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Pituitary Magnetic Resonance Imaging and Function in Patients with Growth Hormone Deficiency with and without Mutations in GHRH-R, GH-1, or PROP-1 Genes

Unidade de Endocrinologia do Desenvolvimento (M.G.F.O., S.M., A.A.L.J., A.C.L., V.E., B.B.M., I.J.P.A.), Laboratório de Hormônios e Genética Molecular, Laboratório de Investigação Médica/42, Divisão de Endocrinologia, and Departamento de Radiologia (L.S.S.L., C.C.L.), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 01065-970 São Paulo, Brazil

Address all correspondence and requests for reprints to: Ivo J. P. Arnhold, M.D., Laboratório de Hormonios, Hospital das Clínicas, Av. Eneas de Carvalho Aguiar 155, PAMB 2 Andar Bloco 6, 05403-900 São Paulo, Brasil. E-mail: iarnhold{at}usp.br.

Abstract

Pituitary stalk interruption and ectopic posterior lobe on magnetic resonance imaging (MRI) are frequently observed in patients with GH deficiency (GHD), but their pathogenesis remains controversial. We performed pituitary stimulation tests, MRI, and studied GH-1, GHRH receptor (GHRH-R), and Prophet of Pit-1 (PROP-1) genes in 76 patients with GHD. Of 33 patients with isolated GHD, 4 had GH-1 deletions and 4 had GHRH-R mutations; of 43 patients with combined pituitary hormone deficiency, 1 had PIT-1 and 5 had PROP-1 mutations. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequency of consanguinity (57 vs. 2%, P < 0.001), familial cases (21 vs. 3%, P < 0.05), and lower frequency of breech delivery or hypoxemia at birth (0 vs. 39%, P < 0.005). On MRI, all patients with mutations had an intact stalk, whereas it was interrupted or thin in 74% without mutations (P < 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations against 13% without mutations (P < 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP-1 and PIT-1 mutations and suggestive of hypothalamic origin in 81% without mutations. Perinatal insults were associated with thin/interrupted pituitary stalk, ectopic posterior lobe, and hypothalamic origin of hormonal deficiencies. In contrast, GH-1, GHRH-R, and PROP-1 mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. We conclude that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiological diagnosis of GHD.

MORPHOLOGICAL ALTERATIONS OF the hypothalamic-pituitary region on magnetic resonance imaging (MRI), such as pituitary stalk interruption and an ectopic posterior lobe, have been associated with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) (1, 2, 3, 4). The origin of these alterations is still controversial. Because of the difficulties in establishing cut-off values for normal responses to GH stimulation tests, these changes on MRI have been considered adjunctive for the diagnosis of permanent GHD.

Craft et al. (5) reported a high frequency of perinatal insults, such as breech delivery and/or neonatal hypoxemia, in children with idiopathic hypopituitarism. Fujisawa et al. (6) and Kikuchi et al. (7) reported stalk transection and ectopic posterior pituitary at MRI in patients with hypopituitarism who had a history of perinatal insults and suggested that the traumatic-ischemic injury of the pituitary stalk or median eminence was the primary cause of the pituitary hormonal deficiencies.

In contrast, Argyropoulou et al. (8) did not find an association between transection of pituitary stalk and perinatal abnormalities in patients with idiopathic GHD. Triulzi et al. (9) reported frequent association of breech delivery with central nervous system (CNS) abnormalities in patients with pituitary dwarfism. Presence of familial cases, association with congenital CNS abnormalities, facial defects, morphologic alterations of the sella turcica, or micropenis in patients with hypopituitarism and MRI abnormalities suggested that the alterations of the hypothalamic-pituitary region were the result of an antenatal developmental defect (9, 10). In addition, subnormal length associated with relative adiposity at birth in children with hypopituitarism and MRI alterations could also be suggestive of a prenatal onset of the hormonal deficiency (11). Scotti et al. (1) postulated that, in some cases, perinatal abnormalities could be the result, rather than the cause, of hypopituitarism.

More recently, molecular studies of genes involved in the organogenesis of the pituitary gland and in GH secretion have elucidated the etiological diagnosis of many patients with GHD (12). Imaging studies of the hypothalamic-pituitary region of these patients with genetic defects may shed light on the controversial origin of the morphological abnormalities of this region in patients with hypopituitarism.

We investigated the etiology of GHD in 76 patients by screening for the most common molecular alterations in GH-1, GHRH-receptor (GHRH-R) and Prophet of Pit-1 (PROP-1) genes and verified whether their clinical data, hormonal responses to stimulation tests, and MRI studies of the hypothalamic-pituitary region are useful to indicate the origin of GHD and to select patients for molecular studies.

Subjects and Methods

Informed parental consent, patient assent, and approval by the Hospital Ethics Committee were obtained before initiating the studies. Among patients with short stature who were referred to the Hospital das Clinicas, 76 patients (50 males and 26 females), belonging to 74 unrelated families, with chronological ages 1.6–34.2 yr and heights between -2 and -9.7 SD were selected because of GHD (Tables 1 and 2). Patients with CNS tumors or meningoencephalocele were excluded. Patients 1–3 (13), 34 and 35 (14), and 38 (15) were previously reported. Patient 39 had a previously identified mutation (R271W) in POU1F1 (PIT-1) gene, and her hormonal and MRI results were included in this study (16).

All subjects were diagnosed with GHD after failure of GH stimulation by both a clonidine and combined insulin-TRH-GnRH stimulation test, and all were submitted to MRI of the hypothalamic-pituitary region. According to the hormonal response to the combined test, patients were classified as IGHD or CPHD, and patients with CPHD were further divided in hypothalamic or pituitary origin based on their TSH and prolactin (PRL) response.

Clinical evaluation

Heights were measured with a stadiometer and height SD was calculated using British reference standards (17). Bone age was determined by the standards of Greulich and Pyle (18), and pubertal development was rated using Tanner stages (19, 20). Weight and height at birth were considered to be low when they were less than the 10th percentile for gestational age (21), and neonatal hypoxemia was defined as an Apgar score less than 6 at 5 min or a history of neonatal resuscitation. Micropenis was defined as a penis length shorter than -2.5 SD (22).

Hormonal assays

GH was measured before and 60, 90, and 120 min after clonidine stimulation (0.1 mg/m², po). Glucose, cortisol, GH, TSH, PRL, LH, and FSH were measured in basal state and 15, 30, 45, 60, and 90 min after a combined stimulation test (0.1 U/kg insulin, 200 µg TRH, and 100 µg GnRH, iv). T3, T4, dehydroepiandrosterone sulfate, estradiol, and testosterone levels were measured at baseline.

Initially, GH was measured by immunoradiometric assay and TSH, PRL, LH, FSH, and cortisol by RIA. Subsequently, TSH was measured by enzyme immunoassay (EIA), and more recently these hormones, except cortisol, were measured by fluorometric assays (FIAs). T₄ was measured by RIA and FIA. All reagents were obtained from Wallac, Inc. (Turku, Finland), with the exception of TSH and T₄ RIA (Abbott, Abbott Park, IL) and cortisol (INCSTAR Corp., Stillwater, MN). Intraassay and interassay coefficients of variation were less than 8% and 10%, respectively, for all hormones.

Basal and stimulated levels of cortisol, TSH, PRL, LH, and FSH were compared with normal controls for chronological age (23, 24). GHD was considered when peak GH after clonidine and hypoglycemia stimulation tests was less than 7 µg/liter measured by immunoradiometric assay or less than 3.2 µg/liter measured by FIA. Cortisol response to hypoglycemia was considered normal when peak was 497 nmol/liter or greater. Antidiuretic hormone (ADH) deficiency was diagnosed in patients who had urinary density lower than 1010 and urinary volume above 50 ml/kg in 24 h (25).

Pituitary origin of CPHD was defined by a blunted response to TRH stimulation of TSH (peak, <5.6 mU/liter by RIA or <3.5 mU/liter by EIA) or PRL (peak, <20 µg/liter by RIA). Hypothalamic origin of CPHD was suggested by at least one of the following conditions: 1) high basal levels of TSH (>4.5 mU/ml by RIA or >3.4 mU/ml by EIA); 2) high basal levels of PRL (>30 µg/liter by RIA or >14.5 µg/liter by FIA); 3) peak TSH post-TRH stimulation above the upper limit of the normal range for normal controls (>33.2 mU/ml by RIA or >22.1 mU/ml by EIA); and/or 4) 60-min level of TSH post-TRH stimulation above the 15-min value or above the upper limit of the normal range (>3.2 mU/ml for EIA) (26).

DNA analysis

Genomic DNA was isolated from peripheral blood by standard methods. Patients with IGHD were initially screened for GH-1 gene deletions by SmaI digestion of PCR-amplified fragments flanking the GH-1 gene according to previously described methods (13, 27). The IVS1 + 1G>A mutation in the GHRH-R gene, responsible for IGHD in a large kindred from northeastern Brazil, was screened in IGHD patients by amplifying exon 1 and part of intron 1 with a set of primers containing a GC-clamp at 5' (28). The amplified products were separated by denaturing gradient gel electrophoresis at constant voltage (160 V) for 6 h at 60 C through 10% polyacrylamide gels (17). Fragments with abnormal migration compared with normal controls were sequenced. Subsequently, in all patients with IGHD, the whole coding region of GH-1 gene as well as intron-exon boundaries was amplified using GH-1-specific primers (primer sequence and conditions are available on request) and the promoter region (from -327 to -42), 13 exons, and the corresponding intron-exon boundaries of GHRH-R gene were also individually amplified by PCR, using primers and conditions previously described (28, 29), and both GH-1 and GHRH-R were sequenced.

All patients with CPHD were screened for the common 301–302delAG mutation in PROP-1 gene. This deletion mutation creates a BcgI restriction endonuclease site in exon 2 of the PROP-1 gene, as previously described (14). Exon 2 of each patient with positive digestion was sequenced to confirm the 2-bp deletion. In all patients with CPHD of pituitary origin, exons 1–3 of the PROP-1 gene were amplified by PCR and then sequenced as previously described (15).

Pituitary MRI

MRI scans were performed in a 1.5 Tesla unit (Signa, GE, Milwaukee, WI) using T1-weighted sagittal and coronal scans with TR:350 msec and TE:20 msec. The coronal images were obtained using 3.0-mm slice thickness with 10% gap before and after administration of 0.1 mmol/liter of a paramagnetic contrast (gadolinium). Maximal height of the pituitary gland was measured perpendicular to the sella turcica and considered hypoplastic when less than -2 SD, compared with normal controls (30). We considered a normal pituitary stalk when we identified a normal diameter from the level of the optic chiasm to its insertion on the pituitary gland. The stalk was considered thin when it had a continuous but extremely thin appearance and its proximal and distal diameter size were below normal. Optic nerves and midline structures, such as septum pellucidum and corpus callosum, were examined.

Statistical analysis

The ² test with Yates correction or the one-tailed Fisher test was used to compare features of patients with and without mutations and among patients without mutations, those with IGHD, and those with CPHD.

Results

According to the response to the combined pituitary stimulation test, 33 patients had IGHD (patients 1–33) and 43 patients had CPHD. Of these, in 11 of pituitary origin (patients 34–44), 30 of hypothalamic origin (patients 45–74), and 2 patients (patients 75 and 76), this distinction was not possible because TSH and PRL in the combined test were normal. Clinical data, hormonal responses to stimulation tests, and MRI findings of the patients with IGHD are shown in Table 1 and patients with CPHD are shown in Table 2.

Patients with IGHD

GH-1 gene. Digestion of PCR products from patients 1, 2, and 4 with Sma I produced two fragments of 1470 and 446 bp, indicating that they were homozygous for a 6.7-kb GH-1 deletion (13). Digestion of PCR products from patient 3 with Sma I produced only one fragment of 1900 bp, indicating that she was homozygous for a 7.6-kb GH-1 deletion (13). Digestion of PCR fragments of patients 5–33 and normal controls produced four fragments of 1900, 762, 711, and 446 bp, as expected in the absence of deletions. Sequencing the coding region and intron-exon boundaries of the GH-1 gene revealed heterozygous D143D in patient 13 and T149T in patients 20 and 30. These mutations were previously described as silent polymorphisms and do not change predictions of splice sites (31).

GHRH-R gene. The screening for the IVS1 + 1G>A mutation, in PCR fragments from patients 5–8 showed abnormal migration on denaturing gradient gel electrophoresis, compared with normal controls. Direct sequencing of these fragments revealed the IVS1 + 1 G>A mutation in the GHRH-R gene in a homozygous state in patients 5–7 and heterozygous state in patient 8. Sequencing the promoter region, 13 exons, and intron-exon boundaries identified in patient 8 an additional heterozygous IVS4 -2 A>G mutation, which disrupts the normal acceptor splice site, predicting retention of intron 4 and an abnormal receptor (32). In all the remaining patients, the sequence was normal or contained previously recognized polymorphisms [promoter nt 1972 T>C, A57T, E121D, and M422T (33, 34)].

MRI findings of patients with genetic and idiopathic IGHD are in Table 1. No patient had evidence of optic nerve hypoplasia or defects in midline structures. Patients 1, 2, and 4 with IGHD caused by a GH-1 deletion of 6.7 kb (Fig. 1) and patients 5–8 with GHRH-R mutations had a normal pituitary stalk and posterior lobe in normal location (except for a nonvisible posterior lobe in patient 5). Patient 3 with a GH-1 deletion of 7.6 kb had a normal stalk but an ectopic posterior lobe located in the median eminence (Fig. 2). Pituitary heights were normal in patients 1, 2, 4, 6, and 7 and diminished in patients 3, 5, and 8. Among patients with idiopathic IGHD, pituitary height was augmented in one patient (patient 9), normal in 11, and diminished in 13 patients; pituitary stalk was normal in 10, thin in 7, and interrupted in 8 patients; and posterior lobe was in normal location in 7, ectopic in 17, and not visualized in 1 patient (Tables 3 and 4).

View larger version (152K): [in this window] [in a new window]   Figure 1. Upper panel, sagittal (A) and coronal (B) pituitary imaging studies of patient 1 with IGHD caused by GH-1 gene deletion of 6.7 kb showing intact stalk, normal pituitary gland (black arrow) and posterior lobe (white arrow). Lower panel, sagittal (C) and coronal (D) views of patient 20 with idiopathic IGHD showing stalk interruption, an ectopic posterior lobe (white arrow), and pituitary gland hypoplasia (black arrow).

View larger version (58K): [in this window] [in a new window]   Figure 2. Sagittal (A) and coronal (B and C) pituitary imaging studies of patient 3 with IGHD caused by GH-1 gene deletion of 7.6 kb showing intact stalk, reduced pituitary gland (black arrow), and an ectopic posterior lobe in the median eminence (white arrow).

Patients 34–36, 38, 41–44, 45, 46, 48, 51, 53–56, 58, 59, 63, 65–68, 70, 73, and 74 were retested at pubertal age with the acute GnRH test, and all had subnormal peak LH levels measured by FIA (23) (data not shown). In addition to their hormonal deficiencies of the anterior pituitary gland, patient 54 also had ADH deficiency. Patients 34 and 36 were submitted to another combined test, at 15.2 and 29 yr, respectively, and presented a blunted cortisol response to hypoglycemia (cortisol peak 331 and 91 nmol/liter, respectively), suggesting evolving partial ACTH deficiency (14).

PROP-1 gene. In patients 34–37, exon 2 of the PROP-1 gene was entirely cleaved with BcgI in three fragments, as expected with homozygous 301–302 AG deletion, which was confirmed by direct sequencing (14). PCR products of patients 38 and 40–76 and normal controls were not cleaved by this enzyme.

Sequencing of exon 2 of patient 38 with CPHD of pituitary origin revealed homozygosity for a transition of thymidine to cytosine in nucleotide 263 of the PROP-1 gene, resulting in the substitution of a highly conserved phenylalanine by serine in codon 88 (F88S) (15). Sequencing of exons 1–3 of patients 40–44 did not show any alteration in the PROP-1 gene.

Patient 34 with the 301–302 delAG mutation in the PROP-1 gene had at 8.8 yr an enlarged anterior pituitary lobe (height of 8 mm vs. 4.5 ± 0.6 mm in controls) and hyperintensity on T1-weighted image at coronal and sagittal views on MRI. At 15 yr, MRI was repeated and showed a marked reduction of pituitary height (2 mm vs. 5.3 ± 0.8 mm in controls) (14). Patient 37 with 301–302 delAG PROP-1 had a normal pituitary height at 12.5 yr, whereas patients 35 and 36 with 301–302 delAG and patient 38 with F88S mutation in PROP-1 had a pituitary gland of reduced size at 27, 19, and 9 yr, respectively. Patient 36 had another MRI performed at 30 yr, and pituitary height decreased further to 3.0 mm (-10 SD). Patient 37 with CPHD caused by R271W mutation of the PIT-1 gene had a hypoplastic anterior pituitary lobe at MRI at 14.2 yr. All patients with CPHD caused by inactivating mutations in the PROP-1 or PIT-1 genes had a normal pituitary stalk and a normally located posterior lobe on MRI (Tables 3 and 4).

Comparison between patients with GHD of genetic origin with those without mutations (Tables 3 and 4)

Patients 1–4 with IGHD caused by GH-1 deletions, patients 5–8 with GHRH-R mutations, patients 34–38 with CPHD caused by inactivating mutations in the PROP-1 gene, and patient 39 in the PIT-1 gene were classified as cases with GHD of genetic origin whereas the remaining patients, in whom no mutations in these genes were identified, were labeled as idiopathic GHD, either IGHD or CPHD.

Parental consanguinity was present in 8 of 14 patients (57%) with GHD in whom a genetic origin was identified, a significantly higher frequency than 1 of 62 (2%) referred in patients with GHD of idiopathic origin (P < 0.001). Frequency of familial cases was higher in GH-deficient patients of genetic origin, 3 of 14 (21%), than in patients with idiopathic GHD, 2 of 62 (3%, P < 0.05).

No patient with genetic origin of GHD (0 of 14) had breech presentation or hypoxemia at delivery, whereas at least one of these incidents was present in 24 of 62 patients (39%) with idiopathic GHD (P < 0.005). The frequency of breech delivery was higher in patients with idiopathic CPHD (14 of 37, 38%) than in patients with idiopathic IGHD (3 of 25, 12%, P < 0.05).

All patients with CPHD of genetic origin (6 of 6) had hormonal responses in the combined test indicating pituitary hormonal deficiencies, whereas most patients with idiopathic CPHD (30 of 37, 81%) had a pattern of hormonal response suggestive of deficiency of hypothalamic releasing factors (P < 0.01).

At first MRI, the pituitary gland was hypoplastic in 50% of patients (7 of 14) with GHD of genetic origin and in 73% of patients (45 of 62) with idiopathic GHD (P = 0.12, NS). The frequency of hypoplastic pituitary gland was significantly higher in patients with idiopathic CPHD (32 of 37, 86%) than in patients with idiopathic IGHD (13 of 25, 52%, P < 0.01).

The pituitary stalk was visible and of normal thickness on MRI in all patients with GHD of genetic origin (14 of 14) but only in 13 of 62 (21%) of idiopathic cases (P < 0.001). The frequency of normal stalk was significantly higher in patients with idiopathic IGHD (10 of 25, 40%) than in those with idiopathic CPHD (3 of 37, 8%, P < 0.01). Most patients with GHD of idiopathic origin had an interrupted or thin pituitary stalk on MRI (46 of 62, 74%), whereas no patient with genetic GHD had any of these alterations (P < 0.001).

When the posterior lobe was visible on MRI, it was located in the normal position in all but one patient with GHD of genetic origin (12 of 13, 92%) and only in a minority of patients with idiopathic GHD (8 of 61, 13%, P < 0.001). Posterior lobe was ectopic in most patients with GHD of idiopathic origin (53 of 62, 85%) and was significantly higher in idiopathic CPHD (36 of 37, 97%) than in idiopathic IGHD patients (17 of 25, 68%, P < 0.01).

Discussion

This study analyzed the etiology of GHD in a large cohort of patients by studying the three most common genes responsible for IGHD or CPHD deficiency—GH-1, GHRH-R, and PROP-1—and compared this diagnosis with the morphology of the hypothalamic-pituitary region on MRI. When a genetic abnormality was not identified, the patients were labeled with idiopathic GHD, although an abnormality in a gene not studied cannot be excluded.

Pituitary gland hypoplasia on MRI was present in patients with both genetic and idiopathic GHD. The pituitary stalk was normal in all patients with genetic GHD, whereas it was thin, interrupted, or not visualized in 79% of patients with idiopathic GHD. This stalk abnormality was also more frequent in patients with idiopathic CPHD than in patients with idiopathic IGHD. In patients with GHD of genetic origin when posterior lobe was visible on MRI, it was in normal position in 12 of 13 patients (92%). Patients with idiopathic IGHD had a more preserved hypothalamic-pituitary region on MRI than those with idiopathic CPHD, and therefore the presence of more than one hormonal deficiency could be attributed to more severe abnormalities of the pituitary gland, as has been also previously observed (35, 36, 37, 38).

Brooks et al. (39) reported an ectopic location of the posterior lobe in only 9 of 1500 (0.006%) subjects without any apparent endocrinopathy submitted to MRI of the hypothalamic-pituitary region. These authors suggested that ectopic posterior lobe could not be a variation of normal in the population (39). Surgical transection of the pituitary stalk results in a newly formed ectopic posterior lobe at the proximal stump, which secretes ADH (40). El Gammal et al. (41) reported an ectopic posterior lobe on MRI in 8 of 13 patients after resection of sellar or parasellar tumors. Similarly, the regeneration of the nerve fibers of the hypothalamoneurohypophyseal tracts, after a perinatal insult, could explain the presence of an ectopic posterior lobe in 35% (22 of 62) of our patients with idiopathic GHD. The frequency of breech delivery in our patients with idiopathic CPHD was 38% (14 of 37), compared with 2% in the normal population (42) and all patients with GHD and breech delivery had an ectopic posterior lobe on MRI. This association of perinatal insults in patients with idiopathic CPHD corroborates with the hypothesis of a traumatic-ischemic origin for morphological abnormalities and hypofunction of the pituitary gland.

In contrast, the origin of the ectopic posterior lobe in the patient with GH-1 gene deletion, who did not refer any perinatal insult, was not elucidated. She was born to consanguineous parents and involvement of another autosomal gene cannot be excluded. Pinto et al. (43) reported stalk interruption on MRI in familial cases of GHD without perinatal insults. Furthermore, two familial cases and one with parental consanguinity, labeled as idiopathic GHD, suggest a genetic cause that was not detected by the methods used. However, these patients are exceptions and represent only 5% of our cohort of patients with idiopathic GHD. Mutations in genes responsible for normal posterior pituitary lobe descent and stalk development could explain some of the cases considered idiopathic. Recently, ectopic posterior pituitary lobe on MRI was reported in some, but not all, patients with mutations in HESX1 (44) and LHX4 (45) genes.

In contrast to ectopic posterior pituitary lobe, a nonvisualized posterior lobe could be more common in the normal population, mainly in the elderly (41). Colombo et al. (46) observed a positive correlation between age and nonvisualized posterior lobe. In addition, an association between a nonvisualized posterior lobe and ADH deficiency has been reported (47, 48, 49). However, association between nonvisualized posterior lobe and the loss of its function was not observed by Proto et al. (50), and in the present study, both patients with ADH deficiency had an ectopic posterior lobe, one of small size.

Longitudinal hormonal and pituitary imaging changes of patient 34 with CPHD caused by 301–302delAG PROP-1 mutation were previously reported (14). At 8.8 yr, patient 34 presented GH, TSH, and PRL deficiencies with a normal cortisol response to hypoglycemia and an enlarged pituitary gland with a diffusely hyperintense T1-weighted image at MRI. At 15 yr, a new MRI revealed a marked reduction of pituitary height and an insufficient cortisol response to hypoglycemia indicating late partial ACTH deficiency (14). Patient 36, also with 301–302delAG in PROP-1, evolved from 19 to 30 yr with shrinkage of an already small pituitary on MRI and from normal to low cortisol response to hypoglycemia. This late ACTH deficiency has been confirmed in other patients with the 301–302delAG in PROP-1 (51, 52, 53). Interestingly, an enlarged pituitary has also been observed in patients with mutations in LHX3, another transcription factor involved in pituitary organogenesis (54). The mechanism for pituitary enlargement in these patients has not been clarified.

Similar to our findings, a more preserved hypothalamic-pituitary region at MRI was also reported in individual patients or small series of patients with genetic causes of IGHD (55, 56, 57) and CPHD (12, 14, 15, 16, 51, 52, 58, 59, 60, 61). A reduced adenohypophysis on MRI associated with a nonsense mutation in GHRH-R (Glu50 Stop) was reported by Netchine et al. (56) in siblings (age 9 and 10 yr) and Murray et al. (57) in four related patients aged 22–29 yr. We observed both small and normal pituitaries, among four patients (10–25 yr) belonging to three different families and carrying two different mutations in the GHRH-R gene. A common feature in all patients with GHRH-R mutations was a normal pituitary stalk and normal posterior lobe.

TSH response to TRH stimulation has been used as an aid to distinguish hypothalamic from pituitary forms of idiopathic hypopituitarism (24, 26). Pinto et al. (43), studying 51 patients with GHD and stalk interruption on MRI, observed that most of their patients with CPHD had hormonal features suggesting hypothalamic hypopituitarism. Among our patients with CPHD, 70% had a hormonal response suggestive of hypothalamic hypopituitarism (associated in all with an ectopic posterior lobe) and 26% were compatible with pituitary hypopituitarism. In 55% of patients with CPHD of pituitary origin, a genetic defect was identified. All patients with CPHD of genetic origin had pituitary hypopituitarism. PIT-1 deficiency was not investigated in all patients but is an unlikely cause because four of the five patients with CPHD without mutations were gonadotropin deficient, and gonadotropin secretion is not impaired in PIT-1 deficiency (12).

Cogan et al. (62) identified homozygous 301–302delAG in the PROP-1 gene in 5 of 10 familial and in 2 of 21 sporadic cases of CPHD. When these authors considered all sporadic patients with CPHD, the frequency of 301–302delAG was 12% (5 of 42 alleles), but this frequency increased to 50% (3 of 6 alleles) if only patients with CPHD of pituitary origin were considered (62). The 301–302delAG in PROP-1 was not found in patients with CPHD of hypothalamic origin (62). In this study we expanded the number of patients, and the frequency of 301–302delAG of PROP-1 was 0% (0 of 60 alleles) in patients with CPHD of hypothalamic origin and 36% (8/22 alleles) in patients with CPHD of pituitary origin.

The diagnosis of GHD has been established when GH levels fail to rise above 10 ng/ml after two stimulation tests. However, this cut-off level needs to be revised when using newer monoclonal antibody-based assays (63). We used a cut-off based on clonidine tests and immunofluorometric assays performed in normal children in our population. Using these criteria for the diagnosis of GHD, pituitary stalk abnormalities and/or ectopic posterior lobe were found in 54 of 76 (71%) of patients: Only 1 of 14 (7%) with a genetic cause and in a high frequency (53 of 62, 85%, P < 0.001) of patients in whom mutations were not detected. Ninety-five percent of our patients with GHD had either a genetic defect or hypothalamic-pituitary abnormalities at MRI. Recent studies, using less stringent cut-off values, reported that when MRI abnormalities were absent, the likelihood of permanent GHD and the response to treatment with GH were smaller (64, 65). Therefore, we suggest that in the absence of MRI abnormalities in a patient with GHD, either a genetic cause or mild/transient GHD should be considered and that auxological data should be useful for this differential diagnosis.

Compared with patients with idiopathic IGHD, patients with idiopathic CPHD had a significantly higher frequency of breech delivery, pituitary stalk interruption, ectopic posterior lobe, and pituitary gland hypoplasia, suggesting a more severe hypothalamic insult in this group.

In this study, GHD of genetic origin was characterized by a high frequency of consanguineous marriages, familial cases, intact pituitary stalk, and posterior lobe in the normal location on MRI. All patients with genetic CPHD had hormonal responses in the combined test compatible with hypopituitarism of pituitary origin. The presence of normal pituitary stalk and posterior lobe in patients with GHD because of proven molecular defects in genes involved in GH secretion indicates that morphologic abnormalities of these structures on MRI are not necessary for the diagnosis of permanent GHD. In contrast, patients with GHD in whom no genetic defect was identified had a high frequency of pituitary stalk interruption and ectopic posterior lobe on MRI, in many patients associated to perinatal insults, suggesting a traumatic-ischemic origin of GHD.

We conclude that MRI of the hypothalamic-pituitary region and pituitary hormonal response to stimulation tests are useful in the selection of patients and candidate genes to be studied to elucidate the etiology of GHD.

Acknowledgments

We are very grateful to M. Y. Nishi for technical assistance; T. Kamijo, M. R. S. Krishnamani, J. D. Cogan, and J. A. Phillips III for the molecular study of patients 1–3; and J. S. Parks, M. R. Brown, and D. L. Hurley for the molecular diagnosis of patient 39.

Footnotes

This work was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) (98/16598-0, to M.G.F.O.; 99/10692-8, to S.M.; and 00/14092-4) and from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (301246/95-5, to B.B.M.; and 300859/98-8, to I.J.P.A.).

Abbreviations: ADH, Antidiuretic hormone; CNS, central nervous system; CPHD, combined pituitary hormone deficiency; EIA, enzyme immunoassay; FIA, fluorometric assay; GHD, GH deficiency; GHRH-R, GHRH receptor; IGHD, isolated GHD; MRI, magnetic resonance imaging; PRL, prolactin; PROP-1, Prophet of Pit-1.

Received December 5, 2001.

Accepted August 8, 2002.

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