Case 2: An unusual case of delayed puberty

An 18-year-old man was referred for evaluation of delayed puberty. History revealed that he had never grown facial, axillary or pubic hair, his voice had not changed, and he rarely had acne or body odour. His mother recalled that he was quite small as a young child but, after five years of age, seemed to grow normally. She also reported that his energy level was quite low and he rarely left the house except for school. He missed approximately five days of school each month because of illness.

The patient had a difficult delivery requiring admission to the neonatal intensive care unit, but the details surrounding this event were unclear. His mother reported that his “heart stopped”. He was subsequently seen by paediatricians at three years of age for speech delay, nine years of age for undescended testes and 14 years of age for cognitive delay. No other concerns were noted at these visits.

The patient’s vitals were normal. His height was within 3 cm of his mid-parental height. His body mass index was in the 85th percentile. He appeared younger than his actual age. His fundi and visual fields were normal. His thyroid gland was not enlarged. He had no axillary or pubic hair. His phallus measured 3 cm and both testes were palpable and approximately 2 mL in volume. He was Tanner Stage 1 for pubertal development.

Blood work and imaging revealed the diagnosis.

CASE 2 DIAGNOSIS: CONGENITAL HYPOPITUITARISM

Blood work revealed a testosterone level of <0.3 nmol/L (prepubertal <1 nmol/L) with a lutenizing hormone (LH) level of <0.2 IU/L (prepubertal 0 IU/L to 1 IU/L) and a follicular stimulating (FSH) hormone level of 0.64 IU/L (prepubertal 0.5 IU/L to 3 IU/L). There was no response to gonadotropin releasing hormone stimulation testing. Additional hormone evaluation was as follows: thyroid-stimulating hormone (TSH) 4.90 mIU/L (0.46 mIU/L to 5.8 mIU/L), free thyroxine (FT4) 4.6 pmol/L (8 pmol/L to 22 pmol/L), prolactin 38 μg/L (6 μg/L to 24 μg/L) and insulin-like growth factor 1 >25 μg/L (163 μg/L to 584 μg/L). It is important to note that both TSH and FT4 testing should be ordered if one is concerned about the possibility of central hypothyroidism. In this case, a normal TSH level is inappropriate given a low FT4. Cortisol level at baseline was 18 nmol/L (150 nmol/L to 690 nmol/L) and only stimulated to 82 nmol/L on an adrenocorticotropic hormone stimulation test. A complete blood count, electrolytes, and morning serum and urine osmolalities were within normal limits.

The patient’s bone age was determined to be 14 years. Magnetic resonance imaging of his pituitary gland demonstrated an ectopic posterior pituitary in the hypothalamic location, agenesis of the pituitary infundibulum and a hypoplastic anterior pituitary gland in the sella. The optic nerves were unremarkable. There was no evidence of tumour. A diagnosis of congenital hypopituitarism was made.

The patient was immediately started on hydrocortisone. Thyroxine treatment was delayed by one week to avoid precipitating an adrenal crisis. Subsequently, he was started on monthly injections of testosterone to initiate puberty. Further testing revealed no response to growth hormone stimulation and, because his bone age was significantly delayed, growth hormone therapy was also initiated.

In most boys, pubertal changes begin at between 10 and 13 years of age, with a normal range of nine to 14 years. The first visible sign is enlargement of the testes (>4 mL or 2.5 cm indicates that puberty has begun), followed by pubic hair and penile growth, and then attainment of peak height velocity. Delayed puberty in boys is defined as the absence of secondary sexual characteristics by 14 years of age. Pubertal delay may be present despite the growth of axillary/pubic hair and the development of axillary odour because these are stimulated by adrenal androgens, which are independent of the hypothalamic-pituitary-gonadal axis.

The initial investigation of delayed puberty in boys should include measurement of testosterone, LH and FSH. A low testosterone level in conjunction with high concentrations of LH and FSH is indicative of primary gonadal failure (1,2). This may be caused by abnormal gonadal development or gonadal injury/insult. The most common cause of abnormal gonadal development is Klinefelter syndrome, which occurs in males with an extra X chromosome. These boys typically present with delayed puberty and abnormally small testes; a karyotype will confirm the diagnosis. Some of the most common causes of gonadal injury/insult include radiation exposure, chemotherapy, infection, surgery and testicular torsion.

Low or normal levels of LH and FSH suggest either constitutional delay or central gonadotropin deficiency. Central causes include functional gonadotropin deficiency (chronic illness), isolated gonadotropin deficiency (idiopathic or associated with Kallman syndrome) and multiple pituitary hormone deficiencies (congenital or acquired) (1,2). Constitutional delay is the most common reason for delayed puberty in boys. Unfortunately, it can be difficult to distinguish between constitutional delay and other more worrisome central causes using LH and FSH levels alone because there is much overlap. However, boys with constitutional delay are typically shorter than their peers and have a positive family history of the same. Their bone age is also delayed by approximately two years, making this an important diagnostic tool. If the diagnosis remains uncertain, further workup may include gonadotropin releasing hormone stimulation testing as well as evaluation of other pituitary hormones followed by cranial imaging if there was evidence of hypopituitarism.

This was the approach taken for the workup of this particular patient. Surprisingly, congenital hypopituitarism from a structural pituitary defect was found to be the cause of his delayed puberty. Given his age at presentation, an acquired central nervous system lesion, such as a craniopharyngioma or pituitary adenoma, seemed more likely. This is because deficiency of growth and thyroid hormones usually results in significantly shorter stature, prompting evaluation at a much earlier age. It is remarkable that this patient reached his expected height potential (Figure 1). Possible explanations include partial growth hormone deficiency, increased weight driving linear growth or high levels of insulin, and prolactin or leptin promoting linear growth (3). Furthermore, diminished adrenocorticotropic hormone secretion leads to secondary adrenal insufficiency, which causes significant fatigue and may cause hypoglycemia and difficulty handling common illnesses or surgery. Infants are often diagnosed because of temperature instability, microphallus, undescended testes, prolonged jaundice and/or craniofacial midline abnormalities (4). The present patient’s symptoms went undetected for several years.

Figure 1).

Growth chart

CLINICAL PEARLS

• A good history, including a family history of delayed puberty, and a good physical examination, including examination of testicular volume, are essential in evaluating delayed puberty.

• The initial laboratory evaluation of delayed puberty in boys should include testosterone, LH and FSH levels, as well as bone age.

• Magnetic resonance imaging is an essential investigation when working up pituitary hormone deficiencies.

• Congenital hypopituitarism should be included in the differential for a central cause of delayed puberty even though most children present with growth failure at a much younger age.