: Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ERs) α and β, encoded by ESR1 and ESR2 genes, respectively.Objective: The study's aim was to describe a family in which 3 members presented with estrogen insensitivity.Design and setting: Clinical evaluation and genetic and mutational analysis were performed in an academic medical center.Patients and interventions: An ESR1 mutation was identified in 2 sisters and 1 brother, originating from a consanguineous Algerian family, who did not enter puberty and presented with delayed bone maturation consistent with estrogen insensitivity. The 2 sisters had enlarged multicystic ovaries. Hormonal evaluation as well as genetic and mutational analysis were performed.Results: Hormonal evaluation revealed extremely high plasma 17β-estradiol (>50-fold normal range) associated with elevated gonadotropin levels (greater than threefold normal range), highly suggestive of estrogen resistance. The 3 affected patients carried a homozygous mutation of a highly conserved arginine 394 for which histidine was substituted through an autosomal recessive mode of transmission. Structural and functional analysis of the mutant ERα revealed strongly reduced transcriptional activity and the inability to securely anchor the activating hormone, estradiol, compared with wild-type ERα. A group of other potential ER activating ligands were tested, but none overcame the estrogen insensitivity in these patients.Conclusion: Description and analysis of this family of patients with mutant ERα provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition