Isolated Congenital Hypogonadotropic Hypogonadism
A rare disorder of sexual maturation characterized by gonadotropin (Gn) deficiency with low sex steroid levels associated with low levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH).
Epidemiology
Exact prevalence is unknown but is likely to be around 1/5,000.
Clinical description
CHH may be suspected at birth in males with micropenis (often associated with cryptorchidism), during adolescence due to the absence of puberty or during adulthood as a result of infertility. CHH is referred to as isolated (IHH) when the deficiency is restricted to the gonadal axis. Two subtypes of IHH have been defined: Kallmann syndrome (CHH with anosmia) mainly associated with abnormal embryonic migration of the Gn-releasing hormone (GnRH)-synthesizing neurons, and normosmic IHH (nIHH), in which HH is the only manifestation, mainly associated with anomalies in the regulation of GnRH signaling and secretion. CHH may also occur in association with other endocrine diseases such as multiple pituitary hormone deficiency, leptin deficiency, prohormone convertase-1 deficiency and adrenal hypoplasia. CHH is also a feature of several syndromes including the Prader-Willi, Bardet-Biedl, Laurence-Moon and CHARGE syndromes.
Diagnostic methods
Diagnosis is based on clinical evaluation of the hypogonadism (using the Tanner scale for patients diagnosed during adolescence) and laboratory findings from LHRH tests and measurements of LH and FSH levels to confirm the Gn deficiency. Laboratory tests should be performed either in the first six months of life or after patients reach a bone age of 13 years. Molecular analysis of candidate genes is also a useful diagnostic strategy. The following investigations are useful for guiding the molecular diagnosis and for determining the cause of CHH: familial and patient history, tests for anosmia and hearing loss, evaluation for signs associated with dental agenesis and developmental anomalies of the hands and feet, and MRI for identifying olfactory bulb and/or sulcus anomalies and for detecting developmental anomalies of the pituitary or pituitary stalk interruption syndrome.
Differential diagnosis
Differential diagnoses should include other causes of micropenis and cryptorchidism at birth (syndromic or isolated), transitory HH (associated with constitutional delay of puberty), hypothyroidism, and secondary causes of HH (hypothalamic-pituitary tumors or adenomas, surgical or radiation therapy-induced sequelae, etc.).
Genetic counseling
Genetic counseling may be proposed depending on the underlying disorder (syndromic or isolated) and mode of transmission (X-linked, or autosomal recessive or dominant).
Management and treatment
Management depends on the age of the patient: hormone therapy for treatment of micropenis during the neonatal period, induction of puberty at adolescence (estrogen therapy for females and testosterone for males), and fertility in adulthood.
Prognosis
The prognosis is generally good, with the outcome for fertility depending on the severity of the sex hormone deficiency and the age of initiation of treatment. Rare cases of complete resolution have been described but the physiopathology of the disease in these patients is not understood.