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Department of Endocrinology (S.V.-K., P.J., T.B.), Centre Hospitalier Universitaire (CHU) Timone, Marseille, France 13385; Laboratoire ICNE (S.V.-K., A.B., A.D., M.M., I.P.-B., P.J., A.E., T.B.), CNRS UMR 6544, IFR Jean Roche, Marseille, France; Department of Endocrinology (C.T., J.L.C.), Hôpital Saint Vincent de Paul, 75014 Paris, France; Department of Endocrinology (F.B.), Hôpital de l’Antiquaille, 69005 Lyon, France; Department of Endocrinology (P.B.), Hôpital Saint Antoine, 75012 Paris, France; and Department of Endocrinology (R.B.), Hôpital Necker-Enfants Malades, 75015 Paris, France
Address all correspondence and requests for reprints to: Thierry Brue, M.D., Ph.D., Hopital de la Timone, 264 rue St. Pierre, 13385 Marseille Cedex 5, France. E-mail tbrue{at}ap-hm.fr
Abstract
Alterations of the gene encoding the pituitary transcription factor PROP1 were associated with congenital forms of multiple pituitary hormone deficiencies in several families. Among 23 patients with multiple pituitary hormone deficiencies screened for a PROP1 gene abnormality, nine belonging to eight unrelated families had homozygous PROP1 gene defects. All mutations were located in exon 2 and affected only two different sites: a homozygous AG deletion at codons 99/100/101 (n = 5); homozygous point mutations affecting codon 73: R73C (n = 2) or R73H (n = 1), and a R73C/R99X double-heterozygous mutation (n = 1). R73H and R99X were never described. All patients were born to unaffected parents, and consanguinity was documented in two patients. They had complete GH, LH-FSH, and TSH deficiencies and normal basal levels of PRL. Delayed ACTH deficiency was diagnosed in four of nine patients. At magnetic resonance imaging the anterior pituitary was hypoplastic in seven patients and hyperplastic in two. This study found two novel mutations (R73H and R99X) and underlines the high incidence of PROP1 gene alterations in patients with multiple pituitary hormone deficiencies. A corticotroph deficiency was frequently observed in association with GH, TSH, and gonadotropin deficiencies and should be carefully sought during follow-up.
DEFICIENCY IN GH, produced by the somatotrophs in the anterior pituitary, is a common cause of short stature. GH deficiency (GHD) of genetic origin is a heterogeneous condition because it appears transmitted by several distinct modes of inheritance (1, 2, 3). Moreover, it may present either as isolated or as a multiple pituitary hormone deficiency (MPHD) when GHD is associated with diverse combinations of deficiencies affecting one or more of the other anterior pituitary hormones (4). These include PRL, TSH, gonadotropins (LH and FSH), and corticotropin (ACTH), each of these hormones being produced by specific anterior pituitary cell types, respectively, lactotrophs, thyrotrophs, gonadotrophs, and corticotrophs.
During the past decade, new findings have helped to entangle the
clinical, hormonal, and genetic heterogeneity of MPHD (3, 5). Studies on animal models indeed have shown that naturally
occurring dwarf mouse mutants displaying GH, PRL, and TSH deficiencies
are characterized by alterations affecting distinct loci and alleles.
Two dwarf mouse strains were first recognized to have different allelic
alterations of the pituitary-specific transcription factor Pit-1/GHF1
(or POU1F1) associated with the MPHD phenotype. Snell dwarf mice were
found to have a point mutation at codon 261 changing a tryptophan into
a cysteine (W261C), and Jackson dwarf mice had a much larger alteration
of the Pit-1 gene (6). Interestingly,
involvement of the Pit-1 gene locus had been ruled out in a
third murine dwarf mouse strain (Ames mice) in which GH, PRL, and TSH
deficiencies were associated with decreased LH and FSH gene expression
(7, 8, 9). The MPHD phenotype was more recently found in Ames
mice to be due to a homozygous point mutation (S83P) in the newly
recognized Prophet of Pit-1 (PROP1) gene that encodes
another anterior pituitary transcription factor whose expression
precedes and induces that of Pit-1, and hence named Prophet of Pit-1
(10). The human PROP1 gene, cloned in 1998
(11, 12), includes three coding exons, and encodes a
223-amino acid nuclear protein expressed in the developing anterior
pituitary. It belongs to the family of paired-type transcription
factors, and contains a C-terminal transactivation domain, and a
paired-type homeodomain with three putative 
helices. In recent
literature, nine distinct homozygous alterations of the human
PROP1 gene have been described in 27 unrelated families
(11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). The 2-bp (AG) deletion of the PROP1
gene located in exon 2 at position 296 to 302 corresponding to codons
99, 100, and 101 was previously found in patients from distinct genetic
backgrounds and described as a high mutability site
(14).
The aim of the present multicenter study was to screen families and patients suffering from MPHD for PROP1 gene alterations to determine the frequency of such alterations and to analyze the phenotype of the affected patients.
Patients and Methods
Patients
We launched a multicentric study in France to screen for PROP1 gene anomalies in patients with MPHD. Patients were included on the basis of GH deficiency associated with at least one other pituitary hormone deficiency, in the absence of ectopic posterior pituitary or stalk interruption, hyperprolactinemia, and any identified cause of hypopituitarism. The age of onset of each deficiency was not taken into consideration for inclusion in the study. At the time of the present report, we have collected DNA samples from 23 patients belonging to 20 unrelated families that originate from seven different countries.
Hormonal studies
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: an insulin tolerance test (ITT) (0.05 U/kg) and an additional GHRH infusion test (80 µg, Somatoreline, Choay/Sanofi, Gentilly, France) or a propanolol-glucagon test (0.25 mg/kg propanolol orally and 1 mg glucagon, im).
Investigation of the lactotroph axis was performed when MPHD was suspected. A TRH test was carried out in eight of nine patients, with measurements of PRL and TSH performed at 0, 30, and 60 min after an iv bolus (200 µg Protirelin, Roussel, Paris, France).
Plasma thyroid hormone levels (normal range of free T3 and T4, 3.8–6.8 pmol/liter and 7–17 pmol/liter, respectively) and TSH concentrations (normal range 0.2–3.5 mIU/liter) were measured repeatedly during follow-up.
Investigation of the gonadotroph axis was performed by measurement of LH and FSH levels at baseline and 30 and 60 min after a GnRH provocative test (100 µg iv Gonadorelin, Ferring Pharmaceuticals Ltd., Gentilly, France), together with determination of plasma T or E2 levels.
Plasma ACTH and cortisol concentrations were measured at 0800 h by different RIA kits. The plasma ACTH and cortisol response was studied with an insulin tolerance test (0.05 U/kg) in a subset of patients.
Radiological imaging
Pituitary magnetic resonance imaging (MRI) was performed in all patients, using precontrast coronal spin echo T1-weighted images, followed by postgadolinium T1-weighted imaging. The T1-weighted sequences provided reformatted images in the coronal plane, the oblique plane oriented along the pituitary stalk, and the axial plane oriented along the sellar floor.
Genomic analysis of the PROP1 gene
All three exons of the PROP1 gene were PCR amplified from genomic DNA using primers flanking the exons for direct sequencing. DNA was extracted from the peripheral lymphocytes using the QIAamp blood kit (QIAGEN S.A., Courtaboeuf, Yvelines, France). Exon 2 and then 1 and 3 of the PROP1 gene of each affected patient were amplified by PCR, using three sets of flanking intronic primers: F1 5'-ACCTACACACACATTCAGAGACAG-3', R1 5'-TGGAGCCTATGCTTTCAGC-3', F2 5'-AAAGACTGGAGCAGCACAGGACGCA-3', R2 5'-CTCAATGCAGTTGCTCCGATG-3', and F3 5'-GCCTTGTGGAAGAGCTTTACTCC-3', R3 5'-ATTTCTAATCGGTGAGCTGACCC-3'. Amplification was carried out in a 50-µl reaction, using 200 ng genomic DNA, 0.25 nmol/liter of each deoxy-NTP, 25 pmol of each primer and 1.5 U of Pfu DNA polymerase (Promega Corp., Lyon, France). The reaction consisted of 3 min at 95 C, followed by 30 cycles of 30 s at 95 C, 30 s at 55 C for exons 1 and 3 and 60 C for exon 2, 2 min at 72 C, and 5 min at 72 C. The PCR products were purified using the Qiaquick PCR purification kit (QIAGEN). Direct sequencing of the double-stranded PCR fragments was carried out according to the thermal cycle sequencing big dye terminator protocol (ABI Prism 310 genetic analyzer, Perkin-Elmer Corp., Paris, France) using the same PCR primers. Mutations were confirmed by repeat PCR and subsequent sequencing of PCR products. If a mutation was found in exon 2; exons 1 and 3 were not sequenced.
Results
Nine of the 23 patients, belonging to 8 of the 20 (40%)
families screened, proved to have PROP1 gene mutations (Fig. 1
), confirming the high frequency of this
genetic defect in this clinical setting. Although screened in France,
the families originated from five different countries (Table 1). The 14 remaining MPHD-affected
patients, who had no PROP1 gene anomaly, all presented with
GH deficiency, and additional pituitary anterior deficiencies included
TSH (71.4%), gonadotrophins (64.3%), ACTH (35.7%), and PRL
(21.4%).
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There were three male and six female patients, five sporadic (the
index case was the only known subject presenting with MPHD in this
family), and four familial cases of hypopituitarism (Table 1
). Failure
to thrive was the main reason leading to diagnosis of hypopituitarism.
Indeed, growth failure was observed between the ages of 2 and 8 yr in
our patients. All patients were born to parents of normal height and
had normal length at birth. Along with the main clinical features
summarized in Table 1, additional features of particular interest will
be discussed hereafter.
Eight patients were treated by GH and responded well on therapy. Five patients were treated before 14 yr of age, and their final height ranged from -1.5 to +1 SD. The three remaining patients were GH treated after 14 yr with a smaller final height (from -7 to -4 SD), although they had a good growth velocity (from 4 to 7 cm per year) during the GH treatment. The only untreated patient (no. 6) had an adult final height of 91.5 cm.
The female patient (no. 8), in whom complete GH deficiency was revealed by a failure to thrive at 5 yr, was treated by GH from 5 to 9 yr, permitting normalization of her height. TSH deficiency was diagnosed at 8 yr and treated by L-thyroxin replacement. After stopping GH therapy, the patient had an ongoing paradoxical growth despite complete GH deficiency and normal insulin levels. Indeed, she gained 23 cm from 9 to 15 yr and reached a final height of 160 cm (weight = 62 kg).
The female patient (no. 4), aged 41 yr, who had an adult height of 125 cm, was referred for hypothyroidism. A diagnosis of hypothyroidism had been suspected at 12 yr and treated by L-thyroxin replacement therapy for only 24 months. Growth failure had been observed at 7 yr but had not been treated, and her bone age was 12 yr at chronologic age 41. She was given GH, L-thyroxin, and estrogen replacement therapy and gained 9 cm after 2 yr of treatment (final height: 134 cm).
None of the patients entered puberty spontaneously. Two children had a microphallus (patients 2 and 3) and one had cryptorchidism (patient 3).
In one patient (no. 7, family VI), identification of the
PROP1 gene mutation in the index case led to diagnosis in
another sibling. Both affected sisters were treated by recombinant
gonadotropin therapy that failed to induce a pregnancy but resulted in
an ovarian overstimulation. In vitro fertilization was then
performed and was successful at the second attempt in the oldest
sister. After an uneventful pregnancy, a 2.5 kg/43.5 cm normal girl was
delivered at 39 wk. No neonatal hypoglycemia or other complication was
observed. Maternal feeding was made impossible by the absence of
spontaneous lactation. This child born to a mother with a homozygous
PROP1 gene defect developed normally (47 cm length at 3 wk
of life) and was heterozygous for the same PROP1 gene
deletion (Fig. 1B3).
Patient 9 presented with a congenital ichthyosis, and two of his siblings also presented with congenital hypopituitarism and ichthyosis. Genomic DNA of these latter patients could not be obtained.
Hormonal data
Endocrine evaluations are summarized in Table 1 showing baseline
and stimulated values of anterior pituitary hormones.
GHD was complete in all cases and confirmed by two different
provocative tests. The peak value during the ITT did not exceed 1.4
µg/liter. In eight cases, GHD initially appeared as isolated as shown
in Table 1, and it was constant in this population after 13 yr of
age.
Interestingly, baseline PRL levels were normal in eight of the nine patients, but PRL response to TRH was blunted in all patients tested. One female patient presented with low basal PRL levels when evaluated at age 41 yr.
TSH deficiency was present in all patients, although it appeared 2–5
yr after the onset of GH deficiency (Table 1). TSH was initially found
to be inappropriately normal with decreased peripheral thyroid hormone
levels and then declined with time to reach low or undetectable
values.
All patients had complete hypogonadotrophic hypogonadism with a lack of gonadotropin response to GnRH and decreased T or E2 levels.
Cortisol was initially found normal in all patients, but delayed ACTH deficiency was observed in four patients aged between 12 and 41 yr, as evidenced by low baseline ACTH and cortisol values and a blunted cortisol and ACTH response to ITT in two. These patients were given cortisol replacement therapy that relieved their mild to moderate asthenia. No symptomatic hypoglycemia was noted.
Neuroradiological data
At MRI, the pituitary gland was hypoplastic in seven patients. In
these patients, pituitary height ranged between 2 and 3 mm (mean
± SD: 2.3 ± 0.5 mm). In contrast, two of the
patients (1, 2) had previously been found to have pituitary
hyperplasia as shown in Fig. 2. One of
them (patient 2) had a small intrasellar mass at MRI, 14 mm in height,
with signal hyperintensity on T1 sequences (Fig. 2A), leading to
consider a diagnosis of Rathke’s cleft cyst or craniopharyngioma. The
lateral skull x-ray of this patient showed an enlarged sella turcica
(Fig. 2A). This child was not operated on, and a new MRI performed 2 yr
later disclosed a marked reduction in size of the intrasellar mass that
was 5 mm in height (Fig. 2B). The other patient (no. 1) was a girl who
was found at age 11 yr to have a slightly enlarged pituitary gland (8
mm), subsequently found at age 16 yr with a hypoplastic pituitary.
Patient 6 had a pituitary hypoplasia (2 mm in height) on MRI performed
at 27 yr of age, but the lateral skull x-ray of this patient showed an
enlarged sella turcica, similar to patient 2. In patient 3, pituitary
hypoplasia had been noted as early as 4 yr of age, illustrating the
timing phenotypic variability in this condition. Importantly, in
keeping with inclusion criteria, the pituitary stalk was normal in all
patients, and none had posterior pituitary ectopia.
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Of a total of 23 patients analyzed, we found nine patients with
MPHD caused by a PROP1 gene defect (Fig. 1, Table 1). All
mutations were present on both alleles and were located in exon 2 of
the PROP1 gene (Fig. 3). In
two pedigrees (families VI and VII), genomic analysis of both
unaffected parents revealed heterozygosity for the mutant allele (Fig. 1, B3 and C), confirming the recessive mode of inheritance of this
disorder.
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2) and resulting in a frame shift and a premature termination at
codon 109.
Three patients from three unrelated families were homozygous for a
point mutation affecting codon 73 (Fig. 1A). Indeed, we found a R73C
mutation in two cases and a novel R73H mutation in one patient.
Interestingly, one patient was a compound heterozygote for the R73C
mutation and for a previously unrecognized mutation that introduces a
stop codon at position 99: R99X (Fig. 1, A4 and B4).
Polymorphic sites
In the 14 remaining patients in whom sequencing of the three coding exons revealed no PROP1 gene alterations, we found the three previously described polymorphic sites located in exon 1, exon 3, and intron 1 (11, 14). The polymorphic site in exon 1 was located at codon 9 (GCT to GCC) yielding an identical substitution of Ala to Ala (n = 7/28 chromosomes; 25%). The polymorphic site in exon 3 was at codon 142: a G-to-A transition resulted in a substitution of Ala to Thr (A142T) (n = 6/26; 23%). This replacement located outside the homeodomain region was found in patients with MPHD and also in normal subjects in literature (11, 14). Moreover, the residue corresponding to Ala at position 142 is a Thr at codon 139 in the mouse PROP1 protein (12). The polymorphic site observed in intron 1 was located at nt 109 + 3 (n = 4/28; 14.3%).
Discussion
A cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineage in pituitary organogenesis (22, 23, 24, 25, 26, 27). The PROP1 gene mutation in the Ames dwarf mice causes a dramatic dysmorphogenesis in the developing pituitary gland. Although no direct transcriptional effect of PROP1 on the transcription of the Pit-1 gene has been demonstrated, there is an associated general loss of Pit-1 gene activation with a severe depletion of the three Pit-1-dependent cell types (10). Before cloning of the PROP1 gene, it had been noted that plasma levels of both LH and FSH were markedly decreased in Ames dwarf mice (9). Defects in the human PROP1 gene cause a similar phenotype with deficiency of Pit-1-dependent pituitary hormones, in addition to gonadotroph and occasionally corticotroph deficiencies (16, 17, 18).
The prevalence of PROP1 gene alterations among patients with MPHD has been found to be relatively high, compared with Pit-1 gene defects (14, 28). In a series of 15 MPHD-affected patients, only one mutation of the Pit-1 gene was detected in one patient (6.7%) (28). Similarly a single Pit-1 gene mutation has been identified in our center and previously described (29, 30). In the series gathered by Deladoey et al. (14), a PROP1 gene defect could be found in a total of 35 of 73 MPHD-affected patients (48%) belonging to 18 of 36 unrelated families (50%). In our series that includes only previously unpublished cases, 9 of the 23 (39%) MPHD patients from 8 of 20 unrelated families (40%) were attributable to a PROP1 gene defect, confirming that the PROP1 gene is an important etiological factor in MPHD. No phenotypic criteria allowed to differentiate these patients from the population of MPHD patients without PROP1 gene alteration. Studies on several different candidate genes and other genetic approaches may permit identification of other gene defects in this clinical setting as reviewed elsewhere (31).
In keeping with previous reports (14, 18, 20), we found no
correlation between phenotype and genotype, as illustrated in Table 1.
Indeed, manifestations of the different deficiencies varied
substantially for a given mutation in terms of intensity or age of
onset. GH deficiency was diagnosed between ages 2 and 13 yr and could
appear as isolated at 2–5 yr. TSH deficiency was constant but delayed,
diagnosed between 4 and 15 yr of age. In our population, all of the
patients had undetectable basal and GnRH-stimulated levels of
gonadotropins and never entered puberty spontaneously. In contrast, in
some previously reported cases, gonadotroph deficiency was evidenced
between 15 and 22 yr. A spontaneous puberty was initiated in up to 33%
of patients in one series (14, 19). Noteworthy, four of
our nine MPHD patients (44%) with a PROP1 gene defect
presented with a corticotroph deficiency, diagnosed between 12 and 46
yr. In a limited number of patients, other authors have observed a
tendency toward ACTH and cortisol deficiencies with age
(16, 17, 18). Such a progressive ACTH deficiency with age is
not observed in Ames dwarf mice (10). Moreover, it was not
linked to a given mutation. This suggests that a more complex mechanism
than simple failure of embryonic development of the corticotroph cell
lineage may be involved, as proposed by Pernasetti et al.
(17).
Another interesting observation in the phenotype of PROP1 mutants concerns their pituitary gland size. Pituitary hypoplasia detected by MRI is the most frequently observed aspect (14), a possible consequence of the effects of PROP1 on both differentiation and proliferation of several anterior pituitary cell types (32). Two of our nine patients, however, presented with a hyperplastic pituitary that appeared spontaneously regressive. In one patient, this intrasellar mass spontaneously enhanced on T1 MRI sequences and hypointense on T2 sequences was initially considered as a Rathke’s cleft cyst or a craniopharyngioma. Such a radiologic abnormality had previously been described in one other MPHD patient (16) but was not observed in the Ames dwarf mice that present with a hypoplastic pituitary (10). In the absence of biopsy and microscopic analysis, the nature of such a spontaneously regressive intrasellar mass remains speculative. A similar pituitary enlargement has also been found in one case of MPHD owing to a defect in the Lhx3 gene (33).
We thus found four different mutations of the PROP1 gene
causing MPHD, as presented in Table 1. All mutations found in the eight
unrelated families presented in this paper concerned the same 2 codons
localized in exon 2, and include 2 novel mutations, as summarized in
Fig. 3. Three patients were homozygous for a point mutation affecting
codon 73, each owing to a single base pair change, making this site a
new hot spot in the PROP1 gene. The R73C had previously been
observed in two other unrelated MPHD patients (11, 14).
Such missense mutations occur in a region highly conserved among
paired-like homeodomain proteins that contains a CpG doublet. The
previously described 2-bp deletion at codon 99/100/101, which was
present in five of our patients, has been found in patients from
distinct genetic backgrounds around the world, suggesting that it is
not due to a founder effect (14). It is more likely due to
the presence of three tandem repeats (GAGAGAG), known to be a common
cause of human genetic disease because it may interfere with the normal
process of DNA replication, repair, and recombination
(11). Both of the codons affected in this population as
well as the majority of previously reported mutations are found in exon
2 that encodes the paired homeodomain of the molecule known to be
involved in the binding of the transcription factor to its cognate DNA
target sites. The functional consequences of four PROP1 gene
mutations performed in two studies showed a complete or partial loss of
function of the PROP1 mutants (12, 20). Further studies
are underway to investigate the functional consequences of other
genetic defects to elucidate the mechanisms whereby such mutations may
alter the transcriptional activity of this factor.
Acknowledgments
We thank the following physicians for sending genomic DNA as well as clinical and biological data on their patients: Prof. Jean-Pierre Bercovici, Brest; Dr. Chantal Bully, Lyon; Prof. Pierre Chatelain, Lyon; Dr. Sophie Christin-Maitre, Paris; Dr. Jens Otto Jorgensen, Aarhus, Denmark*; Dr. Isabelle Leroy, Paris; Prof. Georges Malpuech, Clermont-Ferrand; Dr. Marc Nicolino, Lyon; Prof. Vincent Rohmer, Angers; Dr. Chantal Stuckens, Lille; Dr. Claude Swanepoel, Salon de Provence; Prof. Antoine Tabarin, Bordeaux; and Dr. Marie-Pierre Teissier, Limoges. Prof. Catherine Adamsbaum (Paris) and Prof. Nadine Girard (Marseille) kindly provided neuroimaging data. *All other cities mentioned are located in France.
Footnotes
This work was supported by grants from the French Ministry of Health (Program Hospitalier de Recherche Clinique, PHRC 1996), and from the Association pour le Développement de la Recherche Médicale au Center Hospitalier Universitaire de Marseille (ADEREM).
Abbreviations: GHD, GH deficiency; ITT, insulin tolerance test; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging; PROP1, Prophet of Pit-1.
Received February 8, 2001.
Accepted May 3, 2001.
References
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