Search

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. Treatment with setmelanotide, a new-generation MC4R agonist, provides durable weight loss in hyperphagic, leptin receptor–deficient patients, suggesting a pharmacological avenue to treat patients with various MC4R pathway defects.

Mit den Fortschritten in der molekulargenetischen Diagnostik und den verbesserten Moglichkeiten einer Beweisfuhrung der sich daraus ergebenden Storungen z. B. im Modellorganismus ist es prinzipiell moglich, fur viele Erkrankungen, deren Ursache wir bis heute nicht kennen, eine Klarung herbeizufuhren und schlieslich darauf basierende Therapien zu entwickeln. Inzwischen sind mehr als 6000 unterschiedliche seltene Erkrankungen bekannt. Es werden stetig mehr, denn durch die Untersuchung des gesamten Genoms wird es moglich sein, Erkrankungen, die bislang nur unter beschreibenden Sammelbegriffen zusammengefasst werden, genauer zu definieren. Dies ist die Basis fur eine individualisierte Medizin, die besser als Prazisionsmedizin bezeichnet werden sollte, die eine Diagnose und die Therapie einer Vielzahl von angeborenen seltenen Erkrankungen moglich machen wird. Daher werden neue integrierte Versorgungs- und Forschungszentren benotigt, die eine rasche Umsetzung neuer Erkenntnisse in die Klinik ermoglichen und eine fur die seltenen Erkrankungen spezialisierte breite Expertise dauerhaft vorhalten. Im deutschen Nationalen Aktionsplan fur Menschen mit Seltenen Erkrankungen (NAMSE) wurde in einem breiten Konsens aller Beteiligten hierfur eine Strukturierung entwickelt. In diesem Beitrag wird das Berliner Centrum fur Seltene Erkrankungen (BCSE) als ein Beispiel vorgestellt, bei dessen Etablierung einige der im NAMSE vorgegebenen Kriterien bereits berucksichtigt wurden

Disorders/diversity of sex development (dsd) is an umbrella term for congenital conditions often diagnosed within childhood. As most parents are unprepared for this situation, psychological support (PsySupp) is recommended. The aim of this study was to analyse the extent to which parents express a need for PsySupp. Three hundred twenty-nine parents of children with dsd were included; 40.4 % of the parents indicated to have a need for PsySupp, only 50 % of this group received it adequately. The diagnoses partial gonadal dysgenesis, partial androgen insensitivity syndrome (pAIS) and disorders of androgen synthesis are associated with a high need for PsySupp in parents (54, 65, and 50 %). Sex assignment surgery neither reduced nor increased the need for PsySupp. Taking a picture, radiography, laparoscopy, gonadal biopsy, gonadectomy and hormonal puberty induction are associated with a high need for PsySupp. There was no association between the need for PsySupp and the parents' perception of the appearance of the genitalia.Having a child with dsd is associated with a high need for PsySupp in parents. In particular, parents of children with XY-dsd with androgen effects other than hypospadias expressed a high need of PsySupp. PsySupp for parents should be an obligatory part of interdisciplinary care to reduce fears and concerns. What is known • In parents, having a child with dsd provokes insecurities and fears. Hence, psychological support is recommended as part of the interdisciplinary care. What is new • This is the first study investigating the subjective need for psychological support in a large sample of parents of children with dsd in Germany. We present data on the subjective need for psychological support of the parents, related diagnoses and factors, which should be considered in psychological counselling.

Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases.

Die Gonaden sind zunachst unabhangig vom chromosomalen Geschlecht als undifferenzierte Primordien angelegt. Die entscheidende Grundlage fur die Entwicklung der bipotenten Gonade in Hoden ist die Expression des Y-chromosomalen Gens sry. Dies induziert die Differenzierung von Sertoli-Zellen, die ihrerseits die Entwicklung der Muller-Gange unterdrucken und die von Leydig-Zellen fordern. Zudem induzieren sie eine Kaskade der die Hodenentwicklung unterstutzenden Transkriptionsfaktoren. Entwicklungsstorungen der Hoden gehen meist mit einer mangelnden Virilisierung von Feten mit mannlichem Karyotyp einher. Molekulare Ursachen konnen Mutationen der Gene fur WT-1, SF-1, DAX-1, SOX-9, INSL-3 oder den LH-Rezeptor sein. insl-3-Mutationen sind fur die haufigste Storung der Hodenentwicklung, den Maldeszensus, verantwortlich. Die von den primaren Entwicklungsdefekten des Hodens abzugrenzenden Storungen der Androgensynthese und Androgenrezeptordefekte stellen die haufigste Ursache eines Pseudohermaphroditismus masculinus dar. Die Defekte der Hodenentwicklung beruhen haufig auf heterozygoten Funktionsverlustmutationen.

Background\ud\udRecently, the orphan G-protein coupled receptor 83 (GPR83) was identified as a new participant in body weight regulation. This receptor is highly expressed in the hypothalamic arcuate nucleus and is regulated in response to nutrient availability. Gpr83 knock-out mice are protected from diet-induced obesity. Moreover, in a previous study, we designed and characterized several artificial constitutively activating mutations (CAMs) in GPR83. A particular CAM was located in the extracellular N-terminal domain (eNDo) that is highly conserved among GPR83 orthologs. This suggests the contribution of this receptor part into regulation of signaling, which needed a more detailed investigation.\udFindings\ud\udIn this present study, therefore, we further explored the role of the eNDo in regulating GPR83-signaling and demonstrate a proof-of-principle approach in that deletion mutants are characterized by a strong increase in basal Gq/11-mediated signaling, whilst none of the additionally characterized signaling pathways (Gs, Gi, G12/13) were activated by the N-terminal deletion variants. Of note, we detected basal GPR83 MAPK-activity of the wild type receptor, which was not increased in the deletion variants.\udConclusions\ud\udFinally, the extracellular portion of GPR83 has a strong regulatory function on this receptor. A suppressive - inverse agonistic - effect of the eNDo on GPR83 signaling activity is demonstrated here, which also suggests a putative link between extracellular receptor activation and proteolytic cleavage. These new insights highlight important aspects of GPR83-regulation and might open options in the development of tools to modulate GPR83-signaling.

Hintergrund. In Berlin wurde 1992 die Bestimmung des 17-Hydroxyprogesterons (17-OHP) im Filterpapier als Neugeborenenscreening zur Fruherkennung des Adrenogenitalen Syndroms (AGS) eingefuhrt. Diagnose. Seither wurden nahezu 250.000 Neugeborene untersucht, und bei 26 Kindern wurde die Diagnose eines klassischen AGS (21-Hydroxylase-Mangel) gestellt und durch spezifische Steroiduntersuchungen im Serum und die molekulargenetische Diagnostik gesichert. Dies entspricht einer Haufigkeit von 1:9594 Neugeborenen, die den Erfahrungen anderer weltweit durchgefuhrter Screeningprogramme entspricht und doppelt so hoch wie die Haufigkeit aufgrund klinischer Diagnose ist. Es waren 14 Madchen und 12 Jungen betroffen, wobei alle Jungen und 8 Madchen ein AGS mit Salzverlust (77% aller Patienten) aufwiesen. Die Diagnose wurde zwischen dem 2. und 10. Lebenstag (im Mittel 6. Lebenstag) gestellt, und in der Regel wurde bereits am nachsten Tag mit der Substitutionstherapie begonnen. So konnte in allen Fallen eine Stoffwechselkrise vermieden werden. Bei nur 7 der 14 Madchen bestand der klinische Verdacht aufgrund eines intersexuellen Genitales, sodass bei allen Jungen und der Halfte der Madchen die Diagnose allein durch das Screening gestellt wurde. Durch die Anwendung gestationsaltersabhangiger Perzentilen der 17-OHP-Spiegel gelang es, die Recallrate bei Fruhgeborenen gering zu halten (0,6%). Resumee. Das so durchgefuhrte Screening erwies sich im Sinn der Kosten-Nutzen-Analyse als geeignet, die Diagnose und Therapie des AGS im Sinn der Qualitatssicherung zu verbessern.

Isolated TSH deficiency leading to hypothyroidism seems to be a rare condition, escaping the diagnosis by neonatal screening programs, which are based on the primary determination of TSH. This is the first report of a case with an autosomal recessive TSH defect caused by a homozygous mutation of the betaTSH gene that was diagnosed in the early neonatal period. Hypothyroidism in the first child of apparently unrelated parents was suspected because of the classical symptoms of congenital hypothyroidism, which were fully expressed already on the 11th day of life. Routine neonatal TSH-screening on the 4th day of life had been normal, but subsequent determination of serum thyroid hormone levels revealed almost undetectable levels and thyroid hormone substitution was immediately started. Because there was no indication for other pituitary hormone deficiencies, sequence analysis of the betaTSH gene was initiated. A homozygous T deletion in codon 105 was found resulting in a change of a highly conserved cysteine to valine followed by eight altered amino acids and a premature stop codon due to the frame-shift. This altered betaTSH is a biologically inactive peptide. Because of the early development of severe symptoms, it is possible that this altered TSH suppresses the physiologic constitutive activity of the unliganded TSH receptor. Rapid molecular diagnosis in this patient clarified the diagnosis without additional endocrine and imaging studies and it is concluded, that symptoms of hypothyroidism in the neonatal period should result always in an immediate comprehensive work-up of thyroid function including molecular genetic studies irrespective of the screening result.

Mutations in the WT1 gene causing Wilms tumors were first reported in WAGR syndrome (Wilms tumor, Aniridia, Genitourinary malformation, mental Retardation) and Denys Drash syndrome (pseudohermaphroditism, Wilms tumor, nephropathy), but only in a few patients with hypospadias and cryptorchidism without other signs of Denys Drash (DDS) or WAGR syndrome WT1 mutations were identified. We report a boy, who was born in 1989 with hypospadias and bilateral cryptorchidism. Previous karyotyping and endocrine studies had ruled out any known cause of male pseudohermaphroditism. Subsequently, he developed a bilateral Wilms tumor, which was detected by palpation at the age of 15 months during a routine visit by the general pediatrician. Because of its extensive size, surgery and chemotherapy were needed for treatment. Analysis of the WT1 gene was performed 5 y after diagnosis and revealed a C to T transition in one allele generating a stop codon at codon 362 and subsequently leading to a truncated protein with loss of its ability to bind to DNA. No signs of DDS or WAGR syndrome are present in the boy. The work up of this patient and the so far known few comparable cases from the literature lead to the conclusion that in newborns with severe urogenital malformations not due to known chromosomal or endocrine disorders mutational screening of the WT1 gene should be performed, to evaluate the high risk of developing a Wilms tumor. We favor mutational screening in these patients as an easy tool for investigation, because in the future it will probably decrease the necessity of frequent control visits in patients without a WT1 mutation.

In four children with hypoparathyroidism and deafness as initial major manifestations of Kearns-Sayre syndrome, a unique pattern of mitochondrial DNA rearrangements was observed. Hypocalcemic tetany caused by PTH deficiency started between age of 6-13 y and was well controlled by small amounts of 1.25-(OH)2-cholecalciferol. Rearranged mitochondrial genomes were present in blood cells of all patients and consisted of partially duplicated and deleted molecules, created by the loss of 7813, 8348, 8587, and 9485 bp, respectively. The deletions were localized between the origins of replication of heavy and light strands and encompassed at least eight polypeptide-encoding genes and six tRNA genes. Sequence analysis revealed imperfect direct repeats present in all rearrangements flanking the break-points. The duplicated population accounted for 25-53% of the mitochondrial genome and was predominant to the deleted DNA (5-30%) in all cases. The proportions of the mutant populations (30-75%) correlated with the age at onset of the disease. We conclude that, unlike heteroplasmic deletions, pleioplasmic rearrangements may escape selection in rapid-dividing cells, distribute widely over many tissues, and thus cause multisystem involvement. Hypoparathyroidism and deafness might be the result of altered signaling pathway caused by selective ATP deficiency.

15N-T and IGF 1-GT were studied by correlating shortterm effects to subsequent growth velocity (GV) during therapy.

Inasmuch as recombinant human growth hormone is now more generally available for the treatment of different types of short stature, there is a need for better short-term indicators of treatment success. In healthy children, serum concentrations of antigens related to the aminoterminal propeptide of type III procollagen (P-III-NP) closely follow the growth velocity curve. P-III-NP was measured longitudinally in 20 children with growth hormone deficiency during 6 months of human growth hormone substitution therapy. Two different radioimmuno-assay systems were used; one recognizes predominantly the intact propeptide showing a lesser affinity to a smaller monomeric peptide (RIAgnost assay), while the other assay detects both forms equally (FAB assay). These results were compared to the growth response [median 5.6 (0.4 to 13.9) cm in 6 months] and to other established growth correlated parameters (somatomedin C, alkaline phosphatase). A relatively better growth response correlated significantly with high pretreatment P-III-NP (RIAgnost assay) values (r = 0.56) and delayed bone age (r = −0.70). A combination of these parameters in multiple regression analysis increased the cumulative prediction value to above 60% (r2 = 0.61). On the other hand, P-III-NP (FAB assay) values proved to be best in monitoring treatment, correlating with the individual growth rate during the first 3 months (r = 0.40; p < 0.05), during the consecutive 3 months (r = 0.66; p < 0.001), and during the total 6-months period (r = 0.46; p < 0.05). All other parameters showed associations to growth only during some treatment periods. Ease of measurement and good correlation with the growth response support the use of the P-III-NP determination in monitoring of human growth hormone therapy.

Screening for hypothyroidism shows that use of PVP-Iodine as desinfectant may cause TSH elevations in the newborns. In order to examine if these elevations are a pathological symptom,we determined TSH,T4,T3 and fT4 and the iodine excretion on days 1,3 and 5 in 23 mothers and their newborns after use of PVP-I.for different periods of time before delivery (7-14o h.mean 25h). Results are shown below (mean values, mother = M, newborn = NB, day = D).

In children with autoimmune thyroiditis and hypothyroidism thyreoglobulin (Tab) and microsomal antibodies (Mab) are present, but not in children with NH. In contrast, thyroid growth blocking antibodies have been detected frequently in newborns with connatal hypothyroidism by our and other groups. This study presents data on cytotoxic thyroid autoantibodies in children with hypothyroidism. ADCC was measured using a 51Cr- release assay in human thyroid cells (JCEM 59: 734, 1984). 12 of 37 (32%) NH newborns were positive for this antibody, 6 of 12 (50%) older children with NH T4-treated for more than 4 years, and 4 of 4 children (100%) with autoimmune thyroiditis were positive, too. ADCC studies in 29 mothers of 37 NH newborns revealed positive titers in 7 (28%), and these had delivered 6 of 12 positive newborns. In addition, 2 of 7 mothers of older NH children with positive titers were positive for ADCC. 2 mothers and their NH newborns were also positive for Mab and Tab. We conclude that ADCC is a frequent finding not only in acquired but also in NH which might be of pathogenetic significance. The persistence of ADCC in older children suggests independent antibody production in the fetus and newborn. Since ADCC in inflammatory autoimmune thyroiditis leads to destruction of thyroid tissue accompanied by hypothyroidism, similar etiological factors {e.g. viral, HLA, environmental) may be responsible for the destruction of the fetal organ.

GHRH-TEST AND SOMATOMED IN C (SMC) GIVE ADDITIONAL INFORMATION IN THE DIAGNOSTIC PROCEDURE OF SHORT STATURE IN CHILDREN

The prognostic value of 15N-(stable isotope nitrogen)-retention (mass-spectrometry) and serum levels of fragments of type 1 collagen (bone and Interstitial fibrils) and type III procollagen (interstitial fibrils) (both by RIA) was studied in 20 hGH deficient children (median age: 10 ys). Patients showing good responses to hGH-therapy (increases above 1 SDS of height for chronological age after 1 year of treatment) had higher mean collagen levels during treatment (Type I: 214 ± 14 vs. 200 ± 14 ng/ml; Type III: 43.3 ± 13.7 vs. 39.5 ± 8.0 ng/ml) than those with smaller responses. The median increase after 3 days of hGH (21U/m2/dle) was higher in those with better responses (Type I: 22 vs. 10 ng/ml; Type III: 13.5 vs. 7.2 ng/ml). Cumulative renal 15N-excretion decreased from pretreatment median values of 0.91 to 0.54 mg/15N/kg. However. 15N-rctention (in %) was identical for good and poor hGH responders (44 %). Short-term administration (3 × 21U/m2) in patients with Turner's Syndrome (n=5) showed no median change of type III collagen (1.7 ng/ml) and 15N retention (9.2%). Therefore, longterm hGH-treatment with such doses in Turner patients are not likely to induce optimal growth responses. Furthermore, these results suggest studies of both 15N-retention test, as well as type I and type III collagen serum levels to predict the response before initiation of longterm hGH-treatment.

The influence of maternal autoimmune thyroid disease and placental transfer of antithyroid antibodies has been discussed as one cause of congenital hypothyroidism. In order to evaluate this hypothesis thyroid microsomal antibodies(anti-M), thyroglobulin antibodies (anti-T) and TSH-receptor antibodies(anti-TSH-R) were determined in serum samples of 36 newborns with confirmed permanent hypothyroidism. TSH receptor antibodies were found to benegative in all newborns. In four patients anti-M and in two of these also anti-T were detected. These results and the thyroid scan findings are listed in the table. The mother of patient 4 with a high anti-M titer also had a significant anti-M titer of 1:400.000,while anti-T were absent. Thyroid function tests in the mother were normal and she was clinically euthyroid. Thyroid antibodies in the child decreased during the first six monthsof life and remained undetectable since then. 123 J Thyroid Scan at two years of age revealed the absence of any thyroid tissue. The incidence of thyroid antibodies in our children with congenital hypothyroidism detected by TSH-screening is 11%. The absence of thyroid tissue was found only in the patient with high antibody titers suggesting a causal relationship between fetal thyroid growth and maternal antithyroid antibodies.

Serum P-III-NP reflects fibriliogenesis. To study whether P-III-NP can be used to monitor growth, it was determined by two different radioimmunoassays. One recognizes predominantly the intact triple-stranded propeptide showing a lesser affinity to the smaller monomeric peptide (RIAgnost), while the other detects both forms equally (FAB). In healthy children (n=375, aged 0 to 16 years) p-III-NP determined with either assay followed closely growth velocity. Patients with Turner's-Syndrome (n=11: 17±4/90± 22 (RIAgnost/FAB in ng/ml respectively)), constitutional short stature (n=16: 19±5/105±27) and growth hormone deficiency (GHD) (n=23: 16±8/82±29) had low levels, while those with tall stature (n=11: 56±45/174±38) had high levels, which declined during estradiol-therapy in girls (n=3: 23±4/125±22). In GHD during recombinant growth hormone therapy (n=20) p-III-NP values increased after only 3 injections (p

Prednisone inhibits growth more potently than hydrocortisone. Supression of GH secretion has been discussed as one possible mechanism. In a retrospective study GH, IGF 1 and procollagen type III propeptide (P-III-NP and FAB), which correlates to growth velocity, were determined longitudinally in sera of 9 children with CAH (age: 6 to 11 ys) during an intermittent period of prednisone substitution (4mg/m2bid) for 6 to 24 months and a subsequent period of hydrocortisone substitution (20mg/m2/tid) for 24 months. Prednisone treatment led to a deceleration of mean growth velocity (0.5 to −4.7 SDS for bone age) without delay of scetetal maturation resulting in a mean decrease of final height prediction of 6 cm. While IGF 1 (4.7 ± 2.1 vs. 4.3 ± 1.2 U/ml, mean ± 1 SD) and GH (5.6 ± 6.1 vs. 4.0 ± 6.9 ng/ml) did not differ during both periods, P-III-NP (13.1 ± 3.5 vs. 28.6 ± 7.4 ng/ml) and FAB levels (63 ± 18 vs. 128 ± 29 ng/ml) were reduced (p