Kallmann Syndrome
Summary
Kallmann Syndrome (KS) is a rare genetic condition characterised by Hypogonadotropic Hypogonadism (HH) combined with Anosmia or Hyposmia (Absent or reduced sense of smell). It results from failure of GnRH (Gonadotropin-Releasing Hormone) neurons to migrate from the olfactory placode to the hypothalamus during embryonic development, coupled with abnormal development of olfactory structures. This leads to a deficiency of LH and FSH secretion, resulting in failure to enter or complete puberty and infertility. Males typically present with absent/delayed puberty, micropenis, cryptorchidism, and infertility. Females present with primary amenorrhoea and lack of breast development. KS can be inherited in X-linked (KAL1/ANOS1), Autosomal Dominant, or Autosomal Recessive patterns, Or occur sporadically. Treatment involves Hormone Replacement Therapy (Sex steroids for development, Gonadotropins or Pulsatile GnRH for fertility). [1,2,3]
Clinical Pearls
"Can't Smell + No Puberty = Kallmann": The combination of anosmia and absent puberty is the classic clue.
"Test Smell at Presentation": Always formally assess olfaction in patients with delayed puberty or hypogonadism.
"Fertility is Achievable": Unlike primary gonadal failure, patients with Kallmann can often achieve fertility with gonadotropin or GnRH therapy.
"Look for Associated Features": Cleft lip/palate, Renal agenesis, Mirror movements, Hearing loss – Suggest specific genetic subtypes.
Demographics
| Factor | Notes |
|---|---|
| Prevalence | ~1 in 8,000 males. ~1 in 40,000 females. |
| Sex | Male >> Female (4-5:1). |
| Genetics | X-linked (KAL1/ANOS1 – ~10-15%), Autosomal Dominant, Autosomal Recessive, Sporadic (~50%). |
Associated Features (Vary by Genotype)
| Feature | Genes Associated |
|---|---|
| Anosmia / Hyposmia | Core feature. All subtypes. |
| Cleft Lip / Palate | KAL1 (ANOS1) |
| Unilateral Renal Agenesis | KAL1 (ANOS1) |
| Synkinesia (Mirror Movements) | KAL1 (ANOS1) |
| Hearing Loss | CHD7 (CHARGE overlap) |
| Dental Agenesis | FGF8, FGFR1 |
| Obesity / Metabolic Syndrome | Leptin receptor pathway genes |
| Bimanual Synkinesis | KAL1 (ANOS1) |
Embryology
| Step | Normal | Kallmann Syndrome |
|---|---|---|
| GnRH Neuron Origin | Olfactory placode (Nose). | Normal. |
| Migration | GnRH neurons migrate along olfactory nerves to hypothalamus. | Migration fails. GnRH neurons remain in olfactory region/nasal area. |
| Olfactory Bulb Development | Olfactory bulbs form normally. | Olfactory bulb hypoplasia/aplasia (Visible on MRI). |
| Result | GnRH neurons in hypothalamus → Normal puberty. | No GnRH in hypothalamus → Low LH/FSH → Low sex steroids → No puberty. |
Hormonal Axis
- Hypothalamus: No GnRH release.
- Pituitary: Low/Absent LH and FSH (Gonadotropins).
- Gonads: Low testosterone (Males) / Low oestrogen (Females). Gonads potentially functional but unstimulated.
Distinguishing from Isolated HH (IHH)
| Condition | Anosmia | Pathology |
|---|---|---|
| Kallmann Syndrome | Present | GnRH neuron migration failure + Olfactory bulb hypoplasia. |
| Isolated Hypogonadotropic Hypogonadism (IHH / nIHH) | Absent (Normosmic) | GnRH neuron dysfunction but normal migration. |
Males
| Feature | Notes |
|---|---|
| Absent / Incomplete Puberty | By age 14. No virilisation. Eunuchoid body proportions (Long limbs). |
| Micropenis | Small penis (May be noted at birth). |
| Cryptorchidism | Undescended testes (Bilateral or Unilateral). |
| Infertility | Due to lack of gonadotropin stimulation. Spermatogenesis absent. |
| Anosmia / Hyposmia | May not notice (Lifelong). Ask directly and test. |
| Gynaecomastia | May occur (Especially if treated with testosterone without hCG). |
| Low Libido | Due to low testosterone. |
| Osteoporosis | If untreated (Low sex steroids). |
Females
| Feature | Notes |
|---|---|
| Primary Amenorrhoea | Never had a period. |
| Absent Breast Development | Tanner Stage 1. |
| Anosmia / Hyposmia | |
| Infertility | |
| Osteoporosis | If untreated. |
Physical Examination
| Finding | Notes |
|---|---|
| Eunuchoid Proportions | Arm span > Height. Upper/Lower segment ratio reduced. |
| Tanner Staging | Prepubertal (Stage 1-2). |
| Testicular Volume | less than 4ml (Prepubertal). |
| Olfaction Test | Use standardised tests (UPSIT, Sniffin' Sticks). |
| Midline Defects | Cleft lip/Palate. |
Hormone Profile
| Test | Findings |
|---|---|
| LH | Low or Inappropriately Normal (For low sex steroids). |
| FSH | Low or Inappropriately Normal. |
| Testosterone (Males) | Low (less than 8 nmol/L typically). |
| Oestradiol (Females) | Low. |
| Prolactin | Normal (Rule out prolactinoma). |
| Other Pituitary Hormones | TSH, Free T4, Cortisol – Usually normal (But check to exclude combined pituitary deficiency). |
Olfaction Testing
| Test | Notes |
|---|---|
| Formal Smell Testing | UPSIT (University of Pennsylvania Smell Identification Test), Sniffin' Sticks. Confirms anosmia/Hyposmia. |
| Self-Reported | Often unreliable. Patients may not realise they have anosmia. |
Imaging
| Modality | Findings |
|---|---|
| MRI Brain (Olfactory Region) | Olfactory bulb hypoplasia/aplasia. Olfactory sulci shallow or absent. Confirms diagnosis. |
| MRI Pituitary | Usually normal. Rule out pituitary mass. |
| Renal USS | Screen for renal agenesis (KAL1/ANOS1 mutations). |
Genetics
| Test | Notes |
|---|---|
| Genetic Testing | Can identify causative mutation in ~50% (KAL1/ANOS1, FGFR1, FGF8, PROKR2, PROK2, CHD7, etc.). Not essential for diagnosis but useful for counselling. |
Bone Health
| Test | Notes |
|---|---|
| DEXA Scan | Assess bone density. Osteopenia/Osteoporosis common if untreated. |
| Condition | Key Features |
|---|---|
| Kallmann Syndrome | HH + Anosmia. Low LH/FSH. Olfactory bulb aplasia on MRI. |
| Isolated Hypogonadotropic Hypogonadism (IHH / nIHH) | HH WITHOUT anosmia. Normal sense of smell. |
| Constitutional Delay of Puberty | Common. Family history. Eventually enter puberty spontaneously. LH/FSH may be low. GnRH stimulation test may help differentiate. |
| Primary Hypogonadism (Gonadal Failure) | High LH/FSH (Hypergonadotropic). Klinefelter's, Turner's, Gonadal dysgenesis. |
| Prolactinoma | Elevated Prolactin suppresses GnRH. MRI shows pituitary adenoma. |
| Chronic Illness / Anorexia | Functional HH. Reversible. |
Management Algorithm
SUSPECTED KALLMANN SYNDROME
(Absent puberty + Anosmia)
↓
CONFIRM DIAGNOSIS
- Hormone profile: Low LH/FSH + Low sex steroids
- Formal olfaction testing
- MRI Brain: Olfactory bulb hypoplasia/aplasia
- Rule out other causes of HH
↓
ASSESS ASSOCIATED FEATURES
- Renal USS (Renal agenesis)
- Hearing test
- Cleft lip/Palate
- Cardiac (If CHD7 suspected)
- Genetic testing (Optional)
↓
TREATMENT GOALS
1. Induce and maintain puberty
2. Achieve fertility (When desired)
3. Psychological support
↓
PUBERTAL INDUCTION / MAINTENANCE
┌──────────────────────────────────────────────────────────┐
│ **MALES** │
│ - Testosterone Replacement │
│ - Start low (e.g., 50mg IM every 4 weeks) │
│ - Gradually increase to adult dose │
│ - Gel, Undecanoate injection, Patches │
│ - Does NOT induce spermatogenesis │
│ │
│ **FEMALES** │
│ - Oestrogen (Low dose initially, Increase) │
│ - Add Progesterone after 1-2 years (Cyclical HRT) │
│ - Standard combined HRT regimen for maintenance │
│ │
│ **BOTH** │
│ - Bone protection (Adequate sex steroids) │
│ - DEXA monitoring │
└──────────────────────────────────────────────────────────┘
↓
FERTILITY TREATMENT (When Desired)
┌──────────────────────────────────────────────────────────┐
│ **MALES** │
│ - Stop Testosterone (Suppresses FSH/LH) │
│ - **hCG (Human Chorionic Gonadotropin)** alone or │
│ + **hMG/FSH** (To stimulate spermatogenesis) │
│ - OR **Pulsatile GnRH** (If hypothalamic defect pure) │
│ - Takes 12-24 months for sperm production │
│ │
│ **FEMALES** │
│ - **Pulsatile GnRH** or **hMG/FSH + hCG** (Ovulation │
│ induction) │
│ - High success rates │
└──────────────────────────────────────────────────────────┘
↓
MONITORING
- Regular hormone levels
- DEXA for bone health
- Psychological support
Treatment Summary
| Goal | Males | Females |
|---|---|---|
| Puberty Induction | Testosterone | Oestrogen → Add Progesterone |
| Maintenance | Testosterone | Cyclical HRT |
| Fertility | hCG ± FSH/hMG or Pulsatile GnRH | Pulsatile GnRH or Gonadotropins |
Fertility Outcomes
| Sex | Notes |
|---|---|
| Males | ~80% can achieve spermatogenesis with gonadotropin therapy. May take 1-2 years. Baseline testicular size predicts response. |
| Females | High success with ovulation induction. |
| Complication | Notes |
|---|---|
| Osteoporosis | If untreated (Low sex steroids). |
| Infertility | Primary concern. Treatable. |
| Psychosocial Impact | Delayed puberty. Body image. |
| Metabolic Syndrome | Associated with some genetic subtypes. |
| Cardiac Anomalies | If CHD7 mutation (CHARGE syndrome overlap). |
| Factor | Notes |
|---|---|
| Puberty | Fully achievable with hormone replacement. |
| Fertility | Achievable in majority with gonadotropin therapy. |
| Quality of Life | Good with appropriate treatment and support. |
| Reversal | ~10-20% of HH patients may experience spontaneous reversal (Late puberty). More common in nIHH than KS. |
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Congenital HH | Endocrine Society | Diagnosis criteria. Testosterone for males. Gonadotropins for fertility. |
What is Kallmann Syndrome?
Kallmann Syndrome is a rare condition where puberty does not happen naturally because the hormones that trigger puberty are missing. It is also linked to a reduced or absent sense of smell.
What causes it?
It happens because special nerve cells (GnRH neurons) that control puberty do not develop properly before birth. These cells also help the sense of smell develop, Which is why both are affected.
What are the signs?
In boys:
- Not going through puberty by age 14 (No growth spurt, Voice not deepening, No facial hair).
- Small testicles.
- Difficulty having children.
In girls:
- No periods starting.
- No breast development.
- Difficulty having children.
Both:
- Cannot smell or reduced sense of smell.
Is there treatment?
Yes! Hormone treatment can help you go through puberty and develop normally. With special fertility treatment, Most people with Kallmann Syndrome can have children.
Will I be okay?
With proper treatment, People with Kallmann Syndrome live healthy, Full lives. Support is available for any emotional challenges.
Primary Sources
- Boehm U, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism–pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547-564. PMID: 26194704.
- Dodé C, Hardelin JP. Kallmann syndrome. Eur J Hum Genet. 2009;17(2):139-146. PMID: 18781183.
- Young J, et al. Clinical management of congenital hypogonadotropic hypogonadism. Endocr Rev. 2019;40(2):669-710. PMID: 30742578.
Common Exam Questions
- Defining Features: "What is the classic combination of features in Kallmann Syndrome?"
- Answer: Hypogonadotropic Hypogonadism + Anosmia (Absent/Reduced sense of smell).
- Pathophysiology: "What is the underlying embryological defect?"
- Answer: Failure of GnRH neuron migration from the olfactory placode to the hypothalamus.
- MRI Finding: "What is the characteristic MRI finding?"
- Answer: Olfactory bulb hypoplasia/aplasia.
- Fertility in Males: "How can fertility be achieved in males with Kallmann Syndrome?"
- Answer: hCG ± FSH/hMG injections or Pulsatile GnRH (To stimulate spermatogenesis).
Viva Points
- Low LH/FSH + Low Testosterone = Hypogonadotropic Hypogonadism: Vs High LH/FSH (Hypergonadotropic = Gonadal failure).
- Test Smell: Always in delayed puberty patients.
- X-Linked (KAL1/ANOS1): Associated with cleft lip/palate, Renal agenesis, Mirror movements.
- Fertility Achievable: Unlike primary gonadal failure.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.