Kallmann syndrome

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Classification according to ICD-10
E23.0 Hypopituitarism
ICD-10 online (WHO version 2019)

The Kallmann syndrome (KS) is a congenital disease with a combination of developmental disorder of the gonads ( gonads ) and reduced to a lack of sense of smell ( anosmia ). The dysfunction of the testes or ovaries is caused by a deficiency in gonadoliberin (gonadotropin-releasing hormone, GnRH) with the result of hypogonadotropic hypogonadism . The disorder of the olfactory function is caused by hypo- or aplasia of the olfactory bulb .

Synonyms are: olfactogenital syndrome; de Morsier-Sy; Síndrome de Maestre-Kallman-Morsier

The syndrome is named after the psychiatrist Franz Josef Kallmann .

The other name refers to the Swiss neurologist Georges de Morsier .

The syndrome was first mentioned in 1856 in a publication by Aureliano Maestre de San Juan (1828–1890). In Spanish-speaking parts of the world, the syndrome is still named after this one.

frequency

The prevalence is estimated at 1 / 8,000 or 1 in 10,000 or 1 in 86,000 for males and 1 / 40,000 for females.

Kallmann syndrome is more common in men (1: 10,000) than in women (1: 50,000).

Most cases are sporadic, but familial forms have also been described.

It can also occur in the context of syndromes :

  • Brachytelephalangia - Dysmorphism - Kallmann Syndrome
  • Kallmann syndrome - cardiopathy

Causes and classification

The cause of the Kallmann syndrome are mutations that affect proteins that play a decisive role in the development of the olfactory bulb and certain core areas of the hypothalamus. If the pulsatile secretion of GnRH does not occur, LH and FSH are not released . As a result, sex hormones are not produced in the gonads during puberty, and the gonads do not mature (without substitution with gonadotropins).

Depending on the inheritance and the underlying mutation , a distinction can be made between:

  • Type 1 , x-linked - recessive mutations in KAL1 - gene at locus p22.31 encoding the protein Anosmin-1 (a 95 kD glycoprotein) which has a key role in the migration of GnRH neurons plays and olfactory neurons.
  • Type 2 , autosomal dominant , more common form, mutations in the FGFR1 gene in chromosome 8 at p11.23, loss of function of the fibroblast growth factor , mostly haploinsufficiency
  • Type 3 , autosomal dominant, mutations in the PROKR2 gene on chromosome 20 at p12.3 in the prokineticin receptor
  • Type 4 , autosomal dominant, mutations in the PROK2 gene in chromosome 3 at p13 in the ligand for the prokineticin receptor
  • Type 5 , autosomal dominant, mutations in the CHD7 gene in chromosome 8 at q12.2
  • Type 6 , autosomal dominant, mutations in the FGF8 gene in chromosome 10 at q24.32. FGF signals may increase the effects of anosmin-1 at a very early stage in the development of the olfactory bulb
  • Type 7 , autosomal recessive, mutations in the GNRHR gene in chromosome 4 at q13.2
  • Type 8 , autosomal recessive, mutations in the KISS1R gene in chromosome 19 at p13.3
  • Type 12 , autosomal recessive, mutations in the GNRH1 gene on chromosome 8 at p21.2
  • Type 23 , autosomal recessive, mutations in the LHB gene on chromosome 19 at p13.33

It is not yet clear whether other genes may be involved in the genesis of KS.

Clinical manifestations

Clinical criteria are (untreated):

  • Gonadotropin deficiency due to a lack of hypothalamic GnRH
    • Asymptomatic in children before puberty
    • in males, small testicles, possibly cryptorchidism (with an increased risk of malignant diseases), sparse secondary sexual characteristics (broken voice, body hair, beard growth), absent or delayed puberty and eunuchoid body proportions if substitution started late
    • in the female sex little development of estrogen-related secondary sexual characteristics, primary amenorrhea
  • infertility
  • Hyp- to anosmia, often the only observable symptom, can lead to subjectively embarrassing and sometimes dangerous situations ( fire , food poisoning )
  • normal mental development and intelligence
  • normal life expectancy .

In type 1 and type 2 there may be other anomalies such as:

In the course of the disease, further (secondary) symptoms such as:

  • Anemia (common)
  • Osteoporosis , especially if the substitution is too late, is aggravated by greater fatigue and, as a result, insufficient physical activity
  • Gynecomastia (rare)

diagnosis

The clinical diagnosis is often delayed in the case of late onset or less obvious symptoms, sometimes not until the third decade of life. The focus of the diagnosis is on the olfactory and endocrinological symptoms. A cryptorchidism or an inguinal testicle as well as delayed or absent puberty ( pubertas tarda ) can be the first clues.

The blood test shows decreased or low-normal serum levels of LH and FSH and pre-pubertal sex hormones.

With medical imaging , the delayed skeletal age can be detected in the X-ray image , and the missing olfactory bulb in magnetic resonance imaging .

Detection of the mutation and normal sex chromosomes in the human genetic examination , as well as human genetic counseling at the request of the person concerned.

An olfactory test ( olfactometry ) can only be carried out from the age of about five.

Differential diagnostics

Other causes of hypogonadism , the isolated congenital gonadotropin deficiency (without olfactory disorder) and the CHARGE syndrome must be distinguished .

Further:

therapy

The most important points in the therapy of KS are hormone replacement and prophylaxis of osteoporosis. Although the normal pulsatile release of GnRH and thus FSH and LH is defective in KS, the actual success hormone testosterone in men (in some cases also human chorionic gonadotropin ) or the analogous sex hormones ( estrogens , progesterone ) are substituted for economic and medical reasons ) in the woman. From injections to gels and plasters (transdermal systems) there are many application options. With the help of this substitution therapy (replacement therapy) normal puberty is initiated and those affected can lead a reasonably normal life, possibly also fathering or having children. A longitudinal study reported on five patients with KS who had a spontaneous reversibility of hypogonadotropic hypogonadism after several years of hormone replacement.

Family planning

If the patient wishes to have children, they are substituted with gonadotropins. In many cases this leads to normal spermatogenesis or completion of oogenesis . Cases of child generation without prior substitution are also known.

Psychological peculiarities in Kallmann syndrome

Quote from a 50 to 60 year old anonymous patient with KS:

“There have been more lows than highs in my life due to a lack of confidence. When I was a teenager I knew there was a problem, but no help for it. I tried to get on with my life but found it very difficult. Fortunately, no one ever made fun of me, but I never reached my full potential due to a lack of trust. The incidents that occurred during this period and throughout my life sometimes made me think of suicide. "

Like all other genetic strains, KS also requires the affected person to be able to adapt. This adjustment becomes more difficult because a condition that goes hand in hand with hypogonadism affects the intimate sphere and sexuality of the person and communication with others is not possible without further trust. There is no social support for the time being. With regard to KS, however, there are no sexual functional restrictions once it has been adequately substituted. Those affected are known to be able to be very creative with others due to the higher adaptability that a genetic burden demands. This creativity can of course also extend to partnerships and sexual areas. If Kallmann syndrome is suspected, after the necessary diagnostic measures, substitution should be started sooner rather than later in order to counteract psychological and social disadvantages. At the age of 16, “late bloomer” is not an adequate medical diagnosis!

The psychologist P. Neemuchwala names the following possible complications:

Harm to self-image and self-esteem
If puberty is delayed until hormone replacement begins, self-esteem can suffer. The patient starts with a positive self-esteem, which ultimately turns into a negative when he is left behind in development by his peers. The self-image may change from good to neutral to insufficient, depending on the circumstances. This can have long-term consequences for personal behavior and the ability to enjoy oneself. Excessive smoking, drinking, workaholism, grumpy behavior and even psychosomatic complaints (headaches, insomnia, etc.)
Chronic waiting, self-rejection and compensatory behavior result from the fact that those affected look younger than their age. Problems caused by ongoing insulting remarks or a lack of understanding of the environment.

According to P. Neemuchwala: "It's not like you can force puberty if you just try harder . I can only imagine the complications and frustration of looking five years younger than the chronological age" . The developmental delay can make it difficult to interact with your peers. This can occur as early as the age of twelve and last at least until appropriate treatment is started. If this gets out of hand, or if treatment is too long in coming, something can occur long after the insults have subsided that is psychologically circumscribed as internalizing the aggressor. According to many psychologists, this internalization can lead to mental impairments. B. [Depression] etc. Compensatory behavior, such as being the best in school, in certain activities, sports, can also be a possible consequence.

Difficulty with trust and intimacy
Many patients report a lack of trust and intimacy, let alone physical intimacy. There appears to be a loss of faith and confidence, especially when the diagnosis is made several years late. However, some patients also report fulfilled partnerships and family life.
Tendency to be shy
Particularly during puberty, contact with the opposite sex is extremely determined by KS. Most sufferers do not have the courage to tell a potential partner about their "abnormality" and remain partnerless for a long time.
Low sexual confidence
Iatrogenic mood swings caused by hormone replacement
The iatrogenic (medical intervention) caused mood swings in hormone replacement therapy are related to the current hormone levels. Shortly after the injection there is a so-called "high" in which libido and activity are increased, but the person affected can also feel more impulsive, nervous and aggressive. When the level drops, there can be a so-called “low” with side effects of ineffectiveness, sadness, etc., which can develop into depression if the mood is unfavorable . According to those affected and endocrinologists, this can be circumvented in individual cases by changing the substitution therapy. B. long-acting sustained-release preparations. Small mood swings are usually unavoidable, but in the opinion of those affected, unproblematic as long as people know the cause and the person affected is not simply labeled as "moody". In individual cases, we refer to endocrinological and psychological experts.
Trouble at being treated as a medical curiosity rather than a sentient human being
Due to the increasing specialization of the medical professions and the cost pressure in the healthcare system, there is not much room for the emotional concerns of a patient with KS. On the other hand, those affected often perceive this as insensitive behavior by doctors.
Specific fears with regard to side effects of the syndrome and questions about the desire to have children and family planning as well as the communicability of these questions and fears to the environment represent an additional challenge.

Since, in the opinion of those affected and psychologists, these mental phenomena are not a necessary consequence of the syndrome, but result from the way those affected as well as relatives and acquaintances deal with the syndrome, psychological counseling and education makes sense, because P. Neemuchwala also says:

“KS patients are below the norm in terms of endocrinology, but may be above norm in terms of e.g. B. intelligence, creativity, table tennis, graphic design, personal charisma etc. concerns. Endocrinology is only part of life. Nobody is either okay or not okay. Neither of us is perfect, and each of us could find a few things about ourselves that we would change if we could. "

“It will work out in the end. You gotta believe. " Jimmy Scott

literature

  • B. Meyenburg, V. Sigusch: Kallmann's syndrome and transsexualism. In: Archives of sexual behavior. Volume 30, Number 1, February 2001, pp. 75-81, doi : 10.1023 / a: 1026420824200 , PMID 11286006 .
  • N. Pitteloud: Reversible Kallmann Syndrome, Delayed Puberty, and Isolated Anosmia Occurring in a Single Family with a Mutation in the Fibroblast Growth Factor Receptor 1 Gene. In: J. Clin. Endocrinol. Metab. Vol. 90, 2005, pp. 1317-1322, PMID 15613419
  • R. Quinton et al .: Kallmann's syndrome: is it always for life? In: Clinical Endocrinology Vol. 50, 1999, pp. 481-485, PMID 10468907 .
  • C. Dode et al .: Kallmann syndrome mutations in the genes encoding prokineticin-2 and prokineticin receptor-2 . In: PLoS Genet . Vol. 2, 2006, p. E175, PMID 17054399 .
  • Johannes Hofmann, Meike Watzlawik, Hertha Richter-Appelt : Living with Kallmann Syndrome. In: Journal for Sexual Research. 26, 2013, pp. 99-121, doi: 10.1055 / s-0033-1335629

Web links

Individual evidence

  1. ↑ a b c d e Kallmann syndrome. In: Orphanet (Rare Disease Database).
  2. ↑ a b Bernfried Leiber (founder): The clinical syndromes. Syndromes, sequences and symptom complexes . Ed .: G. Burg, J. Kunze, D. Pongratz, PG Scheurlen, A. Schinzel, J. Spranger. 7., completely reworked. Edition. tape 2 : symptoms . Urban & Schwarzenberg, Munich et al. 1990, ISBN 3-541-01727-9 .
  3. ↑ a b c emedicine
  4. ↑ FJ Kallmann, WA Schönfeld, SE Barrera: The genetic aspects of primary eunuchoidism. In: Am. J. Ment. Defic. Vol. 48, 1944, pp. 203-236.
  5. ^ G. De Morsier: Etudes sur les dysraphies cranio-encephaliques. I. Agenesis of lobes olfactifs (telencephaloschizis lateral) et des commissures calleuse et anterieure (telencephaloschizis median): la dysplasia olfacto-genitale. In: Swiss Archive for Neurology and Psychiatry. Archives suisses de neurologie et de psychiatrie. Archivio svizzero di neurologia e psichiatria. Volume 74, Numbers 1-2, 1954, pp. 309-361, PMID 14385744 .
  6. ↑ Maestre de San Juan A .: Teratologia: falta total de los nervios olfactorios con anosmia en un individuo en quien existía una atrofia congénita de los testículos y miembro viril. In: El Siglo Med . tape 3 , 1856, pp. 211-221 .
  7. ^ M. Fromantin, J. Gineste, A. Didier, J. Rouvier: Les impubérisms et les hypogonadisms à l'incorporation. Étude statistique. In: Problemes actuels d'endocrinologie et de nutrition. Volume 16, May 1973, pp. 179-199, PMID 4147392 .
  8. ↑ G. Filippi: Klinefelter's syndrome in Sardinia. Clinical report of 265 hypogonadic males detected at the time of military check-up. In: Clinical genetics. Volume 30, Number 4, October 1986, pp. 276-284, PMID 3791676 .
  9. ^ Brachytelephalangia - dysmorphism - Kallmann syndrome. In: Orphanet (Rare Disease Database).
  10. ↑ Kallmann syndrome - cardiopathy. In: Orphanet (Rare Disease Database).
  11. ^ Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1).  In: Online Mendelian Inheritance in Man . (English)
  12. ^ Hypogonadotropic hypogonadism 2 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  13. ↑ C. Dode, JP Hardelin: Kallmann syndrome: fibroblast growth factor signaling insufficiency? In: J Mol Med Vol. 82, 2004, pp. 725-734, PMID 15365636 .
  14. ^ Hypogonadotropic hypogonadism 3 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  15. ^ Hypogonadotropic hypogonadism 4 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  16. ^ Hypogonadotropic hypogonadism 5 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  17. ^ Hypogonadotropic hypogonadism 6 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  18. ↑ hypogonadotropic hypogonadism 7 without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  19. ^ Hypogonadotropic hypogonadism 8 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  20. ^ Hypogonadotropic hypogonadism 12 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  21. ^ Hypogonadotropic hypogonadism 23 with or without anosmia.  In: Online Mendelian Inheritance in Man . (English).
  22. ↑ J. Albuisson et al .: Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). In: Hum. Mutat. Vol. 25, 2005, pp. 98-99, PMID 15605412 .
  23. ↑ hypogonadism, hypogonadotropic normosmischer, congenital form. In: Orphanet (Rare Disease Database).
  24. ↑ Translated quote from the article "Psychological Aspects of Pubertal Delay" by Phiroze Neemuchwala in the newsletter for HYPOHH members, issue 2 from 1998, page 2 ( memento of the original from September 24, 2015 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 191 kB) @1@ 2Template: Webachiv / IABot / www.hypohh.net
  25. ↑ Translated quote from the article "Psychological Aspects of Pubertal Delay" by Phiroze Neemuchwala in the newsletter for HYPOHH members, issue 2 of 1998, page 3 ( memento of the original from September 24, 2015 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 191 kB) @1@ 2Template: Webachiv / IABot / www.hypohh.net