Archives of Disease in Childhood 1997;77:305–309 305 Androgen insensitivity syndrome: a survey of Arch Dis Child: first published as 10.1136/adc.77.4.305 on 1 October 1997. Downloaded from diagnostic procedures and management in the UK R M Viner, Y Teoh, D M Williams, M N Patterson, I A Hughes Abstract single gene disorder that results in a normal Objective—A two year survey of androgen female phenotype, and typically presents in insensitivity syndrome (AIS) to assess early adult life with primary amenorrhoea, current diagnostic and management although a significant number present with strategies. inguinal hernias in infancy. The significance of Methods—Cases were ascertained by in- the relative rarity of bilateral inguinal hernias in clusion on the British Paediatric Surveil- girls is often not appreciated; it is estimated lance Unit monthly report card for 24 that 1–2% of such infants have complete AIS.4 months. The diagnosis is confirmed in both forms of Results—Fifty one of 139 notifications AIS by a male karyotype and normal testoster- were confirmed as AIS; 29 cases were one production and metabolism, in the pres- complete AIS and 22 cases partial AIS. ence of normal testicular histology, and gener- Seventy six per cent of complete AIS pre- ally the absence of müllerian duct remnants. sented with an inguinal hernia, and half Partial AIS is a clinically heterogeneous dis- the complete AIS patients had an estab- order and presents a more complicated diag- lished family history of the disorder. Pres- nostic problem.25 The degree of androgen entation in the partial AIS group was unresponsiveness is variable, so the aVected through ambiguous or undermasculinised infant presents at birth with undermasculinised genitalia; 59% of partial AIS were raised external genitalia of varying severity. Charac- as male. teristically, there is micropenis with chordee, a Conclusions—The importance of karyo- bifid scrotum, and a perineal urethral opening, typing girls with inguinal hernias is con- and gonads that may or may not be palpable firmed, and further attention should be within the bifid scrotum. The partial AIS phe- given to genetic counselling for families of notype must be diVerentiated from other con- complete AIS patients. A large number of ditions with a 46XY karyoptype, which can cases were misreported as partial AIS, give rise to the same genital abnormality such emphasising the importance of undertak- as defects in testosterone biosynthesis, 5á- reductase deficiency, mixed gonadal dysgen- ing a comprehensive diagnostic evaluation http://adc.bmj.com/ in intersex states. A large percentage of esis, and true hermaphroditism.67 Accurate children with partial AIS were raised as early diagnosis is important and has a profound boys despite severe genital undermascu- bearing on the sex of rearing, genetic counsel- linisation, indicating the current lack of ling, and subsequent management; a trial of validated measures that predict genital androgen treatment in early infancy to assess response to androgen treatment. The the growth of penile erectile tissue may provide management of AIS is discussed and diag- important information on androgen respon- nostic guidelines provided to improve the siveness. There is a lack of knowledge regard- on October 2, 2021 by guest. Protected copyright. ing the criteria used to decide the management Department of diagnostic yield in AIS. Paediatrics, (Arch Dis Child 1997;77:305–309) of infants with partial AIS, particularly with University of respect to sex of rearing. Analysis of the cases Cambridge, Keywords: androgen insensitivity syndrome; inguinal identified through our survey suggests that Addenbrookes hernia; intersex guidelines for clinicians on the appropriate Hospital diagnostic and management strategies for AIS Y Teoh patients, particularly in the case of suspected D M Williams A two year national survey of the androgen partial AIS, would be helpful. M N Patterson insensitivity syndrome (AIS) was undertaken I A Hughes via the British Paediatric Surveillance Unit to University College determine existing diagnostic procedures and Methods London Hospitals, management strategies. A pilot study of SURVEY PROCEDURE Great Ormond Street patients with the partial form of AIS had shown Cases were ascertained by active surveillance Hospital, and that data on gonadal histology, anatomy of the via inclusion on the surveillance unit monthly Middlesex Hospital, internal genitalia, and steroid hormone con- report card for a two year period. Previous London 1 K M Viner centrations were incomplete. AIS defines a studies using multiple ascertainment methods female or ambiguous phenotype in a 46XY have suggested that this reporting procedure Correspondence to: male with testes and normal testosterone alone provides between 60–80% case ascer- Professor I A Hughes, production and metabolism.2 As androgens are tainment rates.8 Cases were defined as an Department of Paediatrics, Addenbrookes Hospital, essential for normal male sexual development infant or child under 16 years of age with a Level 8, Box 116, Hills Road, and fertility, defects in androgen action are 46XY karyotype and with either normal female Cambridge CB2 2QQ. associated with abnormal sexual differentiation external genitalia (defined as complete AIS) or Accepted 10 June 1997 and fertility.3 Complete AIS is a rare X linked abnormal external genitalia that are consistent 306 Viner, Teoh,Williams, Patterson, Hughes with the partial AIS phenotype, that is, esection. Also, as part of a separate study, if a micropenis/clitoromegaly, bifid scrotum, peri- partial AIS patient was undergoing surgery to Arch Dis Child: first published as 10.1136/adc.77.4.305 on 1 October 1997. Downloaded from neoscrotal hypospadias. Clinicians were asked the external genitalia, clinicians were asked to to report any child under their care who satis- provide (after parental consent) a genital skin fied the case definitions, including those newly biopsy specimen as part of the surgical diagnosed in the past month, and those procedure in order to establish fibroblast children diagnosed before the start of the study cultures. Systematic case ascertainment was and who were still 16 years of age, or less, at the confined to the surveillance unit reporting time of the study. scheme. Ethical approval was granted by the Once a case was notified, the referring clini- Cambridge local ethics committee. cian was asked to complete a questionnaire detailing further information about the clinical Results phenotype, family history, imaging studies of Table 1 details notifications during the survey internal genitalia, gonadal histology, results of period. Fifty one of the total 139 notifications endocrine investigations, and management were confirmed as cases of AIS. There was decisions on sex of rearing and hormone treat- insuYcient information to make a diagnosis ment. Determination of diagnosis was made from 37 notifications. The diagnostic criteria from information provided in consultation with for complete AIS and partial AIS were fulfilled referring clinicians. If a case of AIS was in 29 and 22 cases, respectively. confirmed as part of separate studies, referring clinicians were asked to collect blood samples COMPLETE AIS from the index case and family members for All complete AIS patients had normal female DNA extraction, the venesection being coordi- genitalia and were reared as females. Presenta- nated with other investigations requiring ven- tion in complete AIS was predominantly by the discovery of a hernia in an apparently female Table 1 Cases notified to surveillance unit (n=139) infant (76%); other cases were identified on the basis of a family history of the X linked disor- Total notifications No der, or from the determination of a karyotype Exclusions (n=63) for other reasons (table 2). Regardless of the Over age at study 21 Duplicate notifications 5 mode of presentation, inguinal hernia was Unconfirmed cases—no return of questionnaire 37 present in 28 (90%) of complete AIS patients; Cases reported and questionnaire received (n=76) nine (31%) were unilateral, 17 (59%) bilateral. Confirmed complete AIS 29 Confirmed partial AIS 22 Table 3 shows details of gonadal position and Total AIS 51 histology. One or two palpable testes were Other diagnoses: present in approximately 80% of complete AIS Abnormal or dysplastic testes 6 Gonadal dysgenesis 6 patients. Gonadal histology was consistent with Biosynthetic defect (17-hydroxydehydrogenase 1 AIS in all patients in whom histological deficiency) examination of the testes was performed (table Drash syndrome 1 Hypogonadism 1 3). Apart from the report of a ‘vestigial’ uterus Hypopituitarism 1 in one complete AIS patient, female internal http://adc.bmj.com/ Hypospadias 2 Smith-Lemli-Opitz syndrome 2 genitalia were absent in all AIS patients. WAGR syndrome 1 Unknown diagnosis 4 PARTIAL AIS Drash=Wilms’ tumour, male pseudohermaphroditism, and Presentation in partial AIS was through nephropathy. ambiguous or undermasculinised genitalia. In 59% of the partial AIS cases, the sex of rearing Table 2 Mode of presentation in CAIS (n=29) was male. Factors that appeared to aVect sex of rearing in partial AIS were the degree of labio- on October 2, 2021 by guest. Protected copyright. No (%) of cases scrotal fusion, site of urethral opening, whether Bilateral hernia 13 (45) the testes were palpable, and phallus size. All Unilateral hernia 9 (31) Family history 4 (14) infants with unfused labia (n=4) were raised as Amniocentesis 1 (3) female and a further five infants with fused Adoption karyotype 1 (3) labia were also raised as female. All those raised Unknown l (3) as male (n=13) had fused labioscrotal folds. Micropenis was reported in 54% of infants Table 3 Details of gonad position and histology; values are number (%) raised as males, although equal numbers were reported as having normal phallus size. App- Partial AIS roximately 80% of partial AIS patients had one Complete AIS Reared male Reared female or two palpable testes. Infants with palpable (n=29) (n=13) (=9) testes at diagnosis were more likely to be raised Gonad position male, and only one infant without palpable tes- Bilateral intra-abdominal 6 (21) 1 (8) 3 (33) tes was raised as a male (table 3).