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Original Studies |
Cys at Codon 120 (R120C)1
Division of Pediatric Endocrinology, University Children’s Hospital (C.F., J.D., K.R., A.E., U.M., P.E.M.), 3010 Bern, Switzerland; and Howard Hughes Medical Institute, University of California-San Diego (W.W.), La Jolla, California 92093-0648
Address all correspondence and requests for reprints to: Prof. Dr. Primus E. Mullis, Department of Pediatrics, Pediatric Endocrinology, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.ch
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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We report on the follow-up of two consanguineous families (n =
12), with five subjects affected with CPHD (three males and two
females) caused by the same nucleotide C to T transition, resulting in
the substitution of Arg
Cys in PROP1 at codon 120.
Importantly, there is a variability of phenotype, even among patients
with the same mutation. The age at diagnosis was dependent on the
severity of symptoms, ranging from 9 months to 8 yr. Although in one
patient TSH deficiency was the first symptom of the disorder, all
patients became symptomatic by exhibiting severe growth retardation and
failure to thrive, which was mainly caused by GH deficiency (n =
4). The secretion of the pituitary-derived hormones (GH, PRL, TSH, LH,
and FSH) declined gradually with age, following a different pattern in
each individual; therefore, the deficiencies developed over a variable
period of time. All of the subjects entered puberty spontaneously, and
the two females also experienced menarche and periods before a
replacement therapy was necessary.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As pituitary function depends on the integrity of the hypothalamic-pituitary axis, any defect in the development and organogenesis of this gland may account for a form of combined pituitary hormone deficiency (CPHD), which denotes impaired production of GH and, in addition, the lack of one or more of the other hormones derived from the pituitary anterior gland.
Although Pit-1 was one of the first factors identified, many other homeodomain and transcription factors have been characterized as being involved in different developmental stages, such P-Lim, P-OTX, ETS-1, and Brn-4 (5, 6, 7, 8). Most recently, a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (PROP1) has been identified. A mutation in this gene was found, causing the Ames dwarf (df) mouse phenotype, and subsequently, three different PROP1 gene alterations (mutations and deletions) were reported that are responsible for CPHD in humans (9, 10).
As PROP1 seems to be involved in the ontogenesis of pituitary gonadotropes as well as somatotropes, lactotropes, and caudomedial thyrotropes, we were looking for PROP1 gene defects in patients with CPHD suffering from GH, PRL, TSH, LH, and FSH deficiencies. To date, we have found 11 families with different PROP1 gene defects and have realized that the clinical phenotype varied not only among the different gene mutations but also among the affected siblings with the same mutation in the same family.
The aim of the present report is to focus on the variability of the
phenotype of CPHD in five affected subjects from two families with the
same C to T transition within the PROP1 gene, resulting in
the substitution of Arg Cys at codon 120 (R120C) in the PROP1
protein. We conclude that as adults, the affected patients are GH, PRL,
TSH, and gonadotropin deficient, but the time scale of the occurrence
of the different deficiencies varies considerably.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Two consanguineous families with a total of 12 individuals were studied. There is no evidence that the 2 families are related in any way to a common founder. Each family was represented by 2 parents and 4 offspring. Three siblings in 1 family and 2 more subjects in the other family were affected and presented with the symptoms of CPHD, which developed with age. These families were studied and followed over more than 20 yr. Informed consent was obtained from parents and all family members studied. Clinical phenotypes, results of hormonal stimulation tests, as well as molecular biological analyses are described.
Clinical studies and hormonal assays
Study patients received GH provocative testing, using only arginine stimulation before the age of 2 yr; thereafter, both arginine-induced (0.5 mg/kg; Pharmacia & Upjohn, Stockholm, Sweden) and insulin-induced (ITT; 0.15 U/kg, iv; Novo Nordisk A/S, Gentofte, Denmark) hypoglycemia and adequate hypoglycemia (blood glucose, <2.0 mmol/L) were achieved in all cases. The stress of ITT results normally in an increased secretion of ACTH and hence corticoids. Basal cortisol was measured before ITT, and peak values were assessed after the response to the insulin-induced hypoglycemia. This test was combined with the exogenous administration of TRH (200 µg; Ferring Pharmaceuticals Ltd., Zurich, Switzerland) and GnRH (100 µg; Ferring) to test the remainder of the hypothalamic-pituitary axis. Before the availability of the TRH, pituitary TSH reserve was studied using an antithyroid drug. After discontinuing the blocking agent, the increased TSH enhances hormone production of the thyroid gland, and therefore, the rebounding 131I uptake in the thyroid gland during the following 36 h represents TSH reserve (11). Furthermore, PRL secretion was tested using TRH stimulation. The criteria for GH deficiency included a peak GH level of less than 2 ng/mL after stimulation (arginine stimulation test and ITT) and a decreased height velocity below -2.5 SD score (12). Magnetic resonance imaging of the skull was performed in all patients and was evaluated by the same neuroradiologist.
Stimulation tests
The stimulation test were performed as described in the The Bart’s Endocrine Protocols (13). All samples were immediately analyzed, and the remainder were stored at -70 C. We retested the samples using the methods that are now in use in our laboratory and compared the data with the results obtained using the old test procedures. The correlations among the different tests were between r = 0.81 and 0.96. In the tables, the original values are stated.
GH assays
Originally, GH was measured by RIA (SmithKline Beecham, Norristown, PA), with intra- and interassay coefficients of variations (CVs) of 5% and 6%, respectively, at 4 ng/mL (14). Thereafter, serum hGH concentrations were measured using a Tandem immunoradiometric kit (Hybritech, Nottingham, UK) (15). The interassay CV at GH concentration of 2 ng/mL was 9.2%, and the intraassay CV at GH concentrations of 0.7, 2.0, 6.5, and 13.0 ng/mL were 10.6%, 6.3%, 3.5%, and 3.2%, respectively. The actual kit used is HGH MAIAclone (Biodata Diagnostics, Freiburg, Germany), which incorporates two high affinity monoclonal antibodies into an immunoradiometric assay. The interassay CVs were 2.3%, 2.4%, and 2.2% at 2, 9, and 24 ng/mL, respectively. The intraassay CVs were 2%, 1.7%, and 1.7% at 2, 9, and 24 ng/mL.
TSH assay
TSH was measured by RIA (Abbott, Diagnostics Division, Delkenheim, Germany) and immunoradiometric assay (Seronokit, NIH, Bethesda, MD), with intra- and interassay CVs of 3.2% and 5.4%, respectively, at 1.7 mIU/L (16). TSH was later measured using an immunochemiluminometric assay, and then highly sensitive TSH assays were used (Cornings, Nichols Institute Diagnostics, San Juan Capistrano, CA). Intra- and interassay CVs were 2.2%, 1.8%, and 2 mIU/L, respectively. Recently, a TSH assay using automated direct chemiluminometric methodology has been used (Chiron Diagnostics Corp., East Walpole, MA). Inter- and intraassay CVs were 6.1% and 4.3%, respectively, at 0.3 mIU/L and 5.2% and 5.8% at 4.7 mIU/L.
LH and FSH assays
The measurements were performed according to the method previously described (Hazelton Biotechnologies, Vienna, VA) (17, 18). The detection limits and the intra-, and interassay CVs for the LH and FSH assays (at the ED50) were as follows: 0.6 IU/L, 2%, 9% for LH; and 0.6 IU/L, 4%, and 9.5% for FSH. Recently, FSH and LH have been measured using Dade fluorometric enzyme immunoassays (Stratus, Dade, Miami, FL). For FSH, inter- and intraassay CVs were 1.6% and 3.8% at 4 IU/L and 2.7% and 2.9% at 20 IU/L; cross-reactivities between LH and TSH were 0.5% and 0.01%, respectively. For LH, inter- and intraassay CVs were 7.5% and 5.8% at 2.5 IU/L and 2% and 2.7% at 20 IU/L; cross-reactivities between TSH and FSH were 0.02% and 0.001%, respectively.
PRL assay
PRL was determined by a fluorometric enzyme immunoassay (Baxter Diagnostics, Inc., Unterschleissheim, Germany). The interassay CV was 4.1%, and the intraassay CV was 4% at 3.8 µg/L. Recently, PRL has been measured using a fluorometric enzyme immunoassay (Stratus, Dade). Inter- and intraassay CVs were 5% and 4.3% at 4.5 µg/L and 4.8% and 3.2% at 59 µg/L.
Genomic analysis of the Prop-1 gene
DNA was extracted from the peripheral lymphocytes as previously reported (19). One hundred nanograms of human genomic DNA were used as a template in a volume of 20 µL. The coding sequence of PROP1 was PCR amplified with a 5'-sense primer (5'-CGAACATTCAGAGACAGAGTCCCAGA-3') and a 3'-antisense primer (5'-GAATTCACCATGATCTCCCA-3') to generate a 3.5-kb fragment. The reaction consisted of 1 min at 94 C, followed by 35 cycles of 30 s at 94 C, 30 s at 56 C, and 10 min at 68 C. Thereafter, PCR products were purified by gel electrophoresis followed by agarose gel DNA extraction. Direct sequencing of the double stranded PCR fragments was carried out according to the thermal cycle sequencing protocol (PE Applied Biosystems, 373 DNA Sequencer, Perkin Elmer, Rotkreuz, Switzerland) using a 5'-sense primer (5'-TCTGGCCATGCTGAGAAG-3') and a 3'-antisense primer (5'-TTCTAGTCGCTGAGCTGAC-5').
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The pedigrees of the two families studied are shown in Fig. 1
. The parents are second cousins in good
health and with height and weight within normal limits for the Swiss
population (12). The growth charts of all of the affected subjects as
well as of the unaffected male member of family 1 (subject 1.5) are
presented in Fig. 2. In addition, height,
bone ages (20), and therapies given are indicated. All children were
born at term after normal pregnancies. Deliveries and peri- and
postnatal courses were uncomplicated. Birth weights and lengths were
within normal standards (12).
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After an uneventful childhood, the growth retardation became
evident at the age of 8 yr. The boy was referred to a local hospital
and, at the age of 15 yr, to our clinic. Initially, anterior pituitary
function was assessed with basal investigations followed by dynamic
tests. The data are presented in Table 1.
At this age, pituitary-derived GH replacement therapy at a dosage of 10
mg/m2·week in three injections was started. One year
later, TSH deficiency became apparent, and T4 treatment was
initiated. Because of a lack of GH, the treatment was stopped when the
patient was 19 yr old, and for reasons of noncompliance, T4
treatment was interrupted at around the same time. Importantly, puberty
was delayed, starting at a chronological age of 17 yr and a bone
age of 12.5 yr, which is adequate for this stage of development. At the
age of 19 yr, he presented with a nearly adult pubertal stage (Tanner
stage, P4, G4), and testis volumes of 8 and 10 mL (21, 22). However, at
the age of 20 yr he became partly gonadotropin deficient (Table 1), and
testosterone replacement was started. His school
performance was normal, and now he earns his living as a truckdriver
and has left home.
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This patient’s history is somewhat similar to that of patient
1.3. His growth retardation was evident at the age of 8 yr, and he was
referred to our out-patient clinic when he was 13 yr and 10 months old.
GH deficiency was confirmed, and replacement was given
(pituitary-derived GH, 10 mg/m2·week, three injections).
Two years later, TRH testing revealed TSH deficiency, which was not
present at the beginning of the GH replacement, and T4
therapy was initiated. In addition, GnRH stimulation was performed, but
LH and FSH levels were in the prepubertal range (Table 1
). He started
puberty rather late at a chronological age of 16 yr (bone age, 12.5
yr), reached Tanner stages P3, G3, presented testis sizes of 5 and 6
mL, and became gonadotropin insufficient by the age of 18 yr.
Thereafter, testosterone injections were given. At the age
of 29 yr, he was retested and was diagnosed as being GH, PRL, TSH, and
gonadotropin deficient. His school performance was normal, and at
present, he works in an office.
Patient 1.5
This boy does not have the defect and represents the normal growth pattern of this family.
Patient 1.6
This girl was presented for the first time to our out-patient
clinic at the age of 4 yr. Endocrine testing revealed no abnormalities
(Table 1). She was already small but growing normally parallel to the
third percentile (-3.2 SD score; Fig. 2). When she was 8
yr old, a decrease in height velocity (from -0.5 to -3 SD
score) was diagnosed, and GH stimulation tests were performed,
confirming GH deficiency. Growth-promoting therapy was started.
Initially, pituitary-derived GH was given, and before changing to
recombinant GH (15 U/m2·week, six injections),
oxandrolone (2.5 mg/day) was used after the ban of pituitary-extracted
hormone. Because of the diagnosis of CPHD in her brothers, GnRH and TRH
stimulations were performed at regular intervals. Interestingly, a
continuous decrease with age in LH, FSH, and TSH secretion was noticed.
However, she presented normal pubertal development and experienced her
menarche at the age of 16 yr, with a bone age of 14 yr. Nevertheless,
when she was 17 yr of age, gonadotropin deficiency became evident. One
year later, TSH deficiency was noticed, and T4 treatment
was initiated. Finally, she entered a convent, and a complete
reassessment revealed a total lack of GH, PRL, TSH, LH, and FSH.
Patient 2.5
Shortly after birth, this girl presented with a lack
of TSH secretion, and T4 treatment was necessary.
Thereafter, because of a constant decrease in her height velocity
(-0.5 to -2 SD score) resulting in a progressive falling
below the third percentile, repetitive GH stimulation tests were
performed (Fig. 2 and Table 2). Initially
(during the first 2 yr of life) only arginine stimulation tests for
assessment of GH secretion were performed, whereas later both arginine
stimulation and ITT were performed. Over the years, GH secretion
gradually became insufficient (GH peak value >2 but <7 ng/mL) and was
deficient by the age of 6 yr (GH peak value <2 ng/mL). GH replacement
at a dose of 15 U/m2·week divided into six injections per
week was started, and she progressed normally through puberty, reaching
menarche at the age of 14 yr. At the age of 15 yr, GnRH-stimulated LH
and FSH secretion was still normal, but decreased compared to previous
values (Table 2).
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This boy presented with the clinical phenotype of GH deficiency at the age of 1 yr. Arginine-stimulated GH secretion was abnormal at the age of 2 yr, and GH treatment (15 U/m2·week, six injections) was started. Over the years he became TSH deficient, and T4 treatment was initiated when he was 5 yr old. His pubertal development started at the age of 12 yr at a bone age of 11 9/12 yr (20). At the age of 14 yr, his actual pubertal stage according to Tanner is P4, G3, and testis volumes are 8 and 10 mL (22). It is important to stress that his actual GnRH-stimulated peak values of LH and FSH are those that would normally be found in pubertal stage 2 and, therefore, are not appropriate to his pubertal stage. This might indicate that testosterone substitution will be needed in the future (17).
Genomic analysis of the PROP1 gene
PCR was used to amplify genomic DNA fragments from the
PROP1 sequence. Sequence analysis revealed the same mutation
in these two families. A nucleotide C to T transition resulted
in the substitution of ArgCys at codon 120 (R120C; amino acid 52 in
the third helix of the homeodomain; Fig. 3). Functional testing was previously
performed (10). In addition, compared to that of the wild-type protein,
DNA binding of R120C altered PROP1 protein was reduced
(8-fold), and the trans-activation ability of the mutated
form was impaired as well (10).
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Patients with a PROP1 defect have a lack not only of
GH, PRL, and TSH but also of LH and FSH, whereas the production of ACTH
is preserved. ACTH reserve was tested after insulin-induced
hypoglycemia; cortisol peak levels were all above 550 nmol/L and,
therefore, were normal (Tables 1 and 2). None of the subjects was ACTH
deficient.
Magnetic resonance imaging
The pituitary glands were variably hypoplastic in all affected
patients (Fig. 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the Snell (dw/dw) and Ames (df/df) dwarf mice, two recessive murine mutations causing dysorganogenesis of the pituitary gland have been described (9, 23). Although Snell and Ames mice are indistinguishable from normal littermates at birth, the phenotype is readily evident by 3 weeks of age, and the affected adults exhibit proportional dwarfism and hypothyroidism. In addition, these mice may display infertility, although male Ames mice are occasionally fertile.
The Snell dwarf phenotype results from mutations in a gene for a pituitary-specific transcription factor, called Pit-1 (23). Pit-1, expressed in thyrotropes, somatotropes, and lactotropes, is required for the continued expression of the Pit-1 gene itself and for the proliferation and survival of these three cell types (24, 25). Although most of our understanding of the role of Pit-1 in pituitary development has come from rodent animal studies, it is known that Pit-1 performs a similar function in humans (26), as humans with mutations in the Pit-1 gene have GH, TSH, and PRL deficiencies. The occurrence of these different deficiencies varies, but the patients became symptomatic, presenting with severe growth retardation and failure to thrive, before the age of 12 months and were normally diagnosed before the age of 2 yr (27). In the Ames mouse, Sornson et al. cloned and described a new gene, Prophet of Pit-1 (PROP1), a pituitary-specific, paired-like homeodomain transcription factor that was shown to be important for determination of the Pit-1 lineages as well as gonadotrope differentiation in the pituitary gland (9). Therefore, patients with a PROP1 defect have a lack not only of GH, PRL, and TSH but also of LH and FSH.
We present two families carrying the R120C substitution in the
homeodomain of the PROP1 protein. The disorder is caused by a CT
transition and followed the autosomal recessive pattern of inheritance.
The affected patients (three males and two females) were homozygous for
the genetic defect. The age at diagnosis was dependent on the severity
of symptoms and varied between 9 months and 8 yr; a detailed endocrine
investigation was performed to confirm the clinical diagnosis between 3
months and 6 yr later. Initial presentation in all patients was that of
growth retardation and failure to thrive caused by either TSH
deficiency (n = 1) or GH deficiency (n = 4). Interestingly,
in these patients, the decrease in height velocity became clinically
obvious, then, as seen in patients 1.6 and 2.5, the GH deficiency
developed only gradually with age. However, it is important to stress
that the diagnosis of CPHD was not made until TSH deficiency became
clinically evident. At that time, PRL determinations were not part of
the initial endocrine work-up, but later whenever CPHD was suggested
and GH deficiency was present, no PRL was measurable.
Central hypothyroidism was diagnosed at the early age of 12 months in only one patient, namely patient 2.5. As seen with the development of GH deficiency, the appearance of TSH deficiency was a gradual process that lasted between 1–19 yr. Although peripheral thyroid hormonal levels were just below normal levels for age-matched controls before the initiation of GH replacement, hypothyroidism was not unmasked in our patients shortly after the start of the GH treatment, as has been reported in patients with Pit-1 gene alterations (26, 27). This clinical observation suggests a progressive deterioration of thyrotrope function over time, and a clear-cut TSH deficiency was mainly observed after puberty. Data from studies in the Ames mouse may help to explain these findings in humans. No abnormalities were detected in df/df pituitary gland up to embryonic day 12 (e12), when the rostral tip thyrotrope, corticotrope, and gonadotrope cell types appear. Then, a striking dysmorphogenesis becomes apparent only at e13.5 (9). The first cell populations of thyrotrope cells are PROP1 independent, appearing around e12 and disappearing shortly after birth (9, 28). Whether such a thyrotrope cell subpopulation also exists in humans is unknown. The observation of delayed development of TSH deficiency in our patients supports the hypothesis of the existence of two distinct thyrotrope populations in humans. However, we have to bear in mind that in one patient, central hypothyroidism was the first clinical symptom of the PROP1 gene defect. In contrast to findings in rodents, the putative Pit-1-independent thyrotrope cell population could remain functional for several years after birth and only disappear with advancing age. Alternatively, variations in pituitary hormone deficiency could be due to the particular mutation or the genetic background of an individual patient.
All of our patients presented a loss of gonadotropin secretion with age but entered puberty spontaneously. Moreover, the two affected females experienced menarche at the age of 14 and 16 yr, respectively. The gonadotropes among the first three cell lineages, determined between e11-e13, are unaffected in Ames mice, indicating that for gonadotrope cell type determination, PROP1 is not needed (9). However, the loss of gonadotropins in humans and the reduced expression in PROP1-defective Ames dwarf mice emphasize the possibility that PROP1 plays a role in the specification and/or differentiation of the gonadotropin lineage via precursors of the Pit-1 cell lineage produced before terminal differentiation events. In addition to PROP1, many other transcriptional or hormonal factors might play a part in the variability of gonadotrope cell function. Synergistic or restrictive interference or other transcription factors with PROP1 target genes, as described for the Ames mouse, might also explain this observation (9). As a consequence of the df defect, the expression of a number of transcription factors, including Brn-4 and Rpx, becomes temporally extended (9). Furthermore, ultrastructural studies have identified an unusual cell in df pituitaries that may be a precursor of one or more of the missing cell types (29). In addition, the observation that spontaneous fertility can occur in the normally infertile Ames male mouse also suggests that at least some GH and TSH must be produced in these mice to allow sexual maturation and fertility (30).
Phenotype variability also applies to pituitary size in our patients. Magnetic resonance imaging of the sellar regions showed variable sizes of the pituitary glands, which are generally hypoplastic in this disorder. These data are in contrast to the clinical finding in patients suffering from Pit-1 defects where both are reported, namely pituitary glands of normal and hypoplastic sizes (31). However, Ames mice present a profound anterior pituitary hypocellularity due to a general lack of thyrotropes, somatotropes, and lactotropes. These cell types are dependent on the Pit-1 transcription factor. Thus, the crucial role of PROP1 may be in lineage-specific proliferation and not in cytodifferentiation. This speculation would explain the discrepancies between PROP1- and Pit-1-defective patients.
In conclusion, we report two families with an R120C-altered PROP1 protein causing familial combined pituitary hormone deficiency. Importantly, there is a variability in phenotype even among patients with the same mutation, whereas the main variance may be between the affected families, which, however, cannot be explained in terms of the specific PROP1 mutation. The age of diagnosis is obviously dependent on the severity of symptoms and ranged from 9 months to 8 yr. Although in one patient, TSH deficiency was the first symptom of the disorder, all patients became symptomatic by exhibiting severe growth retardation and failure to thrive, mainly caused by GH deficiency (n = 4). The secretion of pituitary-derived hormones (GH, PRL, TSH, LH, and FSH) declined gradually with age, following a different pattern and time scale in each individual. Therefore, our patients, who have been tested at regular intervals, developed their hormone deficiencies over a variable period of time. The loss of gonadotropins became obvious only after puberty, and the two females experienced their periods before hormone replacement therapy was necessary.
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Acknowledgments |
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Footnotes |
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Received April 24, 1998.
Revised June 18, 1998.
Accepted July 2, 1998.
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 L. E. Cohen and S. Radovick Molecular Basis of Combined Pituitary Hormone Deficiencies Endocr. Rev., August 1, 2002; 23(4): 431 - 442. [Abstract] [Full Text] [PDF]
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J. C. Achermann, G. Ozisik, J. J. Meeks, and J. L. Jameson Genetic Causes of Human Reproductive Disease J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2447 - 2454. [Full Text] [PDF]
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S. N. Kalantaridou and G. P. Chrousos Monogenic Disorders of Puberty J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2481 - 2494. [Full Text] [PDF]
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 L. E. Olson and M. G. Rosenfeld Perspective: Genetic and Genomic Approaches in Elucidating Mechanisms of Pituitary Development Endocrinology, June 1, 2002; 143(6): 2007 - 2011. [Abstract] [Full Text] [PDF]
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P. Kopp Perspective: Genetic Defects in the Etiology of Congenital Hypothyroidism Endocrinology, June 1, 2002; 143(6): 2019 - 2024. [Abstract] [Full Text] [PDF]
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 L C Layman Human gene mutations causing infertility J. Med. Genet., March 1, 2002; 39(3): 153 - 161. [Abstract] [Full Text] [PDF]
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F. G. Riepe, C.-J. Partsch, O. Blankenstein, H. Monig, R. W. Pfaffle, and W. G. Sippell Longitudinal Imaging Reveals Pituitary Enlargement Preceding Hypoplasia in Two Brothers with Combined Pituitary Hormone Deficiency Attributable to PROP1 Mutation J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4353 - 4357. [Abstract] [Full Text] [PDF]
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J.-M. Vuissoz, J. Deladoey, A. Buyukgebiz, P. Cemeroglu, G. Gex, S. Gallati, and P. E. Mullis New Autosomal Recessive Mutation of the TSH-{beta} Subunit Gene Causing Central Isolated Hypothyroidism J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4468 - 4471. [Abstract] [Full Text] [PDF]
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S. Vallette-Kasic, A. Barlier, C. Teinturier, A. Diaz, M. Manavela, F. Berthezene, P. Bouchard, J. L. Chaussain, R. Brauner, I. Pellegrini-Bouiller, et al. PROP1 Gene Screening in Patients with Multiple Pituitary Hormone Deficiency Reveals Two Sites of Hypermutability and a High Incidence of Corticotroph Deficiency J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4529 - 4535. [Abstract] [Full Text] [PDF]
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 W. E. Winter and M. R. Signorino Molecular Thyroidology Ann. Clin. Lab. Sci., July 1, 2001; 31(3): 221 - 244. [Abstract] [Full Text] [PDF]
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 L. J. Cushman, D. E. Watkins-Chow, M. L. Brinkmeier, L. T. Raetzman, A. L. Radak, R. V. Lloyd, and S. A. Camper Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility Hum. Mol. Genet., May 1, 2001; 10(11): 1141 - 1153. [Abstract] [Full Text] [PDF]
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G. Agarwal, V. Bhatia, S. Cook, and P. Q. Thomas Adrenocorticotropin Deficiency in Combined Pituitary Hormone Deficiency Patients Homozygous for a Novel PROP1 Deletion J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4556 - 4561. [Abstract] [Full Text]
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M. G. F. Osorio, P. Kopp, S. Marui, A. C. Latronico, B. B. Mendonca, and I. J. P. Arnhold Combined Pituitary Hormone Deficiency Caused by a Novel Mutation of a Highly Conserved Residue (F88S) in the Homeodomain of PROP-1 J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2779 - 2785. [Abstract] [Full Text]
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R. H. Skelly, M. Korbonits, A. Grossman, G. M. Besser, J. P. Monson, J. F. Geddes, and J. M. Burrin Expression of the Pituitary Transcription Factor Ptx-1, But Not That of the Trans-Activating Factor Prop-1, Is Reduced in Human Corticotroph Adenomas and Is Associated with Decreased {alpha}-Subunit Secretion J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2537 - 2542. [Abstract] [Full Text]
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 O. Fofanova, N. Takamura, E.-i. Kinoshita, A. Vorontsov, V. Vladimirova, I. Dedov, V. Peterkova, and S. Yamashita MR Imaging of the Pituitary Gland in Children and Young Adults with Congenital Combined Pituitary Hormone Deficiency Associated with PROP1 Mutations Am. J. Roentgenol., February 1, 2000; 174(2): 555 - 559. [Abstract] [Full Text] [PDF]
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F. Pernasetti, S. P. A. Toledo, V. V. Vasilyev, C. Y. Hayashida, J. D. Cogan, C. Ferrari, D. M. Lourenço, and P. L. Mellon Impaired Adrenocorticotropin-Adrenal Axis in Combined Pituitary Hormone Deficiency Caused by a Two-Base Pair Deletion (301-302delAG) in the Prophet of Pit-1 Gene J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 390 - 397. [Abstract] [Full Text]
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Heritable Disorders of Pituitary Development J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4362 - 4370. [Abstract] [Full Text]
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J. Deladoëy, C. Flück, A. Büyükgebiz, B. V. Kuhlmann, A. Eblé, P. C. Hindmarsh, W. Wu, and P. E. Mullis "Hot Spot" in the PROP1 Gene Responsible for Combined Pituitary Hormone Deficiency J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1645 - 1650. [Abstract] [Full Text]
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, hormone levels are decreased compared with those in normal
controls but are still measurable.
