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Article: Adrenal Hypoplasia Congenita: A Rare Cause of Primary Adrenal Insufficiency and Hypogonadotropic Hypogonadism.

Loureiro, Marta / Reis, Filipa / Robalo, Brígida / Pereira, Carla / Sampaio, Lurdes

Pediatric reports

2015 Volume 7, Issue 3, Page(s) 5936

Abstract: ... of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in NR0B1 gene. Despite its rarity, AHC ... in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During ... and hypogonadotropic hypogonadism. ...

Abstract	Primary adrenal insufficiency is defined by the impaired synthesis of adrenocortical hormones due to an intrinsic disease of the adrenal cortex. Determining its etiology is crucial to allow adequate long-term management and genetic counseling. We report the case of a male adolescent that presented in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During follow-up, adrenal hypoplasia congenita (AHC) was suspected given his persistently raised adrenocorticotropic hormone levels, with markedly low 17-OH progesterone and androstenedione levels. DNA sequence analysis revealed a mutation in NR0B1 gene (c.1292delG), confirming the diagnosis. Delayed puberty and persistent low levels of gonadotropins led to testosterone replacement therapy. X-linked AHC is a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in NR0B1 gene. Despite its rarity, AHC should be considered in patients who present with primary adrenal failure, low levels of 17-OH progesterone and hypogonadotropic hypogonadism.
Language	English
Publishing date	2015-09-28
Publishing country	Italy
Document type	Case Reports
ISSN	2036-749X
ISSN	2036-749X
DOI	10.4081/pr.2015.5936
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Article ; Online: Nueva Variante Patogénica en el Gen NR0B1 Asociada a Hipoplasia Adrenal Congénita.

García-Medina, Judith S / Sarmiento-Ramón, María Paula / Lopera-Cañaveral, María V / Zuluaga-Espinosa, Nora A / Forero-Torres, Adriana C / Toro-Ramos, Martín / Pineda-Trujillo, Nicolás

Andes pediatrica : revista Chilena de pediatria

2023 Volume 93, Issue 4, Page(s) 585–590

Abstract: X-linked adrenal hypoplasia congenita is a rare cause of primary adrenal insufficiency. Mutations ... of the pediatric patient with adrenal insufficiency and hypogonadotropic hypogonadism. Clinical Case: A 4-year-old ... with the association of primary adrenal insufficiency and hypogonadism. ...

Title translation	A Novel Pathogenic variant in NR0B1 gene associated with Congenital Adrenal Hypoplasia.
Abstract	X-linked adrenal hypoplasia congenita is a rare cause of primary adrenal insufficiency. Mutations in the NR0B1 gene cause a loss of function in the DAX1 receptor, which activates genes involved in the development and function of the hypothalamic-pituitary-gonadal axis. Objective: To describe a case of adrenal hypoplasia congenita secondary to a mutation in the NR0B1 gene and identified the differential diagnoses of the pediatric patient with adrenal insufficiency and hypogonadotropic hypogonadism. Clinical Case: A 4-year-old male patient with no relevant history and from a rural area was admitted to the emergency room due to a 15-days of emesis, asthenia, adynamia, myalgia, and ataxic gait. On the physical examination, hypotension, hyponatremia, and hyperkalemia, as well as mucosal hyperpigmentation and bilateral cryptorchidism were observed, therefore, adrenal crisis was diagnosed, starting fluid resuscitation with saline solution, hydrocortisone, and fludrocortisone, which stabilized the patient. Adrenal hyperplasia congenita, innate metabolic error, and infectious or autoimmune etiology were ruled out as etiology. A clinical exome test was performed which iden tified the variant c.1275A > T; p.Arg425Ser (Transcript ENST00000378970.5) in the NR0B1 gene consistent with X-linked adrenal hypoplasia congenita. Management of the patient continued with glucocorticoids and mineralocorticoids with favorable clinical course at 7 years of follow-up. Con clusion: A novel pathogenic variant associated with X-linked adrenal hypoplasia is described. Variants in the NR0B1 gene should be a differential diagnosis in a male patient with the association of primary adrenal insufficiency and hypogonadism.
MeSH term(s)	Child, Preschool ; Humans ; Male ; Addison Disease/diagnosis ; Addison Disease/genetics ; Adrenal Insufficiency/diagnosis ; Adrenal Insufficiency/genetics ; Adrenal Insufficiency/congenital ; DAX-1 Orphan Nuclear Receptor/genetics ; Genetic Diseases, X-Linked/diagnosis ; Genetic Diseases, X-Linked/genetics ; Genetic Diseases, X-Linked/pathology ; Hypoadrenocorticism, Familial/genetics ; Mutation
Chemical Substances	DAX-1 Orphan Nuclear Receptor ; NR0B1 protein, human
Language	Spanish
Publishing date	2023-11-01
Publishing country	Chile
Document type	Case Reports ; English Abstract ; Journal Article
ISSN	2452-6053
ISSN (online)	2452-6053
DOI	10.32641/andespediatr.v93i4.4019
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Article ; Online: New insights into X-linked adrenal hypoplasia congenita from a novel splice-site variant of NR0B1 and adrenal CT images.

Jiang, Yuqing / Peng, Huifang / Zhao, Rui / Chang, Yina / Liu, Jie / Fu, Liujun / Li, Liping / Ma, Yujin / Li, Wei / Jiang, Hongwei

Molecular genetics & genomic medicine

2023 Volume 11, Issue 6, Page(s) e2171

Abstract: ... as primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), and caused by variants of NR0B1, most of which are ... Background: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder, often manifesting ... from the increased thickness of adrenal to adrenal atrophy).: Conclusion: X-linked adrenal hypoplasia congenita is ...

Abstract	Background: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder, often manifesting as primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), and caused by variants of NR0B1, most of which are frame-shifting variants, and few splice-site variants. Methods and results: Here, a novel splice-site variant of NR0B1 (NM_000475.4), c.1169-2A>T (patient 1), and a stop-loss variant of NR0B1 c.1411T>C (patient 2) are described in this study. We perform minigene assays for the splice-site variant (c.1169-2A>T) and determine that the variant causes exon 2 skipping. Moreover, the defect of NR0B1 protein may bring about the severe phenotype of the patient. Through 8 years of follow-up, we compare the CT images from 8 years ago with the latest image, and observe the CT image change of adrenal in patient 2 (from the increased thickness of adrenal to adrenal atrophy). Conclusion: X-linked adrenal hypoplasia congenita is produced by variants of NR0B1. We report a case that presents a novel splice-site variant, which has been verified that it could lead to the exon 2 skipping in the RNA splicing progress. Moreover, we report the adrenal CT image change of patient 2, which has never been referred to before, and expand the spectrum of X-linked AHC characteristics.
MeSH term(s)	Humans ; Hypoadrenocorticism, Familial/genetics ; Adrenal Insufficiency/diagnostic imaging ; Adrenal Insufficiency/genetics ; Exons ; Hypogonadism/genetics ; DAX-1 Orphan Nuclear Receptor/genetics ; Tomography, X-Ray Computed
Chemical Substances	DAX-1 Orphan Nuclear Receptor ; NR0B1 protein, human
Language	English
Publishing date	2023-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2734884-2
ISSN	2324-9269 ; 2324-9269
ISSN (online)	2324-9269
ISSN	2324-9269
DOI	10.1002/mgg3.2171
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Article ; Online: Neonatal adrenal insufficiency – beyond the common causes

Inês Pires Duro / Sara Mosca / Graça Araújo / Joana Lorenzo / Catarina Figueiredo / Joana Freitas / Maria João Oliveira / Teresa Borges

Journal of Pediatric and Neonatal Individualized Medicine, Vol 11, Iss 1, Pp e110108-e

2021 Volume 110108

Abstract: ... glucocorticoid insufficiency at birth or in early infancy. In adolescence, hypogonadotropic hypogonadism ... Background: Primary adrenal insufficiency (PAI) can be caused by multiple etiologies. One ... of the rarest is X-linked adrenal hypoplasia congenita (AHC), a disorder of adrenal development that results ...

Abstract	Background: Primary adrenal insufficiency (PAI) can be caused by multiple etiologies. One of the rarest is X-linked adrenal hypoplasia congenita (AHC), a disorder of adrenal development that results from mutations in the NR0B1/DAX1 gene and in which half of the affected males present with salt loss and glucocorticoid insufficiency at birth or in early infancy. In adolescence, hypogonadotropic hypogonadism with absent or arrested pubertal development occurs. Pharmacological intervention is mandatory. Case presentation/discussion: We report 2 male brothers that presented in early infancy with a salt-wasting crisis. Congenital adrenal hyperplasia (CAH) was the presumptive diagnosis, and treatment was instituted accordingly. However, 17-hydroxyprogesterone levels were normal, requiring the search for alternative causes of adrenal insufficiency. In case 2, treatment was discontinued, and he lost follow-up, but he remained well. When he was evaluated due to generalized skin hyperpigmentation, the association of PAI in 2 male brothers raised the suspicion of X-linked AHC and allowed the definitive diagnosis. Conclusions: These 2 cases highlight the importance of a high index of suspicion when facing a male newborn with PAI in which CAH was excluded in order to allow appropriate management. Despite similar initial presentations and carrying the same mutation, these brothers had different clinical courses, which emphasizes the phenotypic heterogeneity and inherent genotype-phenotype correlation difficulties of X-linked AHC. Careful monitoring and regular follow-up should be warranted, due to phenotypic characteristics that can appear in later stages and may benefit from therapeutic interventions, such as delayed/precocious puberty. Genetic counseling is essential in order to detect female heterozygotes and offer prenatal testing.
Keywords	primary adrenal insufficiency ; neonatal adrenal insufficiency ; x-linked adrenal hypoplasia congenita ; hypogonadotropic hypogonadism ; Medicine ; R ; Pediatrics ; RJ1-570
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Hygeia Press di Corridori Marinella
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Identification of a novel point mutation in DAX-1 gene in a patient with adrenal hypoplasia congenita.

Choi, Han Saem / Kwon, Ahreum / Chae, Hyun Wook / Suh, Junghwan / Song, Kyung Chul / Lee, Jin-Sung / Kim, Ho-Seong

Annals of pediatric endocrinology & metabolism

2021 Volume 26, Issue 2, Page(s) 126–129

Abstract: ... with primary adrenal insufficiency in infancy or early childhood and present hypogonadotropic hypogonadism during adolescence ... X-linked adrenal hypoplasia congenita caused by a mutation in NR0B1/DAX-1 is a rare ... hypoplasia congenita and then treated with human choriogonadotropin for the induction of spermatogenesis ...

Abstract	X-linked adrenal hypoplasia congenita caused by a mutation in NR0B1/DAX-1 is a rare inherited disorder. Patients with adrenal hypoplasia congenita are usually diagnosed with primary adrenal insufficiency in infancy or early childhood and present hypogonadotropic hypogonadism during adolescence. Our patient first presented with adrenal crisis at the age of 2 months, which was managed with glucocorticoids and mineralocorticoids. At the age of 17 years, testicular volumes of 5 mL each and a stretched penile length of 4 cm were noted. A combined pituitary function test showed a peak luteinizing hormone level of 2.68 mIU/mL, testosterone 13.5 ng/dL, confirming hypogonadotropic hypogonadism. After whole-exome sequencing, a new variant of DAX-1, c.881T>C (p.Leu294Pro), was found. He was diagnosed with X-linked adrenal hypoplasia congenita and then treated with human choriogonadotropin for the induction of spermatogenesis as well as with steroid replacement therapy.
Language	English
Publishing date	2021-06-30
Publishing country	Korea (South)
Document type	Case Reports
ZDB-ID	2800460-7
ISSN	2287-1292 ; 2287-1012
ISSN (online)	2287-1292
ISSN	2287-1012
DOI	10.6065/apem.2040088.044
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Article ; Online: Adult‑onset X‑linked adrenal hypoplasia congenita caused by a novel mutation in DAX1/NR0B1: A case report and literature review.

Wang, Yuhan / Liu, Xiufen / Xie, Xiaona / He, Jingjing / Gao, Ying

Experimental and therapeutic medicine

2022 Volume 24, Issue 4, Page(s) 628

Abstract: ... with primary adrenal insufficiency and hypogonadotropic hypogonadism. ... Adrenal hypoplasia congenita (AHC) is a rare X-linked recessive disease caused by mutations ... hypogonadotropic hypogonadism was described. The patient initially presented with nausea, vomiting, fatigue and dizziness ...

Abstract	Adrenal hypoplasia congenita (AHC) is a rare X-linked recessive disease caused by mutations in the nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene, which is also referred to as dosage-sensitive sex-reversal, adrenal hypoplasia congenita, in the critical region of the X chromosome, gene 1 (DAX1). This gene is expressed in the hypothalamus, anterior pituitary and steroidogenic tissues, including the gonads and adrenal cortex. Adult-onset forms of X-linked AHC are a significant cause of concern. In the present study, the case of a 21-year-old male who exhibited adrenal insufficiency and hypogonadotropic hypogonadism was described. The patient initially presented with nausea, vomiting, fatigue and dizziness. The laboratory results demonstrated that the patient had hyponatremia, a low basal cortisol concentration and increased adrenocorticotropic hormone levels. Molecular genetic examination revealed a novel frameshift mutation (c.1005delC, p.V336Cfs*36). Following steroid supplementation, the patient's vomiting, fatigue and dizziness rapidly improved. To the best of our knowledge, the present study was the first case report of adult-onset X-linked AHC with this novel frameshift mutation. Furthermore, the present study highlighted differences in the clinical presentation of adult-onset forms of X-linked AHC. This may therefore alert medical professionals to the need to perform genetic analysis for DAX1 mutations in adolescents and adults with primary adrenal insufficiency and hypogonadotropic hypogonadism.
Language	English
Publishing date	2022-08-19
Publishing country	Greece
Document type	Case Reports
ZDB-ID	2683844-8
ISSN	1792-1015 ; 1792-0981
ISSN (online)	1792-1015
ISSN	1792-0981
DOI	10.3892/etm.2022.11565
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Article ; Online: Identification and Analysis of a Novel NR0B1 Mutation in Late-Onset Adrenal Hypoplasia Congenita and Hypogonadism.

Hasegawa, Yutaka / Takahashi, Yoshihiko / Kezuka, Yuichiro / Obara, Wataru / Kato, Yoichiro / Tamura, Shukuko / Onodera, Ken / Segawa, Toshie / Oda, Tomoyasu / Sato, Marino / Nata, Koji / Nonaka, Takamasa / Ishigaki, Yasushi

Journal of the Endocrine Society

2020 Volume 5, Issue 2, Page(s) bvaa176

Abstract: ... by primary adrenal insufficiency and hypogonadotropic hypogonadism (HHG) caused by mutations of the : Case presentation: Herein ... Objective: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized ...

Abstract	Objective: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadotropic hypogonadism (HHG) caused by mutations of the Case presentation: Herein, we report a Japanese patient with a novel missense mutation of the Results: The Conclusions: We identified a novel missense mutation of the
Language	English
Publishing date	2020-11-13
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/jendso/bvaa176
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Article ; Online: A rare occurrence of central precocious puberty in adrenal hypoplasia congenita

Rajesh Joshi / Karthik Shroff

Sri Lanka Journal of Medicine, Vol 29, Iss 1, Pp 32-

2020 Volume 34

Abstract: AHC (X-linked adrenal hypoplasia congenita) is a rare cause of adrenal insufficiency due ... presenting with primary adrenal insufficiency at age of 1 ½ months and developing central precocious puberty ... in an infant with adrenal insufficiency and in whom CAH is ruled out may deter the physician from further ...

Abstract	AHC (X-linked adrenal hypoplasia congenita) is a rare cause of adrenal insufficiency due to mutations in the DAX1 gene. It traditionally causes hypogonadotropic hypogonadism. We present a boy with AHC presenting with primary adrenal insufficiency at age of 1 ½ months and developing central precocious puberty (CPP) at 7 months. Common perception with DAX1 mutation is hypogonadism. Therefore, precocious puberty in an infant with adrenal insufficiency and in whom CAH is ruled out may deter the physician from further investigating the aetiology of primary adrenal insufficiency. Knowledge of such an uncommon presentation may guide the physician to test for DAX1 gene. This also gives a better insight into our understanding of the DAX-1 gene.
Keywords	central ; nuclear receptor dax-1 ; precocious puberty ; x-linked adrenal hypoplasia congenita ; Medicine ; R
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	The Kandy Society of Medicine
Document type	Article ; Online
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Article ; Online: Adrenal hypoplasia congenita

Marta Loureiro / Filipa Reis / Brígida Robalo / Carla Pereira / Lurdes Sampaio

Pediatric Reports, Vol 7, Iss

a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism

2015 Volume 3

Abstract	Primary adrenal insufficiency is defined by the impaired synthesis of adrenocortical hormones due to an intrinsic disease of the adrenal cortex. Determining its etiology is crucial to allow adequate long-term management and genetic counseling. We report the case of a male adolescent that presented in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During follow-up, adrenal hypoplasia congenita (AHC) was suspected given his persistently raised adrenocorticotropic hormone levels, with markedly low 17-OH progesterone and androstenedione levels. DNA sequence analysis revealed a mutation in NR0B1 gene (c.1292delG), confirming the diagnosis. Delayed puberty and persistent low levels of gonadotropins led to testosterone replacement therapy. X-linked AHC is a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in NR0B1 gene. Despite its rarity, AHC should be considered in patients who present with primary adrenal failure, low levels of 17-OH progesterone and hypogonadotropic hypogonadism.
Keywords	Primary adrenal insufficiency ; hypogonadotropic hypogonadism ; adrenal hypoplasia congenita ; Medicine ; R ; Pediatrics ; RJ1-570
Subject code	630
Language	English
Publishing date	2015-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Adrenal hypoplasia congenita - an uncommon reason of primary adrenal insufficiency.

Fichna, M / Zurawek, M / Gut, P / Sowiński, J / Nowak, J

Annales d'endocrinologie

2010 Volume 71, Issue 4, Page(s) 309–313

Abstract: Adrenal hypoplasia congenita (AHC) is a rare inherited condition characterised by primary adrenal ... failure and hypogonadotropic hypogonadism. Most cases arise from mutations in the NR0B1 gene (Xp21.3 ... allows genetic counselling in family members. Autoimmunity remains the major cause of adrenal failure ...

Abstract	Adrenal hypoplasia congenita (AHC) is a rare inherited condition characterised by primary adrenal failure and hypogonadotropic hypogonadism. Most cases arise from mutations in the NR0B1 gene (Xp21.3), which encodes an orphan nuclear receptor DAX-1. A 20-year-old patient was recently diagnosed with AHC. Adrenal failure had been recognized and treated since his infancy. During adolescence, gradual decrease in growth velocity and low body mass were noted. Lack of puberty and skeletal immaturity were observed. Serum DHEA-S and testosterone were undetectable. Low gonadotropin levels failed to rise after stimulation. Neither dysfunction of the somatotropic nor pituitary-thyroid axis was found and no hypothalamo-pituitary pathology was visible on MRI. Androgen replacement therapy induced the development of secondary sexual characteristics, remarkably improved patient's growth and advanced his bone age. NR0B1 mutation screening revealed nucleotide transversion C>A, resulting in premature stop codon (Y399X). Same mutation was previously identified in a Scottish family, however, phenotypic differences suggest the role of additional factors modifying the disease course. Although it does not change therapeutic strategy, accurate molecular diagnosis allows genetic counselling in family members. Autoimmunity remains the major cause of adrenal failure; however, other rare conditions should always be considered.
MeSH term(s)	Adrenal Hyperplasia, Congenital/diagnosis ; Adrenal Hyperplasia, Congenital/drug therapy ; Adrenal Hyperplasia, Congenital/genetics ; Adrenal Insufficiency/genetics ; Androgens/therapeutic use ; Chorionic Gonadotropin/therapeutic use ; DAX-1 Orphan Nuclear Receptor/genetics ; Dehydroepiandrosterone Sulfate/blood ; Genetic Diseases, X-Linked/diagnosis ; Genetic Diseases, X-Linked/drug therapy ; Genetic Diseases, X-Linked/genetics ; Humans ; Hypoadrenocorticism, Familial ; Hypogonadism/genetics ; Male ; Point Mutation ; Testosterone/blood ; Young Adult
Chemical Substances	Androgens ; Chorionic Gonadotropin ; DAX-1 Orphan Nuclear Receptor ; NR0B1 protein, human ; Testosterone (3XMK78S47O) ; Dehydroepiandrosterone Sulfate (57B09Q7FJR)
Language	English
Publishing date	2010-06-12
Publishing country	France
Document type	Case Reports ; Journal Article
ZDB-ID	299-9
ISSN	2213-3941 ; 0003-4266
ISSN (online)	2213-3941
ISSN	0003-4266
DOI	10.1016/j.ando.2010.04.003
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