Isolated congenital hypogonadotropic hypogonadism (ORPHA:238666)
A rare, genetic pituitary hormone deficiency characterized by gonadotropin (Gn) deficiency with low sex steroid levels associated with low levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). This disorder may be associated with a normal (normosmic) or impaired sense of smell (Kallmann syndrome).
Epidemiology
Exact prevalence is unknown but is estimated to be between 1/5,000 and 1/10, 000.
Clinical description
Congenital hypogonadotrophic hypogonadism (CHH) is isolated when the deficiency is restricted to the gonadotrope axis. Diagnosis is typically during adolescence due to the absence or incomplete pubertal development although it may be suspected at birth in males with micropenis (often associated with cryptorchidism). Later diagnosis during adulthood is possible, but less frequent, as a result of infertility. Isolated CHH can be associated with normal sense of smell (normosmic CHH) or anosmia/hyposmia with hypoplasia or aplasia of the olfactory bulbs (Kallmann syndrome). Untreated adult males exhibit absent or reduced virilization and usually have decreased bone density and muscle mass, decreased testicular volume (< 4 mL), erectile dysfunction, diminished libido and infertility. Untreated adult females almost always experience primary amenorrhea with absent, little or even normal pubic hair and breast development. Kallmann syndrome may be associated with addition anomalies including sensorineural deafness, renal agenesis and midline defects.
Etiology
Isolated CHH is the result of the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), the master hormone regulating the reproductive axis. This is frequently due to failure of GnRH neurons in the hypothalamus to differentiate, develop (Kallmann syndrome) or secrete GnRH. In a subgroup of patients, the defect is due to GnRH resistance in pituitary gonadotropic cells (e.g. loss of function mutations in the GnRH receptor). Many genes have been implicated in the pathogenesis.
Diagnostic methods
Diagnosis is based on clinical evaluation of the hypogonadism and hormone testing to confirm gonadotropin deficiencies (FSH and LH) caused by GnRH deficiency. Laboratory tests should be performed either in the first six months of life or after 12-13 years of age. Further investigations may include familial and patient history, tests for anosmia and hearing loss, and MRI for identifying olfactory bulb and/or sulcus anomalies. However, the current increased use of next generation sequencing (targeted exome) in clinical practice allows the identification of causative genes without necessarily completing an exhaustive search for associated signs.
Differential diagnosis
Differential diagnoses should include other causes of micropenis and cryptorchidism at birth (syndromic or isolated), transitory hypogonatorphic-hypogonadism (associated with constitutional delay of growth and puberty), functional hypogonatorphic-hypogonadism associated with caloric restriction or undernutrition, hypothyroidism, and secondary causes of HH (hypothalamic-pituitary tumors / adenomas or infiltrations (iron overload), surgical or radiation therapy-induced sequelae, as well as other endocrine diseases).
Antenatal diagnosis
Fetal ultrasound monitoring of anomalies associated with Kallmann syndrome may be useful but genetic prenatal diagnosis is generally not considered because of the good prognosis and the usual absence of major disability.
Genetic counseling
The inheritance patterns of congenital hypogonadotropic hypogonadism vary and include X-linked recessive, autosomal recessive, autosomal dominant, oligogenic as well as sporadic forms. Genetic counseling should be offered accordingly.
Management and treatment
CHH is one of the rare treatable causes of male infertility. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the possible psychological effects. In most cases, fertility can be induced using specialized treatment regimens, best deployed in a reference center, and patients typically require life-long treatment and monitoring in order to maintain sexual function and secondary sexual characteristics, although ~10-20% of patients exhibit a spontaneous recovery of reproductive function and some men seem to sustain reversal of the disease after discontinuation of hormonal therapy.
Prognosis
The prognosis is generally good, with the outcome for fertility depending, particularly in affected males, on the severity of the sex hormone deficiency and the age of initiation of treatment. Rare cases of complete resolution have been described.

                            Last update: 
                            March 2021


                            - Expert reviewer(s): 
                            Pr Jacques YOUNG