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Departments of Pediatrics (R.R.) and Endocrinology (M.G., A.S., S.V.-K., T.B., A.B.), Centre Hospitalo Universitaire Timone, 13385 Marseille Cedex 5, France; Laboratory of Biochemistry and Molecular Biology (A.S., A.E., A.B.), Centre Hospitalo-Universitaire Conception, 13385 Marseille Cedex 5, France; and Laboratory Interactions Cellulaires Neuroendocriniennes (R.R., A.S., A.E., T.B., A.B.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 6544, Institut Fédératif Jean Roche, Faculté de Médecine, Université de la Méditerranée, 13284 Marseille Cedex 7, France
Address all correspondence and requests for reprints to: Dr. Anne Barlier, Laboratoire de Biochimie et Biologie Moléculaire, Hôpital de la Conception, 13385 Marseille Cedex 5, France. E-mail: barlier.anne{at}ap-hm.fr.
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Abstract |
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Objective: A genetic screening strategy, based on endocrine and neuroradiological phenotype according to published knowledge, was applied to establish the prevalence of gene defects in each category of patients and provide a useful framework for clinicians to determine the genetic etiology and recurrence risks for individuals and families.
Design: One hundred ninety-five CPHD patients from the international GENHYPOPIT network were studied, according to their phenotype, for POU1F1, PROP1, LHX3, LHX4, and HESX1.
Patients: Patients selected had two pituitary hormone deficiencies or at least one deficiency with intracerebral malformations.
Results: Total prevalence of mutations was 13.3 and 52.4% in 20 patients with familial CPHD history. No mutation of HESX1 was observed in 16 patients harboring septooptic dysplasia. A mutation of LHX4 gene, previously reported, was found in one familial case from 39 patients bearing pituitary stalk interruption syndrome. In 109 patients without extrapituitary abnormalities, 20 had PROP1 mutations, including eight patients with a family history of CPHD. Among 20 patients without pituitary stalk interruption syndrome, no LHX3 gene defect was found, even with a neck rotation deficit. One POU1F1 gene defect was found in one patient presenting the rare postpubertal association of thyrotroph (TSH deficiency) and somatotroph (GH deficiency) deficits.
Conclusions: Mutation of PROP1 gene remains the first to be looked for, and POU1F1 mutations should be sought in GH deficiency and TSH deficiency postpubertal population without extrapituitary malformations. Identification of gene defects allows early treatment of any deficit and prevention of their potentially fatal consequences. Genotyping appears highly beneficial at an individual and familial level.
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Introduction |
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Human mutations in POU1F1, also known as Pit-1, have been reported in patients presenting GH, prolactin (PRL), and TSH deficits. These sporadic or familial CPHDs are transmitted as either an autosomal recessive or a dominant trait (4, 5, 6). However, only a few POU1F1 mutations were found in several cohorts with CPHD (6, 7), and no mutation of POU1F1 was found with pituitary stalk interruption syndrome (PSIS) or posterior pituitary ectopia (PPE) in literature (8, 9, 10).
Human PROP1 gene mutations induce CPHD that includes gonadotroph and sometimes late corticotroph deficiencies (11, 12). The phenotypes of affected children vary widely, both within and between pedigrees. Note that the pituitary is hypoplastic, normal, or hyperplastic with subsequent involution. To date, PROP1 mutations represent the most frequently reported etiology of CPHD (12, 13, 14). However, two recent studies (10, 15) failed to identify any mutations within PROP1 in a series of patients with CPHD. No PROP1 mutation was reported in CPHD patients (n = 111) with PSIS or PPE in several series (10, 15, 16, 17, 18, 19).
Two LIM homeodomain transcription factors, LIM class of homeodomain protein (LHX3 and LHX4), also play a crucial role in pituitary gland organogenesis (20, 21). Three human LHX3 mutations have been reported in five patients from three consanguineous families (22, 23). All patients exhibited CPHD but had intact ACTH secretion. They presented with stubby neck and a neck rotation deficit. Anterior pituitary was hypoplastic or hyperplastic or with microadenoma. No mutation of LHX3 was reported among two series of patients with PPE [n = 17, (16, 18)]. A dominant intronic mutation of LHX4 was recently found in a familial case presenting with a complex disease phenotype: GH, TSH, and ACTH deficiencies, hypoplastic pituitary, PSIS, and extrapituitary abnormalities [pointed cerebellar tonsils and poorly developed sella turcica (24)].
HESX1 is a paired like transcriptional repressor factor (1). Its repressive actions seem to be required for initial pituitary organ commitment. Progression beyond the appearance of the first pituitary lineage (corticotroph) requires both loss of Hesx1 expression and actions of Prop1, expressed in sequential, overlapping temporal patterns. Mutations of HESX1 have been reported in a broad spectrum of phenotypes such as septooptic dysplasia (SOD), variable pituitary deficit, from isolated GHD to panhypopituitarism, and ectopic posterior pituitary (25, 26, 27, 28). SOD is characterized by the classical triad of optic nerve hypoplasia, pituitary hypoplasia, and midline defects mainly combined with neuroradiological abnormalities, such as agenesis of corpus callosum and hypoplastic septum pellucidum. However, mutations of HESX1 remain rare and were not found in several series (10, 13, 16).
A large variability of phenotypes is thus associated with distinct gene defects. Yet in many CPHD patients, genetic screenings failed to identify alterations in any of these genes (6, 7, 10, 13, 16, 18, 19). In many series only patients with identified mutations are reported, giving a biased idea of the pattern of molecular causes of CPHD. Clinical practitioners need a useful framework for requesting genetic study and genetic counseling purposes.
Using a phenotype-based strategy, we thus screened relevant transcription factor genes in a series of 195 patients from 165 unrelated pedigrees. Several categories of patients were considered: patients with or without SOD or PSIS, postpubertal patients with or without gonadotroph deficiency, and prepubertal patients. Genotyping included coding exons of HESX1, LHX4, PROP1, LHX3, and POU1F1. We reported a new PROP1 mutation and the prevalence of all polymorphisms in our CPHD population. A functional study allowed us to classify a new POU1F1 point allelic variation as a polymorphism. The present study thus allowed us to determine the prevalence of gene defects in each category of patients, according to a genetic screening strategy (Fig. 1
).
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Subjects and Methods |
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The GENHYPOPIT network was launched as a multicentric study in both national and international pediatric and adult endocrinology centers (France, Tunisia, Egypt, Argentina, Turkey, Belgium, Lebanon, Switzerland) to screen pituitary transcription factor genes in patients with CPHD. Patients or parents of minor patients gave their written informed consent to participate in this study, which was approved by the local ethics committee. Patients bearing GHD, associated with at least one additional anterior pituitary hormone deficiency or with intracerebral malformation, and patients bearing two nonsomatotroph pituitary hormone deficiencies were selected. Hormonal studies and intracranial imaging were performed in all index patients in each referring medical center. Hormone assays were performed using several commercial RIA kits, and normal values for each center were taken into account. The plasma GH response was studied with at least two provocative tests in each patient: insulin intolerance test (0.05 U/kg), GHRH infusion test (80 µg, Somatoreline; Choay/Sanofi, Gentilly, France) or propanolol-glucagon test (0.25 mg/kg propanolol orally and 1 mg glucagon, im). A diagnosis of TSH deficiency (TSHD) was made if serum T4 concentration was subnormal (free T4 < 12.0 pmol/liter) or total T4 < 65 nmol/liter) with an inappropriately low serum TSH concentration (<5 µU/ml). Basal plasma ACTH and cortisol were measured at 0800 h (normal range for cortisol: 210–560 nmol/liter). The plasma ACTH and cortisol response was also determined during an insulin tolerance test. Gonadotroph axis was investigated only in patients of postpubertal age, i.e. over 15 yr for female and 17 yr in male subjects. FSH-LH deficiency was diagnosed on the basis of delayed or absent pubertal development with low serum testosterone or estradiol levels and blunted LH/FSH response to a GnRH stimulation test. We chose not to take PRL function into account because the diagnosis of PRL deficiency cannot be made on the basis of basal PRL levels only, and a minority of centers had performed TRH testing in the past. Intracranial imaging was obtained by magnetic resonance imaging (MRI) using precontrast coronal spin echo T1-weighted images followed by postgadolinium T1-weighted imaging. Malformations, in particular limited neck rotation or features of SOD, were systematically sought and recorded in all patients. Patients with a known postnatal cause of acquired hypopituitarism were excluded.
Genomic analysis of transcription factors
Genomic analysis of HESX1, LHX3Ia and Ib, LHX4, PROP1, and POU1F1 genes was performed by sequencing. All coding exons of these genes were amplified from genomic DNA as previously described (29) using exon-flanking primers (sequence posted on-line). The promoter, enhancer, and ß-isoform of the POU1F1 gene were also analyzed. The same primers were used for sequencing, using CEQ 8000 sequencer (Beckman Coulter, Fullerton, CA).
Plasmid constructs and site-directed mutagenesis
Wild-type human POU1F1 cDNA was inserted into the plasmid pcDNA3. The various reporter constructs containing POU1F1 binding sites within the context of different gene-regulatory regions were fused to a firefly luciferase gene. The PRL reporter construct from the proximal promoter regions of the human PRL gene (PRL luc) contained three POU1F1 binding sites (gift of J. A. Martial, Liege, Belgium). The proximal promoter of the human GH gene (GH luc) contained two Pit-1 response elements (gift of N. L. Eberhardt, Rochester, MN). A reporter construct containing the positive autoregulatory site of the human POU1F1 promoter gene was used (PIT luc) (gift of M. Delhase, San Diego, CA).
Wild-type human PROP1cDNA was inserted into the plasmid pcDNA3. The target vector in which the paired transcription factor consensus sequence PRDQ9 was inserted as three contiguous copies (PRDQ3), as previously described (29, 30).
In vitro site-directed mutagenesis was achieved using the QuickChange kit (Stratagene cloning system, La Jolla, CA) according to the manufacturer’s instructions using mutagenesis primer sequence (sequence posted online).
Cell culture and cotransfection
The transactivation capacities of wild-type and mutant POU1F1 were studied by transient cotransfection experiments in Hela cells as previously described (6). Each experimental condition was tested in triplicate in at least three different sets of transfections, with 0.6 µg/well of each target promoter (PRL-, GH-, or PIT-luc promoters), 0.6 µg/well of effector (empty vector or wild-type or mutant POU1F1) constructs and 0.1 µg for the pCEP4 ß-galactosidase construct.
Transactivation capacities of wild-type and mutant PROP1 were studied in similar experimental conditions (29, 30). Total transfected DNA was per well (1.6 µg): 0.25 µg of the empty pcDNA3, the wild-type or mutant PROP1 vectors (150delA or 629delC), 1.25 µg of the PRDQ3 target vector, and 0.1 µg of the pCEP4 ß-galactosidase construct.
Statistical analysis
Fisher test was used to compare the incidence of mutations in familial vs. sporadic cases. In transfection experiments, the fold increases of luciferase activity obtained with mutant and wild-type POU1F1 or PROP1 vectors were compared using the Mann-Whitney test.
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Results |
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DNA samples from 195 patients belonging to 165 unrelated families were collected. Among the 165 index cases (100 males and 65 females), 21 had a family history of CPHD. The total prevalence of HESX1, LHX3, LHX4, PROP1, and POU1F1 mutations was 13.3% (22/165); it was 52.4% (10/21) when only familial cases were considered (Table 1).
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Among the 165 index cases, 16 patients (including nine of prepubertal age) presented features of SOD, diagnosed on MRI, in association with at least one endocrine deficiency (five had anterior panhypopituitarism, six isolated GHD, and five double or triple deficiencies including GHD). Six patients also had PSIS. None of these patients had a family history of CPHD. No mutation of HESX1 was detected in genomic DNA, and no polymorphic nucleotide change was identified.
LHX4 gene
Patients bearing at least one hormonal pituitary deficiency associated with PSIS without SOD on MRI were selected for LHX4 analysis (Table 1C
). Thirty-nine unrelated patients (32 postpubertal), three of whom belonged to a family with CPHD history, were analyzed. Any relevant data from the perinatal period were reported. The majority of patients of postpubertal age, 21 of 32 (66%), had anterior panhypopituitarism. Gonadotroph function was normal in only three of these patients. In patients of prepubertal age (n = 7), four had GHD, ACTH deficiency, and TSHD; one newborn had isolated GHD; and the other two had GHD-ACTH deficiency and GHD-TSHD, respectively. Other abnormalities of sella turcica and median skull base were present in some of them: reduction in size or absence of anterior pituitary in 27 patients, and two patients had Chiari malformation characterized by tonsillar herniation. Finally, a poor development of sella turcica was found in three patients. Among the latter, one LHX4 gene defect was detected. It was a heterozygous intronic point mutation involving the splice-acceptor site preceding exon 5 (Table 1C). This patient, bearing Chiari malformation hypoplastic sella turcica and panhypopituitarism, had already been reported by Machinis et al. (24). c.248 + 46C>A polymorphism had been found in a Turkish population. c.248 + 65G>A, c.778 + 14G>T, c.778 + 31C>A, and c.778 + 36G>A polymorphisms were found in several families without cosegregation with the disease CPHD (Table 2).
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PROP1 gene screening was performed in 109 unrelated patients (89 postpubertal) without PSIS or SOD. A detailed endocrine phenotype of these patients is shown in Fig. 2. Twenty (20 of 109 = 18.3%, n = 11 females) had a PROP1 gene defect, of whom 10 had been mentioned in our previous reports (12, 29, 30). In the postpubertal age group (n = 89), all of the 18 PROP1 mutations were associated with gonadotroph and somatotroph deficiencies. At prepubertal age, two of 20 patients carried a PROP1 mutation. Both cases were corticotroph, thyrotroph, and somatotroph deficient.
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). The single nucleotide deletion at the end of exon 3 (c.626delC) had never been reported so far. Patient with an unreported double-heterozygous mutation [c.150delA]+[c.629delC]
This male, born to nonconsanguineous parents, was referred to the endocrinology department for pubertal retardation at the age of 16 yr. He was previously treated for GHD at age 5 yr. The patient had no sign of spontaneous puberty and his height was 167 cm (midparental height 165 cm). Endocrine investigations showed panhypopituitarism (TSHD, FSH and LH deficiency, ACTH deficiency, PRL deficiency, and GHD), and pituitary MRI examination was normal. Hydrocortisone, L-thyroxine, and testosterone were started, and GH substitution continued. At the age of 18 yr, he achieved his final height (179 cm). He was found to have a double-heterozygous deletion: [c.150delA] and [c.629delC] of PROP1 gene. The first deletion was previously described as a mutational hot spot (12, 14, 31). The [c.626delC] allelic variation causes a frameshift that starts at Pro210 and modifies the transactivation domain with a change of the 17 following amino acids and addition of eight. The patient’s older brother was heterozygous for the PROP1 gene [c.626delC] but was not endocrine deficient (final height 179 cm, spontaneous puberty). Unfortunately, parental genetic screening was unavailable.
Functional studies of 629delC PROP1
Cotransfection of wild-type PROP1 and the paired-like transcriptional factor response element PRDQ9 resulted in a strong stimulation of luciferase reporter gene relative to that of the empty vector. Activation by 629delC PROP1 mutant was reduced to 67.8% of the wild-type (P < 0.005). 150delA PROP1 mutant resulted in a similar stimulation of luciferase reporter gene relative to that of the empty vector (Fig. 3A).
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Twenty unrelated patients, without PSIS or any skull base abnormality, bearing hypopituitarism excluding corticotroph deficiency were selected for LHX3 gene analysis. PROP1 gene was normal in all of them. Two patients had a stubby neck and a neck rotation deficit (23). Three patients had a familial CPHD history. However, no mutation was found in any of these patients.
POU1F1 gene
POU1F1 gene was analyzed in all patients bearing only GHD and TSHD without PSIS or SOD (n = 17). This series included five prepubertal and 12 postpubertal patients. The association of GHD and TSHD without FSH/LH deficiency and ACTH deficiency was rare: among 90 patients of postpubertal age with normal gonadotroph function, only 12 (8%) had this double deficit. Only one POU1F1 mutation (Table 1B) was found, in a patient belonging to a subgroup of three patients with CPHD familial history (32). Furthermore, a heterozygous sequence variant that changed Gly 89 to Arg was found in one symptomatic patient and in his unaffected mother.
Functional studies of POU1F1 (G89R)
The in vitro-transactivating capacities of the mutant did not differ from that of the wild type, suggesting that it was a polymorphism (Fig. 3B).
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Discussion |
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) based on the phenotype of animal models on literature data in humans and the experience of our laboratory through the GENHYPOPIT network. We give an actual frequency of mutations in a selected population according to this strategy tree. Our genetic screening was performed by direct sequencing, a technique that cannot detect complex abnormalities such as large deletion or insertion in the locus. The most significantly predictive feature in finding a genetic defect was family history of CPHD. Indeed, in our series, the overall incidence of HESX1, LHX4, PROP1, LHX3, and POU1F1 defects was 8% in the group of sporadic cases (n = 12 of 144 index cases), compared with 51% (n = 10 of 21) in the family history group. This result agrees with other studies (10, 19) and the characteristic feature of autosomal recessive transmission mode of inherence for PROP1, LHX3, and the majority of POU1F1 defects.
Note that all of our genetic analyses performed in patients not bearing GHD were unsuccessful. In all patients harboring mutations reported in the present study, GHD was indeed the constant feature at some point of the endocrine follow-up. However, GHD was not necessarily the presenting pituitary deficiency: TSHD and gonadotroph deficiency could be diagnosed before GHD in some patients with PROP1 mutation (14, 29, 34).
Our proposed screening algorithm (Fig. 1) was first based on the neuroradiological MRI phenotype. Description of SOD on MRI led to genetically screen HESX1 gene. In 16 individuals bearing SOD who had neither a family history of CPHD nor consanguinity, no HESX1 mutation was found. Our results are in line with other large screening studies, in which human HESX1 gene mutations remained rare in individuals with SOD. Up to now, only nine missense human HESX1 mutations have been described (25, 26, 27, 28). Family history seems to be an important factor to take into account when performing HESX1 screening. SOD usually occurs sporadically, and in such cases, other genes or environmental agents could also contribute to this phenotype (35).
The second abnormality carefully looked for on pituitary MRI was PSIS. The endocrine deficit phenotype did not appear as a highly relevant distinctive feature in this setting. Indeed, anterior pituitary deficiency was usually complete in PSIS patients of postpubertal age as in 66% of patients in our series. According to literature data, presence of PSIS on MRI practically may exclude PROP1, POU1F1, and LHX3 gene defects. Thus, no mutation was found in 111 patients with PSIS for PROP1 (10, 15, 16, 17, 18, 19), 91 patients with PSIS for POU1F1 (6, 8, 9, 10, 16), and 17 patients with PPE for LHX3 (16, 18). Before designing our strategy tree, we unsuccessfully performed 23 PROP1 and two POU1F1 gene analyses in CPHD patients with PSIS (data not shown). PSIS may be associated with LHX4 defects as previously reported [(24) and an unpublished report (36)]. To date, LHX4 screening may probably be limited to this subgroup of patients. A mutation of LHX4 was found in one of three unrelated familial cases from our series of 39 patients bearing PSIS. Note that poor development of sella turcica and an Arnold Chiari malformation were associated. Only a better endocrine and radiological characterization of a larger number of patients with LHX4 defects will optimize the selection of potential candidate patients for LHX4 gene screening.
The third phenotypic feature that was taken into account was gonadotroph function (Fig. 1). Patients had been classified into two groups according to their pubertal status: postpubertal age group, with well-characterized gonadotroph function, and a prepubertal age group. At postpubertal age, gonadotroph deficiency with GHD strongly suggested a PROP1 gene defect. We found a PROP1 mutation in 24% (18 of 73) of such postpubertal patients. In the postpubertal group, normal gonadotroph function excluded a PROP1 mutation. Finally, the family history is once again important: the prevalence of PROP1 mutations was 13.2% in sporadic cases, reaching 44% in familial cases in our series. In previously reported CPHD population without SOD or PSIS, the prevalence in familial cases was about 50% (14, 16, 19). PROP1 mutations represented the most frequently identified genetic cause of CPHD in our population as in other series (13, 14, 19).
Among other genes that might be involved in PROP1-negative patients, LHX3 represents a potentially interesting candidate gene: our study was the first to look for genetic defects of LHX3 in a series of patients without ACTH deficiency, SOD, and PSIS (n = 20). No LHX3 mutation was found, even in those presenting with a rigid cervical spine (n = 2) or a family history of CPHD (n = 3). LHX3 mutations thus remain a rare cause of CPHD (16, 18).
The fourth phenotypic feature in our genetic screening algorithm (Fig. 1) was based on corticotroph status. Normal gonadotroph and corticotroph function at postpubertal age should lead genetic screening toward a possible POU1F1 defect. In fact, association of TSHD and GHD at postpubertal age is rare: 12 of 90 in our population, two of 33 in the series of McLennan et al. (15). Because detailed information on PRL function was unavailable in most of our patients, only GHD and TSHD were considered. We found only one POU1F1 mutation in the 12 (8%) postpubertal index cases with this constellation of deficits (32). POU1F1 gene defects remained rare, even in patients carefully selected with respect to their endocrine phenotype: two of 14 in a series of Rainbow et al. (10), one of 12 in a Russian population (7).
Our cohort contained 100 males and 65 females. This difference is of interest because recent advances emphasize possible involvement of X-linked mechanisms of hypopituitarism. First described in association with mental retardation (37), changes of gene dosage of SOX3 (located in Xq27) have been reported in association with variable hypopituitarism without mental retardation (38). Neuroradiological findings in patients with SOX3 gene alterations were variable including PPE, infundibular abnormalities, or corpus callosum hypoplasia. The incidence of SOX3 abnormalities in the CPHD population remains to be defined.
In practice, a major consequence of the delayed onset of pituitary deficiencies in PROP1 or POU1F1 defects (12, 14, 32) is the need for a careful follow-up of pituitary functions during childhood for patients bearing an apparently isolated GHD. Evolution in the pattern of pituitary hormone deficiencies requires reassessing genetic analysis. In childhood, considering the rarity of POU1F1 mutations in comparison with PROP1 defects, it seems advisable to start genetic screening by PROP1 gene analysis.
In conclusion, a rational and cost-effective genetic screening of CPHD should be performed after careful selection of patients with respect to the endocrine and neuroradiological phenotypes and family history. When CPHD is not associated with extrapituitary abnormalities, a mutation of the PROP1 gene has to be looked for first, and POU1F1 mutations should be sought in the postpubertal population bearing GHD and TSHD. Identification of a PROP1 or POU1F1 gene defect will serve to anticipate the future pattern of pituitary hormone deficiencies, thus allowing early treatment of any deficit and prevention of their potentially fatal consequences if left untreated. Such a genotyping thus appears highly beneficial at both individual and familial levels. Based on literature, when extrapituitary malformations such as PSIS or SOD are present, genetic analysis of PROP1, POU1F1, and LHX3 does not appear to be required. Future reports may modify our decision tree to include other genes involved in hypopituitarism such as SOX3 or other yet-unidentified genes. Finally, when the sequencing of one of the likely candidate genes does not detect any abnormality, it should be kept in mind that other mechanisms such as an ALU insertion (28) or a complete deletion or insertion of one allele may be looked for.
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Acknowledgments |
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Footnotes |
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First Published Online May 30, 2006
Abbreviations: CPHD, Combined pituitary hormone deficiency; GHD, GH deficiency; LHX, LIM class of homeodomain protein; MRI, magnetic resonance imaging; PPE, posterior pituitary ectopia; PRL, prolactin; PSIS, pituitary stalk interruption syndrome; SOD, septooptic dysplasia; TSHD, TSH deficiency.
Received October 3, 2005.
Accepted May 19, 2006.
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