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Kallmann syndrome in a female adolescent: a new mutation in the FGFR1 gene.

ABSTRACT: The Kallmann syndrome is characterised by the association of hypogonadotropic hypogonadism and hypo/anosmia. It represents a phenotypically and genotypically heterogeneous clinical entity, with six genes identified so far in the literature-KAL1, FGFR1, PROKR2, PROK2, CHD7 and FGF8. Mutations in the FGFR1 gene can be found in approximately 10% of the patients. The authors present the case of a female adolescent with hypogonadotropic hypogonadism and impaired olfactory acuity in the presence of hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs. The molecular analysis of the fibroblast growth factor receptor 1 identified a heterozygous mutation c.1377_78insA (p.V460SfsX3) in exon 10 of FGFR1 gene. This mutation has not yet been reported in the literature. A theoretical review of clinical features and therapeutic approach of this syndrome is also presented.

SUBMITTER: Novo A

PROVIDER: S-EPMC4543024 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Kallmann syndrome in a female adolescent: a new mutation in the FGFR1 gene.

Novo Ana A Guerra Isabel Couto IC Rocha Felisbela F Gama-de-Sousa Susana S Borges Teresa T Cerqueira Rita R Tavares Purificação P Fonseca Paula P

BMJ case reports 20120629

The Kallmann syndrome is characterised by the association of hypogonadotropic hypogonadism and hypo/anosmia. It represents a phenotypically and genotypically heterogeneous clinical entity, with six genes identified so far in the literature-KAL1, FGFR1, PROKR2, PROK2, CHD7 and FGF8. Mutations in the FGFR1 gene can be found in approximately 10% of the patients. The authors present the case of a female adolescent with hypogonadotropic hypogonadism and impaired olfactory acuity in the presence of hy ...[more]

PMID: 22751423

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Project description:Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in more than 24 genes, which are scattered across the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause KS are not fully understood.

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Project description:The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.

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Project description:Kallmann syndrome (KS) is a developmental disease that expresses in patients as hypogonadotropic hypogonadism and anosmia. KS is commonly associated with mutations in the extracellular D2 domain of the fibroblast growth factor receptor (FGFR). In this study, for the first time, the molecular basis for the FGFR associated KS mutation (A168S) is elucidated using a variety of biophysical experiments, including multidimensional NMR spectroscopy. Secondary and tertiary structural analysis using far UV circular dichroism, fluorescence and limited trypsin digestion assays suggest that the KS mutation induces subtle tertiary structure change in the D2 domain of FGFR. Results of isothermal titration calorimetry experiments show the KS mutation causes a 10-fold decrease in heparin binding affinity and also a complete loss in ligand (FGF-1) binding. (1)H-(15)N chemical perturbation data suggest that complete loss in the ligand (FGF) binding affinity is triggered by a subtle conformational change that disrupts crucial structural interactions in both the heparin and the FGF binding sites in the D2 domain of FGFR. The novel findings reported in this study are expected to provide valuable clues toward a complete understanding of the other genetic diseases linked to mutations in the FGFR.

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Project description:The first mutation in a gene associated with a neuronal migration disorder was identified in patients with Kallmann Syndrome, characterized by hypogonadotropic hypogonadism and anosmia. This pathophysiological association results from a defect in the development of the GnRH and the olfactory system. A recent genetic screening of Kallmann Syndrome patients revealed a novel mutation in CCDC141. Little is known about CCDC141, which encodes a coiled-coil domain containing protein. Here, we show that Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration. Our findings in human patients and mouse models predict that CCDC141 takes part in embryonic migration of GnRH neurons enabling them to form a hypothalamic neuronal network to initiate pulsatile GnRH secretion and reproductive function.

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Project description:This study aimed to investigate the genetic mutation characteristics of Kallmann syndrome (KS) with CHARGE syndrome through the clinical features and genetic analysis of a pediatric patient with KS in one pedigree.Developmental disorders with olfactory abnormalities, developmental lag, heart malformations, external genital malformations.KS combined with some clinical characteristics of CHARGE syndrome. Molecular genetic analysis found that mutation occurred in the CHD7 gene.One pediatric patient's clinical data were collected and genomic DNA extracted from the peripheral blood. Nextgeneration gene sequencing technology was used to detect pathogenic genes, and the Sanger method was applied to perform pedigree verification for the detected suspicious pathogenic mutations.Gene detection revealed there to be a heterozygous mutation in the CHD7 gene of the patient, which was a missense mutation c.6571G > A (p.E2191K). The father's genotype was wild type, whereas it was the mutant type for the mother and younger brother. The distribution frequency of this mutation was zero in the dbSNP database, Hapmap, 1000 genomes database, and ExAC. Neither the mother nor the younger brother showed any clinical feature of KS or CHARGE syndrome.This study reports 1 case of KS with some clinical features of CHARGE syndrome as determined via clinical and genetic analysis, and found a new mutation in the CHD7 gene, suggesting that KS has an incomplete penetrance. Meanwhile, data suggested that mutation in the CHD7 gene could be detected in the setting of incomplete clinical manifestations of CHARGE syndrome, or without the usually believed manifestations of combined deafness as well as morphological abnormalities of the ear, providing new evidence for the differential diagnosis of KS with CHARGE syndrome in the future.

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