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Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

ABSTRACT: BACKGROUND:PAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment. METHODS:We collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen receptor (AR) mutations, including two previously uncharacterized variants (I899F; Y916C). Patients were grouped as follows; EMS at birth <5 and???5 (EMS in normal males is 12; median EMS in PAIS is 4·7) and pubertal outcomes compared. FINDINGS:Only 6/9 patients (67%) with EMS <5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ?5 (p?=?.03). Only 1/6 patients (17%) with EMS <5 developed adult genitalia reaching Tanner stage 4 or 5, versus 11/13 (85%) with EMS ?5 (p?=?0·01). There was no significant difference between the two groups of patients in being prescribed androgen replacement, who reached adult testicular volume???15?ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, and mastectomy. No correlation was observed between EMS and in vitro AR function. INTERPRETATION:In PAIS with AR mutation, birth EMS is a simple predictor of spontaneous pubertal onset and satisfactory adult genitalia. This provides useful information when discussing the likely options for management at puberty. FUND: European Commission Framework 7 Programme, NIHR Cambridge Biomedical Research Centre, BBSRC DTP.

SUBMITTER: Lek N

PROVIDER: S-EPMC6197786 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

Lek Ngee N Tadokoro-Cuccaro Rieko R Whitchurch Jonathan B JB Mazumder Bismoy B Miles Harriet H Prentice Philippa P Bunch Trevor T Zielińska Karolina K Metzler Veronika V Mongan Nigel P NP Heery David M DM Hughes Ieuan A IA

EBioMedicine 20181011

<h4>Background</h4>PAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment.<h4>Methods</h4>We collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen rece ...[more]

PMID: 30316867

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Project description:BackgroundAndrogens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS).ObjectiveThe aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR.Materials and methodsTwo hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants.ResultsFive missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient.ConclusionAR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.

Project description:Abstract Background: Partial Androgen Insensitivity Syndrome (PAIS) (OMIM # 312300) is one of the causes of Disorders/Differences of Sex Development with 46,XY karyotype and normal or increased testosterone secretion that results in atypical genitalia. In general, it is caused by inactivating mutations on AR gene (Xq12 - OMIM * 313700), therefore it presents an X-linked recessive inheritance. Individuals raised as males have incomplete puberty with micropenis, sparse hairs, gynecomastia and increased LH, testosterone and estradiol serum levels. Therefore, the use of aromatase inhibitor in these cases becomes a logical indication aiming to increase testosterone levels in the tentative of supplanting its peripheral resistance and decreasing estrogen levels. Objective: To present clinical and laboratory data during the first year of use of aromatase inhibitor in puberty of three boys with confirmed molecular diagnosis of PAIS. Results: All subjects used letrozole (2.5 mg daily during 12 months). None reported significant side effects. Cases 1 and 2 are brothers (p.Ala596Tre). Case 1: Onset of treatment at age 12; height changed from 158 cm (z = +1.15) to 166 cm (z = +1.21), Tanner from G2P2T2 to G3P3T1, penis from 4.0 to 6.5 cm, LH from 7.5 to 18.3 IU/L (NR: 1.5 to 9.3 IU/L), testosterone from 361 to 1,347 ng/dL (NR: 165 to 763 ng/dL), estradiol from 35 to <5.0 pg/mL (NR: < 40 pg/mL) and bone age remained at 13 years. Case 2: Onset of treatment at age 11; height changed from 156 cm (z = +1.71) to 163 cm (z = +1.80), Tanner from G2P2T2 to G3P3T1, penis from 3.5 to 5.5 cm, LH from 4.8 to 12.4 IU/L (NR: 1.5 to 9.3 IU/L), testosterone from 259 to 1,069 ng/dL (NR: 165 to 763 ng/dL), estradiol from 28 to <5.0 pg/mL (NR: < 40 pg/mL) and bone age remained at 12.5 years. Case 3 (p.Ser597Arg): Onset of treatment at age 12; height changed from 153 cm (z = +0.49) to 161 cm (z = +0.55), Tanner from G2P2T1 to G3P3T1, penis from 4.0 to 7.0 cm, LH from 8.5 to 17.2 IU/L (NR: 1.5 to 9.3 IU/L), testosterone from 280 to 889 ng/dL (NR: 165 to 763 ng/dL), estradiol from 32 to <5.0 pg/mL (NR: < 40 pg/mL) and bone age remained at 13.5 years. Discussion: There are no reports in the literature of the use of aromatase inhibitor in PAIS. The results of this pilot study (gynecomastia regression, significant testosterone level increases with decrease in estradiol levels, increment in height without bone age advancing, progression of puberty and penile growth) are sustaining for the indication of this treatment in boys with PAIS during puberty.

Dataset Information

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

Publications

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

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