History

Fact Explanation
Delayed or absent puberty GnRH pulsatile secretions that occur at adolescence initiate the hormonal changes of puberty which are followed by development of secondary sexual characteristics of both sexes and menstruation in females. Patients with Kallmann syndrome (KS) have GnRH deficiency so their onset of puberty is either delayed or absent.[1][2][3][4]
Impaired/abset sense of smell Occurs due to absent (aplasia) or poorly developed (hypoplasia) olfactory bulbs and tracts.[1][2][3][4]
Primary amenorrhoea Results from the lack of gonadotrophins which are necessary to initiate and mantain the normal menstrual cycle.[2][3][4]
Small testis in males Occurs as a result of the congenital GnRH deficiency seen in KS[1][3][4]
Undescended testes in males Occurs as a result of the congenital GnRH deficiency seen in KS[1][3][4]
Lack of breast development in females Due to the low estradiol levels in females with KS.[1][3]
Hearing difficulties Sensorineural hearing loss is seen mainly with patients having the X-linked form of KS[1][3][4]The underlying defect is believed to occur during the organogenesis period of the embryo.[4]
Cleft lip or cleft palate Occur in some patients with KS, particularly those with KAL2 gene defect.[1][2]
Abnormalities of teeth Is seen in some patients with KS. Which may have resulted from abnomalities that occur during embryonic development[1][2][4]
Lack of facial hair growth in males Occurs due to low level of testosterone which determines secondary sexual characteristcs development in males[1][3]
Difficulty in doing tasks that require the hands to move separately (eg;- playing a musical instrument) Some patients with KS bimanual synkinesis, in which the movements of one hand are mirrored by the other hand so that it is difficult to do tasks that require hands to move separately.[1][2][3][4]
Dyspareunia Due to lack of vaginal lubrication due to estrogen deficiency[3]
Subfertility Spermatogenesis in mals and ovulation in females is impaired due to deficient secretion of hormones in the hypothalamo-pituitary-gonadal axis, when they have KS[1][3]
Loss of libido Occurs due to low levels of testosterone[3]
Erectile Dysfunction Seen in some men with KS[3]
References
  1. Genetic Home Reference. Kallmann syndrome.[online] Reviewed: August 2008 Published: April 28, 2014.[viewed on 5May 2014] Available from; http://ghr.nlm.nih.gov/condition/kallmann-syndrome
  2. Catherine D.Jean-P.H.Kallmann syndrome.European Journal of Human Genetics.[online] Feb 2009; 17(2): 139-146[viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986064/#!po=40.6250
  3. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/
  4. AbuJbara A.M.Hamamy H.A.Jarrah N.S.Shegem N.S. AjlounI K.M. Clinical and inheritance profiles of Kallmann syndrome in Jordan. Reproductive Health[online] 2004; 1: 5.[viewed on 5 May 2014] Available from; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC533860/#__ffn_sectitle

Examination

Fact Explanation
Reduced/ absent sense of smell Patients with KS have absent (aplasia) or poorly developed (hypoplasia) olfactory bulbs and tracts.[1][2][3][4]
Eunuchoid body habitus (i.e., arm span exceeds height by ≥5 cm) Sex hormones are needed for the fusion of growth plates in bones. Due to the absence of sex hormones the growth plates fail to fuse resulting in a eunuchoid body habitus [3]
Undescended testes (cryptorchidism) in males Occurs due to congenital GnRH deficiency[1][3][4]
Small penis (microphallus) in males Also occurs due tocongenital GnRH deficiency[1][3][4]
Absent facial hair and decreased body hair in men Due to low plasma testosterone levels, secondary sexual characteristics development is deficient[1][3]
Absent deepening of voice in males Tetosterone deficiency seen in KS affects development of secondary sexual characteristics[1][3]
Prepubertal testicular volume (i.e., <4 mL)is seen in males Results from gonadotrophin deficiency. Men with KS typically have Tanner stage I-II genitalia.[3]
Prepuberta breast size present in females Females with KS typically have Tanner stage I breast development due to deficiency of estradiol[1][2][3]
Unilateral absent kidney May result from the developmental failures that occur during the organogenesis period of the embryo.[1][2][3]
cleft lip with or without a cleft palate Occur in some patients with KS, particularly those with KAL2 gene defect.[1][2]
Abnormal eye movements Is seenin some patients with KS[1][2][3]
Abnormalities in teeth Is seen in some patients with KS. Which may have resulted from abnomalities that occur during embryonic development[1][2][3]
Impaired hearing Sensorineural hearing loss is seen mainly with patients having the X-linked form of KS[1][3][4]The underlying defect is believed to occur during the organogenesis period of the embryo.[4]
Bimanual synkinesis Mirror movements of hands or bimanual synkinesis seen in KS is attributed to an abnormal projection of the corticospinal tract[1][2][3][4]
High arched palate A fetal developmental abnormality seen in KS patients with genetic mutations such as KAL1,CHD7 [2][3]
References
  1. Genetic Home Reference. Kallmann syndrome.[online] Reviewed: August 2008 Published: April 28, 2014.[viewed on 5May 2014] Available from; http://ghr.nlm.nih.gov/condition/kallmann-syndrome
  2. Catherine D.Jean-P.H.Kallmann syndrome.European Journal of Human Genetics.[online] Feb 2009; 17(2): 139-146[viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986064/#!po=40.6250
  3. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/
  4. AbuJbara A.M.Hamamy H.A.Jarrah N.S.Shegem N.S. AjlounI K.M. Clinical and inheritance profiles of Kallmann syndrome in Jordan. Reproductive Health[online] 2004; 1: 5.[viewed on 5 May 2014] Available from; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC533860/#__ffn_sectitle

Differential Diagnoses

Fact Explanation
Normosmic idiopathic hypogonadotrophic hypogonadism A main differential diagnosis of KS. Has clinical features similar to KS.Dffers from KS because sensation of smell is normal[1]
CHARGE syndrome An important differential diagnosis of KS. Most CHARGE patients have both olfactory bulb aplasia or hypoplasia and hypogonadotrophic hypogonadism which are the two defining features of KS. In addition to these the CHARGE defining features are coloboma, heart anomalies, choanal atresia, retardation of growth and/or development, genital and ear anomalies.[1][2][4]
CNS or pituitary tumors Can present with clinical features of hypogonadism[2]
Pituitary apoplexy Also present with clinical features of hypogonadism[2]
Functional gonadotrophin deficiency May result from hyperprolactinemia, chronic systemic illness, eating disorders, malnutrition, hypothyroidism, diabetes mellitus, Cushing’s disease etc.[2]
Hereditary Hemochromatosis(HH) This is an autosomal recessive disorder that disrupts the body's regulation of iron leading to excess iron deposition in body organs. Hypogonadism is a recognized clinical presentation of HH.[2][3]
Hypothyroidism Can present with amenorrhoea and subfertilty.[5] Which are seen in KS also. [2]
References
  1. Catherine D.Jean-P.H.Kallmann syndrome.European Journal of Human Genetics.[online] Feb 2009; 17(2): 139-146[viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986064/#!po=40.6250
  2. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/
  3. Crownover B.K.Carlton J. C. Hereditary Hemochromatosis.Am Fam Physician. 2013 Feb 1;87(3):183-190.[viewed on 3 May 2014] Available from; http://www.aafp.org/afp/2013/0201/p183.html
  4. Pinto G, Abadie V, Mesnage R, et al. CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development. Journal of Clinical Endocrinology and Metabolism.[online] 2005;90:5621–5626.[viewed on 4 May 2014] Available from; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708033/
  5. Gaitonde D.Y.Rowley K.D.Sweeny L.B.Hypothyroidism: An Update. Am Fam Physician.[online] 2012 Aug 1;86(3):244-251 [viewed on 4 May 2014] Available from; http://www.aafp.org/afp/2012/0801/p244.html

Investigations - for Diagnosis

Fact Explanation
Urine beta-human chorionic gonadotropin To exclude pregnancy in females wtih amenorrhoea[5]
Serum ferritin To exclude hereditary haemochromatosis[4]
Serum total testosterone Total testosterone level <100 ng/dl is seen among males with KS[1][3]
Serum estradiol Estradiol level <20 pg/dl is seen among adult females with KS [3]
Serum luteinizing hormone(LH) Low basal level of LH is present in both males and females with KS[1][2][3]
Serum follicle-stimulating hormone(FSH) Low basal level of FSH is present in both males and females with KS[1][2][3]
Serum prolactin Proactin levels are normal in patients with Kallmann syndrome. This test is done to exclude hyperprolactinemic conditions that can cause hypogonadism[1]
Magnetic resonance imaging(MRI) of the brain To show the hypoplasia or aplasia of the olfactory bulbs and tracts. MRI is also useful to exclude hypothalamic or pituitary lesions as the cause of hypogonadotrophic hypogonadism.[1][2][3]
Genetic testing KS results from gene defects such as KAL1, FGFR1, PROKR2, PROK2, CHD7, and FGF8 which can be detected by genetic testing methods like Deletion/duplication analysis and Sequence analysis.[1]
Serum TSH To exclude hypothyroidism in patients with amenorrhoea[5]
LH-RH stimulation test Patients with hypogonadotrophic hypogonadism show a suboptimal increase in serum LH level in response to LH-RH stimulation.[3][7]
Anterior pituitary imaging (with either contrast enhanced computed tomography [CT] or MRI) Anterior pituitary adenomas causing hyperprolactinaemia may result in hypogonadism with clinical features similar to KS. Gadolinium-enhanced MRI should be performed to detect anterior pitutary adenomas. CT is less effective than MRI in diagnosing small adenomas, but may be used if MRI is unavailable or contraindicated.[6]
References
  1. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/
  2. Catherine D.Jean-P.H.Kallmann syndrome.European Journal of Human Genetics.[online] Feb 2009; 17(2): 139-146[viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986064/#!po=40.6250
  3. Mousa A.A. Hanan A.H.Kamel M.A.Clinical and inheritance profiles of Kallmann syndrome in Jordan.Reproductive Health.[online] 2004;1:5[viewed on 3 May 2014] Available from; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC533860/
  4. Crownover B.K.Carlton J. C. Hereditary Hemochromatosis.Am Fam Physician. 2013 Feb 1;87(3):183-190.[viewed on 3 May 2014] Available from; http://www.aafp.org/afp/2013/0201/p183.html
  5. Hunter T.M.Heimana D.L. Amenorrhea: Evaluation and Treatment.Am Fam Physician. 2006 Apr 15;73(8):1374-1382.[viewed on 3 May 2014] Available from;http://www.aafp.org/afp/2006/0415/p1374.html
  6. Felipe F et al.Blackwell Publishing Ltd Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clinical Endocrinology.[online] 2006; 65, 265–273.[viewed on 10 May 2014] Available from; http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2006.02562.x/pdf
  7. Hemchand K. P. Vaman V.K. Rahul J. Anuradha V. K. Sanjay K.L. Evaluation of GnRH analogue testing in diagnosis and management of children with pubertal disorders. Indian Journal of Endocrinology and Metabolism. [online] 2012 May-Jun; 16(3): 400–405.[viewed on 10May 2014] Available from; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354848/#__ffn_sectitle

Investigations - Followup

Fact Explanation
Serum LH To monitor response to treatment[1]
Serum FSH To monitor response to treatment[1]
Serum total testosterone To monitor adequacy of testosterone replacement therapy.[1]
Serum estradiol in females To monitor adequacy of estrogen replacement therapy.[1]
Dual-energy radiographic absorptiometry (DXA) Paients with KS are at an increased risk of developing osteoporosis. This test assesses bone mineral density and it can detect the presence of osteopenia or osteoporosis.[1]
References
  1. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/

Investigations - Screening/Staging

Fact Explanation
Ultrasound sacan of abdomen To detect unilateral renal agenesis (absent kidney) seen in some patients with KS.[1][2]
Smell testing To detect anosmia/hyposmia which is a key feature of KS. University of Pennsylvania smell identification test (UPSIT) is an example for a formal smell test that can be used.[1]
Audiometry To detect sensorineural hearing loss.[1]
Dual-energy radiographic absorptiometry (DXA) To assess bone mineral density as patients with KS are at an increased risk of developing osteoporosis.[1][3]
Skeletal survey To detect limb/spine bony abnormalities.[1]
References
  1. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/
  2. Campion J.M. Maricic .M.J. Osteoporosis in Men. Am Fam Physician. 2003 Apr 1;67(7):1521-1526.[viewed on 3 May 2014] Available from; http://www.aafp.org/afp/2003/0401/p1521.html
  3. Catherine D.Jean-P.H.Kallmann syndrome.European Journal of Human Genetics.[online] Feb 2009; 17(2): 139-146[viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986064/#!po=40.6250

Management - General Measures

Fact Explanation
Genetic Counseling Genetic counselling involves providing individuals and families with information on the nature, inheritance, and implications of KS to help them make informed medical and personal decisions.[1]
Calcium and vitamin D Individuals with KS have an increased risk to develop osteoporosis. There fore optimal calcium and vitamin D intake should be encouraged.[1][2]
Bisphosphonates Treatment with bisphosphonates should be considered in KS patients who have decreased bone mass. [1][2]
Psychological counseling This is helpful in patients who have problems coping with thier condition.[1]
References
  1. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/
  2. Campion J.M. Maricic .M.J. Osteoporosis in Men. Am Fam Physician. 2003 Apr 1;67(7):1521-1526.[viewed on 3 May 2014] Available from; http://www.aafp.org/afp/2003/0401/p1521.html

Management - Specific Treatments

Fact Explanation
Hormone replacement therapy to initiate and maintain, virilisation in males and breast development in females To initiate virilisation, testosterone replacement therapy is given for males. Human chorionic gonadotropin (hCG)is an alternative to testosterone therapy. For females initial treatment should consist of unopposed estrogen replacement to allow optimal breast development. Once this is achieved a progestin is added for endometrial protection.[1][2][3]
Hormone replacement therapy to induce and maintain fertility Both males and females with KS are given either gonadotropin therapy or pulsatile GnRH therapy to induce and maintain fertility. This treatment helps to achieve spermatogenesis in males and ovulation in females.[1][2][3]
References
  1. Buck C, Balasubramanian R, Crowley WF Jr. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 2007 May 23 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [online]. Seattle (WA): University of Washington, Seattle; 1993-2014. [viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK1334/
  2. Catherine D.Jean-P.H.Kallmann syndrome.European Journal of Human Genetics.[online] Feb 2009; 17(2): 139-146[viewed on 3 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986064/#!po=40.6250
  3. Mousa A.A. Hanan A.H.Kamel M.A.Clinical and inheritance profiles of Kallmann syndrome in Jordan.Reproductive Health.[online] 2004;1:5[viewed on 3 May 2014] Available from; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC533860/