Review and evaluation of patient-centered psychosocial assessments for children with central precocious puberty or early puberty

Patient-centered concepts in central precocious puberty

Among the identified studies of precocious puberty or early pubertal maturation, the most frequently assessed concepts were depression/depressive symptoms and anxiety, behavior and behavioral problems, body image and self-esteem and personality type/characteristics. Other concepts explored less frequently but nonetheless relevant included HRQOL, psychosocial adjustment and stress. ‎Table S-2 in the Supplemental Material summarizes the identified patient-centered concepts, references, study population and country.

Qualitative research on the subjective experience of central precocious puberty

Baumann and colleagues [8] described a study of 19 Swiss girls mean onset of puberty at 4½ years, treated with gonadotropin-releasing hormone (GnRH) agonists. Participants reported feelings of shame and insecurity, “mostly because of tallness and breast development”; 47.4% “often” or “always” felt older or more mature than peers, and 47.4% were subjected to remarks about their sexual characteristics from peers “sometimes” or “often”. Most (84.2%) reacted with frequent or occasional withdrawal. The authors suggested that precocious puberty was a source of stress and insecurity for young patients [8].

Xhrouet-Heinrichs and colleagues [9] reported a longitudinal Belgian study of 20 girls with CPP (15 treated with GnRH for 2 years). Girls had breast development at 5–8 years of age. During semistructured interviews with patients, parents and their pediatric endocrinologist, conducted 1 month after diagnosis, all 20 patients expressed concerns about comments from peers regarding physical differences, primarily relating to breast development and embarrassment over pubertal differences. Most patients reported a fear of sexuality (17/20, including 12 girls from treated group) and feelings of loneliness and having no or few friends (14/20). Seven patients expressed concern about menstruation, including one girl who had already begun to menstruate, and one expressed concern about possible short adult stature. One month after diagnosis, parents of 10 patients reported that their daughters exhibited intense emotional reactions, including crying easily, shyness, and clinginess, and parents of eight patients reported that their daughters exhibited “aggressive behavior”. Twenty-four months after diagnosis, 13 of the 20 patients were still concerned about physical differences from peers. However, embarrassment about pubertal development was no longer a concern in 6 of 15 treated girls, five of whom experienced regression of breast development [9].

In addition to the published studies, a 2016 University of Washington Public Health master’s thesis, Identifying Areas of Needed Support for Young Girls with Central Precocious Puberty (CPP), was identified online [10]. That study detailed 14 qualitative interviews conducted with caregivers of 16 girls aged 6–10 years with idiopathic CPP; 13 were undergoing treatment at the time of the study, two had completed treatment and one was untreated. The impacts of CPP as described by caregivers were primarily negative and included severe mood swings, irritability, and emotional outbursts affecting relationships with peers (100%) and caregivers (86%); physical changes leading to social effects or awkwardness (14%); and social effects including feeling isolated and alone (43%), being bullied (14%) and becoming a bully (6%). Communication with caregivers was negatively affected and emotionally charged (86%). For a few patients, positive psychosocial effects of CPP were identified, such as becoming a leader among peers and enjoying being taller than peers. Caregivers whose daughters were undergoing treatment (81%) or who had completed treatment (13%) noted psychosocial improvements within 1–4 weeks after treatment was initiated (31%) or more than 1 month after treatment initiation (62%).

Studies assessing patient-centered outcomes in central precocious puberty

Key studies assessing patient-centered concepts in CPP or precocious puberty are summarized in Table 1; one was interventional and nine were observational. Eight of these studies included the Child Behavior Checklist (CBCL), and only a few other outcome assessments were used. The most relevant assessments identified in the literature are described in detail in the Instrument Review section.

One single-arm interventional study evaluated 54 female patients treated with leuprolide acetate depot over 24 weeks. The CBCL Problem Behavior total score, (p = 0.0072) and Other Problems (p < 0.0001) and Sociality (p = 0.0464) subscale scores were significantly lower (i.e. improved) between baseline and week 24. However, the CBCL subscales Problem Behavior Syndrome, Anxiety/Depression, Shrinking/Depression, Somatization, Social Immaturity, Thought Problems, Attention Problems, Violation of Regulations and Offensive Behavior were not significantly different at 24 weeks [11].

Among the observational studies, some CBCL subscales showed significant problems in patients with CPP versus healthy controls or population norms, and whereas others found no significant differences. Significant differences in CBCL scores included Externalizing and Internalizing Problems, total Behavioral Problems and Attention Problems [3], [8], [12], [13], [14]. Another observational study used the Children’s Social Behavior Scale – Parent Report to evaluate relational anxiety and the Revised Child Anxiety and Depression Scale – Parent Report to evaluate anxiety and depressive symptoms and found that pubertal development was significantly associated with relational aggression, anxiety and depression [15].

Only one of the nine studies included boys who may have had CPP [16]. Although these children did not necessarily have a diagnosis of CPP, they participated at each follow-up (ages 6–7, 8–9 and 10–11 years), and their parents provided information about pubertal development at ages 8–9. Mensah and colleagues [16] compared behavior difficulties and psychosocial adjustment between children who experienced early-onset puberty (8–9 years) and those with later onset. They also examined data collected from the ages of 4–11 years to determine whether differences precede and/or continue beyond early puberty at age 8–9 years and whether differences remained after adjusting for body mass index, socioeconomic status, and ethnicity. Among girls, there was little difference in the Strengths and Difficulties Questionnaire (SDQ) total difficulties scores across age groups for those with puberty onset (as assessed by parents) at 8–9 years versus those with later onset of puberty. Boys who experienced early puberty had higher SDQ total difficulties scores at 8–9 years versus those who did not; differences were also observed earlier in childhood, at 4–5 and 6–7 years, and were maintained through ages 10–11 years. Compared with subjects who did not experience early puberty, both boys and girls who experienced early puberty had poorer Pediatric Quality of Life Inventory (PedsQL) summary scores consistently across age groups [16].

Instruments identified from the central precocious puberty literature (Table 2)

The CBCL is a widely used parent-, caregiver- or teacher-reported questionnaire designed to assess the competencies, adaptive functioning and behavioral/emotional problems of children aged 18 months to 18 years [17], [18]. The version for children aged 1½–5 years and the version for children and adolescents aged 6–18 years are completed by parents. The CBCL contains approximately 100 problem items and 20 competence items. The items use a three-point graded response scale and varying recall periods (e.g. “now or within the past 6 months” or “now or within the past 2 months”). Items are scored as eight Syndrome scales: Aggressive Behavior, Anxious/Depressed, Attention Problems, Rule-Breaking Behavior, Social Problems, Somatic Complaints, Thought Problems, and Withdrawn/Depressed. In addition, there are four CBCL Competency scales: Activities, School, Social, and Total Competence, as well as two higher-order psychopathology scales: Internalizing and Externalizing. The CBCL appears to be content valid for assessing the competencies, functioning and behavioral/emotional problems of children and adolescents in a broad population. Items were generated in consultation with professionals and parents and modified based on the results of pilot studies [17], [18]. The CBCL is widely used, and there are numerous studies documenting its psychometric properties [19], [20], [21], [22], [23], [24].

Several of the CBCL items appear potentially relevant to young children with CPP (e.g. gets teased a lot; self-conscious or easily embarrassed; Sexual problems [describe] _____; Stubborn, sullen or irritable; Sudden changes in mood or feelings; Temper tantrums or hot temper; Unhappy, sad or depressed; and Withdrawn, does not get involved with others). Moreover, the CBCL (including a Korean translation of the CBCL) has been used relatively frequently in studies of CPP – 9 times in the literature reviewed. However, the questionnaires are quite lengthy and include many irrelevant items (e.g. questions related to bathroom habits, appetite or medical symptoms). The recall periods are also very long if there is interest in assessing onset of treatment action.

The Pediatric Quality of Life Inventory version 4.0 Generic Core Scales (PedsQL) is a widely used pediatric HRQOL instrument that encompasses childhood and adolescence (2–18 years) and measures the three broad domains of HRQOL – physical, emotional and social functioning – as well as school functioning [25]. The PedsQL comprises 23 items yielding four subscale scores: Physical Functioning (eight items), Emotional Functioning (five items), Social Functioning (five items) and School Functioning (five items); a Psychosocial Health summary score is computed from the Emotional, Social and School Functioning items. The PedsQL for children aged 2–4 years is in proxy format only; for children aged 5–18 years, the instrument is both self-report and proxy-report, with the PedsQL self-report for children aged 5–7 years being administered through interviews. Response options for patients aged 8–18 years are graded on a five-point scale. The self-report form for children aged 5–7 years has a three-point scale, with each response option anchored to a happy, neutral or sad face. In all cases, a 1-month recall period is used, and the PedsQL takes approximately 5 min to complete.

The PedsQL has demonstrated highly satisfactory reliability and validity in healthy children [26] and in specific pediatric populations, such as children with cancer, heart disease, diabetes and asthma [27], [28], [29], [30]. The PedsQL has been shown to have satisfactory known-groups validity [31], [32], [33], capable of discriminating between healthy children and those with chronic illness. Although the PedsQL has had very limited use in studies of CPP, it is interesting that both boys and girls who experienced early puberty had poorer PedsQL summary scores consistently across childhood [16].

Additional potentially relevant instruments (Table 3)

The CHQ is a multidimensional measure of physical and psychosocial functioning and well-being [34], [35]. Designed and normed for children 5–18 years of age, there is a self-report version for children and adolescents aged 10–18 years and a proxy-reported version for parents of children aged 5–18 years. The self-report CHQ includes 87 items, and the parent-reported CHQ includes 28 or 50 items, each with a 4-, 5- or 6-point ordered response scale. The recall periods vary from “the past 4 weeks” to “compared to 1 year ago”. In addition to an overall CHQ summary score, the CHQ yields physical and psychosocial subscale scores: Physical Functioning, Role/Social-Physical, General Health Perceptions, Bodily Pain, Parental Time Impact, Parental Emotional Impact, Role/Social-Emotional/Behavioral, Self-Esteem, Mental Health, General Behavior, Family Activities, Family Cohesion and Change in Health. CHQ items of potential use include questions about “argued a lot”, “had tantrums”, “felt lonely” and “acted bothered or upset”. There are also questions on the 28-item parent-reported CHQ that ask about the parent’s or family’s well-being like (“How much emotional worry or concern did each of the following cause you: your child’s physical health? your child’s emotional well-being or behavior?”).

The CHQ has been widely used and psychometrically evaluated in a wide range of patient populations. Little is known about the CHQ item development process, except that it was based on a conceptual framework. A number of studies document the satisfactory internal consistency, construct validity, and discriminating ability of the CHQ in its various forms in a number of therapeutic areas and healthy populations [34], [36], [37]. The CHQ has not been used in studies of CPP but is of interest here because it includes a variety of concepts that appear relevant in CPP. Although the FDA prefers that patients self-report when possible, the 87-item child-report version of the CHQ is prohibitively long.

The SF-10 Health Survey for Children is a parent-completed questionnaire intended to assess the health status of children aged 5–18 years [38]. The SF-10 is part of the Quality Metric Pediatric Health Surveys and was adapted from the CHQ. The 10 items of the SF-10 use a 4-week recall period and yield physical and psychosocial health summary scores based on the following physical and psychosocial concepts: physical functioning, role/social-physical, general health perceptions, bodily pain, role/social-emotional/behavioral, self-esteem, mental health and general behavior. There is evidence supporting the reliability, validity, and discriminating ability of the SF-10 in the general US population of children with or without a chronic condition or disability [38], [39] but nothing regarding its responsiveness. The SF-10 is exclusively parent-reported and has not been used in studies of CPP or referenced in a product label.