Kallmann Syndrome

Kallmann syndrome is congenital hypogonadotropic hypogonadism with anosmia or hyposmia. Gonadotrophin releasing hormone deficiency causes absent or arrested puberty.

It affects about 1 in 30,000 to 50,000 males and is about four times less common in females. Inheritance is X-linked (ANOS1), autosomal dominant (FGFR1, FGF8, CHD7, SOX10), autosomal recessive (PROKR2, PROK2) or oligogenic. Sporadic cases are common.

Associated features include renal agenesis (ANOS1), bimanual synkinesis, cleft lip or palate, dental agenesis, hearing loss, short metacarpals and scoliosis. About 10 to 20% of patients recover reproductive function.

Pathophysiology.

Gonadotrophin releasing hormone neurons and olfactory neurons migrate together from the olfactory placode to the hypothalamus. Defective migration leaves the hypothalamus without these neurons and causes absent olfactory bulbs.

Pituitary gonadotrophs and gonads are normal and respond to treatment.

• Absent puberty, micropenis, cryptorchidism, small testes, eunuchoid proportions and low libido.
• Anosmia or hyposmia (often unrecognised), mirror movements, cleft lip or palate, single kidney and hearing loss.
• Females: primary amenorrhoea and absent breast development.

Red flags.

• Visual loss or headache (pituitary mass, not Kallmann syndrome).
• Other pituitary hormone deficiency.

• Low testosterone or oestradiol with low or inappropriately normal LH and FSH. Other pituitary axes normal, normal ferritin and prolactin.
• Formal smell testing, and MRI showing absent or hypoplastic olfactory bulbs and sulci with a normal pituitary.
• Renal ultrasound, hearing assessment, bone density, karyotype and genetic testing (ANOS1, FGFR1, PROKR2, CHD7 and others).
• In boys, low inhibin B and anti-Müllerian hormone and a poor response to human chorionic gonadotrophin help to separate it from constitutional delay.

Differential diagnosis.

• Constitutional delay of puberty.
• Normosmic congenital hypogonadotropic hypogonadism, CHARGE syndrome, and acquired hypogonadotropic hypogonadism.
• Combined pituitary hormone deficiency and primary hypogonadism (LH and FSH raised).

• Induce puberty in boys: testosterone enanthate 50 mg intramuscularly every 4 weeks, increased every 6 months over 2 to 3 years to adult doses. In girls: oral oestradiol 0.25 mg daily, increasing every 6 months to 2 mg daily, with a progestogen after breakthrough bleeding or 2 years.
• Fertility in men: human chorionic gonadotrophin 1500 to 2500 units two to three times weekly with FSH (75 to 150 units three times weekly) if sperm count remains low after 6 months. Pulsatile gonadotrophin releasing hormone is an alternative. Before puberty, FSH priming can improve testicular volume.
• Adult men not wishing fertility: testosterone gel 50 mg daily or undecanoate 1000 mg intramuscularly every 10 to 14 weeks after a 6 week loading dose.
• Women wishing fertility: gonadotrophins or pulsatile gonadotrophin releasing hormone.
• Test treatment free periods in adults to detect reversal.

Special groups. Genetic counselling: risk depends on inheritance pattern and incomplete penetrance; test relatives when a variant is found. Psychological support for body image and fertility.

Monitoring. During puberty induction and testosterone treatment: growth, pubertal stage, testosterone trough, haematocrit, PSA and bone density. Test for reversal yearly in adults.

Referral and escalation. Paediatric or adult endocrinology with a fertility service and clinical genetics.