1. NGS panel - Genetic testing for Kallmann syndrome and hypogonadotropic hypogonadism

Kallmann syndrome and hypogonadotropic hypogonadism

August 22, 2017

Clinical features

Kallmann syndrome (KS) is a developmental genetic disorder characterized by delayed or absent puberty and impaired sense of smell and it belongs to isolated gonadotropin-releasing hormone deficiencies. Deficient hypothalamic gonadotropin-releasing hormone (GnRH) secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation.

Incidence of Kallmann syndrome was estimated to be 1:30,000 in males and 1:125,000 in females in Finland with the male-to-female ratio of nearly 4:1 1.

Patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism may not experience puberty or may experience incomplete puberty and have symptoms associated with hypogonadism. For men, these symptoms include decreased libido, erectile dysfunction, decreased muscle strength, and diminished aggressiveness and drive 2, 3. For women, symptoms include amenorrhea and dyspareunia. Family members of patients with idiopathic hypogonadotropic hypogonadism may have a history of delayed, although otherwise normal, puberty 2, 3.

The impaired olfactory function in Kallmann syndrome can be either hyposmia or complete anosmia 2, 3. Most individuals with impaired sense of smell are otherwise asymptomatic. Isolated gonadotropine deficiency is associated with a normal sense of smell (“normosmic”) in approximately 40% of affected individuals and with an impaired sense of smell (Kallmann syndrome) in approximately 60% of affected cases 2, 3.

Laboratory findings of Kallmann syndrome and hypogonadotropic hypogonadism include reduced levels of testosterone in males and estradiol in females, as well as very low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone). Levels of other anterior pituitary hormones are typically normal.

Mutations in more than 20 genes have been associated with Hypogonadotropic hypogonadism and/or Kallmann syndrome, including ANOS1, CHD7, DUSP6, FEZF1, FGF17, FGF8, FGFR1, FLRT3, FSHB, GNRH1, GNRHR, HESX1, HS6ST1, IL17RD, KISS1, KISS1R, LHB, NSMF, PROK2, PROKR2, SEMA3A, SPRY4, TAC3, TACR3, WDR11 (see table).

Overview of single genes associated with Kallmann syndrome and hypogonadotropic hypogonadism

Locus Associated syndromes Mutation frequency
Xp22.31 Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) (308700) 5%-10% 3
12% 4
8q12.2 Hypogonadotropic hypogonadism 5 with or without anosmia (612370);
CHARGE syndrome (214800)
5%-10% 3
>90% for CHARGE syndrome 5
12q21.33 Hypogonadotropic hypogonadism 19 with or without anosmia (615269) 5/386 6
7q31.32 Hypogonadotropic hypogonadism 22, with or without anosmia (616030) Two families 7
8p21.3 Hypogonadotropic hypogonadism 20 with or without anosmia (615270) 3/386 6
10q24.32 Hypogonadotropic hypogonadism 6 with or without anosmia (612702) <2% 3
8p11.23 Hypogonadotropic hypogonadism 2 with or without anosmia (147950);
Pfeiffer syndrome (101600);
Jackson-Weiss syndrome (123150);
Encephalocraniocutaneous lipomatosis (613001);
Hartsfield syndrome (615465);
Osteoglophonic dysplasia (166250 );
Trigonocephaly 1 (190440)
5% for Pfeiffer syndrome 1 8
>95% for Hartsfield syndrome 9
20p12.1 Hypogonadotropic hypogonadism 21 with anosmia (615271) 3/386 6, 3
11p14.1 Hypogonadotropic hypogonadism 24 without anosmia (229070) Rare10
8p21.2 Hypogonadotropic hypogonadism 12 with or without anosmia (614841) Rare 3
4q13.2 Hypogonadotropic hypogonadism 7 without anosmia (146110) Rare 3
3p14.3 Combined pituitary hormone deficiency (182230) Several families 3
Common for septo-opric dysplasia 11
2q14.3 Hypogonadotropic hypogonadism 15 with or without anosmia (614880) Rare 12
3p14.3 Hypogonadotropic hypogonadism 18 with or without anosmia (615267) 2%-5% 3, 6
1q32.1 Hypogonadotropic hypogonadism 13 with or without anosmia (614842) <2% 3
19p13.3 Precocious puberty, central, 1 (176400);
Hypogonadotropic hypogonadism 8 with or without anosmia (614837)
<2% 3
19q13.33 Hypogonadotropic hypogonadism 23 with or without anosmia (228300) Rare
9q34.3 Hypogonadotropic hypogonadism 9 with or without anosmia (614838) Rare
3p13 Hypogonadotropic hypogonadism 4 with or without anosmia (610628) <1% 3
20p12.3 Hypogonadotropic hypogonadism 3 with or without anosmia (244200) ~5% 3
7q21.11 Hypogonadotropic hypogonadism 16 with or without anosmia (614897) <2% 3
5q31.3 Hypogonadotropic hypogonadism 17 with or without anosmia (615266) Several patients 6
12q13.3 Hypogonadotropic hypogonadism 10 with or without anosmia (614839) <2% 3
4q24 Hypogonadotropic hypogonadism 11 with or without anosmia (614840) Rare
10q26.12 Hypogonadotropic hypogonadism 14 with or without anosmia (614858) 1 patient 3
6/201 persons 13

A major treatment for Kallmann syndrome is hormone replacement therapy, based on the use of testosterone in males and estradiol in females. In addition, human chorionic gonadotropin (hCG) injections in males or progestin in females can be used in order to stimulate spermatogenesis or folliculogenesis. If conception fails despite spermatogenesis in a male or ovulation induction in a female, in vitro fertilization may be an option.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for the Kallmann syndrome and Hypogonadotropic hypogonadism panel (genes: ANOS1, CHD7, DUSP6, FEZF1, FGF17, FGF8, FGFR1, FLRT3, FSHB, GNRH1, GNRHR, HESX1, HS6ST1, IL17RD, KISS1, KISS1R, LHB, NSMF, PROK2, PROKR2, SEMA3A, SPRY4, TAC3, TACR3, WDR11). We also offer single gene tests for each gene included in the panel.

Differential diagnosis

The differential diagnosis of Kallmann syndrome related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Amenorrhea
  • Borjeson-Forssman-Lehmann syndrome
  • CHARGE syndrome
  • Constitutional growth delay
  • Erectile dysfunction
  • Follicle-stimulating hormone abnormalities
  • Infertility
  • Klinefelter syndrome
  • LEOPARD syndrome
  • Laurence-Moon-Biedl syndrome
  • Luteinizing hormone deficiency
  • Luteinizing hormone–releasing hormone deficiency
  • Martsolf syndrome
  • Prader-Willi syndrome
  • Rothmund-Thomson syndrome
  • Turner syndrome
  • Septooptic dysplasia.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Kallmann syndrome using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Kallmann syndrome panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Kallmann syndrome panel, we further recommend continuing the bioinformatics analysis of the data with whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for Kallmann syndrome gene testing:

  • Individuals with a family history of Kallmann syndrome and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling Kallmann syndrome
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of Kallmann syndrome related genes should be performed in all individuals suspected of having this particular phenotype. In parallel, other genes reported to be related with Kallmann syndrome should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Kallmann syndrome, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s Kallmann syndrome and hypogonadotropic hypogonadism panel can be found in our genetic test catalogue.