Which conditions are associated with a hypergonadotropic hypogonadism etiology of microphallus?

Updated: Nov 30, 2020
  • Author: Karen S Vogt, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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Answer

Anosmia (lack of sense of smell) or hyposmia is a prominent feature of Kallmann syndrome, which occurs in 1 per 10,000 males. The underlying abnormality is failure of migration of gonadotropin-releasing hormone (GnRH) and olfactory neurons from the olfactory placode to their proper locations in the hypothalamus and olfactory bulb, respectively. About half of males with Kallmann syndrome are born with a micropenis. The inheritance pattern is autosomal dominant (FGFR1/KAL-2 gene, among others), autosomal recessive, or X-linked recessive (KAL-1 gene). Associated anomalies may include cleft lip and palate, renal agenesis, sensorineural hearing loss, visual abnormalities, synkinesia (mirror image movements), cerebellar ataxia, agenesis of the corpus callosum, short metacarpals, or pes cavus. Abnormal or absent olfactory bulbs or sulci (folds) are seen on brain MRI in 90% of patients. [17, 18]

Isolated hypogonadotropic hypogonadism

Sense of smell is normal in this condition, differentiating it from Kallmann syndrome. [17]  An observational cohort study by Bonomi et al indicated that there is a greater tendency for a severe and complex phenotype to arise in Kallmann syndrome than in normosmic isolated hypogonadotropic hypogonadism. [19]

Multiple pituitary hormone deficiencies

Hypoglycemia may occur due to growth hormone and adrenocorticotrophic hormone (ACTH) deficiencies. Midline defects and cholestatic liver disease can be associated. Hypopituitarism may be secondary to transcription factor mutations (eg, PROP-1, LHX3); however, in most instances, genetic evaluation is not part of the routine diagnostic evaluation. [20, 21]

Septo-optic dysplasia (SOD)

Major features of SOD include the triad of absent septum pellucidum, optic nerve hypoplasia, and hypopituitarism. Wandering nystagmus may be present. The multiple pituitary hormone deficiencies may be present at birth or develop over years. Mutations in the HESX1 gene (RPX) have been associated with SOD. [20, 21]


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