Page 260 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Although the age at onset of puberty and at first menstru- ation remained delayed in TDT patients compared with the general French population (i.e., 10.5 years in girls and 12 in boys, 12 years for menarche),10 the frequency of delayed puberty in this study was lower than previously reported under well-conducted deferoxamine (DFO) treatment,5,7,11 and rarely evolved into hypogonadism.
Height was moderately reduced at the age of 10 years (-0.8 Standard Deviation [SD] in girls, -0.7 SD in boys), then going down to -1.2 SD for both genders reflecting pre-pu- bertal inflection. Most patients then experienced pubertal growth spurt, with a median of 18 cm in girls and 22 cm in boys. Final height, reached in 35/50 patients, was only moderately reduced (-0.7 SD), with a median height of 161 cm in girls (-0.3 SD) and 168.5 cm in boys (-0.8 SD) (Online Supplementary Figure S1). Patients with impaired pubertal development or hypogonadism had a median final height of -0.3 SD (Table 2). Six patients (4 boys, 2 girls) had growth hormone (GH) deficiency, of whom 3 had a history of severe iron overload before puberty. Age at GH treatment onset ranged from 12 to 15 years. There was no difference in final height when GH-treated patients were excluded. Despite pubertal spurts lower than those reported for the general population (25 cm in girls and 28 cm in boys),10 final heights have improved in comparison with those previously reported under DFO in the French registry (-1.2 SD).4 Another study found that final height was -1.9 SD in patients exclusively chelated by DFO, compared with -1.2 SD in patients who had been chelated with DFX for at least six years.5 This difference could be due in part to the well-documented direct deleterious effect of DFO on growth in young children. Regarding other endocrine disorders, one patient devel- oped central hypothyroidism during adolescence and one patient had type 1 diabetes, which was not related to iron overload as it occurred early in childhood (7 years old) with evidence of autoantibodies. No cardiac or hepatic disorders were reported. One patient with severe iron overload and HH died at 17 years from septic shock; this was the only death reported in the cohort.
Deferasirox was first marketed in the European Union in 2007 and since then has been the most widely prescribed iron chelator for TDT patients in Europe and the United States. This oral chelation therapy has been associated with decreased frequency of endocrine complications including hypogonadism in adult patients.12 Scarce published data (few patients studied) document the frequency of puber- tal delay in TDT adolescents receiving DFX. An American study found a rate of pubertal disorders (both simple delay and hypogonadism) in 4 out of 15 adolescents.13 In another study, incidence of simple pubertal delay was evaluated at 15%, i.e., 3 out of the 20 TDT patients who had been pre-pubertal at the start of the study and had received at least three consecutive years of DFX.9
It remains difficult to distinguish between an improved global control of iron overload and a possible specific effect
of DFX on the prevention of pubertal disorders secondary to iron overload. Indeed, the once-daily oral administration of DFX improved adherence with the daily lifelong chelation therapy prescribed.14 Additionally, DFX, with its prolonged half-life and permanent blood exposure could allow better pituitary protection, secondary to continuous chelation of non-transferrin-bound iron.
To our knowledge, our study is the first to provide detailed information on puberty development and to document its improvement in a large cohort of 50 adolescents treated with DFX. This is a retrospective multicenter registry study and data concerning family history of growth and puber- ty or adherence to chelation are missing, and there is no systematic uniform endocrinological follow-up of puberty. Thus, while in girls, objective events such as the occur- rence of the first menstruation and the regularity of cycles provide a simple means to monitor puberty, assessment is more difficult in boys. This less accurate monitoring means that the rate of arrested puberty or early hypogonadism in boys is probably underestimated. Given the impact of pubertal and growth disorders on patients’ quality of life and on future fertility, the systematic integration of an en- docrinologist in the healthcare team of TDT children and adolescents is currently recommended in national and in- ternational guidelines. Additionally, the patients studied are still young and cannot yet be assessed for the occurrence of hypogonadism in adulthood, the frequency of which in- creases with age.4,7,15 It is, therefore, important in the near future to accurately evaluate the effect of long-term DFX chelation therapy on the prevention of hypogonadism in TDT young adults.
Authors
Mathilde Veneziano Broccia,1,2 Julia Vergier,3 Audrey Benoit,4 Yoann Huguenin,5 Anne Lambilliotte,6 Marie Pierre Castex,7 Stephanie Gourdon,8 Ghislaine Ithier,9 Kamila Kebaili,10 Pierre Rohrlich,11 Corinne Pondarre,12 Abdourahim Chamouine,13 Pauline Simon,14 Kokou Placide Agbo Kpati,15 Slimane Allali,16 Sandrine Baron-Joly,17 Sophie Bayart,18 Nicolas Billaud,19 Valentine Brousse,20 Cecile Dumesnil,21 Nathalie Garnier,10 Isabelle Guichard,22 Laure Joseph,23 Annie Kamdem,24 Julie Maitre,25 Catherine Mathey,1 Catherine Paillard,26 Aurelie Phulpin,27 Cecile Renard,10 Cecile Stoven,28 Mohamed Touati,29 Capucine Trochu,30 Suzanne Mathieu Nafissi,31 Catherine Badens,4 Sarah Szepetowski1,2 and Isabelle Thuret1,2
1Service d’Hematologie, Immunologie et Oncologie Pediatrique, Hopital La Timone Enfants, AP-HM, Marseille; 2Centre de Reference MCGRE, Service d’Hematologie, Immunologie et Oncologie Pediatrique, Hopital La Timone Enfants, AP-HM, Marseille; 3Service de Pediatrie Multidisciplinaire, Hopital de la Timone Enfants, AP-HM, Marseille; 4National Thalassemia Registry (NaThalY), Service de Genetique, Hopital La Timone Enfants, AP-HM, Marseille; 5Service d’Oncologie et d’Hematologie Pediatrique, Hopital Pellegrin, CHU de
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