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James P G Turton, Charles R Buchanan, Iain C A F Robinson, Simon J B Aylwin and Mehul T Dattani

Background: Type II isolated GH deficiency (IGHD type II) is caused by dominant negative splicing or point mutations of the GH-1 gene. Studies have suggested that dominant mutant GH forms prevent the secretion of wild-type GH, resulting in eventual cell death; surprisingly, some patients with these GH mutations develop other hormonal deficiencies (ACTH, TSH).

Subjects: The proband presented at the age of 2.3 years with IGHD. His father, also known to have been treated for IGHD as a child, had subsequently been lost to follow-up, having remained without treatment during this time. At re-evaluation at the age of 38 years, he complained of lack of stamina and poor libido. Clinical and biochemical assessment confirmed severe GHD, borderline ACTH insufficiency, suboptimal basal and stimulated gonadotropins, and a poor prolactin response to provocation. The basal testosterone concentration was low, and he complained of secondary infertility. Magnetic resonance imaging revealed anterior pituitary hypoplasia in both patients. Genetic testing revealed a heterozygous splicing mutation in GH-1 (intervening sequence-3 + 1G>A) in both patients, known to cause IGHD type II.

Interventions: The proband showed an excellent growth response to recombinant human GH (rhGH). His father, also treated with rhGH, showed improved quality of life on rhGH, but testosterone concentrations continued to decline, necessitating treatment with testosterone with symptomatic benefit but no improvement in semen quality.

Conclusions: This case supports recent experimental and clinical observations suggesting that the cytotoxicity associated with accumulation of dominant negative mutant 17.5 kDa GH causes a form of GHD that can evolve into multiple hormone deficiencies. Hence, patients diagnosed initially with IGHD type II require continued long-term clinical follow-up.

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Evelien F Gevers, Suzanne Meredith, Pratik Shah, John Torpiano, Catherine Peters, Neil J Sebire, Olga Slater, Anne White and Mehul T Dattani

Context

Pituitary microadenomas and adrenal tumours are the most common causes for endogenous Cushing syndrome (CS) in children.

Case description

We describe a two-year old girl with Cushing syndrome due to ectopic pro-opiomelanocortin (POMC) production from an abdominal yolk sac tumor. Cortisol concentrations were elevated but adrenocorticotropic hormone (ACTH) concentrations were equivocal. The use of antibodies specifically detecting ACTH precursors revealed that plasma ACTH precursors were elevated. Additionally, an ACTH assay with a low cross-reactivity for precursors showed low concentrations of ACTH. Immunohistochemistry suggested POMC but not ACTH production by the tumour.

Conclusion

We describe a yolk sac tumour as a novel source of ectopic POMC production leading to CS in a young girl.

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Mehul T Dattani, Andrew P Winrow, Anatoly Tuil'Pakov, P Jane Pringle, Peter C Hindmarsh, Charles GD Brook and Nicholas J Marshall

Dattani MT, Winrow AP, Tuil'Pakov A, Pringle PJ, Hindmarsh PC, Brook CGD, Marshall NJ. Evaluation of growth hormone (GH) responses to pulsed GH-releasing hormone administration using the MTT–ESTA bioassay. Eur J Endocrinol 1996;135:87–95. ISSN 0804–4643

We compared the immunoactivity of human growth hormone (hGH) with its bioactivity after stimulation of hGH release into the circulation by the administration of growth hormone-releasing hormone [GHRH(1–29)-NH2] according to a pre-determined protocol to four normal adult volunteers. We used the Hybritech immunoradiometric assay to measure the immunoactive GH concentrations. Bioactive GH concentrations were measured using the highly quantitative and precise eluted stain bioassay system (ESTA). The high sample capacity of the ESTA bioassay permitted us to monitor the bioactivities in closely timed sequential samples, and in far greater detail than has previously been possible. Two pulses of GHRH(1–29)-NH2 were administered intravenously to the four adult male volunteers (aged 24–37 years) on a weekly basis over a 4-week period. Two different doses of GHRH(1–29)-NH2 (0.1 and 1.0 μg/kg) were tested. These were separated by specified time intervals (60 or 120 min). Responses in the four individuals were variable. However, although the immunoand bioactivities generally agreed well, there was a systematic and progressive increase in the bioactivity/immunoactivity (B/I) ratios as half of the response peaks were approached. After these peak concentrations, the B/I ratios subsequently returned to values that were close to unity. The enhanced bioactivity of the peak samples from the two volunteers in whom the largest magnitudes of response were observed was found to be labile after long-term storage at −20°C. We suggest that the preferential rise in GH bioactivity, as opposed to immunoactivity, in response to GHRH(1–29)-NH2 was due to progressive changes in the concentrations of isoforms of GH that are not detectable in the Hybritech immunoassay.

NJ Marshall, Division of Molecular Pathology, University College London, The Windeyer Building, 46 Cleveland Street, London W1P 6DB, UK