Edition 66 - 2017, December / Bibliographic Reviews

Bibliographic Reviews – Ed. 66

Marco A. Rivarola y Alicia Belgorosky

Servicio de Endocrinología, Hospital de Pediatria Garrahan, Buenos Aires, Argentina

For this issue of Endocrinologia Pediatrica On line, we have selected the following publications: 

321

J Clin Endocrinol Metab. 2017 Aug 1;102(8):2836-2843. doi: 10.1210/jc.2017-00161.

Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease. Faucz FR1Tirosh A1,2Tatsi C1Berthon A1Hernández-Ramírez LC1Settas N1Angelousi A1Correa R1Papadakis GZ3Chittiboina P4Quezado M5Pankratz N6Lane J6Dimopoulos A7Mills JL7Lodish M1,Stratakis CA. 1 Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. 2 Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. 3 Department of Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20814. 4 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20824. 5 Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892. 6 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota 55455. 7 Epidemiology Branch, Division of Intramural Population Health Research, National Institutes of Health, Rockville, Maryland 20852.

Abstract

CONTEXT: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed. OBJECTIVE: We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas. DESIGN AND METHODS: The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations. RESULTS: Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009). CONCLUSION: Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options.

Extracted Paragraphs.

As in adults, adrenocorticotropic hormone (ACTH)-producing pituitary adenomas are the most common cause of endogenous hypercortisolemia in children, especially after the age of 7 years. Childhood Cushing disease (CD) is characterized by deceleration of the growth velocity with concomitant weight gain, along with other classic clinical features of CD (skin changes such as facial plethora, striae, acne, hirsutism, and easy bruising, disturbed mood, decreased bone mineral density, myopathy, and weakness). The treatment of choice for CD is transsphenoidal surgical resection (TSS) of the pituitary adenoma, with a success rate of 65% to 95%, depending on the treatment center. Patients with recurrence or failure to cure may be treated with repeat surgery, radiation, or medications (ketoconazole, metyrapone, mifepristone, or pasireotide). The molecular background of the corticotroph adenomas has been largely unknown until recently. Mutations in genes that cause syndromes associated with pituitary adenomas, such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (CDKN1B), familial isolated pituitary adenoma (AIP), McCune–Albright syndrome (GNAS1), Carney complex (PRKAR1A), pituitary adenoma with paraganglioma and pheochromocytoma [3PAs-collectively the succinate dehydrogenase complex, subunits A, B, C and D genes (SDHx), and pituitary blastoma (DICER1), do not account for the majority of the corticotropinomas.

A recent study by Reincke et al. reported that somatic mutations of the ubiquitin-specific protease 8 (USP8; Ensembl: ENSG00000138592) gene are found in 40% of corticotroph adenomas. The USP8 gene codes for a protein with deubiquitinase activity that inhibits the lysosomal degradation of the epidermal growth factor receptor (EGFR). The gain-of-function somatic mutations impair binding of the inhibitory 14-3-3 proteins, resulting in increased deubiquitination of EGFR and induction of proopiomelanocortin (POMC) transcription and ACTH secretion. The detection of somatic USP8 gene mutations in corticotroph adenomas has been replicated by other groups, but only one study included pediatric patients. A possibly lower frequency of this genetic defect in the pediatric population (17%) was suggested, but because of the small number of identified pediatric patients, their clinical and biochemical profile was not described separately from the adult population.

Authors screened their cohort of pediatric patients with pathologically confirmed corticotroph adenomas who presented at the National Institutes of Health (NIH) Clinical Research Center between 1997 and 2015, to identify patients with CD who had undergone TSS and for whom germline DNA and tissue from the resected tumor were available for further studies.

In this cohort of 42 patients, there was a predominance of female patients (27 vs 15), with a mean age at diagnosis of 13.7 years and an average duration of symptoms before diagnosis of 2.1 +/- 1.5 years. The mean midnight serum cortisol and 24-hour urinary free cortisol (UFC) levels were 18.9 +/- 13.5 mg/dL and 446 +/- 610 mg/24 hours, respectively. The mean size of the identified pituitary adenomas was 6.2 +/-  6.0 mm, and 4 of the 42 patients (9.5%) presented with evidence of cavernous sinus invasion. Postoperative follow-up was available in 35 patients (73.8%), with mean follow-up of 34.7 +/- 37.9 months and median follow-up of 17 months. Thirty-eight of the patients (90.4%) achieved remission after surgery. Of the 4 patients who did not achieve remission after surgery, 1 underwent sellar radiation therapy, 2 were managed with ketoconazole, and 1 underwent both sellar radiation and ketoconazole treatment. .

Five of the 31 patients with initial remission developed recurrent CD over the course of the study, with a mean time to recurrence 46.4 +/-11.8 months (range 34–66 months). They identified five different somatic mutations in 13 patients, resulting in a frequency of 31% in this cohort. All the mutations were heterozygous, and they were all located in exon 14 of the USP8 gene. They consisted of 3 missence mutations and two deletions of 1 aminoacid. All these mutations are located at the hot spot of the gene, at the 14-3-3 binding motif. Patients harboring somatic USP8 gene mutations had a later mean age at diagnosis of 15.1 +/- 2.1 years, compared with 13.1 +/- 3.6 years for those without USP8 mutations (P = 0.03). They also had lower body mass index (BMI) z scores >2 SD, with fewer patients having a BMI z score.2 SD above the mean (38.5% vs 75.9%; P = 0.02), whereas the height z score was similar in the two groups.

The biochemical profile of the two groups was similar, with no differences in the level of midnight serum cortisol, UFC, or ACTH before treatment. The size of the identified tumors was not significantly different in patients with USP8 mutations compared with the patients without USP8 mutations (diameter 8.0 +/- 7.0 mm vs 5.4 +/- 5.4 mm, respectively; P = 0.2), and the adenoma volumes were comparable in the two groups (200 +/- 234 mm3 vs 191+/- 186 mm3; P = 0.9). There was also no significant difference in the frequency of invasion of the cavernous sinus between the two groups (15.4% vs 6.9%; P = 0.4). All recurrences after initial remission (n = 5) occurred in tumors harboring somatic USP8 mutations. The proportion of patients with recurrence among those with somatic USP8 mutations was 5 in 13 (38.5%), compared with 0 in the remaining group (0 in 29; P = 0.0015). By immunohistochemistry USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors, whereas its expression was more nuclear in the mutated tumors, consistent with findings in previous reports.

They identified 13 patients with somatic mutations demonstrating a high frequency of USP8 gene defects (31%) in their cohort. All identified somatic mutations in this population are located in exon 14, at amino acids 718 to 723, which are highly conserved across species. They result in loss of 14-3-3 protein binding and catalytic cleavage of a 40-kDa fragment of the protein, leading to elevated deubiquitinase activity, “rescue” of EGFR from degradation, and elevated intracellular levels of EGFR. EGFR has been shown in the past to induce POMC expression, with mediation of Erk1/2. Thus the high levels of EGFR, along with a possible independent effect of the mutated USP8 protein, result in increased POMC promoter activation and ACTH production by the corticotroph cells.

The identification of a common molecular etiology explaining the pathogenesis of a large number of ACTH producing pituitary adenomas is of foremost importance, especially because it can provide new treatment targets. In almost one-third (31%) of tumors from patients with pediatric CD, they identified somatic USP8 gene mutations. All defects were present at the hotspot location of exon 14 of the gene; mutations there appear to cause decreased EGFR degradation, which in turn leads to increased POMC expression and ACTH production. Pediatric patients with USP8 mutations had more severe overall disease, with more failures of primary surgical resection and increased rate of recurrences.

322.

Eur J Endocrinol. 2017 Sep;177(3):267-276. doi: 10.1530/EJE-17-0215. Impact of the underlying etiology of growth hormone deficiency on serum IGF-I SDS levels during GH treatment in children. Léger J1,2,3, Mohamed D4,5, Dos Santos S6, Ben Azoun M6, Zénaty D6, Simon D6, Paulsen A6, Martinerie L6,2,3, Chevenne D7, Alberti C2,4,5, Carel JC6,2,3, Guilmin-Crepon S6,4,5. 1. Assistance Publique-Hôpitaux de ParisHôpital Universitaire Robert Debré, Service d’Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du développement, Paris, France, 2. Université Paris Diderot Sorbonne Paris Cité, Paris, France. 3. Institut National de la Santé et de la Recherche Médicale (Inserm) Unité 1141, DHU Protect, Paris, France. 4. Assistance Publique-Hôpitaux de ParisHôpital Universitaire Robert Debré, Unit of Clinical Epidemiology, Paris, France. 5. Inserm. CIC-EC 1426, Paris, France. 6. Assistance Publique-Hôpitaux de ParisHôpital Universitaire Robert Debré, Service d’Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du développement, Paris, France. 7 Assistance Publique-Hôpitaux de ParisHôpital Universitaire Robert Debré, Service de Biochimie-Hormonologie, Paris, France.

Abstract.

CONTEXT: Regular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety. OBJECTIVE: To investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and also, to identify potential determinants of these levels. DESIGN, PATIENTS AND METHODS: This observational cohort study included all patients (n = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data. RESULTS: Over a median of 4.0 (2-5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose (P < 0.01), etiological group (P < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD. Whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect. CONCLUSIONS: These original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions.

Comments

One of the key findings of this study was the first ever demonstration of an interesting association between serum IGF-I SDS during GH treatment and GH etiology, with serum IGF-I SDS significantly higher in patients with acquired GHD than in those with non-acquired GHD. In addition, serum IGF-I SDS during treatment was also found to be positively correlated with BMI SDS, height SDS and GH dose. Consistent with previous findings based on brain MRI imaging for the categorization of GHD severity at the time of diagnosis, before GH treatment, median serum IGF-I SDS at diagnosis was related to disease severity in the various etiological groups of patients with non-acquired GHD. With the exception of patients with craniopharyngioma, values were higher for patients with acquired GHD than for those with non-acquired GHD. The patients with acquired GHD were also taller and had a higher BMI SDS at diagnosis than those with non-acquired GHD. Serum IGF-I SDS increased after treatment initiation in all groups, but, consistent with other reports, was found to be independent of treatment duration, with median values remaining stable from six months after the start of treatment until the final evaluation. They also clearly demonstrated that sex, age, duration of treatment, pubertal stage, hormonal status (IGHF vs MPHD) and initial severity of GHD, as assessed by GH peak in a pharmacological test, had no effect on serum IGF-I SDS during GH treatment. Authors speculated that the higher serum IGF-I SDS values obtained for children with acquired GH deficiency than for those with non-acquired GH deficiency may result partly from insulin resistance.

 

323.

Horm Res Paediatr. 2017 Jun 15. doi: 10.1159/000477240

Prevalence and Physical Distribution of SRY in the Gonads of a Woman with Turner Syndrome: Phenotypic Presentation, Tubal Formation, and Malignancy Risk. Baer TG1, Freeman CE2, Cujar C2, Mansukhani M2, Singh B2, Chen X2, Abellar R2, Oberfield SE1, Levy B2. 1 Division of Pediatric Endocrinology, Diabetes and Metabolism, Columbia University Medical Center, New York, New York, USA. 2 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.

Abstract

Although monosomy X is the most common karyotype in patients with Turner syndrome, the presence of Y chromosome material has been observed in about 10% of patients. Y chromosome material in patients with Turner syndrome poses an increased risk of gonadoblastoma and malignant transformation. We report a woman with a diagnosis of Turner syndrome at 12 years of age, without signs of virilization, and karyotype reported as 46,X,del(X)(q13). At 26 years, cytogenetic studies indicated the patient to be mosaic for monosomy X and a cell line that contained a duplicated Yq chromosome. Bilateral gonadectomy was performed. It revealed streak gonads without evidence of gonadoblastoma. Histological analysis showed ovarian stromal cells with few primordial tubal structures. Fluoresence in situ hybridization (FISH) performed on streak gonadal tissue showed a heterogeneous distribution of SRY, with exclusive localization to the primordial tubal structures. DNA extraction from the gonadal tissue showed a 6.5% prevalence of SRY by microarray analysis, contrasting the 86% prevalence in the peripheral blood sample. This indicates that the overall gonadal sex appears to be determined by the majority gonosome complement in gonadal tissue in cases of sex chromosome mosaicism. This case also raises questions regarding malignancy risk associated with Y prevalence and tubal structures in gonadal tissue.

Comments.

Brief case presentation. The patient is a 26-year-old woman diagnosed clinically with Turner syndrome at age 12. Pelvic ultrasound was performed showing small ovaries and a uterus. She was also found to have aortic insufficiency and a bicuspid valve. She received treatment with growth hormone starting at age 12 until age 16, and underwent induction of puberty with oral estrogen supplementation at age 18. At age 26, physical examination showed a height of 155.4 cm and weight of 120 kg. She had a normal chest shape, with Tanner V breasts and pubic hair. No evidence of clitoral enlargement or posterior labial adhesions was noted. Vaginal mucosa was estrogenized. Her extremities were notable for scooped nails, short broad thumb, and short 4th and 5th toes. At that time, cytogenetic testing was repeated and included karyotype and FISH analysis. Cytogenetic analysis revealed an abnormal mosaic karyotype with approximately 12% of cells showing monosomy X (45,X) and the majority of cells (88%) showing a male genetic constitution with the Y chromosome containing a duplication of the entire euchromatic region of the long arm (46,X,dup(Y)(q.11.21q11.23). The level of mosaicism was estimated from both G-banded and FISH studies which included a total of 250 cells analyzed. Chromosome microarray analysis performed on DNA extracted from peripheral blood showed an 86% prevalence of Y chromosome material with a duplication of the entire euchromatic region of the long arm. On the other hand, chromosome microarray analysis performed on DNA extracted from gonadal tissue paraffin sections showed the same duplicated Y chromosome but at a 6.5% prevalence. The study indicated a very diminished relative presence of Y chromosome material in the gonad, but showed that the long arm remained noticeably increased over the short arm, representing the same structural Y chromosome anomaly, as seen in peripheral blood but at a much lower prevalence. In cases of Turner syndrome where there is evidence of Y chromosome material, streak gonads may also contain tubular structures indicative of potential testes, in addition to gonadoblastoma nests. Microscopic analysis of the streak gonads in the reported subject contained sheets of “ovarian stroma” along with areas showing tubule histology. The distribution of SRY in the gonadal sample correlated exclusively with the areas containing these tubal cells, while the areas with “ovarian stroma” showed the 45,X karyotype. It is also interesting that in this subject, evidence of tubal formation was seen in the streak gonad, despite only a 6.5% prevalence of Y chromosome material. Authors felt that there was no way to predict specific risk of developing gonadoblastoma and malignant transformation, so, they estimated that gonadectomy in this patient was justified, and the most prudent course of management. Whether this pattern of expression confers risk of malignancy is unclear and further investigation in this area is warranted.

324

Horm Res Paediatr. 2017;87(4):244-253. doi: 10.1159/000464142.

Magnetic Resonance Imaging Features as Surrogate Markers of X-Linked Hypophosphatemic Rickets Activity. Lempicki M1Rothenbuhler A2Merzoug V1Franchi-Abella S1,3Chaussain C4,5Adamsbaum C1,6,3Linglart A2,6,7. 1 AP-HP, Bicêtre Paris-Sud Hospital, Department of Pediatric Radiology, Le Kremlin-Bicêtre, France. 2 AP-HP, Bicêtre Paris-Sud Hospital, Department of Pediatric Endocrinology, Diabetology and Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Filière OSCAR and Platform of Expertise Paris-Sud for Rare Diseases, Le Kremlin-Bicêtre, France. 3 LTCI Telecom Paris Tech, Paris Saclay University, Le Kremlin-Bicêtre, France. 4 AP-HP, Bretonneau Hospital, Odontology Department, Paris, France. 5 Paris Descartes University, EA2496, Montrouge, France. 6 Paris-Sud University, Medical School, Le Kremlin-Bicêtre, France. 7 Inserm U1169, Bicêtre Paris-Sud Hospital and Paris-Saclay University, Le Kremlin-Bicêtre, France.

Abstract

OBJECTIVE: X-linked hypophosphatemic rickets (XLH) is the most common form of inheritable rickets. Rickets treatment is monitored by assessing alkaline phosphatase (ALP) levels, clinical features, and radiographs. The objectives of this publication were to describe the magnetic resonance imaging (MRI) features of XLH and to assess correlations with disease activity. STUDY DESIGN: Twenty-seven XLH patients (median age 9.2 years) were included in this prospective single-center observational study. XLH activity was assessed using height, leg bowing, dental abscess history, and serum ALP levels. We looked for correlations between MRI features and markers of disease activity. RESULTS: On MRI, the median maximum width of the physis was 5.6 mm (range 4.8-7.8; normal <1.5), being >1.5 mm in all of the patients. The appearance of the zone of provisional calcification was abnormal on 21 MRI images (78%), Harris lines were present on 24 (89%), and bone marrow signal abnormalities were present on 16 (59%). ALP levels correlated with the maximum physeal widening and with the transverse extent of the widening. CONCLUSIONS: MRI of the knee provides precise rickets patterns that are correlated with ALP, an established biochemical marker of the disease, avoiding X-ray exposure and providing surrogate quantitative markers of disease activity.

Comments. The protein encoded by the PHEX gene (location: Xp22.11) is a transmembrane endopeptidase that belongs to the type II integral membrane zinc-dependent endopeptidase family. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption. Mutations in this gene cause X-linked hypophosphatemic rickets. Alternative splicing results in multiple transcript variants. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption.

Fibroblast growth factor 23 (FGF23), secreted by osteocytes, reduces serum phosphate by inhibiting proximal renal tubular phosphate reabsorption, suppresses the expression of 1-alpha hydroxylase, and stimulates the expression of 24-hydroxylase, thereby limiting the circulating level of 1,25(OH)2D. Elevated concentrations of circulating intact FGF23 favor renal phosphate wasting and hypophosphatemia and prevent the production of 1,25(OH)2D. Chronic hypophosphatemia leads to rickets by a combination of mechanisms, including a lack of endochondral ossification and impaired mineralization. Although in most cases, the XLH phenotype in children is attributable to increased FGF23 activity, the measurement of serum circulating levels of FGF23 has no diagnostic value. Several features of the disease might also be the result of PHEX-deficient proteolytic processing of matrix proteins in mineralized tissues such as bone and teeth. The biological abnormalities seen in untreated children with XLH include low serum phosphate and measurable urinary phosphate (commonly termed phosphate wasting), along with normal or low-normal serum calcium, moderately elevated parathormone, and inappropriately low levels of 1,25(OH)2D. The ALP serum level, a well-established biochemical marker of disease activity, is elevated in untreated patients.

The current standard treatment is a combination of phosphate supplements several times daily and a vitamin D analog (1-alpha hydroxylated vitamin D, calcitriol). There is a need for objective measures of disease activity in order to accurately guide the adjustment of the doses of vitamin D analogs and phosphate supplements. Physicians currently rely on a combination of clinical, radiological, and laboratory parameters, including growth velocity, orthopedic measures of leg bowing, semiquantitative evaluation of rickets on radiographs, and serum ALP levels; however, none of these markers alone – or in combination – has demonstrated accuracy or reproducibility.

MRI is not only an excellent imaging tool but also a non-irradiating imaging technique, which is an important factor in a pediatric population. The primary objective of the study was to provide a detailed description of the MRI features of the distal femur in XLH. The secondary objective was to assess the correlation of MRI patterns with disease activity, based on clinical and laboratory markers, in order to determine whether MRI patterns could serve as a surrogate marker of disease activity.

MRI. Twenty-seven children with XLH underwent MRI of the knee (25 left knees and 2 right knees). The features studied were: (1) The maximum width of the physis. (2) The transverse extent of the widening. (3) The continuity and regularity of the zone of provisional calcification (ZPC). This was considered normal, discontinuous and/or irregular. (4) Any bone signal abnormality studied in a coronal plane and defined as a hyperintense signal on SPAIR and hypointense signal on T1-weighted sequences.

(5) The presence or absence of Harris lines on the T1-weighted coronal plane image. Harris lines are metaphyseal lines which are parallel to the physis, and are hypointense on all sequences. All other structural abnormalities, such as osteochondritis.

Moreover, it is of importance to accurately assess the natural history of the disease and to quantitatively measure the effect of therapies on disease activity. Currently, MRI is the best imaging tool for this, as it is a nonirradiating technique providing exquisite anatomic details.

In addition, it shows that both the degree of physeal widening and its transverse extent may be useful as surrogate markers of recent or semi-recent XLH activity.

On the other hand, technically, MRI is not easily accessible everywhere, and acquisition takes approximately half an hour.  Sedation is therefore often required in young children, and this may prevent its routine use in the follow-up of XLH in early childhood. In addition, the cost of an MRI (approximately EUR 300) is 10 times higher than that of standard radiographs of the knee (approximately EUR 30), which might impede its use in daily practice. MRI allows early detection of mechanical lesions such as osteochondritis (as it did in 2 of the patients), in which the knee deformities likely play a role.

Finally, until larger studies are conducted, MRI scans should be used in XLH, only in the context of clinical research.

325

J Clin Endocrinol Metab. 2017 Aug 1;102(8):3050-3055. doi: 10.1210/jc.2017-00701.

Risk Factors for the Development of Delayed TSH Elevation in Neonatal Intensive Care Unit Newborns.

Zung A1Bier Palmon R2Golan A3Troitzky M4Eventov-Friedman S5Marom R6Keidar R7Kats N8Almashanu S9Flidel-Rimon O10. 1. Pediatric Endocrinology Unit, Kaplan Medical Center, and the Hebrew University of Jerusalem, Rehovot, Israel. 2. Division of Pediatrics, Kaplan Medical Center, Rehovot 76100, Israel. 3. Neonatal Department, Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva 8499000, Israel. 4. Neonatal Intensive Care Unit, The Barzilai Medical Center, affiliated with the Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8499000, Israel. 5. Neonatology Unit, Hadassah Ein Kerem Hospital, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. 6. Neonatology, Tel Aviv Medical Center, Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv 6997801, Israel. 7. Neonatal Intensive Care Unit, Assaf Harofeh Medical Center, Zerifin 70300, Israel. 8. Neonatal Intensive Care Unit, Wolfson Medical Center, Holon 5822012, Israel. 9. National Newborn Screening Program, Department of Community Genetics, Public Health Services, Ministry of Health, Ramat Gan 5265601, Israel. 10. Neonatoloy Unit, Kaplan Medical Center, and the Hebrew University of Jerusalem, Rehovot 76100, Israel.

Abstract

CONTEXT: Delayed thyrotropin (TSH) elevation (dTSH) is defined as elevated TSH at the second neonatal screening (after normal TSH levels at the initial screening) in premature, low-birth-weight, and ill newborns, mostly in the neonatal intensive care unit (NICU) setting. The pathogenesis of dTSH is elusive. OBJECTIVE: To identify the risk factors for dTSH development among newborns in the NICU. DESIGN, SETTING, AND PATIENTS: A retrospective medical record review of neonates with dTSH was conducted in eight university-affiliated NICUs. Two controls were selected for each patient, matched for sex and birth weight. The risk factors for dTSH were identified by univariate analysis, followed by multivariate analysis. MAIN OUTCOME MEASURES: Maternal variables, types of NICU treatments and procedures, syndromes, and various medical conditions were compared between dTSH patients and their matched controls. RESULTS: They enrolled 100 dTSH patients and 200 matched controls, and 46 variables were compared between the two groups. Twelve risk factors for dTSH were identified on univariate analysis: cesarean section, mechanical ventilation, patent ductus arteriosus (PDA), pneumothorax, and administration of cefotaxime, vancomycin, fluconazole, dopamine, ibuprofen, furosemide, insulin, and packed red blood cells. On multivariate analysis, four risk factors were identified: PDA and vancomycin, insulin, and furosemide administration. In 26 twin pairs, in which one twin had dTSH, all variables presented similarly in both twins. CONCLUSIONS: Although some variables had direct effects on pituitary-thyroid axis dysfunction, these variables, altogether, reflect the severity of the clinical conditions in the NICU, which is the common basis for dTSH.

Comments.

A second newborn screening for hypothyroidism is currently recommended for low-birth-weight (weight, 1500 to 2499 g) and very-lowbirth-weight (weight, 1000 to 1499 g) neonates, preterm neonates with a gestational age (GA) of 37 weeks, and ill neonates admitted to the neonatal intensive care unit (NICU). These recommendations are based on the findings that dTSH is rare among normal-birth-weight newborns (>2500 g), increases by an order of magnitude in subgroups of lowbirth-weight and very-low-birth-weight newborns, and is greatest among extremely-low-birth-weight (

The observations from the present study strengthen their previous work in which they reported that dTSH is not associated with GA or birth weight but, rather, is typical of the most severe cases in the NICU. The findings from both studies support a paradigm of performing a second thyroid screening for all NICU patients rather than the selective approach for certain atrisk populations. Although we found certain risk factors were associated with dTSH, further studies are required to elucidate the common pathway by which these different factors contribute to its evolution.

326

Eur J Endocrinol. 2017 Nov;177(5):421-429. doi: 10.1530/EJE-16-1024.

Early growth hormone treatment start in childhood growth hormone deficiency improves near adult height: analysis from NordiNet® International Outcome Study. Polak M1, Blair J2, Kotnik P3, Pournara E4, Pedersen BT5, Rohrer TR6. 1Endocrinologie Gynécologie Diabétologie PédiatriquesHôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris Université Paris Descartes, INSERM U1016, Institut IMAGINE, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Paris, France, 2Department of EndocrinologyAlder Hey Children’s NHS Foundation Trust, Liverpool, UK. 3Department of Pediatric EndocrinologyUniversity Children’s Hospital, University Medical Center Ljubljana, and Medical Faculty, University of Ljubljana, Ljubljana, Slovenia. 4Global Medical AffairsNovo Nordisk Health Care AG, Zürich, Switzerland. 5EpidemiologyNovo Nordisk A/S, Søborg, Denmark. 6Department of Pediatric Endocrinology University Children’s Hospital, Saarland University Medical Center, Homburg, Germany.

Abstract

OBJECTIVE: To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD). DESIGN: NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting. METHODS: Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity 10; boys, >11)) and GHD severity (n = 40 (boys, 70.0%); least squares mean (standard error) -0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); -1.14 (0.15); late, n = 90 (boys, 68.9%); -1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start. CONCLUSIONS: Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.

Comments.

Overall, 16 668 pediatric patients were enrolled in the study up to July 2016. Of these, 9294 patients were diagnosed with GHD, 8166 with isolated GHD and 1128 with multiple pituitary hormone deficiency. As patients were enrolled continuously throughout the study period, only 350 (4.3%) of the 8166 patients diagnosed with isolated GHD achieved NAH within the study period, of whom 172 (2.1%) had a GH stimulation test peak value ≤10 ng/mL. The 172 patients (66.3% male) were included in this analysis.  Median (range) age at treatment start was 10.8 (2.5–16.5) years: 52.3% of patients were included in the late age group (mean (s.d.) age at treatment start, 12.3 (1.4) years), 24.4% in the intermediate (9.7 (0.9) years) and 23.3% in the early (6.4 (1.8) years) age groups. Bone age was slightly retarded compared with chronological age at treatment start in all three age groups. Almost one-quarter (23.8%) of patients had severe GHD; of these, 53.7, 29.2 and 17.1% were in the late, early and intermediate age groups, respectively.

The data from the present study highlight that starting GH treatment early in children with isolated GHD is associated with improved NAH SDS compared with starting GH treatment later. Furthermore, these data being representative of real-life clinical practice may suggest that a proportion of children with isolated GHD start GH treatment late, even though compelling evidence shows that they would benefit most from starting GH treatment at an early age. Correcting the observed referral bias reflecting the predominance of boys will be important to avoid delayed or missed diagnoses in girls. Finally, the results of the study suggest that the severity of GHD is associated with the NAH achieved, but the influence of the GH stimulation test used for measuring GHD severity remains a matter of debate.


Posted in Edition 66 - 2017, December, Bibliographic Reviews
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