Evaluation of catch-up growth in severe pediatric Hashimoto's hypothyroidism.

BACKGROUND: We aimed to evaluate catch-up growth in children with severe Hashimoto's hypothyroidism (HH) after thyroid hormone replacement therapy (HRT). METHODS: A multicenter retrospective study was conducted including children referred for growth slowdown that led to the diagnosis of HH between 1998 and 2017. RESULTS: A total of 29 patients were included, with a median age of 9.7 years (13-172 months). Median height at diagnosis was -2.7 [-4.6; -0.1] standard deviation score (SDS), with a height loss of 2.5 [0.7; 5.4] SDS compared to height before growth deflection (p<0.0001). At diagnosis, the median TSH level was 819.5 mIU/L [100; 1844], the median FT4 level was 0 pmol/L [undetectable; 5.4], and the median anti-thyroperoxidase antibody level was 1601 UI/L [47; 25,500]. In the 20 patients treated only with HRT, there were significant differences between height at diagnosis and height at 1 year (n = 19, p<0.0001), 2 years (n = 13, p = 0.0005), 3 years (n = 9, p = 0.0039), 4 years (n = 10, p = 0.0078), and 5 years (n = 10, p = 0.0018) of treatment but not in the case of final height (n = 6, p = 0.0625). Median final height was -1.4 [-2.7; 1,5] SDS (n = 6), with a significant difference between height loss at diagnosis and total catch-up growth (p = 0.003). The other nine patients were also given growth hormone (GH). They were smaller at diagnosis (p = 0.01); however, there was no difference in final height between those two groups (p = 0.68). CONCLUSION: Severe HH can lead to a major height deficit, and catch-up growth seems to be insufficient after treatment with HRT alone. In the most severe cases, administration of GH may enhance this catch-up.

Long-acting recombinant human growth hormone in the treatment of pediatric growth hormone deficiency, how far have we got?

The widespread availability of recombinant human growth hormone (GH) since 1985 has made it possible to extend growth hormone therapy indications for children with different etiologies of short stature. It is now accepted that GH is effective in increasing height velocity in children with GH deficiency (GHD) and well tolerated in both the short and long terms. Nevertheless, one major factor in the inter-individual variability of the growth response to GH in GHD children is adherence to daily injections. In an attempt to improve patient adherence, there has been a strong effort from industry to create a long-acting form of growth hormone to ease the burden of its use. It is theorized that by decreasing injection frequency, Long-Acting GH (LAGH) would improve adherence and therefore outcomes. These agents can be divided broadly into depot formulations, PEGylated formulations, prodrug formulations, noncovalent albumin-binding GH and GH fusion proteins. In 2021, two LAGH formulations are on the market in China and South Korea, and several promising agents are under clinical investigation at various stages of development throughout the world. A number of safety issues related to LAGH have been identified and need to be further investigated. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

[The role of gonadal peptides in clinical investigation]. / Intérêt clinique du dosage des peptides gonadiques.

Inhibins, activins, and anti-Mullerian hormone (AMH) are gonadal dimeric peptides produced in ovaries and testes by homologous cells, granulosa cells and Sertoli cells, respectively. The production of inhibins is driven by FSH, that of AMH may indirectly depends on FSH, while it is down regulated, at least in the male, by testosterone. In the past decade, measurements of serum inhibin and AMH have provided useful tools for clinical investigation in gonadal disorders: pseudohermaphroditism, androgen insensitivity, anorchidism, gonadal dysgenesis, disorders of pubertal developpement. Inhibins, activins, and AMH are also reliable markers of gonadal tumors. They are extensively used as indexes of fertility: in the male the production of inhibin B reflects the spermatogenetic activity, in women both inhibin B and AMH levels are correlated with the number of preantral and early antral follicles and reflect the ovarian reserve of follicles available for recruitment.

[Prevention of child and adolescent vitamin D deficiency. II. Validation of a decision-making abacus based on sun exposure and vitamin D intakes]. / Prévention de la carence en vitamine D chez l'enfant et l'adolescent. II. Validation d'un abaque décisionnel non invasif prenant en compte l'exposition solaire et les apports exogènes de vitamine D.

OBJECTIVES: Rickets can still be observed among children and adolescents living in Europe, and a significant proportion of healthy children and adolescents presents serum 25-hydroxyvitamin D (25-(OH)D) values below the threshold indicating an insufficient vitamin D status. We have previously proposed detecting at risk individuals with a decision-making abacus based on questionnaires assessing calcium and vitamin D intakes and vitamin D production via sun exposure. METHODS: We tested the validity of this detection by receiver operating characteristic (ROC) analysis, using, as the main outcome measure, the serum 25-(OH)D values measured at the time of questionnaires presentation. In addition, the original questionnaires have been simplified by limiting the items to those significantly associated with 25-(OH)D values. The study group included 116 children and adolescents aged 6 to 17 years, seen at the end of the winter, and randomized in 2 groups: "test", for the development of the tool (n =75), and "validation" (n =41). RESULTS: The present analysis shows that the proposed decision-making abacus has a sufficient ability to detect children at risk of vitamin D deficiency (with 25-(OH)D values below 10 ng/ml): area under the curve 0.748/0.895, sensibility 0.71/0.83, and specificity 0.62/0.80, in the test and validation groups, respectively. CONCLUSION: These questionnaire and abacus may offer a substantial help to detect children and adolescents at risk of vitamin D deficiency in both a private office or hospital environment.

[Neuroendocrine mechanisms of puberty onset]. / Mécanismes neuroendocriniens de la maturation pubertaire.

An increase in pulsatile release of GnRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in GnRH release is still unclear. The GnRH neurosecretory system is already active during the neonatal period but subsequently enters a dormant state by central inhibition in the juvenile period. When this central inhibition is removed or diminished, an increase in GnRH release occurs with increase in synthesis and release of gonadotropins and gonadal steroids, followed by the appearance of secondary sexual characteristics. Recent studies suggest that disinhibition of GnRH neurons from GABA (gamma-aminobutyric acid) appears to be a critical factor in female rhesus monkey. After central inhibition is removed, increases in stimulatory input from glutamatergic neurons as well as new stimulatory input from norepinephrine and NPY neurons and inhibitory input from beta endorphin neurons appear to control pulsatile GnRH release as well as gonadal steroids. Nonetheless, the most important question still remains: what determines the timing to remove central inhibition? Because many genes are turned on or turned off to establish a complex series of events occurring during puberty, the timing of puberty must be regulated by a master gene or genes, as a part of developmental events.

Pseudotumor of the pituitary due to PROP-1 deletion.

Hypopituitarism associated with pituitary mass in childhood is most frequently the consequence of craniopharyngioma or Rathke's cleft cyst. We report a patient with an intrasellar pseudotumor associated with hypopituitarism, which led us to a misdiagnosis of intrasellar craniopharyngioma. After spontaneous involution of the mass, diagnosis was revised. DNA analysis showed a deletion in the Prophet of Pit-1 (PROP-1) gene, a pituitary transcription factor. It is important to recognize that a PROP-1 deletion can cause pituitary pseudotumor that can be mistaken for a craniopharyngioma or Rathke's pouch cyst.

PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.

Alterations of the gene encoding the pituitary transcription factor PROP1 were associated with congenital forms of multiple pituitary hormone deficiencies in several families. Among 23 patients with multiple pituitary hormone deficiencies screened for a PROP1 gene abnormality, nine belonging to eight unrelated families had homozygous PROP1 gene defects. All mutations were located in exon 2 and affected only two different sites: a homozygous AG deletion at codons 99/100/101 (n = 5); homozygous point mutations affecting codon 73: R73C (n = 2) or R73H (n = 1), and a R73C/R99X double-heterozygous mutation (n = 1). R73H and R99X were never described. All patients were born to unaffected parents, and consanguinity was documented in two patients. They had complete GH, LH-FSH, and TSH deficiencies and normal basal levels of PRL. Delayed ACTH deficiency was diagnosed in four of nine patients. At magnetic resonance imaging the anterior pituitary was hypoplastic in seven patients and hyperplastic in two. This study found two novel mutations (R73H and R99X) and underlines the high incidence of PROP1 gene alterations in patients with multiple pituitary hormone deficiencies. A corticotroph deficiency was frequently observed in association with GH, TSH, and gonadotropin deficiencies and should be carefully sought during follow-up.

Lack of effect of GnRH agonists on final height in girls with advanced puberty: a randomized long-term pilot study.

GnRH agonists improve final height in girls with "true" precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 +/- 0.1 yr), a variant of normal called "advanced" puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 +/- 4.3 cm (+0.6 SDS) in group I, 136.1 +/- 4.2 cm (+0.8 SDS) in group II, with target height 157.6 +/- 4.3 cm (group I) and 157.8 +/- 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 +/- 3.9 cm and 155.2 +/- 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 +/- 4.0 cm) and untreated girls (156.1 +/- 5.3 cm) (NS).

Clinical and prognostic aspects of adrenocortical neoplasms in childhood.

BACKGROUND: A retrospective study of 54 children was undertaken to define the clinical presentation and secretory patterns of adrenal tumors and to evaluate the outcome of surgical resection and medical therapy. PROCEDURES: Different factors were studied in univariate and multivariate analysis by using the Cox proportional hazard model. RESULTS: Median age at diagnosis was 4 years. Boys and girls were affected equally. The disease was revealed by virilization (61%) or by a palpable mass (39%) with a 0.1-5.5 year delay from initial symptoms. At initial examination, we found that 76% of children were virilized. Ninety-four percent of the tested tumors secreted androgens, which were associated with glucocorticoids in 36%. Adrenal tumors in children were smaller than in adults. Half of them measured less than 10 cm. There were recurrences in 40% of children. The survival rate at 5 years was 49%, 70% if resection was microscopically complete and 7% if not (P < 0.001). CONCLUSIONS: In children, rare adrenal tumors have different diagnostic and prognostic characteristics than in adults; however, recurrences remain frequent. The efficacy of chemotherapy, mainly o,p'-DDD (Mitotane), remains to be evaluated in comparative trials.

Prognosis of children with malignant pheochromocytoma. Report of 2 cases and review of the literature.

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, (131)I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 +/- 9% (mean +/- SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency.

Prop-1 is a newly isolated pituitary-specific paired-like homeodomain transcription factor whose cDNA sequence is well known in mouse. To study its involvement in human combined pituitary hormone deficiency (CPHD), we have isolated the human cDNA ortholog and determined the exon/intron organization and chromosomal localization of the human gene. A Prop-1 defect was characterized in three CPHD families. One missense mutation (R73C) involves a residue conserved in 95% of the more than 400 homeodomain proteins so far identified; in vitro splicing assays demonstrated the functional importance of the second defect, whereas the remaining mutation is a frameshift. Given the disease phenotype documented in the patients, these data, which will facilitate molecular investigations in other patients, demonstrate the crucial role of Prop-1 in the proper development of somatotrophs, lactotrophs, thyreotrophs and gonadotrophs.

[Adrenocortical carcinoma in children: retrospective study of 54 cases]. / Corticosurrénalomes de l'enfant: analyse rétrospective de 54 cas.

BACKGROUND: Adrenal tumors rarely occur in childhood. Their criteria for malignancy, as well as the effects of chemotherapy remain poorly defined. POPULATION: Fourty-five children (median age: 4 years) with an adrenal tumor diagnosed between 1973 and 1993 were included in this study. RESULTS: Seventy-six percent of the children showed various degrees of virilization. Tumor was palpable in 57%. Most patients (80%) had local disease, 7% loco-regional disease and 13% distant metastases. Forty-five children underwent an apparently complete surgical resection. Recurrence occurred 2 to 17 months after surgery in 18 of them (40%). Twenty-four children received medical treatment (o.p'-DDD or chemotherapy) and one-third had a tumoral response. The overall 5 year survival rate was 49%. CONCLUSIONS: Adrenocortical neoplasms have a poor prognosis in childhood. Complete resection is the only effective and potentially curative treatment. Currently no effective chemotherapy exists, and the value of adjuvant therapy remains unproven. Multicentric studies are underway to evaluate the efficacy of therapeutic approaches.

Prevention of gram-positive infections in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomized controlled trial of vancomycin.

Between January 1986 and June 1988, 155 patients (73 children and 82 adults), who were candidates for bone marrow transplantation, were included in a randomized controlled trial (75 patients in vancomycin group and 80 patients in the group without vancomycin) to evaluate the efficiency of a short course of vancomycin (10 mg/kg i.v. every 6 hours, day-5 to +1) in decreasing the incidence of Gram-positive infections during aplasia after high-dose chemotherapy and bone marrow transplantation. There was no statistical difference in the occurrence of documented septicemia, documented coccus Gram-positive infections, or fever of unknown origins during aplasia in the 2 groups. Thus, short prophylactic treatment with vancomycin proved inefficient in reducing morbidity due to infection after high-dose chemotherapy and bone marrow transplantation.

Pure dysgerminoma of the ovary in childhood: treatment results and sequelae.

Thirty-five children with pure dysgerminoma of the ovary were all treated at the Institut Gustave Roussy (IGR) from 1956-1985. The median follow-up is 8.5 years. The crude 5-year survival rate is 94.1% (+/- 4.1). The disease-free 5-year survival rate is 81.8% (+/- 6.7). Fourteen patients who had stage I disease were treated by unilateral salpingooophorectomy and prophylactic radiotherapy (20 Gy) to ipsilateral iliac, lumbar-aortic, and subclavicular lymph nodes. All are alive without sequelae. Eighteen patients with stage II and III disease were treated by surgery and radiotherapy (30-40 Gy) to the tumor volume. All are alive but radio-induced sequelae are severe. Five relapses of stage I, II, and III tumors occurred and were cured by a second line treatment. Two of the three patients with stage IV disease died. Four patients received a cisplatinum-containing regimen for disseminated disease or because of a relapse before radiotherapy. Three achieved a complete response of measurable tumor. Given the high efficacy of this kind of chemotherapy and the severe sequelae induced by abdomino-pelvic irradiation, we propose initial chemotherapy for widespread disease and radiotherapy in the event of residual tumor.

Tissue-specific alternative splicing of neurofibromatosis 1 (NF1) mRNA.

The neurofibromatosis 1 gene NF1 appears to play a crucial role in regulating the proliferation of cells of neural crest origin. The NF1 gene is a 300 kbp gene, encoding a complex pattern of mRNA related to the presence or absence of two alternative splices. The first splice, in the centre of the coding region of the gene, results in the addition of 63 bp in the GAP-related domain. The second splice located 4203 bp downstream, near the 3' terminus of the coding region of the gene, consists of a 54 bp insert. RT-PCR analysis demonstrates that the most prevalent splice variant in human tissues is the one which contains the GAP-related splice and omits the 3' terminal splice. It is also the form expressed in the peripheral nerve, adrenal medulla, benign NF1 neurofibromas and NF1 neurosarcomas. Conversely, a few organs (brain, muscle) exhibit extensive alternative splicing leading to the co-expression of four distinct transcripts. The reproducibility of the relative levels of each of the splice types in the different organs indicates a tissue-specific splicing pattern of the NF1 gene.

The neurofibromatosis 1 gene transcripts expressed in peripheral nerve and neurofibromas bear the additional exon located in the GAP domain.

A second NF1 messenger differing in the GAP domain was recently described. This type II transcript contains an internal additional sequence consisting of an open reading frame, in phase with the preceding and the following sequences and predicts a 21 amino acid addition in the catalytic domain of NF1 protein. In this report we present analysis of the two forms of NF1 transcripts in several normal human tissues and in primary neurofibromatosis tumors. Our results indicate (i) that the type II NF1 messenger displaying the additional exon is very widely expressed in all the normal adult tissues tested, (ii) that it is the form of NF1 messenger expressed in peripheral nerve and neurofibromas, and (iii) that the additional sequence could encode for a peptide related to a nucleoside triphosphatase.

[Neonatal malignant tumors. Apropos of 75 cases]. / Tumeurs solides malignes néonatales. A propos de 75 cas.

From 1975 to 1986, 75 neonates were treated at the Institute Gustave-Roussy for a malignant solid tumor, comprising 1.7% of the overall oncopediatric population treated during the same period of time. Of these 75 patients, 47 (62%) presented with neuroblastomas, 15 (20%) with mesenchymal tumors, 9 (12%) with germ cell tumors and 4 with various other types of tumors. Treatment consisted of surgery in 63 patients, chemotherapy in 43 and radiotherapy in 18. The 5 year crude survival rate was 77%. Neuroblastomas did the best with a crude survival rate of 89%. The young age of the patients resulted in two types of problems: immediate tolerance and long term sequelae. The therapeutic regimen should take into account the good prognosis of the majority of these tumors in order to decrease delayed effects.