This clinical presentation is consistent with Kallmann syndrome, a type of hypogonadotropic hypogonadism associated with anosmia that results from failure of GnRH-secreting neurons to migrate from the olfactory placode, through the cribriform plate and olfactory bulb, and into the hypothalamus.
A lack of pulsatile GnRH in Kallmann syndrome leads to decreased levels of LH/FSH produced by the anterior pituitary, and a concomitant decline in testosterone production by the testes. Kallmann syndrome involves delayed puberty and anosmia, or an inability to smell, as well as other potential congenital abnormalities (mid-line defects, renal agenesis, or skeletal abnormalities). Laboratory analysis will show low levels of LH/FSH and testosterone, an important finding that distinguishes Kallmann's syndrome from forms of hypergonadotrophic hypogonadism.
Blondell et al. provide a systematic approach to the diagnostic workup of disorders of puberty. They define normal puberty as occurring between 8 and 14 years of age in girls and between 9 and 14 years of age in boys. They discuss the differential diagnosis of delayed puberty, which includes constitutional delay of puberty (treatment is controversial), hypopituitarism, and chromosomal abnormalities.
Kaplan et al. describe six genes that have been associated with Kallmann syndrome, and also argue that patients with features of Kallmann syndrome should have an audiology exam and renal ultrasound. Despite linkage to 6 genes, the authors report that only 30% of patients with a clinical diagnosis of Kallmann syndrome are found to have a mutation in one of these 6 genes. X-linked, autosomal dominant, and autosomal recessive inheritance patterns have all been described.
Illustration A depicts the important GnRH-FSH/LH-testosterone axis that is disrupted in Kallman's syndrome, along with the resulting clinical effects.
Answer 1: This answer suggests syndromes caused by chromosomal aberrations, such as Klinefelter syndrome, where patients have an extra X chromosome (XXY), and are generally tall, with small firm testes, a eunachoid body habitus (as in Kallmann), and mild mental retardation.
Answer 2: This answer suggests a suprasellar tumor such as a craniopharyngioma, which can affect the normal function of the pituitary gland and disrupt puberty; however, this would not explain this patient's anosmia.
Answer 3: Exposure to radiation could potentially affect important reproductive functions such as spermatogenesis, but this would not explain this patient's anosmia.
Answer 5: This answer alludes to conditions such as congenital adrenal hyperplasia, which can cause virilization or delayed sexual maturation (depending on specific type) in children, but would not explain this patient's anosmia.
Blondell RD, Foster MB, Dave KC. Disorders of Puberty. Am Fam Physician. 1999 Jul 1; 60(1):209-218,223-4.
PMID:10414639 (Link to Abstract)
Kaplan JD, Bernstein JA, Kwan A, Hudgins L. Clues to an early diagnosis of Kallmann syndrome. Am Jnl Med Ethics. 2010 Nov; 152(11):2798-2801.
PMID:20949504 (Link to Abstract)