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The first known report of the syndrome was in 1856, when Maestre de San Juan described an autopsy finding of a 40-year-old hypogonadal man with very small testes and absent olfactory bulbs. Kallmann first reported the familial nature of eunuchoidism with anosmia in a description of three families, suggesting a genetic etiology, but the first definitive evidence of a defect in of the hypothalamic-pituitary axis came with the development of assays for urinary gonadotropins. Kallmann's Syndrome was classified as a form of hypogonadotropic hypogonadism. Subsequent studies provided clear evidence for a defect in endogenous gonadotropin-releasing hormone (GnRH) secretion.
Definition and Incidence
Kallmann de Morsier Syndrome refers to the association of congenital hypogonadotropic hypogonadism with anosmia or hyposmia. The syndrome is also referred as olfactogenital dysplasia. Idiopathic hypogonadotropic hypogonadism is a broader term used to describe patients with unexplained isolated gonadotropin deficiency associated or not with anosmia. Even individuals within an affected family can express both isolated gonadotropin deficiency and anosmia, whereas others express isolated gonadotropin deficiency and a normal sense of smell.
Kallmann's Syndrome is a heterogeneous genetic disorder affecting 1 in 10.000 to 60.000 individuals. Males predominate in a ratio of 5:1. The syndrome can occur as an inherited or sporadic disorder. X-linked, autossomal dominant, and autossomal recessive modes of inheritance have been described. The sporadic cases exhibit similar clinical features of the classic inherited disorder. Even in the autossomal dominant transmission, males are still more commonly affected. Regardless of the inheritance pattern, incomplete expression of the known features of the syndrome is commonly noted, because there is a variability in the penetrance of the gene.
Pathophysiology
The basic defect leading to hypogonadism in this syndrome is an abnormality of hypothalamic GnRH secretion secondary to failure of gonadotropin-releasing hormone(GnRH)-producing neurons to migrate from the olfactory placode to the brain, and to agenesis of the olfactory bulbs. Recently it has been demonstrated that in the X-linked inheritance, there is a mutation in gene KALIG-1, which encodes protein with homology to Neural Cell Adhesion Molecule (N-CAM) and that normal migration of GnRH neurons from their site of embryonic origin in the medial nasal placode to the hypothalamus can be blocked in fetal mice with antisera against N-CAM.
Patients with Kallmann's syndrome usually come to medical attention because of a delayed puberty or incomplete sexual development. Anosmia or hyposmia is present in 80% of the patients and establishes the diagnosis of the syndrome in individuals with isolated gonadotropin deficiency. Prepuberal testes, micropenis and cryptorquidism are usually seen. In women pubic and axillary hair are less reliable compared with absence of appearance of breast buds since adrenarche can occur independently of gonodarche.
Other manifestations include: skeletal abnormalities (syndactily, short forth metacarpals, craniofacial asymmetry), mid-line defects (cleft-lip or -palate, color blindness, renal agenesis, nerve deafness), malrotation of the gut, congenital heart disease and neurologic findings (synkinesia, impaired "smooth pursuit" eye movements and cerebellar dysfunction). X-linked disorder can be associated with X-linked ichthyosis, mental retardation, chondrodysplasia punctata, and short stature.
When patients with Kallmann's syndrome are identified after the age of 16, eunuchoidal skeletal proportions are often present. Arm span can exceed height by 6 cm, and the upper to lower body ratio can be decreased.
Diagnosis
Hypogonadotropic hypogonadism is established in adults by the finding of normal or low serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the presence of low concentrations of testosterone in males and estradiol in females. In younger patients, these measurements cannot differentiate individuals with gonadotropin deficiency from those with constitutional delay of puberty. This distinction is very difficult. Failure to initiate puberty by age 14 in boys and 13 in girls defines delayed puberty. No reliable test discriminate reliably these two entities. Prolonged observation is the only way to distinguish Idiopathic Hypogonadotropic Hypogonadism (IHH) from delayed puberty.
Once hypogonadotropic hypogonadism is established, the positive famial history and
the presence of anosmia or associated abnormalities strongly suggests the diagnosis of
the syndrome, IHH remains a diagnosis of exclusion. Thyroid function tests should
include TSH and free T4 and prolactin measurement in indicated in all patients. An ACTH
estimulation test should be performed when necessary. Serum iron,
transferrin saturation, and ferritin are indicated, since hemochromatosis is a
differential diagnosis, as well as a high resolution computed tomography scanning or
resonance imaging. The olfactory threshold should be tested since patients may not be
aware of the diminished sense of smell.
In the differential diagnosis there are common and rare causes
1 - Common: constitutional delay of puberty, idiopathic hypopituitarism, craniopharyngioma, therapeutic irradiation, chronic systemic illness, malnutrition, anorexia nervosa, bulimia, hypothyroidism, hyperprolactinemia, Cushing's syndrome, diabetes mellitus.
2 - Rare: head trauma, post-infectious complications, vascular malformations, other hypothalamic or pituitary tumors, hystiocytosis X, congenital adrenal hypoplasia, and others.
Treatment
A - Men
1)Testosterone replacement
Testosterone enanthate or cypionate 50-100 mg IM q 2 week (initial dose)
Testosterone enanthate or cypionate 200 mg IM q 2 week (adult dose)
2)Induction of Spermatogenesis
It can be initiated in most men with gonadotropin administration or with pulsatile GnRH therapy. Clomiphene is ineffective in IHH. Achieving normal sperm production can take 2 or more years of therapy in some patients.
B - Women
1)Gonadal Steroid Replacement
Cyclic estrogen-progestin replacement.
Conjugated estrogen 0.3 mg PO daily (initial)
Conjugated estrogen 0.625-1.2 mg PO daily day 1-25, plus medroxy progesterone acetate 10 mg PO for last 10-14 days (to initiate and maintain normal menses)
2)Induction of Ovulation
When fertility is desired, ovulation can be achieved with either gonadotropins or pulsatile GnRH therapy.
Prognosis
Induction and maintenance of secondary sexual characteristics are quite successful in Kallmann's syndrome and fertility can be achieved in many affected individuals. Patients with testicular volumes >2.5 cm have a better prognosis
1 - Greenspan, Basic & Clinical Endocrinology, 95, 511, 512f
2 - Wyngaarden, Cecil Textbook of Medicine, 1346
3 - Isselbacher, Harrison’s Principles of Internal Medicine, 1902-1903, 2011, 2027-2028
4 - Christensen RB, Idiopathic Hypogonadotropic Hypogonadism with Anosmia, The Endocrinologist, 332-340, Volume 2, number 5, 1992
5 - Legouis R, Isolation and characterization of the gene responsible for the X chromosome-linked Kallmann syndrome, Biomed Pharmacother, 48: 5-6, 1994, 241-6
6 - Schwanzel-Fukuda M, Luteinizing hormone-releasing hormone (LHRH) and neural cell adhesion molecule (NCAM)-immunoreactivity in development of the forebrain and reproductive system., Ann Endocrinol (Paris), 55: 6, 1994, 235-41
7 - Parenti G, Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene, Am J Med Genet, 57: 3, 1995 Jul 3, 476-8
Acknowlogments to Monica Roberto Gadelha MD, Professor of Endocrinology at Federal University of Rio de Janeiro, for her helpful review of this article.
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