Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis, and Kallmann syndrome due to an Xp deletion

Bick, David; Price, Paul A.; Campbell, Louise; Huff, Robert W.; Shapiro, Larry J.; Moore, Charleen M.

doi:10.1002/pd.1970120104

Cited by 36 publications

(23 citation statements)

References 25 publications

(27 reference statements)

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“…Notably, FGFR1 expression in the mice can be detected in the nasal placode, in developing olfactory bulbs, and along the GnRH migratory pathways, as well as in mature hypothalamic GnRH neurons and their projection (29). Furthermore, mice expressing dominant negative FGFR1 mutants targeted to GnRH neurons demonstrated a 30% reduction in the GnRH neuronal population of the hypothalamus (30). These mice, although fertile, display subtler reproductive phenotypes, such as delayed puberty and premature ovarian senescence.…”

Section: Discussionmentioning

confidence: 99%

Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

Pitteloud

Acierno

Meysing

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

217

183

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Mutations in KAL1 and FGFR1 cause Kallmann syndrome (KS), whereas mutations in the GNRHR and GPR54 genes cause idiopathic hypogonadotropic hypogonadism with normal olfaction (nIHH). Mixed pedigrees containing both KS and nIHH have also been described; however, the genetic cause of these rare cases is unknown. We examined the FGFR1 gene in seven nIHH subjects who either belonged to a mixed pedigree (n ‫؍‬ 5) or who had associated midline defects (n ‫؍‬ 2). Heterozygous FGFR1 mutations were found in three of seven unrelated nIHH probands with normal MRI of the olfactory system: (i) G237S in an nIHH female and a KS brother; (ii) (P722H and N724K) in an nIHH male missing two teeth and his mother with isolated hyposmia; and (iii) Q680X in a nIHH male with cleft lip͞palate and missing teeth, his brother with nIHH, and his father with delayed puberty. We show that these mutations lead to receptor loss-of-function. The Q680X leads to an inactive FGFR1, which lacks a major portion of the tyrosine kinase domain (TKD). The G237S mutation inhibits proper folding of D2 of the FGFR1 and likely leads to the loss of cell-surface expression of FGFR1. In contrast, the (P722H and N724K) double mutation causes structural perturbations in TKD, reducing the catalytic activity of TKD. We conclude that loss-of-function mutations in FGFR1 cause nIHH with normal MRI of the olfactory system. These mutations also account for some of the mixed pedigrees, thus challenging the current idea that KS and nIHH are distinct entities.

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Section: Discussionmentioning

confidence: 99%

Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

Pitteloud

Acierno

Meysing

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

217

183

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“…To our knowledge this is the first time that prenatal diagnosis of KS has been achieved with a non invasive method. One old report, by Bick et al [43], describes prenatal diagnosis of a complex malformative syndrome comprising KS, due to a chromosomal deletion, but the method used was amniocentesis, a far more invasive approach. The family had a contiguous gene syndrome due to deletion of 9.2 megabases of the Xp22 region, which includes the KAL1 , steroid sulfatase ( STS ) and chondrodysplasia punctata ( CDPX1 ) genes.…”

Section: Discussionmentioning

confidence: 99%

Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life

Sarfati

Bouvattier

Bry-Gauillard

et al. 2015

Orphanet J Rare Dis

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Kallmann syndrome (KS) patients carrying FGFR1 mutations can transmit the disorder to their offspring as can asymptomatic female carriers of mutations in KAL1. We describe for the first time two cases in which KS was suspected during fetal life because of the family context and malformation detection by fetal ultrasound: syndactyly or unilateral renal agenesis in subjects with respectively FGFR1 and KAL1 mutations. In relevant family history, ultrasound monitoring can detect KS associated signs before birth and thus enable neonatal diagnosis and early management. These observations also underline the importance of genetic counselling for patients who may transmit KS to their offspring.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0287-9) contains supplementary material, which is available to authorized users.

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“…This was the first gene shown to cause the X-linked form of KS in about 10% of all male KS patients [16,17]. Consistent with a critical role of KAL1/anosmin-1 in olfactory development and GnRH neuron migration [18], the reproductive phenotype of patient with KAL1 mutations is often severe, with high frequency of cryptorchidism and microphallus, absent puberty, and infertility [19,20].…”

Section: Kal1mentioning

confidence: 90%

Complex Genetics in Idiopathic Hypogonadotropic Hypogonadism

Pitteloud

Durrani

Raivio

et al. 2010

Frontiers of Hormone Research

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Idiopathic hypogonadotropic hypogonadism (IHH) is an important human disease model. Investigations of the genetics of IHH have facilitated insights into critical pathways regulating sexual maturation and fertility. IHH has been traditionally considered a monogenic disorder. This model holds that a single gene defect is responsible for the disease in each patient. In the case of IHH, 30% of cases are explained by mutations in one of eleven genes. In recent years, several lines of evidence have challenged the monogenic paradigm in IHH. First, disease-associated mutations display striking incomplete penetrance and variable expressivity within and across IHH families. Second, each locus is responsible for only a small percentage of cases. Third, more than one disease-associated mutation seems to be segregating in some families with IHH, and their combined or separate presence in individuals accounts for the variability in disease severity. Finally, IHH is not strictly a congenital and life-long disorder; occasionally it manifests itself during adulthood (adult-onset IHH); in other cases, the disease is not permanent, as evidenced by normal activity of the hypothalamic-pituitary-gonadal axis after discontinuation of treatment in adulthood (IHH reversal). Together, these observations suggest that IHH is not strictly a monogenic mendelian disease, as previously thought. Rather, it is emerging as a digenic, and potentially oligogenic disease, in which hormonal and/or environmental factors may critically influence genetic predisposition and clinical course. Future investigations of IHH should characterize the extent of the involvement of multiple genes in disease pathogenesis, and elucidate the contributions of epigenetic factors.

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Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis, and Kallmann syndrome due to an Xp deletion

Cited by 36 publications

References 25 publications

Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life

Complex Genetics in Idiopathic Hypogonadotropic Hypogonadism

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