To Örebro University

Introduction: Diagnosing growth hormone (GH) deficiency (GHD) is challenging due to the low specificity of diagnostic tests, particularly in children during the prepubertal and early pubertal stages. Although sex steroid priming increases stimulated GH peak levels, its impact on spontaneous nocturnal GH values has not yet been reported. Priming may reduce discrepancies between spontaneous and stimulated GH testing, potentially improving diagnostic accuracy. We aimed to assess the impact of priming on combined spontaneous and stimulated GH testing and the occurence of divergent test results, as well as to evaluate short-term adverse events associated with priming.

Methods: This was a retrospective chart review of all 132 short children who underwent a nocturnal spontaneous GH secretion test followed by an arginine-insulin stimulation test over 30 years at the Department of Pediatrics, & Ouml;rebro University Hospital, Sweden.

Results: Among the 132 children tested, 25 (19%) received priming prior to GH testing. Compared with nonprimed children, primed children presented higher peak and mean spontaneous GH values (14.2 mu g/L [0.6-22.5] vs. 10.8 mu g/L [0.2-27.0], p = 0.042 and 3.0 mu g/L [0.3-6.9] vs. 2.3 mu g/L [0.1-6.9], p = 0.007, respectively). Divergent results between the two GH tests were less common in primed children (4%) than in nonprimed children (23%, p = 0.027). Mild adverse events occured in three (12%) of the primed children.

Conclusion: Sex steroid priming prior to GH testing is well tolerated, enhances spontaneous nocturnal GH secretion, and reduces the frequency of divergent results between spontaneous and stimulated values. We recommend incorporating priming when evaluating children in prepuberty or early puberty for suspected GHD.

BACKGROUND: Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by FBN2, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.

METHODS AND RESULTS: We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the FBN2 gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The FBN2 deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.

CONCLUSION: Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of FBN2-related phenotypes. The study supports the role of FBN2 variants in growth failure and expands the molecular spectrum of FBN2 variants.

Introduction: Delayed puberty in boys, defined as lack of pubertal onset by the age of 14 years, is often constitutional and self-limited. However, it can lead to feelings of sadness and anxiety. The long-term health consequences of delayed puberty in males are not well understood.

Objective: To study the long-term morbidity in young men exposed to delayed puberty.

Methods: All Swedish men born between 1991 and 1993 who were diagnosed with delayed puberty at the ages of 14.0–17.9 years were identified in nation-wide registries. For each index person, 10 control individuals were randomly selected, matched for sex, year of birth, and county of residence. Swedish nation-wide registries were also used to determine outcomes, including inpatient and outpatient care, prescription of medications, and mortality. The outcomes were tracked annually from the age of 18 until the end of year 2022 (approximately 30 years of age).

Results: 1,245 men with delayed puberty and 12,450 control individuals were identified and included in the study. During the follow-up period, 32% of those with delayed puberty had at least one inpatient care occasion compared to 27% of those without delayed puberty (p < 0.001). Among those with at least one inpa-tient care occasion, men with delayed puberty had more inpatient stays compared to control individuals (median (25–75th percentile) 1 (1–3) vs. 1 (1–2), p = 0.016). A higher proportion of men with delayed puberty had a hospital-based outpatient visit compared to control individuals (90% vs. 86%, p < 0.001). The number of outpatient visits was higher in men with delayed puberty (6 (2–14) vs. 4 (1–10), p < 0.001). In addition, prescriptions of medications were provided more often to men with delayed puberty (16 (6–45) vs. 10 (4–25), p < 0.001). Ten men with delayed puberty and 95 control individuals died during the follow-up (0.80% vs. 0.76%, p = 0.879). Most deaths were due to injuries or intoxications. Among deceased men, those with delayed puberty were older when they died (27.5 years (26–29) vs. 24 years (21–26), p = 0.031).

Conclusion: Delayed puberty in boys is associated with a higher frequency of inpatient stays, outpatient visits, and prescription of medications in young adulthood. This indicates that male delayed puberty is not harmless, and careful follow-up of these patients is needed. Further investigations of the increased need of health care are warranted.

Introduction: The diagnosis of growth hormone (GH) deficiency (GHD) is complicated by the low specificity of GH testing, especially in children before and during early pubertal stages. Sex steroid priming reduces false positive results in pre- and early pubertal children. However, only a small number of studies have assessed its efficacy in improving the diagnostic accuracy of GHD investigations.

Aim: To evaluate the effect of sex steroid priming in GH testing on the prevalence of divergent results of spontaneous nocturnal secretion and arginine-insulin-tolerance test (AITT).

Methods and Materials: This is a retrospective chart review of all 196 children investigated for GHD from January 1, 1993 until February 28, 2023 at the Department of Paediatrics, Örebro University Hospital, Örebro, Sweden. Of them 173 (89%) children had undergone both overnight GH sampling and AITT and 28 of 173 children (16%) had received estrogen priming prior to their tests. A GH peak concentration of ≥ 7.0 μg/L or more was considered normal for both tests.

Results: Children receiving priming (36% girls) had a median age of 12.1 years (6.2–15.0) vs. 8.4 years (1.5 – 15.9) in children not primed (43% girls). Of the 173 children that had undergone both tests, 31 (18%) tested positive (<7.0 μg/L) on both tests, 22 (13%) tested positive on overnight sampling only, and 13 (8%) tested positive on AITT only. Of the 28 children who had received priming ,only one child had divergent results, with a positive result solely from AITT. Amongst non-primed children, 34 of 145 had divergent results with 21 (14.6%) testing positive on AITT, and 13 (9%) exhibiting a positive result on the spontaneous GH test. The frequency of divergent tests was significantly lower (p = 0.016) amongst primed children (3.6%) compared to non-primed children (23.6%).

Conclusion: Our results show that sex steroid priming prio rto GHD testing with overnight sampling and AITT decreases the frequency of divergent results between the two tests and thus suggest that sex steroid priming decreases the risk of false positive results.