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Original Studies |
Department of Reproductive Medicine (F.P., V.V.V., P.L.M.), University of California, San Diego, La Jolla, California 92093-0674; Endocrine Genetics Unit, Department of Medicine, and LIM-25 (S.P.A.T., C.F., D.M.L., C.Y.H.), University of São Paulo, School of Medicine, 02146–903, São Paulo, Brazil; and Department of Pediatrics (J.D.C.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2578
Address correspondence and requests for reprints to: Flavia Pernasetti, Department of Reproductive Medicine. 0674, 9500 Gilman Drive, La Jolla, California 92093. E-mail: fpernase{at}ucsd.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the 52 human CPHD cases reported thus far that are attributable to PROP1 defects, 7 distinct mutations have been identified (15, 16, 17, 18, 19, 20, 21, 22, 23). These PROP1 mutant alleles include 301–302delAG (26 homozygotes, 8 compound heterozygotes), R120C (8 homozygotes), F117I (1 compound heterozygote), 149delAG (5 compound heterozygotes), codon50delA (2 homozygotes), R73C (2 homozygotes), and 342–343delAT (4 homozygotes).
Here, we report the largest CPHD family caused by mutation of the PROP1 gene that has been described thus far. This family includes 10 affected members who are homozygotes for the PROP1 301–302delAG mutation. None had signs of sexual maturation. Interestingly, ACTH/cortisol insufficiency was detected in 5 of 6 (83%) of the family members with CPHD who were older than 43 yr of age. Our results suggest that adrenal insufficiency may be a pleiotropic effect of PROP1 gene defects in some families and should be considered in treatment.
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Subjects and Methods |
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We have studied a population of individuals from 2 close
villages (Alto do Rio Doce and Desterro do Mello) with about 2,000
inhabitants. This is a geographically isolated region in Southeast
Brazil (Minas Gerais State), where most inhabitants live in rural
areas. This region was originally populated in 1790 by Portuguese who
intermarried with the native Indian population. By history, the CPHD
kindred included 18 affected individuals: 12 living and 6 deceased.
Among the 12 living affected family members, 10 were studied, and 9 of
10 were products of consanguineous marriages (Fig. 1
).
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Height was measured in centimeters, using a stadiometer. The SD scores (SDS) for height and height age (HA) were estimated based on World Health Organization growth charts (26). The body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. BMI percentile for HA and for bone age were determined based on US population data for children (27) and adults (28). The lower segment (L) was recorded as the distance from the symphysis pubis to the floor in standing position. The upper segment (U) was taken as height minus lower body segment. Arm span was evaluated with patients leaning against the wall with arms extended horizontally. Bone age was evaluated with hand and wrist x-rays compared with the standards of Greulich and Pyle (29). Arm span minus height and the ratio of upper-to-lower body segment (U/L) for normal chronological, statural and bone age were determined based on Wilkins et al. (30). All stature and bone maturation data were obtained before human recombinant GH treatments.
Pituitary magnetic resonance scans were performed (GE, Sigma, Milwaukee, WI) for sagittal and coronal imaging. The pituitary volume was evaluated in mm3 and compared with normal values (31).
Hormone measurements
GH, LH, FSH, and TSH were measured by immunofluorimetric assay (Wallac, Inc. Turku, Finland) with both intra- and interassay coefficients of variation below 8%. The following kits were used: serum PRL measured by RIA (CIS Medipro SA, Vernier, Switzerland), ACTH measured by immunoradiometric assay (CIS Medipro SA), T4 and free-T4 measured by ELISA, and cortisol measured by fluorimetric assay. IGF-I was measured using RIA after acid-ethanol extraction method (Nichols Laboratory, San Juan Capistrano, CA). IGFBP-3 was measured by immunoradiometric assay (Active IGFBP-3, Diagnostic Systems Laboratories, Inc., Webster, TX).
Stimulation tests
The pituitary combined stimulation was performed by infusing iv 0.05 U/kg body weight of human regular insulin (Eli Lilly Co., Indianapolis, IN), 100 µg GnRH (Wyeth-Ayerst, Philadelphia, PA), and 200 µg TRH (UNIFESP, São Paulo, SP Brazil). Blood samples were collected at -30, -15, 0, 15, 30, 45, 60, 90, and 120 min after injection for measuring glucose, LH, FSH, TSH, PRL, GH, and cortisol levels.
The GHRH (Geref, Serono Laboratories, Inc., Norwell, MA) stimulation test was performed by injecting 1 µg/kg body weight, iv; and blood samples were taken for GH measurements at -30, -15, 0, 15, 30, 45, 60, 90, and 120 min. For chronic stimulation, a similar test was performed after a consecutive 5-day period of daily sc injections of 5 µg/kg GHRH at bedtime.
The CRH stimulation test (Ferring Pharmaceuticals Ltd., Sulfern, NY) was performed using 1 µg/kg administered iv. During 30 sec, blood samples were collected for cortisol and ACTH measurements at -30, -15, 0, 15, 30, 45, 60, 90, and 120 min after injection.
The ACTH (synthetic ACTH 1–24, Organon Lab., Inc., West Orange, NJ) stimulation test was performed with a 250-µg iv injection; and blood was collected for cortisol measurements at -15, 0, 30, and 60 min.
DNA analysis
DNA was extracted from blood samples using Chelex100, following the manufacturer’s protocol (32); 10–20 µL of the extracted genomic DNA were used as a template in a final vol of 50 µL. The three exons and two introns of the PROP1 gene were amplified by PCR using a 5'-sense primer (5'- CGAACATTCAGAGACAGAGTCCCAGA-3') and a 3' antisense primer (5'-GAATTCACCATGATCTCCCA-3') to generate a 3.5-kb fragment. PCR of these long fragments was carried out using the Extender PCR system (Stratagene, La Jolla, CA). The reaction consisted of 1 min at 94 C, followed by 35 cycles of 30 sec at 94 C, 30 sec at 56 C, and 6 min at 68 C. The PCR products were verified on 0.8% agarose gel and purified using the Wizard® PCR Preps DNA Purification Systems (Promega Corp., Madison, WI), following the manufacturer’s protocol. Direct sequencing of the double-stranded PCR fragments was carried out at the UCSD Center for Aids Research Molecular Biology Core using an PE Applied Biosystems(ABI, division Perkin-Elmer Corp., Norwalk, CT) 373 Automated DNA sequencer.
Statistical analysis
The Pearson test was used to detect correlations between age and absolute peak hormone levels. Student’s t test was applied to compare pituitary volumes.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We analyzed the sequence of the PROP1 alleles of all 10 affected
patients and of the parents and nonaffected siblings of patients 1, 3,
and 4 (see Fig. 1
). Sequencing revealed that all of the patients were
homozygous for the 2 base-pair deletion 301–302delAG in exon 2 (15).
Parents were heterozygous for the mutation, whereas nonaffected
siblings were heterozygous or homozygous wild-type (Fig. 2), with inheritance following an
autosomal recessive pattern. This mutation leads to a frameshift in the
coding sequence starting at codon 101, with premature termination at
codon 109, resulting in the loss of the DNA-binding homeodomain and
C-terminal transactivation domain of Prop-1. In vitro tests
show that this mutation leads to a loss of activity of the protein,
both in gel shift and transient transfection assays (15).
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The clinical history was similar for all patients. They were all born at home, from uncomplicated deliveries. Birth weights and heights were reported as normal, and no neonatal problems were noted. Neuropsychomotor development was considered to be normal in all individuals. Growth impairment was noted between 3 and 7 yr, and pubertal development was not observed in any of the patients. No periods of seizures or symptoms of hypoglycemia were reported. Some individuals had limited access to adequate food supply.
Physical examination revealed normal vital signs, severe short stature,
truncal obesity in variable degrees, high-pitched voice, immature
facies (Fig. 3), and symptoms compatible
with slight-to-moderate hypothyroidism (sleepiness, coldness).
No signs or symptoms of adrenal insufficiency were noticed. Wrinkled
skin around the eyes and mouth was observed in all except the three
younger affected individuals. Subtle findings of malnutrition were
detected. Adequate school records and/or intellectual performances were
reported.
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). SDS for height
varied between -5.4 to -10.0, characterizing an extremely severe
short stature. HA of adults varied between 2.7–10 yr; and bone ages,
between 9–17 yr. Partial epiphyseal closure was noted in three older
cases, 51–67 yr, whereas most younger cases had bone ages
corresponding to 3–10 yr. U/L was lower than normal for HA and for
bone age in all patients except patient 8. This indicates that the legs
were growing more than the trunk in all patients, irrespective of age.
Arm span minus height was at least 4 cm greater than normal for height
or for bone age in patients 3, 4, 5, 6, 8, and 9, suggesting
eunuchoidal proportion, particularly in patient 8, with arm span minus
height of 15 cm (Table 2) (33). Limited
elbow extensibility was noted in case 4.
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All patients had severely reduced pituitary dimensions, as evaluated by
MRI, and partially empty sella. Thin pituitary stalks were noted in
three cases but were normal in all other patients (Fig. 4). Pituitary volumes of all patients
ranged between 30–67.5 mm3, compared with the
normal range of 290 ± 68 (P < 0.05) (31).
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The responses of serum GH, TSH, PRL, LH, and FSH to combined
stimuli with GnRH, TRH, and insulin were compatible with severe CPHD of
these hormones (Table 3). LH and FSH
responses to GnRH were compatible with prepubertal-stage patterns. TSH
and PRL responses were low except in the youngest case (case 1),
documenting a low secretory reserve of TSH and PRL.
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-4 androstenedione values were normal to
low in all cases (data not shown).
Cortisol response to insulin-induced hypoglycemia (ITT) (Table 5, Fig. 5)
did not achieve the lowest normal peak level (20 µg/dL) in patients
2, 5, 7, 8, 9, and 10. Furthermore, ACTH responses to CRH stimulation
were abnormally low in cases 7, 9, and 10, and in the low-normal range
in case 8. Moreover, peak cortisol levels after CRH stimulation test
did not increase adequately in cases 5, 7, 8, and 10; whereas the test
could not be performed in cases 1 and 2. These data, taken together,
show limited cortisol/ACTH secretory reserve in 6 of 10 patients. Of
the older cases (43–67 yr), 5 of 6 (83%) had low cortisol peaks
during ITT stimulation, whereas 1 of 4 of the
younger cases had the same low cortisol response. Three of 5 older
affected individuals (60%) had a low ACTH response peak in the CRH
stimulation test. Peak cortisol (P = 0.02) and peak
ACTH (P = 0.02) levels during the CRH stimulation test
presented negative correlation with age. Furthermore, peak cortisol
levels in ITT showed a similar tendency (P = 0.07).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Another phenotypic variation observed amongst PROP1 patients concerns their sexual maturation. Our CPHD cases never entered puberty spontaneously and had undetectable basal levels of gonadotropins. Furthermore, GnRH-stimulated LH and FSH levels were very low, as were serum gonadal steroids. They remained at prepubertal stages even after therapy with T4 and recombinant human GH. The absence of puberty was also noted for other patients with this 301–302AGdel mutation (17, 18, 23) and with the codon 50Adel mutation (19). Pubertal delay was noted in three out of four patients with the PROP1 342–343delAT intronic splice-acceptor mutation (16). Conversely, all five cases with the PROP1 R120C amino acid substitution mutation (22) entered puberty spontaneously; the two women presenting menarche and normal menses, whereas male patients achieved Tanner pubertal stage IV. However, this normal development was followed by gonadal hypofunction 2–3 yr later.
Another variation observed in PROP1 patients’ phenotype concerns their pituitary gland size. Severe pituitary hypoplasia was detected by MRI scans in all of our 10 cases. Surprisingly, normal and even enlarged pituitary sizes have been recently reported in patients with the 301–302delAG mutation (18, 30), whereas other patients with the 301–302delAG mutation and with other PROP1 mutations (15, 20, 21, 22) presented hypoplasia similar to that of our patients. CPHD patients caused by mutations in the PIT1 gene also have highly variable pituitary sizes (35). These conflicting findings may indicate that variations in other genes involved in pituitary development may be exerting effects on the phenotypes. Alternatively, pituitary morphology may be changing over time because of progressive apoptosis.
The family that we have studied exhibited GH and secondary thyroid hormone deficiencies, as previously reported in CPHD caused by PROP1 mutations. In agreement with their severe growth retardation, levels of GH, both basal and following stimulation (ITT and acute and primed GHRH tests), were very low (or even undetectable), indicating severe somatotrope impairment. Lactotrope impairment might be considered less striking, as suggested by variable serum PRL levels. The lack of response to ITT might indicate a low lactotrope reserve, but an absence of lactotrope stimulation caused by hypogonadism cannot be excluded. Secondary hypothyroidism was detected in all 10 subjects by low serum T3 and T4 in the presence of low TSH. TSH slightly increased after TRH stimulation, suggesting partially impaired thyrotrope number and/or function, in agreement with the lack of clinical signs of severe hypothyroidism. Our older untreated patients (nos. 6–8, and 10) surprisingly presented open epyphises until the fifth decade of life, indicating that this could be a natural phenotypic characteristic in the history of the disease.
All affected members of this consanguineous family are homozygotes for a two-base pair deletion (301–302delAG) at the homeodomain of the paired-like transcription factor Prop-1. The nonaffected parents of all affected individuals are heterozygous for the same mutation, following an autosomal recessive pattern of inheritance. A founder effect may be playing a role in this community, because all cases present the same mutation. Settlers may have brought the mutated gene to this area around 1790, when the village was established. Inbred marriages might have occurred not only because of geographic isolation but also as a means of maintaining the ownership of the land.
The mutation found in all of our affected family members leads to a frame shift in the coding sequence starting at codon 101, with premature termination at codon 109. This results in the loss of the DNA-binding homeodomain and C-terminal transactivation domain of Prop-1. Only four PROP1 human mutations [the premature termination 301–302AGdel, two single amino acid substitutions (R120C and F117I), and the splicing mutation 342–343delAT (16)], as well as one mouse (Ames dwarf mouse) single amino acid substitution, S83P, have been characterized in vitro thus far. Of these human mutations, only 301–302AGdel and R120C have been well characterized clinically. The human R120C and the mouse S83P are both missense mutations, causing the substitution of a unique amino acid in the homeodomain of Prop-1 (14, 15). In vitro, the 301–302delAG mutant does not bind a paired-domain DNA-consensus sequence in gel shift assays. In contrast, the human R120C and the mouse S38P mutants do bind this sequence, albeit with reduced affinity (8-fold and 3-fold, respectively), when compared with the wild-type protein. Transfection assays also demonstrate more severe impairment of the function of the protein bearing the 301–302delAG mutation, which lacks all transactivation capacity, whereas both the R120C and the S83P mutants are still able to transactivate the reporter gene, though with significantly reduced efficiency. These data, taken together, show that these mutations affect the functions of their corresponding proteins in distinct ways. The 301–302 delAG mutation seems to cause a complete loss of function, whereas the products of the human R120C and mouse R83P mutations retain some activity. The pituitary gland of Ames mice was shown, by in situ hybridization, to contain gonadotropes and to secrete decreased (but detectable) levels of gonadotropins (14). The residual activity of R120C in vitro might be occurring in vivo, explaining the spontaneous onset of puberty in the Swiss patients bearing this mutation (22). The R120C residual activity could be sufficient for the maintenance of some gonadotrope cells, and production of their hormones, at least in the first decades of the patients’ lives. Furthermore, the ACTH insufficiency we observe in the older 301–302delAG patients may or may not occur with the less severe substitution mutations, because of their residual activity, which could allow maintenance of some corticotrope cells. The Ames mice, with the substitution S83P, show the normal number of corticotrope cells in the pituitary, and they secrete normal levels of ACTH (14).
The progressive ACTH deficiency with age, observed in our patients, suggests that a mechanism more complex than simple failure of embryonic development of the corticotrope cell lineage may be involved. Though little is known about the relationship between the distinct pituitary cells in the adult gland, it is possible that a progressive apoptosis of the corticotrope cells and/or decreased ACTH secretion occurs with age because of the lack of important signals from the other pituitary cell lineages, absent in the pituitary gland of these patients. An example of the importance of signaling in development of the pituitary gland is the expression of T/ebp in the diencephalon area, in direct contact with the Rathke’s pouch. This protein is never detected in Rathke’s pouch; but in T/ebp knockout mice, fibroblast growth factor 8 fails to be activated, indicating the importance of intercellular signaling in the formation of the pituitary primordium (36).
The phenotype-genotype correlation of CPHD PROP1 patients is presently under active investigation. Clear patterns of correlation may help clinicians to better diagnose, treat, and provide genetic counseling for the condition. The observation that the phenotype of CPHD cases caused by PROP1 mutations can vary widely with the mutation, genetic background, and age suggests that life-long and complete monitoring of these cases may be required for proper treatment.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work.
3 Supported by an American Heart Association Postdoctoral
Fellowship.
4 A CNPq (300346/82–4) research investigator.
Received July 8, 1999.
Revised September 29, 1999.
Accepted October 5, 1999.
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References |
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