Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment.

Introduction: Impaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty. Methods: Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded. Results: Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30). Conclusions: a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.

Thyroid Disorders Following Hematopoietic Stem Cell Transplantation in Childhood: Impact of Conditioning Regimen on Thyroid Dysfunction, Volume Changes, and Occurrence of Nodules.

Thyroid late effects are among the most frequent sequelae reported after pediatric hematopoietic stem cell transplantation (HSCT). Although the detrimental effects of radiotherapy on the developing thyroid gland have been extensively assessed, the role of chemotherapy-only conditioning regimens remains controversial. We aimed to describe the occurrence, monitoring, and management of thyroid function disorders (ie, Graves disease, Hashimoto thyroiditis, and nonautoimmune hypothyroidism), nodules, and volumetric changes over a 20-year observation period in a single pediatric transplantation unit. In addition, we assessed the impact of different conditioning regimens on thyroid health. The study population for this retrospective observational analysis comprised 244 pediatric patients who underwent HSCT for malignant or nonmalignant diseases between 1999 and 2018 and for whom at least 4 thyroid function tests and 1 or more thyroid ultrasound(s) assessed sequentially after HSCT were available. The 15-year cumulative incidence of either autoimmune or nonautoimmune thyroid dysfunctions (34%, SE 5.3%) did not differ statistically between total body irradiation (TBI)-based and chemotherapy-based regimens (P = .23). Indeed, the cumulative incidence after busulfan (Bu)-based conditioning was overall superimposable to that recorded after TBI (10-year cumulative incidence, 22.2% versus 25.9%, respectively). Nevertheless, the cumulative incidence of nonautoimmune hypothyroidism was statistically higher after Bu-based conditioning (12.4%, SE 3.7%) than after other chemotherapy-only-based conditioning regimens (3.1%, SE 3.1%; P = .02, 5-year cumulative incidence), treosulfan (Treo) included. The overall cumulative incidence of nodules was low for the first 5 years after HSCT (1.9%, SE .9%) but subsequently increased steeply over time, with a 15-year cumulative incidence as high as 52.1% (SE 7.5%). TBI-conditioned patients had a higher 15-year cumulative incidence of nodules (66.8%, SE 9.1%) compared with patients receiving chemotherapy-only regimens (33.6%, SE 9.5%; P = .02), whereas age >10 years at transplantation showed a protective effect (hazard ratio, .42, 95% confidence interval, .2 to .88). Finally, a systematic sonographic follow-up highlighted a progressive statistically significant reduction in thyroid anteroposterior diameter among patients conditioned with TBI (P = .005), but not in those who received chemotherapy-only regimens. TBI and younger age at HSCT have a statistically significant detrimental effect on the occurrence of thyroid nodules, both benign and malignant. TBI and Bu expose patients to a higher cumulative incidence of thyroid dysfunction compared with other chemotherapy-only regimens, Treo included. Accordingly, Bu can be considered the most thyrotoxic agent among those administered as a part of a chemotherapy-only conditioning regimen. Finally, patients conditioned with TBI, but not those with other regimens, show a progressive decrease in thyroid volume over time, as assessed by sequential ultrasound examinations.

Increased Frequency of Diabetic Ketoacidosis: The Link With COVID-19 Pandemic.

Aims: Diabetic ketoacidosis is the most severe metabolic derangement due to prolonged insulin deficiency as in type 1 diabetes. Diabetic ketoacidosis, a life-threatening condition, is often diagnosed late. A timely diagnosis is mandatory to prevent its consequences, mainly neurological. The COVID-19 pandemic and lockdown have reduced the availability of medical care and access to hospitals. The aim of our retrospective study was to compare the frequency of ketoacidosis at the diagnosis of type 1 diabetes between the lockdown-post lockdown period and the previous two calendar years, in order to evaluate the impact of the COVID-19 pandemic. Patients and Methods: We retrospectively assessed the clinical and metabolic data at the diagnosis of type 1 diabetes in children in the Liguria Region during 3 different time periods: calendar year 2018 (Period A), calendar year 2019 until February 23,2020 (Period B) and from February 24, 2020 onwards to March 31, 2021 (Period C). Results: We analyzed 99 patients with newly-diagnosed T1DM from 01/01/2018 to 31/03/2021. Briefly, a younger age at diagnosis of T1DM was observed in Period 2 compared to Period 1 (p = 0.03). The frequency of DKA at clinical onset of T1DM was similar in Period A (32.3%) and Period B (37.5%), while it significantly increased in Period C (61.1%) compared to Period B (37.5%) (p = 0.03). PH values were similar in Period A (7.29 ± 0.14) and Period B (7.27 ± 0.17), while they were significantly lower in Period C (7.21 ± 0.17) compared to Period B (p = 0.04). Conclusions: An increase in the frequency of diabetic ketoacidosis has been documented in newly diagnosed pediatric patients in the Liguria Region during and after the lockdown period compared to previous calendar years. This increase could have been caused by the delay in diagnosis following the restrictions imposed by the lockdown with consequently reduced access to health care facilities. More information on the risks of ketoacidosis is desirable by means of social and medical awareness campaigns.

Practical Approach to Using Trend Arrows on Real-Time Continuous Glucose Monitoring System in Type 1 Diabetes Adolescents Living Camp Setting Treated With Multiple Daily Injection or Continuous Subcutaneous Insulin Infusion Insulin Therapy.

BACKGROUND: The aim of the study was to determine the effect of an educational intervention on the use of trend arrows of a real-time continuous glucose monitoring (rt-CGM) to manage daily therapy decisions in a group of adolescents with type 1 diabetes attending a camp. The secondary aim was to evaluate the variations in total daily dose (TDD) of insulin requirement. METHODS: Twenty patients (15-17 years) on multiple insulin injections (n = 8) or continuous subcutaneous insulin infusion (n = 12) attended a training session at the beginning of the camp to learn our algorithm for the management of therapy depending on trend arrows. TDD, time in range (TIR), time above range (TAR), and time below range (TBR) (in the 24 hours and in the three hours after breakfast) before the training session (run-in) and at the end of the camp (T1) were analyzed. RESULTS: Data showed a reduction of TAR (run-in 42.6%, T1 32.05%, P = .036) and an increase in TIR (run-in 52.9%, T1 62.4%, P = .013). Reduction of TBR (run-in 42.5%, T1 37.5%, P = .05) and improvement in TIR (run-in 49.0%, T1 57.0%, P = .02) were also observed in the post-breakfast period. Data showed a significant reduction in the TDD (run-in 52.02 ± 17.44 U/die, T1 46.49 ± 12.39 U/die, P = .024). CONCLUSIONS: Statistically significant improvement of glycemic control and reduction of TTD were observed in all patients regardless of therapy type. The improvement between run-in and T1 demonstrates the importance of patients' education on the correct use of rt-CGM with simple algorithms for the management of therapy.

Maxillofacial features and systemic malformations in expanded spectrum Hemifacial Microsomia.

Hemifacial microsomia (HFM) is a rare, multisystemic congenital disease with estimated frequency of 1/26370 births in Europe. Most cases are sporadic and caused by unilateral abnormal morphogenesis of the first and second pharyngeal arches. The aim of this study is to define the types and frequency of maxillofacial and systemic malformations in HFM patients. This is a case series study of patients with HFM evaluated at a single institution. Data were acquired through history, physical examination, photographs, diagnostic radiology, and laboratory and analyzed by the FileMakerPro database on 95 patients (54F; 41M) of which 89 met the inclusion criteria. Mandibular hypoplasia was observed in 86 patients with right-side preponderance (50). One patient had bilateral mandibular hypoplasia. Seventy-four had external ear anomalies (anotia or microtia). Eleven had bilateral malformed ears. Hearing impairment, associated with stenosis or atresia of the external ear canal, was found in 69 patients (eight with bilateral canal defects). Ocular anomalies were seen in 41 (23 with dermoid cysts) and 39 had orbital malformations. Facial nerve paralysis was observed in 38 patients. Cleft lip/palate (10), preauricular tags (55), and macrostomia (41) were also described. A total of 73/86 had systemic malformations, mainly vertebral (40), genitourinary (25), and cardiovascular (28). Sixteen had cerebral anomalies (four with intellectual disability). All patients suspected of HFM should undergo a complete systematic clinical and imaging investigation to define the full scope of anomalies. Since the disease is rare and complex, affected patients should be monitored by specialized multidisciplinary team centers.

Distinctive characteristics of diabetes mellitus after hematopoietic cell transplantation during childhood.

We report on six patients who developed diabetes mellitus after hematopoietic cell transplantation (HCT). The prevalence in our cohort of long-term survivors after HCT performed below 18 yr of age was 3%. The median age at onset of diabetes was 22.4 yr (range 11.3-34.4). The median period between HCT and diabetes was 10.1 yr (range 5.6-22.1). Five out of the six patients received total irradiation therapy and five had other endocrinological abnormalities. The onset of diabetes in all patients was insidious and none had diabetic ketoacidosis. Body mass indexes at diabetes onset were within normal levels. The clinical and laboratory features that characterized our patients with diabetes after HCT make it difficult to classify them as having type-1 or type-2 diabetes. The relatively high prevalence of diabetes and its insidious onset in this group of patients, advocate clinicians to evaluate carefully even slight variations in fasting blood glucose, usually included in the routine biochemistry follow-up. These data also suggest that HbA1c and oral glucose-tolerance test should be added to the follow-up program of late complications if fasting blood glucose levels are slightly increased.

Subclinical hypothyroidism in early childhood: a frequent outcome of transient neonatal hyperthyrotropinemia.

Newborns with high TSH at birth and with normal free T(4) and normal or slightly elevated TSH at the confirmatory examination are considered false positive for congenital hypothyroidism. We evaluated thyroid function, thyroid antibodies, thyroid volume and morphology, thyroperoxidase and TSH receptor genes, and auxological data in 56 false positive children at 16-44 months of age. In these children thyroid function at confirmatory examination was fully normal in 33 (TSH, 0.8-4.9 mU/liter; group I) and nearly normal (borderline elevated TSH, 5.0-11.7 mU/liter) in the other 23 (group II). Compared with 65 control children with normal TSH at birth, false positive children had significantly higher basal serum TSH (mean +/- SD, 4.38 +/- 2.2 vs. 1.4 +/- 0.8 mU/liter; P < 0.01). Subclinical hypothyroidism, indicated by increased basal TSH and/or increased TSH response to TRH, was present in 36% children in group I and 70% in group II. Free T(4) was within the normal range in all children. Compared with the control group, false positive children had significantly higher free T(3) values (4.9 +/- 0.8 vs. 3.7 +/- 1.0 pmol/liter; P < 0.01) and a higher prevalence of antithyroid antibodies (25% vs. 1.5%; P < 0.001). Frequent thyroid morphology abnormalities and frequent thyroperoxidase and TSH receptor gene sequence variations were also observed. In conclusion, newborns classified false positive at congenital hypothyroidism screening have a very high risk of subclinical hypothyroidism in infancy and early childhood.

Meier-Gorlin syndrome (ear-patella-short stature syndrome) in an Italian patient: clinical evaluation and analysis of possible candidate genes.

We report on an Italian boy with the Meier-Gorlin syndrome (ear-patella-short stature syndrome). This rare autosomal recessive disorder comprises the triad of microtia, absent patellae, and growth retardation with prenatal onset. The patient had also an acute torsion of his left spermatic cord, a condition related to a congenital defect of the tunica vaginalis. Because this syndrome had been suggested as the human equivalent of the short ear mouse [Lacombe et al., 1994: Ann. Genet. 37:184-191], a mutation analysis of the BMP5 gene was performed and found normal. The LMX1B and the SHOX genes were also evaluated considering the absent patellae and short stature, respectively, and were found normal as well.