Parent-reported outcomes in young children with disorders/differences of sex development

Parents of children under the age of 7 years attending DSD and Endocrine outpatient clinics at one specialist paediatric centre, were approached between February 2017 and February 2019 (Fig. 1). Exclusion criteria included the need for an interpreter for questionnaire completion, thus, parental eligibility was restricted to those whose primary language was English. Parents were approached at the end of clinic consultations, advised verbally and provided with a cover note that their participation was optional and that the completed questionnaires would be included in their child’s health record as part of routine clinical care. Questionnaires were provided to one parent/carer attending clinic with their child with the exception of four cases for whom both mothers and fathers completed questionnaires. Only two of the respondents who completed the questionnaires were not biological parents of the children, but all were referred to as ‘mothers’ and ‘fathers’. All parents returned completed questionnaires prior to leaving the clinic. A section at the end of the questionnaire sought parental feedback on simplicity of the questionnaire, on acceptability of the length of time for completion and on comprehension of questions. The questionnaire was approved by the research ethics office as part of routine healthcare evaluation. The completed questionnaires were available to the DSD multidisciplinary team assessing care and for discussion at subsequent pre-clinic meetings for evaluation of ongoing care.

The 40-item PSR (Additional file 1: Table S1, Additional file 1: Figure S1) was developed for parents of children aged from birth to < 7 years to assess parental feelings and experiences in relation to their child’s condition (DSD or other Endocrine conditions). The PSR is comprised of 8 domains (Healthcare Communication and Information, Talking to Others, Future Concerns, Medication, Clinic Visit, Surgery, Stigma, and Anxiety/Depression) selected from the previously validated Quality of Life DSD Parent (QOL-DSD-Parent) report [4], parent-focused items of the Experiences and Reactions questionnaire assessing DSD-related experienced or anticipated stigma [5], and the Patient Health Questionnaire-4 (PHQ-4) [19], a screening scale for depression and anxiety (Table 1).

The 30-item PPR (Additional file 1: Table S2, Additional file 1: Figure S2) was developed for parents of children aged 2 to < 7 years to capture their perceptions of the child’s feelings and experiences related to their condition (DSD or other Endocrine condition). Paralleling construction of the PSR, the PPR comprises 8 domains (Anxiety, Depression, Anger, Peer Relationships, Stigma, Clinic Visits, Medications, and Missed School Days) selected from the Quality of Life DSD Proxy (QOL-DSD-Proxy) report [4], child-focused items of the Experiences and Reactions questionnaire [5] and select PROMIS Parent-Proxy scales [18] (Table 1).

DSD reference data were obtained from a previous study validating DSD-specific, parent-reported, health-related quality of life measures for children under the age of 7 years [4]. For both PSR and PPR questionnaires, parents rated their experiences/perceptions on 5-point Likert scales (Additional file 1: Tables S1 and S2). For each domain, a scale average was obtained if at least half of the items were completed, and this was incorporated into the calculation of the median standard deviation score (SDS). Responses were standardised from 0 to 100, with higher scores in the majority of domains indicating better quality of life and more positive adaptation (Table 1). The Experiences and Reactions (Stigma) domain [5] was also scored on 5-point scale, with higher scores indicating a greater level of experienced (or anticipated) stigma. Median SDS, i.e., the number of SDs away from the mean, for questionnaire domains stemming from the QOL-DSD-Parent, QOL-DSD-Proxy reports [4] and the Experiences and Reaction (Parent-Focused and Child-Focused) questionnaire [5], were calculated using separate mother and father means and SDs obtained from reference data (Table 1). Total scores for the PHQ-4 screening scale [19] for depression and anxiety were categorized as normal (0–2), mild (3–5), moderate (6–8), and severe (9–12). On each subscale, a score of 3 or greater was considered positive for screening purposes. As per recommended scoring procedures [23‐26], PROMIS® raw scale scores for Anxiety, Depression, Anger and Peer Relationships were converted to standardized “T scores” (mean 50; SD 10) employing the Health Measures Scoring Service^SM [27] which utilizes norms for healthy 5 to 17-year children in the U.S. general population as the referent sample. For Anxiety, Depression and Anger, a higher score, for example T = 60, was representative of a + 1SD elevation in symptoms relative to the normative sample [23‐25]. In the case of Peer Relationships, T = 60 reflected better social interactions by the same +1SD [26].

Data analysis was performed using Minitab version 18 statistical software (Minitab LLC, State College, PA, USA). All data were described as medians and ranges (minimum, maximum); comparison between groups was performed by the Kruskal-Wallis test for continuous variables and subsequently adjusted for multiple comparisons using false discovery rates [28]. For DSD-specific and generic domains, the mean (SD) derived from previously validated reference data was used in the calculation of median SDS for each domain (Table 1). For DSD-specific domains, the median SDS of mothers and fathers within DSD and Endocrine groups were analysed to enable cross-parent comparisons. For all domains within both questionnaires, the median SDS of the DSD group was compared to the median SDS of the Endocrine group and the median SDS of each group (DSD and Endocrine) was also compared to SDS of zero. Mothers and fathers scores were combined for the PROMIS® measures as per scoring guidelines. A p value of less than 0.05 was considered statistically significant.

For the Parent Self-Report (PSR) questionnaire, data were available for 55 parents (42 mothers and 13 fathers) of 54 children and for the Parent Proxy-Report (PPR) questionnaire, data were available for 25 parents (18 mothers and 7 fathers) of 25 children (Table 2). The median age of the 54 children for whom PSR questionnaires were completed was 1.8 years (range 0.03, 6.8 years) and of these, 44 (82%) were reared as boys. The median age of the 25 children for whom PPR questionnaires were completed was 4.5 years (2.0, 6.65) and of these, 16 (64%) were boys. Amongst the 54 DSD cases, 40 (74%) had 46, XY DSD with 28 (51%) having a diagnosis of a non-specific DSD (e.g. bilateral cryptorchidism or proximal hypospadias). Sex chromosome DSD and 46, XX DSD accounted for 7 (13%) cases each. Of the 54 cases, 16 (30%) had other conditions including cardiorespiratory disease, non-sex chromosome abnormalities or developmental delay.

For the PSR questionnaire, data were available for 43 parents (34 mothers and 9 fathers) of 41 children and for the PPR questionnaire, data were available for 23 parents (17 mothers and 6 fathers) of 22 children (Table 2). The median age of the 41 children for whom parents completed PSR questionnaires was 2.0 years (0.1, 6.8) and of these 41 children, 23 (56%) were raised as boys. The median age of the 22 children for whom PPR questionnaires were available was 5.0 years (2.3, 6.9) and of these, 13 (59%) were boys. The most frequent endocrine diagnoses amongst the 41 children who had PSR questionnaires were conditions associated with short stature or growth hormone deficiency in 14 (34%) children and disorders of bone metabolism in 11 (27%) children. In the 22 children who had PPR questionnaires completed, these two diagnoses were present in 11 (50%) and 4 (18%) children, respectively. Other endocrine diagnoses in cases for whom PSR and PPR questionnaires were completed included thyroid disease (n = 7; n = 4), adrenal insufficiency (n = 3; n = 2), septo-optic dysplasia (n = 2), hyperinsulinism (n = 2), primary polydipsia (n = 1) and premature tooth exfoliation (n = 1); these diagnoses accounted for less than 7% of conditions amongst the endocrine cases. Of the 41 endocrine cases, 17 (41%), had other co-morbidity including cardiac, respiratory or neurological problems.

Fathers of children with DSD had lower median SDS for Future Concerns [SDS -1.60 (− 4.21, 1.00); p = 0.02], indicating greater apprehension, compared to reference data (Table 3, Fig. 2). However, these fathers had a higher median SDS for Medication [SDS 1.80 (1.01, 1.80); p = 0.04] and Clinic Visits [SDS 2.10 (0.16, 2.58); p = 0.02], indicating lesser degrees of stress relating to their child’s medication regimen and clinic visits. Mothers of children with other Endocrine conditions had a higher median SDS for Talking to Others [SDS 0.78 (− 0.83, 1.47); p = 0.02], Future Concerns [SDS 1.17 (− 2.00, 1.73); p = 0.02) and Clinic Visits [SDS 0.70 (− 1.37, 0.99); p = 0.02], indicative of less concerns in each of these domains. Fathers of children with other Endocrine conditions also had a higher SDS for Clinic Visits [SDS 1.37 (0.64, 2.60); p = 0.04], indicating less stress associated with clinic attendances, compared to reference data.

Mothers of children with DSD had lower median SDS for Future Concerns, indicating a greater level of concerns, than mothers of children with other Endocrine conditions [SDS -0.28 (− 2.14, 1.73) vs SDS 1.17 (− 2.00, 7.73); p = 0.02] (Table 3, Fig. 2). Similarly, fathers of children with DSD had a lower median SDS for Future Concerns compared with fathers of children with other Endocrine conditions [SDS -1.60 (− 4.21, 1.00) vs SDS 0.48 (− 2.13, 1.52); p = 0.04] indicating greater concerns in fathers of children with DSD. For both DSD and Endocrine groups, median PHQ-4 scores were not in the range associated with clinically significant symptomology and there was no significant difference in PHQ-4 scores between mothers and fathers of children with DSD compared with mothers and fathers of children with other Endocrine conditions (p > 0.05).

Parents of children with DSD had higher median SDS for Depression [SDS 1.28 (− 1.52, 1.28); p = 0.03] indicative of greater depressive symptoms, compared to reference data (Table 4). Similarly, parents of children with other Endocrine conditions reported more symptoms of Depression [SDS 0.64 (− 1.01, 1.28); p = 0.03]. There was no significant difference in other Proxy-Report domains (including Anxiety, Anger and Peer Relations, Stigma, Clinic Visits and Medication) between parents of children with DSD or other Endocrine conditions, compared to reference data.

There was no significant difference in the PROMIS® scores for Anxiety, Depression, Anger and Peer Relationships between parents of children with DSD and parents of children with other Endocrine conditions (Table 4). In addition, there were no differences between parents of children with DSD compared with other Endocrine conditions with regards to DSD-specific domains including Stigma, Clinic Visits or Medications. Parents of children with DSD reported a median of 0 Missed School Days (0.0, 3.0) over the previous 6-month period compared to 0.5 days (0.0, 5.0) for children with other Endocrine conditions.

Of the 111 children whose parents were approached, the parents of 95 children with DSD or other Endocrine conditions completed the questionnaires (86%).In all cases, parents completed the questionnaires in less than 10 min and all parents reported that the questionnaire was acceptable for the time it took to complete the questionnaire, and questions were ‘easy to understand’ and ‘easy to follow’.