The patient was born full term at 40 weeks via normal spontaneous vaginal delivery to a 32-year old mother and 33-year old father. There were no perinatal complications and the Apgar scores were 4 and 9 at 5 and 10 minutes of life, respectively. She was small for gestational age with a birth weight of 5 lbs. 2 oz. at the 5th percentile and birth length of 18.5 inches between the 5th and 10th percentile. The patient was noted as having dysmorphic features including hypertelorism, low-set ears, epicanthal folds and a flat nasal bridge. During her first year of life she was diagnosed with failure to thrive, including a progressive deceleration in growth rate and global developmental delay. At 14 months of age, her facial dysmorphism, poor growth and developmental delay prompted additional evaluation including a karyotype that revealed tetrasomy X (Figure 1A). The parents' karyotypes were normal. A SNP array was also performed to evaluate the characteristics of the extra X chromosomes (Figure 1B). Her laboratory evaluation was remarkable for a low IGF-1 of 37ng/mL (reference range 49-342 ng/mL) and her bone age was delayed (1 month at chronological age of 17 months (Figure 2A). She also underwent a brain and pituitary MRI which showed delayed demyelination and an 8 x 4 x 13 mm cystic lesion in the sella turcica, indicating a Rathke's cleft cyst (Figure 2B).
With progressively declining growth rate, a low IGF-1 and a Rathke's cleft cyst in the pituitary gland, growth hormone deficiency was strongly suspected, although this could not be confirmed via the growth hormone stimulation test due to difficulties in securing vascular access. Therefore, under clinical suspicion, she was diagnosed with growth hormone deficiency and at 21 months of age she started treatment requiring a low dose of growth hormone (0.13 mg/kg/week), to which she responded with improvement in IGF-1 and growth velocity, as is typical in this management of growth hormone deficiency (Figure 3A). At the time, her thyroid function tests and cortisol peak of 35.1 ug/dL after the standard 250 mcg ACTH stimulation test were appropriately within normal range. Serial MRIs performed over the years showed no change in the size of the cyst (Figure 2C).
At her 8 years and 8 months follow-up visit, she again presented with height deceleration. On further evaluation, diurnal TSH showed a peak increment TSH of 41%, suggesting central hypothyroidism (normal increment >48%). Her ACTH stimulation test showed a peak cortisol of 13.9 mcg/dL at 60 minutes, indicating partial adrenal insufficiency. A physiologic dose of hydrocortisone and of levothyroxine replacement were initiated and her growth improved accordingly (Figure 3B). At age 8, she was prescribed aripiprazole for behavioral outbursts and subsequently had significant weight gain, her BMI percentile increasing from 50th to 85th. The patient had minimal breast development in addition to lipomastia at age 8 years, which was thought to be secondary to peripheral conversion of estrogen from extra adipose tissue: her breasts gradually regressed with dietary control. Her estradiol level was below detection limits. She restarted breast development at age 10 and reached Tanner 3 at age 11 years and 9 months. At that time, she developed an episode of vaginal bleeding which lasted 5 days but did not recur. Her LH was 5.9 U/L, FSH was 2.6 U/L and estradiol was 31.6 pg/mL (Table 1).