A Comparative Phenotypic Study of Kallmann Syndrome Patients Carrying Monoallelic and Biallelic Mutations in the Prokineticin 2 or Prokineticin Receptor 2 Genes

Sarfati, Julie; Guiochon‐Mantel, Anne; Rondard, Philippe; Arnulf, Isabelle; García-Piñero, Alfons; Wołczyński, S; Brailly-Tabard, Sylvie; Bidet, Maud; Ramos-Arroyo, María A.; Mathieu, M; Lienhardt-Roussie, Anne; Morgan, Graeme; Turki, Z.; Bremont, C; Lespinasse, James; Boullay, Hélène Du; Chabbert-Buffet, Nathalie; Jacquemont, Sébastien; Reach, Gérard; Talence, Nicole De; Tonella, Paolo; Conrad, Bernard; Despert, F.; Delobel, Bruno; Brue, Thierry; Bouvattier, Claire; Cabrol, Sylvie; Pugeat, Michel; Murat, A.; Bouchard, Philippe; Hardelin, Jean‐Pierre; Dodé, Catherine; Young, Jacques

doi:10.1210/jc.2009-0843

Cited by 127 publications

(137 citation statements)

References 30 publications

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“…21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3. [48][49][50] Other genes such as FGFR1 or PROKR2 can be mutated in patients with either Kallmann syndrome or CHH (Table 1).…”

Section: Genetics Of Chhmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Section: Genetics Of Chhmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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“…It is characterized by a certain degree of virilization, gynecomastia, and a testicular volume above 4 ml or even close to normal (18,30) (see below). However, with developments in molecular genetics, familial genetic studies and sequencing of relatives now allow very partial forms to be diagnosed in subjects who have not spontaneously consulted a physician, yet who have moderate clinical and endocrine abnormalities (18,30).…”

Section: Clinical Presentationmentioning

confidence: 99%

“…Breast development can be highly variable; it is often present and sometimes almost normal (30,47) (see below). Similarly, pubic hair may be absent, sparse, or even normal.…”

Section: Clinical Presentationmentioning

confidence: 99%

“…The diagnosis is very easy in patients with complete gonadotropin deficiency (which is usually the case), when the total testosterone is below 1 ng/ml (3.467 nmol/l) or even 0.5 ng/ml in the majority of the affected patients (49). The concentration of inhibin B, another testicular hormone, is also low in patients with gonadotropin deficiency (18,30,(50)(51)(52)(53). In the setting of CHH, this points to functional Sertolian cell deficiency, which depends on FSH deficiency (51).…”

Section: Investigationsmentioning

confidence: 99%

“…In the setting of CHH, this points to functional Sertolian cell deficiency, which depends on FSH deficiency (51). However, inhibin B is not a sufficiently sensitive marker for positive diagnosis of hypogonadism, because it can be normal in partial forms; however, in the same way as testicular volume, with which it correlates closely, inhibin B provides useful information on the degree of gonadotropin impairment (18,30,(50)(51)(52)(53).…”

Section: Investigationsmentioning

confidence: 99%

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Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Brioude

Bouligand

Trabado

et al. 2010

European Journal of Endocrinology

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100

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Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a nonendocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

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Human Genetics of GnRH Neuron Function

Topaloğlu

Kotan

2018

The GnRH Neuron and Its Control

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A Comparative Phenotypic Study of Kallmann Syndrome Patients Carrying Monoallelic and Biallelic Mutations in the Prokineticin 2 or Prokineticin Receptor 2 Genes

Cited by 127 publications

References 30 publications

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Human Genetics of GnRH Neuron Function

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