Screening Newborns for Low T Cell Receptor Excision Circles (TRECs) Fails to Detect Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome.

BACKGROUND: Assessment of T-cell receptor excision circles (TRECs) in dried blood spots of newborns allows the detection of severe combined immunodeficiency (SCID) (T cells <300/µL at birth) with a presumed sensitivity of 100%. TREC screening also identifies patients with selected combined immunodeficiency (CID) (T cells >300/µL, yet <1500/µL at birth). Nevertheless, relevant CIDs that would benefit from early recognition and curative treatment pass undetected. OBJECTIVE: We hypothesized that TREC screening at birth cannot identify CIDs that develop with age. METHODS: We analyzed the number of TRECs in dried blood spots in archived Guthrie cards of 22 children who had been born in the Berlin-Brandenburg area between January 2006 and November 2018 and who had undergone hematopoietic stem-cell transplantation (HSCT) for inborn errors of immunity. RESULTS: All patients with SCID would have been identified by TREC screening, but only 4 of 6 with CID. One of these patients had immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 (ICF2). Two of 3 patients with ICF whom we have been following up at our institution had TREC numbers above the cutoff value suggestive of SCID at birth. Yet all patients with ICF had a severe clinical course that would have justified earlier HSCT. CONCLUSIONS: In ICF, naïve T cells may be present at birth, yet they decline with age. Therefore, TREC screening cannot identify these patients. Early recognition is nevertheless crucial, as patients with ICF benefit from HSCT early in life.

Case Report: Rubella Virus-Induced Cutaneous Granulomas in Two Pediatric Patients With DNA Double Strand Breakage Repair Disorders - Outcome After Hematopoietic Stem Cell Transplantation.

We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced naïve T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas.

68Ga-NODAGA-Exendin-4 PET/CT Improves the Detection of Focal Congenital Hyperinsulinism.

Surgery with curative intent can be offered to congenital hyperinsulinism (CHI) patients, provided that the lesion is focal. Radiolabeled exendin-4 specifically binds the glucagonlike peptide 1 receptor on pancreatic ß-cells. In this study, we compared the performance of 18F-DOPA PET/CT, the current standard imaging method for CHI, and PET/CT with the new tracer 68Ga-NODAGA-exendin-4 in the preoperative detection of focal CHI. Methods: Nineteen CHI patients underwent both 18F-DOPA PET/CT and 68Ga-NODAGA-exendin-4 PET/CT before surgery. The images were evaluated in 3 settings: a standard clinical reading, a masked expert reading, and a joint reading. The target (lesion)-to-nontarget (normal pancreas) ratio was determined using SUVmax Image quality was rated by pediatric surgeons in a questionnaire. Results: Fourteen of 19 patients having focal lesions underwent surgery. On the basis of clinical readings, the sensitivity of 68Ga-NODAGA-exendin-4 PET/CT (100%; 95% CI, 77%-100%) was higher than that of 18F-DOPA PET/CT (71%; 95% CI, 42%-92%). Interobserver agreement between readings was higher for 68Ga-NODAGA-exendin-4 than for 18F-DOPA PET/CT (Fleiss κ = 0.91 vs. 0.56). 68Ga-NODAGA-exendin-4 PET/CT provided significantly (P = 0.021) higher target-to-nontarget ratios (2.02 ± 0.65) than did 18F-DOPA PET/CT (1.40 ± 0.40). On a 5-point scale, pediatric surgeons rated 68Ga-NODAGA-exendin-4 PET/CT as superior to 18F-DOPA PET/CT. Conclusion: For the detection of focal CHI, 68Ga-NODAGA-exendin-4 PET/CT has higher clinical sensitivity and better interobserver correlation than 18F-DOPA PET/CT. Better contrast and image quality make 68Ga-NODAGA-exendin-4 PET/CT superior to 18F-DOPA PET/CT in surgeons' intraoperative quest for lesion localization.

Severe Acquired Primary Hypothyroidism in Children and its Influence on Growth: A Retrospective Analysis of 43 Cases.

INTRODUCTION: Severe acquired hypothyroidism in childhood is a rare condition, mostly caused by autoimmune thyroiditis. Scarce and inconsistent data based on small patient numbers exist concerning its impact on growth in height. METHODS: Patient files at a single centre university hospital over 8 years were retrospectively reviewed. We identified 43 patients (mean age 10.6 years, 3.3-15.25, 59% prepubertal, 88% females) in a cohort of children older than 3 years with an initial TSH>30 mIU/l and reduced T4 or fT4; congenital and drug-induced hypothyroidism were excluded. RESULTS: All patients had signs of autoimmune thyroiditis (93% positive autoantibodies, 95% typical ultrasonography, 63% goiter). Median TSH was 100 mIU/l [0.3-4 mIU/l]), median fT4 3.55 pg/ml [8-19 pg/ml], median T4 2.85 µg/dl [5.3-11 µg/dl]. Presenting symptoms included goiter (26%), tiredness (23%), weight gain (19%), and growth retardation (19%). The diagnosis was made incidentally in 26% patients. In 75% growth was retarded (median height standard deviation score (SDS)-0.55), in 17% height SDS was<-2 at diagnosis. Midparental height SDS at diagnosis correlated significantly with T4 and fT4 (r=0.77, p=0.0012 and r=0.53, p=0.021 respectively). Catch-up growth under T4 substitution was significantly greater in prepubertal than in pubertal children (p 0.049). CONCLUSION: This so far largest pediatric cohort with severe acquired hypothyroidism confirms a serious impact on growth which, however in most cases, showed a certain catch-up growth after adequate L-thyroxine therapy. The pubertal state seems to be important for catch-up growth. A significant number of patients were not diagnosed clinically, although affected by severe hypothyroidism.

Open-Source Technology for Real-Time Continuous Glucose Monitoring in the Neonatal Intensive Care Unit: Case Study in a Neonate With Transient Congenital Hyperinsulinism.

BACKGROUND: Use of real-time continuous glucose monitoring (rtCGM) systems has been shown to be a low-pain, safe, and effective method of preventing hypoglycemia and hyperglycemia in people with diabetes of various age groups. Evidence on rtCGM use in infants and in patients with conditions other than diabetes remains limited. OBJECTIVE: This case study describes the off-label use of rtCGM and the use of an open-source app for glucose monitoring in a newborn with prolonged hypoglycemia secondary to transient congenital hyperinsulinism during the perinatal period. METHODS: The Dexcom G6 rtCGM system (Dexcom, Inc) was introduced at 39 hours of age. Capillary blood glucose checks were performed regularly. In order to benefit from customizable alert settings and detect hypoglycemic episodes, the open-source rtCGM app xDrip+ was introduced at 9 days of age. RESULTS: Time in range (45-180 mg/dL) for interstitial glucose remained consistently above 90%, whereas time in hypoglycemia (<45 mg/dL) decreased. Mean glucose was maintained above 70 mg/dL at 72 hours of life and thereafter. Daily sensor glucose profiles showed cyclic fluctuations that were less pronounced over time. CONCLUSIONS: While off-label use of medication is both common practice and a necessity in newborn infants, there are few examples of off-label uses of medical devices, rtCGM being a notable exception. Real-time information allowed us to better understand glycemic patterns and to improve the quality of glycemic control accordingly. Severe hypoglycemia was prevented, and measurement of serum levels of insulin and further lab diagnostics were performed much faster, while the patient's individual burden caused by invasive procedures was reduced. Greater customizability of threshold and alert settings would be beneficial for user groups with glycemic instability other than people with diabetes, and for hospitalized newborn infants in particular. Further research in the field of personal and off-label rtCGM use, efficacy studies evaluating the accuracy of low glucose readings, and studies on the differences between algorithms in translating raw sensor data, as well as customization of commercially available rtCGM systems, is needed.

Newborn Screening for SCID and Other Severe Primary Immunodeficiency in the Polish-German Transborder Area: Experience From the First 14 Months of Collaboration.

In 2017, in the Polish-German transborder area of West Pomerania, Mecklenburg-Western Pomerania, and Brandenburg, in collaboration with two centers in Warsaw, a partnership in the field of newborn screening (NBS) for severe primary immunodeficiency diseases (PID), mainly severe combined immunodeficiency (SCID), was initiated. SCID, but also some other severe PID, is a group of disorders characterized by the absence of T and/or B and NK cells. Affected infants are susceptible to life-threatening infections, but early detection gives a chance for effective treatment. The prevalence of SCID in the Polish and German populations is unknown but can be comparable to other countries (1:50,000-100,000). SCID NBS tests are based on real-time polymerase chain reaction (qPCR) and the measurement of a number of T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and beta-actin (ACTB) as a quality marker of DNA. This method can also be effective in NBS for other severe PID with T- and/or B-cell lymphopenia, including combined immunodeficiency (CID) or agammaglobulinemia. During the 14 months of collaboration, 44,287 newborns were screened according to the ImmunoIVD protocol. Within 65 positive samples, seven were classified to immediate recall and 58 requested a second sample. Examination of the 58 second samples resulted in recalling one newborn. Confirmatory tests included immunophenotyping of lymphocyte subsets with extension to TCR repertoire, lymphoproliferation tests, radiosensitivity tests, maternal engraftment assays, and molecular tests. Final diagnosis included: one case of T-BlowNK+ SCID, one case of atypical Tlow BlowNK+ CID, one case of autosomal recessive agammaglobulinemia, and one case of Nijmegen breakage syndrome. Among four other positive results, three infants presented with T- and/or B-cell lymphopenia due to either the mother's immunosuppression, prematurity, or unknown reasons, which resolved or almost normalized in the first months of life. One newborn was classified as truly false positive. The overall positive predictive value (PPV) for the diagnosis of severe PID was 50.0%. This is the first population screening study that allowed identification of newborns with T and/or B immunodeficiency in Central and Eastern Europe.

Comparative meta-analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia.

BACKGROUND AND OBJECTIVE: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta-analysis. METHODS: Data of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics. RESULTS: Seven new patients were identified with seven different pathogenic variants in KDM6A (n = 4) or KMT2D (n = 3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta-analysis, 24 KS patients with HH had a significantly higher frequency of variants in KDM6A compared to 373 KS patients without HH (50% vs 11.5%, P < .001), and KDM6A-KS was more likely to be associated with HH than KMT2D-KS (21.8% vs. 3.5%, P < .001). Sex distribution and other phenotypic features did not differ between KS with and without HH. CONCLUSION: The higher incidence of HH in KDM6A-KS compared to KMT2D-KS indicates that KDM6A loss of function variants predispose more specifically to beta cell dysfunction compared to KMT2D variants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.

[Therapy Options for Infants with Congenital Cytomegalovirus Infection - Implications for Setting Up Neonatal Screening Programs]. / Therapeutische Optionen bei konnataler Zytomegalievirus (CMV)-Infektion ­ Implikationen für die Einführung eines Screeningprogramms.

INTRODUCTION: The number of diseases covered by universal neonatal screening in Germany has risen steadily from 1 (phenylketonuria) in 1968 to 17 (with hearing impairment and congenital hip dysplasia) in 2018. Treatment, however, of disorders diagnosed by screening may harm children, as failed neuroblastoma screening has shown. There are several pilot studies to detect congenital cytomegalovirus (CMV) infection but no consensus as to the treatment of the infants identified. METHODOLOGY: Systematic search for studies investigating therapy of congenital CMV infection, using PubMed and the WHO International Clinical Trials Registry Platform (ICTRP). RESULTS: We found only one controlled trial that randomized infants with symptomatic congenital CMV infection (involving the central nervous system) to treatment (intravenous ganciclovir for 6 weeks) or no treatment. Treatment was associated with significantly less hearing deterioration. A second trial comparing 6 weeks vs. 6 months of treatment with valganciclovir, an oral prodrug of ganciclovir, found no benefit for hearing but modestly improved developmental outcomes associated with 6 months of treatment. In contrast, an open-label registry reported benefits for infants with congenital CMV infection and isolated hearing who received valganciclovir for 12 months, with hearing improvement in 2/3 of cases after a median follow-up of 4½ years. CONCLUSIONS: Antiviral treatment of neonates with congenital CMV infection and few symptoms including isolated hearing loss remains controversial. A generally accepted therapy, however, is pivotal before introducing universal or targeted screening for congenital CMV infection.

Newborn screening by tandem mass spectrometry confirms the high prevalence of sickle cell disease among German newborns.

Sickle cell disease (SCD) is a severe inherited blood disorder associated with significant morbidity and mortality in early childhood. Since simple interventions are available to prevent early fatal courses, SCD is a target condition of several national newborn screening (NBS) programs worldwide, but not in Germany. Traditionally, the diagnosis of SCD is made by high-performance liquid chromatography (HPLC), isoelectric focusing (IEF), or capillary electrophoresis (CE), but globally, most NBS programs in place are based on tandem mass spectrometry (MS/MS). Recently, several publications have shown that MS/MS is an appropriate screening technique to detect hemoglobin patterns suggestive of SCD in newborns, too. We have studied dried blood spot samples of 29,079 German newborns by both CE and MS/MS and observed a 100% congruence of test results. Seven babies had hemoglobin patterns characteristic of SCD (1:4154). Our study confirms that (a) the suitability of MS/MS as an adequate substitute for CE in NBS for SCD and (b) the high prevalence of SCD among German newborns. Our results support the thesis that German newborns should be screened for SCD by MS/MS.

Characterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy that leads to unfavourable neurological outcome if not treated adequately. In patients with severe diffuse CHI it remains under discussion whether pancreatic surgery should be performed or intensive medical treatment with the acceptance of recurrent episodes of mild hypoglycaemia is justified. Near-total pancreatectomy is associated with high rates of insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency. Little is known about the management and long-term glycaemic control of CHI patients with diabetes after pancreatic surgery. We searched the German/Austrian DPV database and compared the course of 42 CHI patients with diabetes to that of patients with type 1 diabetes mellitus (T1DM). Study groups were compared at diabetes onset and after a follow-up period of 6.1 [3.3-9.7] (median [interquartile range]) years. RESULTS: The majority of CHI patients with diabetes were treated with insulin (85.2% [70.9-99.5] at diabetes onset, and 90.5% [81.2-99.7] at follow-up). However, compared to patients with T1DM, significantly more patients in the CHI group with diabetes were treated with conventional insulin therapy (47.8% vs. 24.4%, p = 0.03 at diabetes onset, and 21.1% vs. 6.4% at follow-up, p = 0.003), and only a small number of CHI patients were treated with insulin pumps. Daily insulin dose was significantly lower in CHI patients with diabetes than in patients with T1DM, both at diabetes onset (0.3 [0.2-0.5] vs. 0.6 IE/kg/d [0.4-0.8], p = 0.003) and follow-up (0.8 [0.4-1.0] vs. 0.9 [0.7-1.0] IE/kg/d, p = 0.02), while daily carbohydrate intake was comparable in both groups. Within the first treatment year, HbA1c levels were significantly lower in CHI patients with diabetes (6.2% [5.5-7.9] vs. 7.2% [6.5-8.2], p = 0.003), but increased to a level comparable to that of T1DM patients at follow-up. Interestingly, in CHI patients, the risk of severe hypoglycaemia tends to be higher only at diabetes onset (14.8% vs. 5.8%, p = 0.1). CONCLUSIONS: In surgically treated CHI patients insulin treatment needs to be intensified in order to achieve good glycaemic control. Our data furthermore emphasize the need for improved medical treatment options for patients with diazoxide- and/or octreotide-unresponsive CHI.

MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome.

CONTEXT: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). OBJECTIVE: To determine the role of LHCGR in transient, pregnancy-induced CS. DESIGN SETTING PATIENT AND INTERVENTION: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. MAIN OUTCOME MEASURES AND RESULTS: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone-positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R. Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient's adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11-deoxycortisol, cortisol, and androstenedione production. CTNNB1, PRKAR1A, ARMC5, and PRKACA gene mutational analyses were negative. CONCLUSION: Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus.

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.

Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

Role of (68)Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: an explorative study.

PURPOSE: To explore the role of (68)Ga-DOTATATE/DOTATOC PET/CT (SR PET/CT) in patients with suspicion of or histopathologically proven pancreatogenic hyperinsulinaemic hypoglycaemia. METHODS: We included 13 patients with histopathologically proven or a high clinical suspicion of pancreatogenic hyperinsulinaemia. All the patients underwent a SR PET/CT scan. The results were correlated with histopathological findings. Normalization of blood glucose levels after resection of the pancreatic lesion, as well as a cytological and/or pathological diagnosis of insulinoma, was considered the diagnostic gold standard for insulinoma. The diagnosis of nesidioblastosis was based on exclusion of an insulinoma and conclusive pathological examination of a segment of the pancreas. Malignant insulinoma was defined as the presence of locoregional or distant metastases. RESULTS: Based on histopathology, 13 patients were found to have pancreatic hyperinsulinaemia: two patients had malignant insulinoma, eight had nonmetastasized insulinoma, and three had nesidioblastosis. SR PET was positive in 11 of the 13 patients (84.6 %) with a final diagnosis of endogenous pancreatic hypoglycaemia. Histopathological staining confirmed 16 foci of hyperinsulinism (insulin positivity). SR PET detected 14 of the 16 lesions, resulting in a sensitivity of 87 %. One intrapancreatic spleen was falsely diagnosed as insulinoma focus on SR PET, resulting in positive predictive value of 93.3 %. Immunohistochemical staining of somatostatin receptor (SSR) subtype 2a was available in ten specimens: two nesidioblastosis, and seven benign and one malignant insulinoma. Eight out of the ten specimens (80 %) stained strongly to moderately positive. Seven of the eight SSR2a-positive lesions were picked up on SR PET. Based on the results of SR PET/CT, nine patients achieved complete remission of the hypoglycaemic events during follow-up. CONCLUSION: This explorative study suggests that SR PET in combination with CT may play a significant role in the detection and management of patients with pancreatogenic hyperinsulinaemic hypoglycaemia. A large proportion of insulinomas express SSR2a, and a larger study is needed to fully assess the diagnostic accuracy of SR PET in patients with insulinoma and nesidioblastosis compared with current localizing studies used in clinical practice.

Management and interpretation of heterogeneous observational data: using insulin-like growth factor-I data from the NordiNet® International Outcome Study.

OBJECTIVE: The NordiNet® International Outcome Study (IOS), a large-scale, non-interventional, multi-centre, real-world study of Norditropin® treatment, registers insulin-like growth factor-I (IGF-I) values, as measured by different assays. This paper considers the potential biases introduced by using a single IGF-I reference data set in analysing NordiNet® IOS data. DESIGN: To evaluate possible biases from different IGF-I assays used across NordiNet® IOS, a mixed-effect linear model was fitted to IGF-I data (analyses on log-transformed data). Pre-growth hormone treatment (pre-GHT) IGF-I values were assumed to depend on diagnosis, sex and age. During GHT, a treatment-effect dependent on these factors was added. Differences between assays were assumed multiplicative on the original scale. Individual measurements were scaled to a common level (Nichols Advantage) giving adjusted IGF-I standard deviation score (SDS) values. RESULTS: In total, 49 495 IGF-I measurements were available from 9481 paediatric patients. Mixed-effect linear modelling showed a systematic difference between IGF-I levels measured by different assays. Differences were minimised when assessing change in IGF-I SDS from the start of GHT to 1-year follow-up. This applied to values adjusted for actual-assay used and for unadjusted delta IGF-I SDS values. Largest differences between unadjusted change in IGF-I SDS values were: for growth hormone deficiency 0.1 (girls) and 0.3 (boys); for small-for-gestational age 0.1; and for Turner syndrome 0.2. Similar magnitude differences were seen for data with unknown assay. CONCLUSIONS: Analysis and modelling suggest the current approach to IGF-I data collection and analyses in the NordiNet® IOS is sound: in a large cohort without assay-used information, potential bias is minimised by analysing changes in IGF-I SDS.

Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by (18) F DOPA-PET/CT scanning.

CONTEXT: Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. (18) F DOPA-PET/CT is an established non-invasive approach to differentiate focal from nonfocal CHI. OBJECTIVE: The purpose of this study was to identify possible limitations of (18) F DOPA-PET/CT scan in patients with focal forms nonfocal CHI. DESIGN: A retrospective chart review of 32 patients (from 2008 through 2013) who underwent (18) F DOPA-PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK. RESULTS: In most cases (n = 29, 90·7%), (18) F DOPA-PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), (18) F DOPA-PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so-called 'giant focus' was detected in histopathological analysis during the surgery. CONCLUSIONS: Our data show that in most patients with focal CHI (18) F DOPA-PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a 'giant focal' lesion (18) F DOPA-PET/CT is unreliable for correct identification of 'giant focus' cases.

Long-term lanreotide treatment in six patients with congenital hyperinsulinism.

BACKGROUND: Medical treatment is a substantial therapeutic measure to achieve glycemic control and prevent hypoglycemic brain damage without surgery in patients with congenital hyperinsulinism (CHI). However, only few drugs are available and even fewer are approved as a medical therapy to maintain normal blood glucose levels. The established therapies are demanding for caregivers and complicated by different side effects such as gastrointestinal symptoms, hypertrichosis, and obesity. Therefore, it is important to develop new strategies to improve blood glucose control. METHODS: We report the use of the very-long-acting somatostatin analogue lanreotide autogel in 6 patients with CHI over a mean duration of 40.8 months. Blood glucose levels before and after the start and dosage titration of lanreotide in these patients are compared. RESULTS: In 3 of 6 patients, switching to lanreotide raised mean blood glucose levels and reduced individually as well as overall the risk for hypoglycemic episodes (odds ratio 0.38) significantly. CONCLUSION: Lanreotide autogel can be used as an alternative pharmacological treatment and may be beneficial in conservatively treated patients with CHI.