Growth Hormone Deficiency, With a Twist

A 20-year-old woman with glycogen storage disease type Ia (GSDIa) presents to an adult outpatient unit, after being referred for investigation of delayed growth.

She reports that throughout her life she has eaten frequent meals and consumed uncooked cornstarch to prevent repeated episodes of low blood sugar. Despite avoiding hypoglycemia, she continues to suffer from hyperlacticacidemia and dyslipidemia before meals. Her initial growth was between one and two standard deviations below normal.

Her medical history includes a birth weight of 3,200 g (7.1 lb) at 35 gestational weeks of age.

At 7 months of age, signs and symptoms included hypoglycemia, lactic acidosis, dyslipidemia, enlarged liver and spleen, and calcium deposits in the kidney, without neutropenia. Diagnosis of GSDIa diagnosis was made by glucose-6-phosphatase enzyme assay and quantitative assessment of glycogen content in a liver biopsy specimen.

At 7 years of age her growth rate began to decline. At age 9, the patient’s growth was below two standard deviations from normal.

At 14 years of age, the patient was evaluated at a pediatric endocrinology department for slow growth and delayed puberty. Thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were all normal. Subnormal growth hormone (GH) responses to thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing hormone (LHRH), and GH stimulation (by L-dopa) tests were obtained.

At 16 years of age, the patient had her first menstrual period. Liver transplantation was refused by the family.

At age 20, her height is 141 cm (4 ft 8 in), while the parental target height is 163 cm (5 ft 4 in). Pubertal development is complete. Liver and kidney function are normal, and she has no hypoglycemia. Evidence of hyperlacticacidemia and severe dyslipidemia include:

• LDL of 212 mg/dL
• Triglycerides of 409 mg/dL
• HDL of 27 mg/dL

Provocative testing of the patient’s pituitary gland function shows normal TSH, FSH, LH, and GH responses to TRH, LHRH, and GH stimulation by insulin-induced hypoglycemia tests.

Morphological evaluation by MRI reveals a hypoplastic adenohypophysis (anterior pituitary height 3 mm) with no abnormality in the neurohypophysis.

Spontaneous overnight GH profiling for 12 hours at 2-hour intervals shows a mean GH level of 0.16 ng/mL, a spontaneous absolute GH peak level of 0.37 ng/mL, and an area under the curve value (mean profile GH time) for the night of 115 ng/min/mL. The patient declines to undergo daytime and more frequent overnight GH testing.

Discussion

Clinicians reporting this case of a patient with GSDIa who is also affected by hypoplastic adenohypophysis suggested that this case is unique. They cited a study showing an altered brain MRI pattern in 57% of patients with GSDI, although the study did not report pituitary abnormality or a hypothalamopituitary imaging pattern.

A laboratory study reported growth inhibition in rats with sustained metabolic acidosis, due to a decrease in amplitude and mean mass of GH pulses, case authors note. Given that metabolic conditions that damage the hypothalamus due to decreased oxygenation are also known to cause hypoplasia of the anterior pituitary, case authors suggested that their patient’s hypoplastic adenohypophysis was likely related to growth hormone neurosecretory dysfunction (GHNSD).

“GHNSD is an abnormality characterized by short stature, growth retardation and abnormal spontaneous GH secretion despite normal GH response to provocative testing,” the case authors wrote. They noted that the additional finding of hypoplastic adenohypophysis in this patient “would formally have satisfied the diagnostic criteria for GHNSD.”

Authors cited guidelines stating that patients with hypothalamic or pituitary disease or a history of cranial irradiation, as well as those with childhood-onset growth hormone deficiency (GHD), are at obvious risk as adults for severe GHD.

Provocative testing should be performed in patients highly suspected for adult GHD with normal IGF-I. Conversely, provocative tests are not necessary in those at high risk for adult GHD (i.e., patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood) in the presence of very low IGF-I levels, which can be considered as definitive evidence for severe GHD.

While dynamic testing of this patient did show a subnormal, but not severe (i.e., <3 ng/mL), stimulated GH response before she reached puberty, reassessment using an insulin-tolerance test when she was 20 years of age showed a normal peak GH response.

“Such a discrepancy between childhood and adulthood peak GH responses has already been reported in GHNSD,” the authors noted. They added that increasing the sampling frequency to less than 2-hour intervals might have revealed significant peaks, especially overnight: “Spontaneous GH secretion may have been underestimated here.”

However, they added that other research that focused exclusively on GH abnormalities following cranial irradiation concluded that “a reduced somatotroph reserve might mimic or seemingly present as GHNSD when hypothalamic compensation fails to restore GH secretion in the case of increased demands such as puberty.”

Authors noted that, because growth hormone-releasing hormone (GHRH) also has a role as a trophic factor for the pituitary gland, evidence of discordant spontaneous and stimulated GH secretion patterns in a patient with an atrophic or hypoplastic pituitary is generally attributed to GHRH deficiency due to GHNSD.

“A normal stimulated GH response in an insulin-tolerance test is defined as a peak of above 5.0 ng/ml,” they wrote. While the 5.18 ng/mL noted in their patient was just above the cut-off level, it might still represent a relatively low response, given the lack of data for GSDIa. “If so, the reduction in both the spontaneous and stimulated GH secretion, which is proportional to somatotroph volume, may be a reflection of primary pituitary hypoplasia rather than GHNSD,” authors concluded.

As noted in the research in cranial radiation referred to above, clinicians assessing patients who may have damage to the pituitary gland itself due to an underlying injury should consider the possibility of primary loss in the somatotroph mass, not only secondary atrophy due to a neurosecretory defect in GHRH secretion. Authors noted that, despite little available data, there may be genetic involvement of the pituitary gland in GSDIa that has yet to be defined.

Conclusion

Case authors concluded that this adult patient with GSDIa plus GH deficiency associated with pituitary hypoplasia whose GH response to provocative testing is relatively normal was not a classical representation of GHNSD.

“In addition to the IGF1 deficiency resulting from primary hepatic involvement, GSDIa also seems to disrupt the hypothalamic-pituitary axis,” they wrote. “To clarify whether the pituitary hypoplasia described in this case is a primary occurrence caused by an unknown mechanism, or a secondary event such as GHNSD, requires further studies to test spontaneous and stimulated GH secretion patterns in people with GSDIa.”