Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, Laboratorio de Hormonios e Genetica Molecular, São Paulo 05403-900, Brazil
Address correspondence to: Ivo J. P. Arnhold, M.D., Hospital das Clinicas da Universidade de São Paulo, Laboratorio de Hormonios e Genetica Molecular, Avenida Eneas de Carvalho Aguiar 155, Predio dos Ambulatorios, 2 andar Bloco 6, São Paulo, 05403-900, Brazil. E-mail: iarnhold{at}usp.br.
To the editor:
We thank Dr. Maghnie and colleagues for their comments. In our study, a high proportion (57%) but not all patients with genetic GH deficiency had consanguineous parents. Dr. Maghnie and colleagues wonder why only 9 of 76 patients with GH deficiency had neither a genetic defect nor an anatomic abnormality on magnetic resonance imaging (MRI). We believe this is due to stringent criteria for diagnosis of GH deficiency. These are consecutive patients with GH deficiency based on failure to respond to two stimulation tests, oral clonidine and insulin-induced hypoglycemia. The cut-off values for the diagnosis of GH deficiency were less than 7 µg/liter when measured by immunoradiometric assay (<5 µg/liter in all but one patient) and less than 3.2 µg/liter by immunofluorometric assay. This last cut-off was based on the GH response to clonidine in normal children (1). Recent retesting of our patients with GH deficiency diagnosed with the above criteria demonstrated definitive GH deficiency in 95% of patients. Use of less stringent criteria may lead to inclusion of patients who are not GH deficient, and it is not surprising that they do not have anatomic abnormalities on MRI.
The TSH and prolactin responses to TRH stimulation proved useful for the distinction of hypothalamic or pituitary origin of the hormonal deficiency in patients with combined pituitary hormone deficiency (CPHD). A test for similar distinction in patients with isolated GH deficiency is desirable but not yet available. All six patients with CPHD and molecular defects in pituitary genes (PROP1, PIT1) had a response compatible with pituitary origin. Interestingly, 15 of 16 patients with CPHD with breech delivery or neonatal hypoxia had an ectopic posterior pituitary lobe, and all of these 15 had a hormonal response compatible with hypothalamic deficiency, suggesting that perinatal insults result in stalk disconnection, ectopic posterior lobe, and a hypothalamic pattern of hormonal deficiency. Therefore, in patients with CPHD, a pituitary hormonal response indicates the search of a defect in a pituitary gene, whereas a hypothalamic response is compatible with perinatal insults or a defect in hypothalamic factors.
Since the publication of our study, Binder et al. (2) reported that MRI in 13 patients with mutations in GH-1 gene showed a normal pituitary stalk and posterior lobe in all patients and normal anterior lobe in 8. In contrast, among 10 patients with isolated GH deficiency of unknown origin (also using stringent criteria, GH < 4 µg/liter), stalk and anterior lobe were hypoplastic in all 10, posterior lobe was ectopic in 9, and 3 of 8 had a history of breech delivery or traumatic birth. In essence, these results confirm our data.
It is important to keep in mind that the standards for pituitary height are based on a few normal individuals in each age group (3), and therefore the finding of anterior pituitary hypoplasia alone should be interpreted with caution.
We agree that MRI abnormalities, when present, are useful to predict severe GH deficiency. However, we also want to stress that both our study and the one by Binder et al. (2) demonstrate that normal pituitary stalk and posterior lobe occur in most patients with genetic GH deficiency. The molecular diagnosis of more patients with GH deficiency will help to further delineate the correlation of etiology, hormonal responses, and morphologic alterations on MRI.
Received December 23, 2002.
References
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