Several genetic conditions can lead to failure of puberty. Kallman syndrome is a type of hypogonadotropic hypogonadism that is associated with anosmia. GnRH-secreting neurons formed in the olfactory placode migrate across the cribriform plate into the olfactory bulb and ultimately reside in the hypothalamus. In Kallman syndrome, the olfactory bulb does not develop normally and the hypothalamus fails to regulate FSH and LH release. Several causative X-linked and autosomal dominant gene mutations have been discovered.
Prader-Willi syndrome, discussed in Chap. 37, is associated with hypogonadism and incomplete sexual development along with other endocrine abnormalities affecting growth and satiety. The Bardet-Biedl syndrome is a heterogenous disorder affecting multiple organ systems. Variable growth retardation, obesity, and diabetes mellitus are seen, along with hypogonadism and anosmia. The causative mutations affect ciliary function at several sites.
In 1901, Froehlich first described this condition characterized by obesity and gonadal underdevelopment, relating the disorder to a pituitary tumor. A few years later Erdheim recognized that the same syndrome could be a manifestation of a lesion involving or restricted to the hypothalamus. In some patients, the clinical state is characterized by loss of vision, aggression, abulia, apathy, and reduced verbal output. DI may be another clinical feature. The usual causes of the Froehlich syndrome are craniopharyngioma and glioma, but many other tumors have been reported (pituitary adenoma, cholesteatoma, lipoma, meningioma, angiosarcoma, and chordoma). The condition bears some clinical similarities to the Prader-Willi syndrome, as discussed in Chap. 37.
Neuroanatomic studies have localized an appetite center in the ventrolateral nucleus and a satiety center in the ventromedial nucleus of the hypothalamus. Lesions in the lateral hypothalamus may result in a failure to eat and, in the neonate, failure to thrive; lesions in the medial hypothalamus may result in overeating and obesity. Bray and Gallagher, who analyzed 8 cases of the latter type, concluded that the critical lesion was bilateral destruction of the ventromedial regions of the hypothalamus. Most of the reported cases of this type have been caused by tumors, particularly craniopharyngioma, and some by trauma, inflammatory disease, and hydrocephalus (Suzuki et al). Reeves and Plum studied one case with prominent hyperphagia in which a hamartoma had destroyed the medial eminence and the ventromedial nuclei bilaterally sparing the lateral hypothalamus. It is evident, however, that in only a tiny fraction of people can obesity be traced to a hypothalamic lesion. Of overriding importance are genetic factors, such as the number of lipocytes that one inherits and their ability to store fat.
A diencephalic syndrome that occurs in infants describes a progressive and ultimately fatal emaciation (failure to thrive), despite normal or near-normal food intake, in an otherwise alert and cheerful infant. The lesion has usually proves to be a low-grade astrocytoma of the anterior hypothalamus or optic nerve (Burr et al).
Extrahypothalamic parts of the brain, if diseased, may also be associated with increased food-seeking behavior, food ingestion, and weight gain. Examples are involvement of limbic structures, as in the Klüver-Bucy syndrome, and basal frontal lobe lesions leading to gluttony. Indeed, the primacy of hypothalamic lesions in causing pathologic weight gain has been challenged in a review of published cases by Uher and Treasure.