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Pituitary Stalk Interruption Syndrome: A Clinical-Biological-Genetic Assessment of Its Pathogenesis¹

Pediatric Endocrinology (G.P., I.N., R.B.) and Radiology (F.B.) Units and Physiology Laboratory (J.C.S.), Université Paris V and Hopital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris, and INSERM U-468 (I.N., M.L.S.), Hopital Henri Mondor, Creteil, France

Address all correspondence and requests for reprints to: Dr. R. Brauner, Hopital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France.

	Abstract

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The detection of pituitary stalk interruption syndrome (PSIS) by magnetic resonance imaging is a diagnostic marker of permanent GH deficiency (GHD), but the pathogenesis of PSIS is unknown.

Fifty-one patients (27 males) with GHD and PSIS were classified according to whether the GHD was isolated (group 1, 16 cases) or associated with other anterior pituitary abnormalities (group 2, 35 cases). The 2 groups had similar characteristics (frequencies of perinatal abnormalities, ages at occurrence of first signs and at diagnosis, height, GH peak response to stimuli other than GHRH), but associated malformations were less frequent in group 1 (12%) than in group 2 (54%; P < 0.01), hypoglycemia occurred in 25% of group 1 and 70% of group 2 (P < 0.01), and the GH peak response to GHRH was less than 10 µg/L in 0% of group 1 (4 cases evaluated) and 57% of group 2 (21 cases; P < 0.05). Thirty-one cases (61%; 25 from group 2) had features suggesting an antenatal origin: familial form (4 cases), microphallus (10 boys), and/or associated malformations (50%; 21 cases). Twenty-seven cases (53%, 22 from group 2) had features suggesting a hypothalamic origin.

The three group 1 patients with a GH peak of 1 µg/L or less had no large GH-N gene deletion. One familial form had no linkage between the GHD phenotype and abnormal GH-N locus, and the only mutation described to date in the GHRH receptor gene was absent. The two patients with low plasma PRL levels had no Pit-1 gene abnormality.

Thus, most of the patients with GHD associated with multiple anterior pituitary abnormalities and PSIS have features suggesting an antenatal origin. The GH-N, GHRH receptor, and Pit-1 genes do not seem to be implicated in PSIS.

	Introduction

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IDIOPATHIC GH deficiency (GHD) occurs in about 1/4,000 to 1/10,000 live births (1). This clinically and biologically heterogeneous condition poses problems for both diagnosis and pathogenesis. The detection of an anatomical abnormality of the hypothalamic-pituitary region by magnetic resonance imaging (MRI) is a diagnostic marker of permanent GHD. The complete form of this abnormality is the pituitary stalk interruption syndrome (PSIS) (2), which includes a lack of visible pituitary stalk and no normal posterior lobe hypersignal in the sella turcica plus a hyperintense nodule in the region of the infundibular recess of the third ventricle. Patients with PSIS form a distinct anatomical and endocrinological group of patients suffering from GHD, differing from those with no abnormality of the pituitary stalk or posterior lobe (3). The pathogenesis of PSIS is unclear. It could be acquired due to injury to this region at birth (4), but some cases have features suggesting an antenatal origin. This plus the familial forms of PSIS (5) suggest that PSIS has a genetic origin, but the genetic counselling of patients with PSIS is a problem because its pathogenesis is unknown.

The clinical-biological data of patients with GHD associated with PSIS have been analyzed to identify the features suggesting an antenatal and/or a hypothalamic origin of the condition and to identify a candidate gene in which to search for molecular abnormalities.

	Subjects and Methods

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Patients

The 51 patients (27 males) all had GHD with PSIS. GHD was diagnosed by a GH peak of 10 µg/L or less after 2 stimulation tests, except in 3 patients with GH peaks of 10.6, 11, and 12 µg/L. Patients were assigned to 1 of 2 groups according to whether the GHD was isolated (group 1, n = 16; Table 1) or associated with other anterior pituitary abnormalities (group 2, n = 35; Table 2), including abnormal secretions of TSH (subgroup 2a) or TSH plus ACTH (subgroup 2b). Informed consent for evaluation (oral) and for molecular analysis (signed form) was given by the parents.

Pre- and perinatal histories were reviewed for gestational age (<36 or >41 weeks), delivery (documented in 46 cases, breech or cesarean section), and neonatal hypoxemia (documented in 45 cases, Apgar score <6 at 5 min or neonatal resuscitation). Weight and height at birth were considered to be low when they were less than the 10th percentile for gestational age (6). Associated malformations were recorded. Microphallus was defined as a penis length of 2.5 cm or less (-2 SD). Endocrine status was evaluated before replacement therapy, except for the second GH evaluation, which was performed after administration of T₄ if necessary. GH secretion was assessed first by the sequential arginine-insulin test or by the glucagon test in patients weighing less than 10 kg or in those who had had hypoglycemia, and then by an ornithine test (chlorydrate ornithine, 14.5 g/m²). GH secretion was also evaluated after a GHRH test in the 25 patients seen most recently (4 in group 1 and 21 in group 2). Other pituitary functions were evaluated by the plasma basal free T₄ and TSH levels (n = 51), the TSH response to TRH (n = 44, not determined in case 9 with normal free T₄ or in 7 patients with low plasma basal free T₄), basal plasma PRL (n = 49), the PRL response to TRH (n = 19), plasma basal cortisol at 0800 h (n = 51), and the gonadotropin response to GnRH in 2 neonates with microphallus and in 4 patients who had no pubertal development or no menstruation despite being of pubertal age. Arginine vasopressin deficiency was excluded in all patients by a 12-h water deprivation test. The normal limits in the plasma were 12–28 pmol/L for free T₄; 0.6–4, 14 ± 7, and 9 or less mIU/L for basal, peak, and 120 min post-TRH stimulation TSH levels; and 5–25 µg/L for basal PRL, except for neonates, who had higher values. ACTH deficiency was diagnosed by plasma basal cortisol values below 40 µg/L in neonates and below 70 µg/L in older children, with no increase during hypoglycemia. All MRI scans were reviewed by an investigator (F.B.) blinded from the clinical-biological data.

Data are expressed as percentages or as the mean ± SE. The percentages within the two groups were compared by the ² test.

Molecular analysis

DNA was extracted from peripheral blood. Deletions from the GH-N gene itself or from the rest of the GH cluster were sought by amplifying the homologous repeated region flanking the GH-N gene followed by digestion with the restriction enzyme SmaI (7). Linkage between the GHD phenotype and the GH-N gene markers was analyzed by determining the dinucleotide repeat polymorphism (8) by PCR (migration of [³³P]deoxy-ATP-labeled PCR products on 6% acrylamide urea gels). The GHRH receptor (GHRH-R) gene was studied by amplifying the region encoding the receptor extracellular domain. The mutation of this receptor (9) was screened by digestion with BfaI. The Pit-1 gene was analyzed by amplifying its six exons (10), followed by single strand conformation polymorphism. DNA was sequenced directly (Sequenase kit, U.S. Biochemical Corp., Cleveland, OH) or after subcloning.

	Results

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There was consanguinity in cases 2, 4, and 24 and four patients from three families (cases 8 and 9 are brother and sister, GHD in the mother of case 18, and GHD plus PSIS in the paternal aunt of case 25).

Phenotype features (Tables 1 and 2)

The phenotypes of the group 1 and 2 patients were similar in terms of sex ratio, frequencies of abnormal gestational age (prematurity in eight and postmaturity in three for the whole population), perinatal abnormalities, and the occurrence of first signs before 6 months of age (Table 3). The mean values at diagnosis for chronological ages (6.4 ± 1.0 yr in group 1 and 4 ± 0.7 yr in group 2), heights (-3.5 ± 0.3 and -3 ± 0.2 SD) and GH peak responses to stimuli other than GHRH (5.2 ± 0.8 and 3.1 ± 0.6 µg/L) were also similar. However, some features were less frequent in group 1 than in group 2; these were associated malformations, hypoglycemia, and a peak GH response to GHRH below 10 µg/L. This peak correlated negatively (r = -0.48; P < 0.05) with age at diagnosis. The pituitary height was significantly (P = 0.01) higher in group 1 (2.4 ± 0.3 mm) than in group 2 (1.5 ± 0.2 mm) and correlated positively (r = 0.41; P < 0.01) with age at MRI.

Four group 2 patients had cryptorchidism (cases 18, 23, 28, and 51). The seven patients of pubertal age whose pubertal development was normal included all six patients from group 1 (cases 6, 7, 10, 11, 14, and 16) and one (case 27) from subgroup 2a. The four subgroup 2b patients of pubertal age had abnormal pubertal development. Three (cases 31, 39, and 40) had complete gonadotropin deficiency, and the fourth (case 33) had no menstruation despite a pubertal gonadotropin response to GnRH test. This patient had congenital septo-optic dysplasia, and her profound GH and ACTH deficiencies and low plasma T₄ level were diagnosed at 18.5 yr when she complained of primary amenorrhea. Her height was 148 cm, and pituitary height was 5 mm. Two boys tested neonatally (cases 43 and 44) also had complete gonadotropin deficiency.

Molecular analysis

Cases 1–3, with profound isolated GHD, had no large GH-N gene deletion. Linkage between the GHD phenotype and the GH-N locus was ruled out in the familial form of isolated GHD (cases 8 and 9). We then looked for a GHRH-R gene mutation (9); this was also ruled out. The Pit-1 gene in the group 1 and 2a patients with low plasma PRL (cases 2 and 18) was analyzed. The six coding exons of this gene were amplified, and the corresponding PCR products of the expected size had normal migration profiles. The coding sequence contained no mutation.

	Discussion

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Phenotype analysis of 2 groups (group 1, isolated GHD; group 2, multiple anterior pituitary abnormalities) revealed more frequent associated malformations in group 2. Only 2 group 1 patients had associated malformations, whereas 19 group 2 patients had them. They were mainly ophthalmic (10 cases), but they also affected the central nervous system (microcephaly, Arnold Chiari syndrome, cerebellar or corpus callosum atrophy, and central respiratory failure), the heart (interventricular septal defect associated with talus valgus foot), or other organs (club foot and single incisor tooth). Three patients also had associated diseases: Fanconi disease, cystic fibrosis, and a neonatal benign pharyngeal tumor without any other indication in one patient, whose sister had a cleft palate and normal height.

A total of 61% of cases, particularly in group 2, had features suggesting that PSIS is of antenatal, and possibly genetic, origin. Half of them were born by breech delivery or cesarean section and/or had neonatal hypoxemia. These characteristics are said to be especially frequent in patients with hypothalamic-pituitary deficiency (11, 12, 13), suggesting that this deficiency is due to injury to this region at birth. Triulzi et al. (4) also reported frequent breech delivery and associated central nervous system abnormalities in patients with multiple pituitary deficiency. This suggests that the mode of delivery and/or the neonatal hypoxemia are not the cause of PSIS, but are the direct or indirect consequence of the hypothalamic-pituitary lesion.

The hypothalamic or pituitary location of the lesion in patients with PSIS is unclear. The capacity of the anterior pituitary to respond to stimulation tests using hypothalamic factors probably depends on the cause of PSIS, the volume of the pituitary, and the age at evaluation. The response of GH to GHRH in patients with idiopathic GHD has implications for pathogenesis and therapy (14). It is lower in older patients (15), as in this study. Kikuchi et al. (16) found no characteristic pattern for the GH response in patients with PSIS; the anterior pituitary gland was normal in isolated GHD and small in multiple deficiencies. Similarly, our group 2 patients had a shorter pituitary height than the group 1 patients. Pombo et al. (17) found no GH response to GHRH stimulation when it was given either alone or with GH-releasing peptide-6 in 7 patients with PSIS and concluded that this test may be a diagnostic tool for PSIS. A GHRH test was routinely performed only in the 25 more recently seen of our patients, but all 4 group 1 patients tested had GH peak responses regardless of their age and GH peaks after stimulation in tests other than that with GHRH. This suggests a hypothalamic abnormality restricted to the control of GH secretion. Only 9 of 21 group 2 patients evaluated had a GH peak response to GHRH stimulation test above 10 µg/L. There was no relationship between their capacities to increase GH and TSH in response to TRH, as some patients with little or no GH response to various stimuli had an increased, prolonged TSH response to TRH. These data, therefore, suggest that PSIS is generally of hypothalamic origin and that its pathogenesis in isolated GHD and that in multiple anterior pituitary abnormalities are different. The capacities of the pituitary cells to secrete GH, TSH, ACTH, and gonadotropins may be dissociated in these subjects.

Four patients from three families in this study had the familial form of pituitary deficiency, with PSIS documented by MRI in five of six patients. A paracentric inversion of the short arm of chromosome 1 was recently reported in twins with PSIS (5). Similarly, one member of a family with a history of congenital GHD had a small nodule at the base of the brain; it was not connected to the pituitary fossa, but lay in the position of the normal pituitary stalk, and there was no anterior lobe (18). Familial multiple pituitary deficiency (GH, TSH, and ACTH) plus subnormal sella turcica and abnormal sphenoid bone morphology have been reported (19), as in three sporadic cases in this study.

The molecular data on patients with idiopathic GHD do not include studies of patients with PSIS. A group of three genes was analyzed in this study depending on the biological phenotype. The three group 1 patients with complete GHD had no large GH-N gene deletion. Although this does not rule out point mutations or small deletions, the exclusion of linkage between the GHD phenotype and the GH-N gene in one family belonging to the same group suggests that other genes are responsible for the disease phenotype. The GHRH-R gene is involved in the control of GH synthesis; the only mutation described to date in this gene (9) was not present in this family. Finally, analysis of the coding region of the Pit-1 gene in the two patients with GH and PRL deficiencies showed no abnormality. These negative results together with the anatomical abnormalities of the hypothalamic-pituitary region that are often associated with other malformations (group 2 patients), suggest that PSIS is due to defects in developmental genes. Molecular studies in patients with GHD should, therefore, be based on the structure of the hypothalamic-pituitary region, as documented by MRI. When this region appears to be normal, the biological phenotype should direct the molecular study toward known candidate genes (encoding GH, GHRH-R, and Pit-1), whereas these genes are not likely to be linked to the disease phenotype in cases with PSIS. However, genes involved in the development of this region are good candidates. Unfortunately, none of these genes is known in humans. The complexity of the embryological development of the hypothalamic-pituitary region (20) together with the phenotypic heterogeneity of PSIS suggest that there is more than one genetic disorder underlying this syndrome.

	Acknowledgments

 
We thank S. Amselem, F. Dastot, P. Duquesnoy, B. Duriez, and M. Goossens (INSERM U-468) for the molecular genetic studies and helpful discussions; J. L. Dufier for the ophthalmic examination; M. C. Perret (Physiology Laboratory) for technical assistance; the nurses of the Pediatric Endocrinology Unit for carrying out the tests; and Dr. O. Parkes for editorial help.

	Footnotes

 
¹ Presented in part at the 34th (Edinburgh, UK, 1995) and 35th (Montpellier, France, 1996) Meetings of the European Society for Pediatric Endocrinology. This work was supported in part by INSERM and a grant from the Direction de la Recherche Clinique de l’Assistance Publique-Hopitaux de Paris.

² Recipient of a fellowship from the Fondation pour la Recherche Médicale.

Received March 25, 1997.

Revised June 25, 1997.

Accepted July 7, 1997.

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