National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Kallmann Syndrome is not the name you expected.
Kallmann syndrome (KS) is a rare genetic disorder in humans that is defined by a delay/absence of signs of puberty along with an absent/impaired sense of smell. A closely related disorder, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), refers to patients with pubertal failure but with a normal sense of smell. Both KS and nIHH are due to an isolated deficiency of a key reproductive hormone called gonadotropin-releasing hormone (GnRH). KS and nIHH occurs in both sexes but males are more commonly diagnosed with this condition.
Patients with KS/nIHH typically present at adolescence due to the delay in the onset of physical changes associated with puberty. KS patients are often aware of their lack of sense of smell but most may not have sought medical advice for this symptom. While these reproductive symptoms predominate in their presentation, non-reproductive features that may be present in KS/nIHH subjects include: facial abnormalities (eg. cleft lip/palate), absence of one kidney, shortened digits, deafness, eye movement abnormality etc. Typically, the diagnosis of KS/nIHH is made by a pediatric/adult endocrinologist. Following clinical examination, biochemical blood testing and various imaging tests are undertaken to confirm the diagnosis. As this is a genetic condition, testing for the various different genetic forms of this disease may also assist in making the diagnosis.
For therapy, initially, hormone replacement therapy (testosterone in males; estrogen and progesterone in females) is used to induce secondary sexual characteristics. Once pubertal maturation is achieved, if KS and nIHH subjects wish to be fertile, either injections of pituitary hormones (the gonadotropins, LH and FSH) or in some instances, therapy with the synthetic peptide, GnRH, whose deficiency causes these syndromes, are required to induce the sex organs (testes or ovaries) to make sperm (males) or eggs (females). While both KS and nIHH are usually life-long in their nature, about 10-15% of patients may experience a recovery of their hormonal system, the reasons for which currently remain unclear.
Normal reproductive axis in humans
The hypothalamus is a special area in the brain that is responsible for control of several hormones in the body. Reproductive function in humans is under the control of a group of ~ 1,200-1,500 cells (neurons) called GnRH (Gonadotropin-Releasing Hormone) neurons. At the time of puberty, these neurons coordinately secrete GnRH, a peptide hormone, in a series of discrete series of bursts or pulses. This pulsatile pattern of secretion of GnRH is the key to stimulating the production of two other glycoprotein hormones from the pituitary which is downstream from the hypothalamus, namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In turn, LH and FSH act on the sex organs or gonads in both sexes (testicles in men; ovaries in women) to do two things that are essential for human reproduction. The first is to stimulate the gonads to secrete sex steroids like testosterone in men and estrogen in women. The second is to produce the germ cells in the gonads (sperm in men and eggs in women).
Pathophysiology of Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH)
GnRH is the master controller or 'pilot light' of reproduction. GnRH neurons are active in stimulating the reproductive axis at birth; become quiet during childhood; and initiate the awakening of the dormant reproductive axis of children at puberty. The GnRH neurons for these processes are unique amongst other hypothalamic neurons in the fact that they have a very complex developmental pattern. During the fetal period, these GnRH neurons originate in the olfactory placode (i.e. the early developing nose); then migrate along the fetal olfactory (smell-related) neurons that also originate in the nose; and eventually enter the brain ultimately wending their way to the hypothalamus, their ultimate residence during early gestation. In both sexes, these GnRH neurons are fully active and functional secreting GnRH soon after birth (neonatal period) and begin to secrete GnRH in a characteristic pulse pattern. However, this GnRH secretory activity, for reasons not entirely clear, becomes quiescent in childhood and mysteriously, reawakens again during adolescence marking the onset of puberty. Defects in either the development of GnRH neurons or their secretory function result in disruption of normal puberty. The condition of KS results when there is failure of the early development and/or migration of the GnRH neurons in the fetus. Therefore, when this migratory journey is interrupted due to various genetic defects, patients develop this unique combination of GnRH deficiency and anosmia (due to loss of olfactory neurons), that define this clinical syndrome. When GnRH deficiency results from either from defective GnRH secretion/action without any developmental migratory deficits, patients present with just GnRH deficiency without any smell defects. This group of patients is labeled as nIHH subjects, the nomosmic counterpart to KS. In both KS and nIHH patients, the rest of the hypothalamic and pituitary hormones are completely normal and the radiographic appearance of the hypothalamic-pituitary region is typically normal. Taken together, both KS and nIHH represent patients with "isolated GnRH deficiency" (IGD), which is the most precise pathophysiologic definition of this disorder.
Historically, it was the KS form of IGD that was recognized first. As early as in the 19th century, the clinical association of anosmia and hypogonadism was recognized by a Spanish pathoglogist, Maestre de San Juan. However, it was Kallmann and Schoenfeld in 1944 who redefined this syndrome in the modern era. They showed the co-segregation of anosmia and hypogonadism in affected individuals from three families and therefore established the hereditary nature of this syndrome (i.e. passing from parents to offspring). Since then, this combination of hypogonadotropic hypogonadim and anosmia is described with the eponymous name, "Kallmann syndrome". However, even in Kallmann's first report, the presence of nIHH individuals was also recognized in some of these families as well as the presence of various non-reproductive clinical features. Since these early reports, both these clinical entities have been well studied and this report summarizes the clinical symptoms, causes, their associated non-reproductive phenotypes, the correct diagnostic work up, and the various treatment options for both KS and nIHH forms of IGD.
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Last Updated: 7/14/2015
Copyright 2012 National Organization for Rare Disorders, Inc.
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