Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes

Costa-Barbosa, Flávia A.; Balasubramanian, Ravikumar; Keefe, Kimberly W.; Shaw, Natalie D.; Tassan, Nada Al; Plummer, Lacey; Dwyer, Andrew A.; Buck, Cassandra; Choi, Jin Ho; Seminara, Stephanie B.; Quinton, Richard; Monies, Dorota; Meyer, Brian F.; Hall, Janet E.; Pitteloud, Nelly; Crowley, William F.

doi:10.1210/jc.2012-4116

Cited by 152 publications

(135 citation statements)

References 48 publications

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“…[101][102][103] Other 'red flags' include congenital hearing impairment with or without pigmentation defects, bimanual synkinesia (mirror movements), dental agenesis, cleft lip and/or palate and crypt orchidism with or without micropenis. 17,28,[104][105][106][107][108] Family history indicative of autosomal inheritance cannot be used as a diagnostic tool, as this feature can be observed in both CHH and CDGP. 109 Adulthood CHH might be diagnosed after adolescence, when patients present for evaluation of infertility or even for osteo poro tic fractures.…”

Section: Adolescentmentioning

confidence: 99%

“…Cleft lip and/or palate and skeletal anomalies indicate mutations in genes encoding components of the FGF8 signalling pathway (for example, FGFR1, FGF8 and HS60ST1). 17,20,21,104,153 Signs associated with CHARGE syndrome (CHARGE: coloboma, heart defects, atresia of choanae, retardation of growth and/or development, genital and/or urinary defects, and ear anomalies and/or deafness) favour screening for mutations in CHD7. [24][25][26]104 Likewise, the association of CHH with congenital hearing impairment should direct screening towards CHD7, SOX10 and/or IL17RD.…”

Section: Genetic Testingmentioning

confidence: 99%

“…17,20,21,104,153 Signs associated with CHARGE syndrome (CHARGE: coloboma, heart defects, atresia of choanae, retardation of growth and/or development, genital and/or urinary defects, and ear anomalies and/or deafness) favour screening for mutations in CHD7. [24][25][26]104 Likewise, the association of CHH with congenital hearing impairment should direct screening towards CHD7, SOX10 and/or IL17RD. 21,28,104 Bimanual synkinesia or renal agenesis are important clinical cues suggestive of KAL1 (ANOS1) mutations.…”

Section: Genetic Testingmentioning

confidence: 99%

“…[24][25][26]104 Likewise, the association of CHH with congenital hearing impairment should direct screening towards CHD7, SOX10 and/or IL17RD. 21,28,104 Bimanual synkinesia or renal agenesis are important clinical cues suggestive of KAL1 (ANOS1) mutations. 101,104,114,154,155 Early onset of morbid obesity associated with CHH suggests mutations in LEP, LEPR or PCSK1.…”

Section: Genetic Testingmentioning

confidence: 99%

“…21,28,104 Bimanual synkinesia or renal agenesis are important clinical cues suggestive of KAL1 (ANOS1) mutations. 101,104,114,154,155 Early onset of morbid obesity associated with CHH suggests mutations in LEP, LEPR or PCSK1. 58,156 Indeed, combining CHH with specific associated phenotypes can increase the probability of finding causal mutations by targeted gene sequencing ( Figure 4).…”

Section: Genetic Testingmentioning

confidence: 99%

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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: Adolescentmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

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

et al. 2015

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The infertile male patient with a genetic cause

Martínez

Agarwal

2021

Assisted Reproduction Techniques

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Novel de novo heterozygous FGFR1 mutation in two siblings with Hartsfield syndrome: A case of gonadal mosaicism

Dhamija

Kirmani

Wang

et al. 2014

American J of Med Genetics Pt A

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Hartsfield syndrome has been recently reported to be associated with mutations in FGFR1 however, to this date; no familial cases have been reported. In this report, we describe two siblings with Hartsfield syndrome and a novel de novo FGFR1 mutation suggesting gonadal mosaicism. The proband presented at our institution at age 6 years with a clinical diagnosis of Hartsfield syndrome and requesting further genetic evaluation. Previous studies included a normal karyotype, oligonucleotide array, and single gene testing for nonsyndromic holoprosencephaly (SHH, SIX3, ZIC2, TGIF). At the age of 6 years, exome sequencing was performed and a de novo novel missense variant was identified in FGFR1 (coding for fibroblast growth factor-1) on chromosome 8p12: c.1880G>C (p.R627T). Subsequently, a younger sibling was born with the same phenotype (holoprosencephaly, ectrodactyly of bilateral hands and feet and bilateral cleft lip and palate). Targeted sequencing of FGFR1 revealed the identical variant that was previously identified in the proband. To our knowledge this observation is the first documentation of familial recurrence of Hartsfield syndrome. As both parents were negative for the sequence variant in FGFR1 gene by testing peripheral blood samples, this suggests gonadal mosaicism. The frequency of gonadal mosaicism in Hartsfield syndrome is not known however given our case, this possibility should be taken in to consideration for recurrence risk estimation in children of clinically unaffected parents.

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Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes

Cited by 152 publications

References 48 publications

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

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

The infertile male patient with a genetic cause

Novel de novo heterozygous FGFR1 mutation in two siblings with Hartsfield syndrome: A case of gonadal mosaicism

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