Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life
© Sarfati et al. 2015
Received: 23 February 2015
Accepted: 20 May 2015
Published: 9 June 2015
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.
KeywordsCongenital hypogonadotropic hypogonadism Kallmann Syndactyly Kidney agenesis Prenatal diagnosis FGFR1 KAL1
Kallmann syndrome (KS; MIM 308700, 147950,244200, 610628, 612370, 612702) is a rare disease characterized by congenital hypogonadotropic hypogonadism (CHH) and an altered sense of smell in both genders [1–3]. KS results from abnormal neural development affecting both the olfactory tracts and GnRH neuron migration. The genetics of KS is complex [1–3]: more than 15 genes have been linked to the disease, with several modes of transmissions [4–16]. Monogenic forms with X-linked, autosomal dominant and autosomal recessive transmission have been identified [2–7]. Digenic and oligogenic forms with less clear modes of transmission were described more recently [2, 3]. The X-linked form is due to mutations in KAL1 (Kallmann syndrome 1), the first responsible gene to be discovered [4, 5], presently called ANOS1 (HUGO nomenclature). In this genetic form, females do not generally develop KS [4, 17] but carry KAL1 mutation in the heterozygous state . KS patients with KAL1 mutations may have a variety of associated disorders of a neurological or urogenital nature [2, 19], the most frequent being mirror movements, renal anomalies (unilateral or bilateral agenesis, horseshoe kidney)  and neurogenic deafness [2, 19, 21]. The second KS responsible gene to be identified was FGFR1 (Fibroblast Growth Factor Receptor 1); loss-of-function mutations of this gene cause a form of KS with autosomal dominant transmission [6, 17, 21]. Other disorders frequently associated with this latter form include midline anomalies (cleft lip or palate) [2, 6, 21, 22], skeletal anomalies of the hands or feet [23, 24], dental abnormalities [6, 25], and deafness [6, 21]. Infertility in men and women with KS can be corrected by gonadotropin administration to induce spermatogenesis  or ovulation [27, 28]. Given the success of these treatments, there is a growing need for genetic counselling [1, 2, 29, 30]. In addition, early diagnosis of KS would enable more timely management of affected newborns .
Herein we report for the first time two cases of KS due to FGFR1 and KAL1 mutations respectively in which the diagnosis was identified before birth via the known genetic basis of KS in the parents and non-invasive monitoring (fetal ultrasound) to identify KS-associated phenotypes. Confirmation of KS at birth enabled early management of the two children.
All the participants or parents gave their written informed consent for hormonal, morphological and genetic analyses, performed as part of a non-interventional study, conducted as part of usual patient care. The study was performed in keeping with the provisions of the French Bioethics Law and the Declaration of Helsinki and after approval by the Bicêtre Hospital ethic committee (Comité de protection des personnes Ile de France, Hôpital Bicêtre).
During the interview she noted no sense of smell (anosmia) that was also present in her maternal grandfather. In addition, she reported poor hearing as well as absent premolars and wisdom teeth (Fig. 1a) [6, 25].
Other antepituitary functions (free T4: 16.5 pmol/L [11–24, 35], TSH: 0.75 mIU/L (0.3–4.5), peak cortisol (25 μg/dL; N > 18) and peak GH (45 mIU/L; N > 20) in the insulin tolerance test were normal, as was the prolactin (11 ng/mL (N = 10–15). Pituitary MRI showed a normal antepituitary size and a normal pituitary stalk. CT Scan showed normal semicircular canals. Audiometry showed partial bilateral deafness predominating at 2000 Hz.
In view of her family history, deafness and dental agenesis suggestive of autosomal KS [2, 6, 21, 25], FGFR1 gene analysis was performed revealing a recurrent heterozygous R254W missense mutation that has previously been shown to be loss-of-function in vitro .
As she wished to have children, genetic counselling was provided, during which she was informed that there was a theoretical 50 % risk of transmitting the disease to her children [1, 2, 6, 21, 22, 30].
At delivery, the newborn’s weight and length were normal (weight of 3830 g and a length of 50 cm), but he had micropenis (15 mm;-3SD), descended testes and bilateral testicular hypoplasia (mean testicular volume 0.33 ml (sonography); −3SD). Hormone assays done at age 1 month showed low [31, 40] circulating gonadotropins (FSH: 0.18 (normal range: 0.2–3.5); LH: 0.04 IU/L (0.5–6.5)), testosterone (0.1 (0.5–4.8)) and low testicular peptide levels (inhibin B 24 pg/mL (75–575); AMH 69 ng/mL (80–154)), confirming the diagnosis of congenital hypogonadotrophic hypogonadism [31, 40]. Molecular studies done at birth showed that he carried the same KAL1 mutation as his mother and maternal uncle. Postnatal sonography follow-up confirmed the left renal agenesis and compensatory right kidney hypertrophy (see Additional file 1: Figure S1), together with bilateral agenesis of the olfactory bulbs on MRI at age 4 months. Synkinesia (mirror movements) were also evident and given the frequent association of KAL1 mutations and hearing loss, additional evaluation at 1 year of age was conducted revealing deafness in the child [1, 2, 19, 21, 41]. This early diagnosis enabled timely prosthetic treatment to improve the sensory deficit. In addition, in view of the severe reproductive phenotype with micropenis , and with approval from our local ethics committee, we proposed to treat the infant with recombinant human gonadotrophins for inducing phallus growth and testicular development . Both parents gave their written consent. Notably, the mother reported a major factor in her decision was her brother’s experience who also had severe KS (cryptorchidism and micropenis) and struggled with sexual disorders and infertility that were not corrected by testosterone treatment or long term combined gonadotropin therapy.
Combination therapy with recombinant human pituitary gonadotrophins (LH and FSH, 75 IU/day each, administered subcutaneously via a pump in order to avoid repeated painful injections) [31, 42] was therefore started when the boy was 1 month old and was continued until the age of 7 months. This treatment was associated with a marked increase in testicle size (from 0.33 to 2.3 ml, at sonography) and penis length (from 15 to 38 mm), both of which became normal for age. Testicular volume, evaluated by sonography, was still normal (0.8 mL) one year after the end of gonadotropin therapy.
We describe two cases of Kallmann syndrome in which the diagnosis was strongly suspected during fetal life, in view of the familial context and ultrasound detection of foot deformities in one case and renal agenesis in the other case. 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. , 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. This prenatal diagnosis was based on the familial context and on a highly elevated DHEAS level in amniotic fluid, indicating severe steroid sulfatase deficiency. Autopsy following therapeutic termination revealed, besides a horseshoe kidney, absent olfactory bulbs and a small penis, indicating that the fetus had KS [4, 5, 43].
In both the cases described here, prenatal screening for signs of KS enabled appropriate management to begin at birth. In the family 2 newborn, diagnostic confirmation by hormonal tests and KAL1 gene analysis enabled us to begin hormone therapy to correct penile and testicular hypotrophy [31, 42]. This early correction of genital hypoplasia is likely to have beneficial consequences for the patient’s sexuality and fertility in adulthood [31, 44–47]. Indeed, previous reports have shown that neonatal combined gonadotropin therapy in patients with CHH/KS and severe reproductive phenotype, diagnosed at birth can have a short term beneficial effect on testicular endocrine function and on genital development particularly by a marked increase in penile length. It is therefore possible that the normalization of penis size in the neonate period will lead, during subsequent postpubertal virilization, to a normal adult penis size and thus avoid the sexual disorders often reported by men with CHH and micropenis [31, 44–47].
Moreover, early knowledge of the genotype prompted us to look for other signs associated with this genetic form; in particular, deafness was detected by means of auditory evoked potentials , enabling timely prosthetic treatment. Postnatal investigations also allowed us to reassess, by urogenital imaging, the renal malformation detected during fetal life. This confirmed left kidney agenesis and revealed compensatory right kidney hypertrophy (Additional file 1: Figure S1) that preserved renal function. The same postnatal imaging studies showed that the renal disorders were not accompanied by other urogenital anomalies. Finally, the discovery of renal agenesis in the family 2 fetus suggests that this defect develops at a very early stage and does not result from secondary, postnatal atrophy, contrary to statement of some reports .
Similarly, in family 1, following prenatal diagnosis with neonatal confirmation, we were able to seek disorders linked to the relevant FGFR1 mutations in a timely manner. Brain MRI performed at 6 months showed only agenesis of the olfactory bulbs; no clinically inapparent malformations of the midline were discovered [2, 23, 50]. Hearing tests were normal.
Thus, early diagnosis of KS and knowledge of the genotype in the two cases reported here allowed us to look for signs that might otherwise have been overlooked at birth, potentially delaying the diagnosis until puberty . Indeed, disorders associated with KS are generally discovered only when KS itself is diagnosed, usually at the age of puberty, ruling out timely treatment . Early diagnosis also avoids unnecessary investigations and possible misdiagnosis, and enables replacement therapy to begin at the physiological age of puberty, thereby avoiding the frequent psychological impact of delayed pubertal development [44–47].
These two cases highlight the frequency of direct transmission of KS by patients carrying mutations in FGFR1 or KAL1 [1, 3, 6]. Likewise, when KS associated with KAL1 mutation is diagnosed in a male patient, it is necessary to conduct exhaustive investigations based on family genetic screening for heterozygous healthy carriers [1, 2, 29, 30]. Indeed, given the almost complete penetrance of this phenotype in this X-linked form, a male fetus that inherits the mutated allele from his mother will have a high probability of developing KS. These family studies are also necessary in autosomal dominant forms, as the risk of disease transmission to the offspring is theoretically 50 %. In the case of FGFR1 mutations, genetic counselling is complicated by the variable penetrance of both cardinal and associated signs, even within the same family [2, 6, 21, 37, 50].
However, even if the mutations in KAL1 and FGFR1 are very penetrant, other genes contributing to oligogenic forms may have variable expressivity and incomplete penetrance or contribute to the severity of phenotypes in patients carrying deleterious KAL1 or FGFR1 mutations [2, 3]. This is a limitation of the experience reported here because not all Kallmann cases associated with KAL1 or FGFR1 mutations will be transmitted as reported herein [2, 3].
One interesting feature of family 1 was the proband’s phenotype. The patient reported having normal pubertal development with menarche at age 14, and said her doctors had not attempted to determine the cause of her oligomenorrhea. In our experience, this is quite a common situation in partial female hypoganodotrophic hypogonadism. Indeed, it is principally the complete form with absent puberty that is taught in medical school and described in textbooks, even though a number of case reports and some studies describe the existence of partial forms of IHH in which breast and pubic hair development are present, despite primary amenorrhea in 95 % of cases [2, 52, 53]. Cases of IHH with oligomenorrhea are far more rarely reported [18, 54]. The case described here stresses the importance of diagnosing these very partial forms of KS before considering medically assisted procreation, given the implications for genetic counselling and the need to closely monitor these pregnancies. Finally, the propositus of family 1 presents a paradigme of cases of female KS patient who are not diagnosed until much later in life. There is a well-reported gender discrepancy between male and female CHH/KS cases with approximately 3–5 males diagnosed for each female case. This may be in fact a bias of ascertainment as females are often started on empiric therapy without a full work-up [2, 18, 51–54].
This work was supported by Agence Nationale de la Recherche (ANR-09-GENO-017–01). We also thank the European COST Action BM1105 for its support.
- Young J. Approach to the male patient with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2012;97:707–18.PubMedView ArticleGoogle Scholar
- Boehm U, Bouloux PM, Dattani M, de Roux N, Dodé C, Dunkel L, et al. European Consensus Statement on Congenital Hypogonadotrophic Hypogonadism: Pathogenesis, diagnosis, and treatment. Nat Rev Endocrinol 2015; in press.Google Scholar
- Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab. 2011;22:249–58.PubMedGoogle Scholar
- Legouis R, Hardelin J-P, Levilliers J, Claverie J-M, Compain S, Wunderle V, et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell. 1991;67:423–35.PubMedView ArticleGoogle Scholar
- Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, et al. A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature. 1991;353:529–36.PubMedView ArticleGoogle Scholar
- Dodé C, Levilliers J, Dupont JM, De Paepe A, Le Dû N, Soussi-Yanicostas N, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003;33:463–5.PubMedView ArticleGoogle Scholar
- Dodé C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006;2:e175.PubMed CentralPubMedView ArticleGoogle Scholar
- Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest. 2008;118:2822–31.PubMed CentralPubMedView ArticleGoogle Scholar
- Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, et al. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2008;83:511–9.PubMed CentralPubMedView ArticleGoogle Scholar
- Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, et al. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2010;87:465–79.PubMed CentralPubMedView ArticleGoogle Scholar
- Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, et al. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A. 2011;108:11524–9.PubMed CentralPubMedView ArticleGoogle Scholar
- Young J, Metay C, Bouligand J, Tou B, Francou B, Maione L, et al. SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Hum Reprod. 2012;27:1460–5.PubMedView ArticleGoogle Scholar
- Hanchate NK, Giacobini P, Lhuillier P, Parkash J, Espy C, Fouveaut C, et al. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet. 2012;8:e1002896.PubMed CentralPubMedView ArticleGoogle Scholar
- Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A, et al. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet. 2013;92:707–24.PubMed CentralPubMedView ArticleGoogle Scholar
- Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013;92:725–43.PubMed CentralPubMedView ArticleGoogle Scholar
- Kotan LD, Hutchins BI, Ozkan Y, Demirel F, Stoner H, Cheng PJ, et al. Mutations in FEZF1 cause Kallmann syndrome. Am J Hum Genet. 2014;95:326–31.PubMed CentralPubMedView ArticleGoogle Scholar
- Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, et al. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab. 2004;89:1079–88.PubMedView ArticleGoogle Scholar
- Shaw ND, Seminara SB, Welt CK, Au MG, Plummer L, Hughes VA, et al. Expanding the phenotype and genotype of female GnRH deficiency. J Clin Endocrinol Metab. 2011;96:E566–76.PubMed CentralPubMedView ArticleGoogle Scholar
- Hardelin JP, Levilliers J, Young J, Pholsena M, Legouis R, Kirk J, et al. Xp22.3 deletions in isolated familial Kallmann’s syndrome. J Clin Endocrinol Metab. 1993;76:827–31.PubMedGoogle Scholar
- Georgopoulos NA, Koika V, Galli-Tsinopoulou A, Spiliotis BE, Adonakis G, Keramida MK, et al. Renal dysgenesis and KAL1 gene defects in patients with sporadic Kallmann syndrome. Fertil Steril. 2007;88:1311–7.PubMedView ArticleGoogle Scholar
- Albuisson J, Pêcheux C, Carel JC, Lacombe D, Leheup B, Lapuzina P, et al. Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum Mutat. 2005;25:98–9.PubMedView ArticleGoogle Scholar
- Dodé C, Fouveaut C, Mortier G, Janssens S, Bertherat J, Mahoudeau J, et al. Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis. Hum Mutat. 2007;28:97–8.PubMedView ArticleGoogle Scholar
- Zenaty D, Bretones P, Lambe C, Guemas I, David M, Léger J, et al. Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1). Mol Cell Endocrinol. 2006;25:78–83.View ArticleGoogle Scholar
- Villanueva C, Jacobson-Dickman E, Xu C, Manouvrier S, Dwyer AA, Sykiotis GP, et al. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations. Genet Med. 2014; 13:doi: 10.1038/gim.2014.166.Google Scholar
- Bailleul-Forestier I, Gros C, Zenaty D, Bennaceur S, Leger J, de Roux N. Dental agenesis in Kallmann syndrome individuals with FGFR1 mutations. Int J Paediatr Dent. 2010;20:305–12.PubMedView ArticleGoogle Scholar
- Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol. 1998;139:298–303.PubMedView ArticleGoogle Scholar
- Kousta E, White DM, Piazzi A, Loumaye E, Franks S. Successful induction ovulation and completed pregnancy using recombinant human luteinizing hormone and follicle stimulating hormone in a woman with Kallmann’s syndrome. Hum Reprod. 1996;11:70–1.PubMedView ArticleGoogle Scholar
- Burgués S. Spanish Collaborative Group on Female Hypogonadotrophic Hypogonadism: The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain. Hum Reprod. 2001;16:2525–32.PubMedView ArticleGoogle Scholar
- Layman LC. Clinical genetic testing for Kallmann syndrome. J Clin Endocrinol Metab. 2013;98(5):1860–2.PubMed CentralPubMedView ArticleGoogle Scholar
- Au MG, Crowley Jr WF, Buck CL. Genetic counseling for isolated GnRH deficiency. Mol Cell Endocrinol. 2011;346:102–9.PubMed CentralPubMedView ArticleGoogle Scholar
- Bouvattier C, Maione L, Bouligand J, Dodé C, Guiochon-Mantel A, Young J. Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2011;8:172–82.PubMedView ArticleGoogle Scholar
- Eloit C, Trotier D. A new clinical olfactory test to quantify olfactory deficiencies. Rhinology. 1994;32:57–61.PubMedGoogle Scholar
- Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, et al. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med. 2009;360:2742–8.PubMedView ArticleGoogle Scholar
- Deb S, Campbell BK, Clewes JS, Pincott-Allen C, Raine-Fenning NJ. Intracycle variation in number of antral follicles stratified by size and in endocrine markers of ovarian reserve in women with normal ovulatory menstrual cycles. Ultrasound Obstet Gynecol. 2013;41:216–22.PubMedView ArticleGoogle Scholar
- Quinton R, Duke VM, Robertson A, Kirk JM, Matfin G, de Zoysa PA, et al. Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol. 2001;55:163–74.View ArticleGoogle Scholar
- Koika V, Varnavas P, Valavani H, Sidis Y, Plummer L, Dwyer A, et al. Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH). Gene. 2013;516:146–51.PubMedView ArticleGoogle Scholar
- Salenave S, Chanson P, Bry H, Pugeat M, Cabrol S, Carel JC, et al. Kallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. J Clin Endocrinol Metab. 2008;93:758–63.PubMedView ArticleGoogle Scholar
- Teixeira L, Guimiot F, Dodé C, Fallet-Bianco C, Millar RP, Delezoide AL, et al. Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions. J Clin Invest. 2010;120:3668–72.PubMed CentralPubMedView ArticleGoogle Scholar
- Kirk JM, Grant DB, Besser GM, Shalet S, Quinton R, Smith CS. Unilateral renal aplasia in X-linked Kallmann’s syndrome. Clin Genet. 1994;46:260–2.PubMedView ArticleGoogle Scholar
- Grumbach MM. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab. 2005;90:3122–7.PubMedView ArticleGoogle Scholar
- Massin N, Pêcheux C, Eloit C, Bensimon JL, Galey J, Kuttenn F, et al. X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene. J Clin Endocrinol Metab. 2003;88:2003–8.PubMedView ArticleGoogle Scholar
- Bougnères P, François M, Pantalone L, Rodrigue D, Bouvattier C, Demesteere E, et al. Effects of an early postnatal treatment of hypogonadotropic hypogonadism with a continuous subcutaneous infusion of recombinant follicle-stimulating hormone and luteinizing hormone. J Clin Endocrinol Metab. 2008;93:2202–5.PubMedView ArticleGoogle Scholar
- Bick DP, Schorderet DF, Price PA, Campbell L, Huff RW, Shapiro LJ, et al. Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis, and Kallmann syndrome due to an Xp deletion. Prenat Diagn. 1992;12:19–29.PubMedView ArticleGoogle Scholar
- Smith N, Quinton R. Kallmann syndrome. BMJ. 2012;345:e6971.PubMedView ArticleGoogle Scholar
- Dwyer AA, Quinton R, Morin D, Pitteloud N. Identifying the unmet health needs of patients with congenital hypogonadotropic hypogonadism using a web-based needs assessment: implications for online interventions and peer-to-peer support. Orphanet J Rare Dis. 2014;9:83.PubMed CentralPubMedView ArticleGoogle Scholar
- Varimo T, Hero M, Laitinen EM, Sintonen H, Raivio T. Health-related quality of life in male patients with congenital hypogonadotropic hypogonadism. Clin Endocrinol (Oxf). 2014; doi: https://doi.org/10.1111/cen.12701.
- Dwyer AA, Quinton R, Pitteloud N, Morin D. Psychosexual development in men with congenital hypogonadotropic hypogonadism on long-term treatment: a mixed methods study. Sex Med. 2015;3(1):32–41. doi:https://doi.org/10.1002/sm2.50.PubMed CentralPubMedView ArticleGoogle Scholar
- Thompson DC, McPhillips H, Davis RL, Lieu TL, Homer CJ, Helfand M. Universal newborn hearing screening: summary of evidence. JAMA. 2001;286:2000–10.PubMedView ArticleGoogle Scholar
- Deeb A, Robertson A, MacColl G, Bouloux PM, Gibson M, Winyard PJ, et al. Multicystic dysplastic kidney and Kallmann’s syndrome: a new association? Nephrol Dial Transplant. 2001;16:1170–5.PubMedView ArticleGoogle Scholar
- Maione L, Benadjaoud S, Eloit C, Sinisi AA, Colao A, Chanson P, et al. Computed tomography of the anterior skull base in Kallmann syndrome reveals specific ethmoid bone abnormalities associated with olfactory bulb defects. J Clin Endocrinol Metab. 2013;98:E537–46.PubMedView ArticleGoogle Scholar
- Kaplan JD, Bernstein JA, Kwan A, Hudgins L. Clues to an early diagnosis of Kallmann syndrome. Am J Med Genet A. 2010;152A:2796–801.PubMedView ArticleGoogle Scholar
- Pitteloud N, Meysing A, Quinton R, Acierno Jr JS, Dwyer AA, Plummer L. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006;254–55:60–9.View ArticleGoogle Scholar
- Bry-Gauillard H, Trabado S, Bouligand J, Sarfati J, Francou B, Salenave S, et al. Congenital hypogonadotropic hypogonadism in females: clinical spectrum, evaluation and genetics. Ann Endocrinol (Paris). 2010;71:158–62.View ArticleGoogle Scholar
- Brioude F, Bouligand J, Trabado S, Francou B, Salenave S, Kamenicky P, et al. Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype-phenotype relationships. Eur J Endocrinol. 2010;162:835–51.PubMedView ArticleGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.