A Patient’s Journey

Kallmann syndrome

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6971 (Published 3 December 2012)
Cite this as: BMJ 2012;345:e6971

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25 January 2013

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sense of smell only about 30% are aware there is anything wrong.4 Smell kits available in clinics are usually badly out of date and the selection of odour type is rarely appropriate.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.

Competing interests: None declared

Christopher Hawkes, Honorary Professor of Neurology

Blizard Neuroscience Unit, 4 Newark St, London E1 2AT

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Further to a Patient Journey with Kallmann syndrome by N Smith and R Quinton1, a current pragmatic challenge in treating men with congenital hypogonadotropic hypogonadism (CHH) is the unavailability of human chorionic gonadotropin (HCG) preparations. Manufacturing shortages of the HCG formulation Pregnyl have rendered its supply in NHS pharmacies patchy at best. As a result, male patients with an indication for gonadotropin treatment are left with an unmet need.

According to the American Society of Health Systems Pharmacy, the supplying company Merck states their product is on allocation in order to prevent use in the grey market2.In the UK the Pharmaceutical Services Negotiating Committee confusingly does not include Pregnyl in the shortages list3. HCG formulations seem to be available to purchase online, however it is uncertain if they have been reviewed for licensed use in the UK, and worryingly they do not require a prescription. A pulsatile gonadorelin infusion, that can be used as an alternative, is many times more expensive and requires the use of specialist skills and resources.

There needs to be more clarity on the issue and justified distribution. As Smith and Quinton state, there is no specific funding stream for gonadotropin treatment of male infertility in the NHS and this results in “buck-passing” between primary and secondary healthcare providers1. One wonders if a structured funding pathway for male infertility would serve the dual purpose of clarifying the funding responsibilities and securing gonadotropin supplies for men with CHH.

References
1N Smith, R Quinton. A Patient Journey: Kallmann Syndrome. BMJ 2012;345:e6971

2http://www.ashp.org/drugshortages/current/bulletin.aspx?id=382 Accessed 06.01.2013

3http://www.psnc.org.uk/pages/manufacturer_quota_schemes_.html Accessed 06.01.2013

Dr Aikaterini Theodoraki, Research Registrar
Professor Pierre-Marc Bouloux, Professor of Endocrinology
Centre for Neuroendocrinology
Royal Free Hospital
Pond Street
Hampstead
NW3 2QG

Competing interests: None declared

Aikaterini Theodoraki, Research Registrar

Professor Pierre-Marc Bouloux, Professor of Endocrinology

Centre for Neuroendocrinology, Royal Free Hospital, Pond Street, Hampstead, NW3 2QG

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19 December 2012

I wrote this article on my story on having Kallmann syndrome in the hope it can help other patients achieve an early diagnosis and treatment.

Through my work with patient groups and forums I frequently come across stories of fellow patients, both men and women, who struggle to get a diagnosis while in their teens and get labelled as "late starters" or "late developers". The psychological damage this can do at an important developmental age can be severe I think.

I hope this article plus the editorial by Prof. Pitteloud will highlight Kallmann syndrome and other forms of hypogonadotropic hypogonadism as a rare, but a possible cause of a failure of puberty in both males and females and that an earlier endocrine review can have a major positive impact on a patient.

Competing interests: None declared

Neil D Smith, neilsmith38@hotmail.com

Patient, Worcester, UK

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