Kallmann syndrome

Smith N, Quinton R. Kallmann syndrome. BMJ. 2012 Dec 3;345:e6971. doi: 10.1136/bmj.e6971.

Sirs, I would like to make further comment on aspects of Kallman’s Syndrome (KS) and testing smell sense. Although KS is typically an X-linked neuronal migration disorder with endocrine deficiency, anosmia and mirror movements, autosomal recessive and dominant forms are recognized. The gene responsible for the typical X-linked recessive form, KAL1, encodes a protein that plays a key role in the migration of gonadotrophin-releasing hormone (GRH) neurons and olfactory nerves to the hypothalamus. It is usually associated with complete anosmia owing to aplasia of the olfactory bulb and tracts in association with hypogonadism.1 Transmitting females often have partial or complete anosmia. In the related condition of congenital maldevelopment of the optic and septal areas (septo-optic aplasia), there is also anosmia and endocrine deficiency.2 An autosomal recessive form of KS has been described which results from mutations in the prokineticin 2 peptide (PROK2) and its receptor PROKR2. If a patient has only one mutant allele the phenotypic variety is wide; some have normal olfaction and pubertal development, others have the endocrine deficiency without anosmia and yet others have anosmia without Endocrinopathy.3

Apart from the variability in olfactory defect mentioned above, the statement that ‘anosmia is 100% ascertainable without formal testing’ is a popular misconception even amongst neurologists. When patients are asked about their sense of smell only about 30% are aware there is anything wrong.4 Smell kits available in clinics are usually badly out of date and the selection of odour type is rarely appropriate. For example oil of cloves has major trigeminal stimulant effect, likewise ammonia and use of these compounds will be guaranteed to produce unreliable results. A simple inexpensive test is the Quick Smell Identification Test (Sensonics Inc.). This consists of three common odors (chocolate, banana and smoke) embedded in scratch pads and the test can be undertaken in one minute. If the patient cannot identify all three odors then there is probably an olfactory defect. If further testing is needed there is a variety of more detailed tests such as the Brief Smell Identification Test and Sniffin Sticks.

Apart from rare disorders like KS, smell testing has now emerged as an important sensory modality particularly relevant for Parkinson’s disease and Alzheimer’s disease where smell impairment is almost invariable and may precede the onset of classical motor or cognitive features.5 Simply asking about smell function in these patients is likewise inadequate

The fault lies within medical schools and their teachers who have never paid due attention to the first cranial nerve. It is time to change this outmoded approach.

Christopher H Hawkes MD FRCP
Honorary Professor of Neurology
Neuroscience Unit
Barts and the London School of Medicine & Dentistry
4 Newark St, London E12AT
c.hawkes@qmul.ac.uk

Competing interest: none.

1. Yousem DM, Geckle RJ, Bilker W, McKeown DA and Doty RL. MR evaluation of
patients with congenital microsmia or anosmia. American Journal of Roentgenology,
1996 166(2), 439–43.

2. de Morsier, G. Median cranioencephalic dysraphias and olfactogenital dysplasia.
World Neurology, 1962, 3, 485–506.

3. Sarfati J, Dodé C, Young J. Kallmann Syndrome Caused by Mutations in the PROK2 and PROKR2 Genes: Pathophysiology and Genotype-Phenotype Correlations. Front Horm Res. 2010;39:121-132. Epub 2010 Apr 8.

4. Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage or disease duration. Neurology 1988; 38:1237-44.

5. Hawkes CH and Doty RL. The Neurology of Olfaction. Cambridge University Press. Chapter 4. 2009.