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Original Studies |
Unidade de Endocrinologia do Desenvolvimento, Disciplina de Endocrinologia, Laboratório de Hormônios e Genética Molecular-LIM/42 (B.B.M., M.G.F.O., A.C.L., V.E., I.J.P.A.), and Departamento de Neuroradiologia e Ressonancia Magnética (L.S.S.L.), Hospital das Clinicas, Universidade de Sao Paulo, Sao Paulo, Brazil
Address all correspondence and requests for reprints to: Ivo J. P. Arnhold, M.D., Disciplina de Endocrinologia, Hospital das Clínicas da USP, Caixa Postal 3671, 01060–970 Sao Paulo SP, Brazil. E-mail: iarnhold{at}usp.br
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A missense mutation in Prophet of Pit-1 (PROP1), a transcription factor expressed temporarily in the fetal anterior pituitary, is the cause of Ames dwarfism in mice (8). This paired-like protein is necessary for the subsequent expression of Pit-1 in somatotrophs, lactotrophs, and thyrotrophs. Therefore, inactivating mutations in the PROP1 gene are candidates to explain a Pit-1 phenotype in patients without any Pit-1 gene abnormalities. Inactivating mutations of PROP1 have been recently identified in four families with CPHD (9). Three of four families had a 2-bp deletion (A301,G302) in exon 2 of the PROP1 gene; two families were homozygous for this mutation, and one was compound heterozygous (A301,G302/F117I). Eleven Russian families with CPHD were studied by Fofanova et al.; a homozygous A301,G302 deletion in PROP1 gene was identified in two families, and compound heterozygosity (delA301,G302/delG149A150) was found in four families (10). Therefore, the A301,G302 2-bp deletion in the PROP1 gene appears to be a common cause of CPHD.
We identified a homozygous PROP1 2-bp deletion (A301,G302) in two unrelated Brazilian patients with CPHD and report longitudinal changes in hormonal function and pituitary imaging.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Informed parental consent, patient assent, and approval by the hospital ethics committee were obtained before the studies.
Eighteen patients with CPHD were screened for a 2-bp deletion (A301,G302) in the PROP1 gene. Two unrelated female patients were homozygous for this 2-bp deletion.
Patient 1 was a 6.6-yr-old Caucasian girl with a height of 101.0 cm (-2.9 SD score), a weight of 18.0 kg (-1.2 SD below the mean), and a bone age of 2.5 yr. She was born by normal delivery, at term, weighing 3780 g. Her target height was 157.5 cm. Early developmental milestones were normal. Failure to thrive was noticed at the age of 3 yr. At the age of 7.1 yr, she was treated with L-T4 (6 µg/kg·day) and recombinant GH (0.1 U/kg day), sc, with good improvement of growth velocity. At the age of 12.6 yr, administration of conjugated estrogens was started at 0.15 mg/day and was progressively increased to 0.625 mg/day; this treatment was combined with medroxyprogesterone acetate (5 mg/day) for 11 days each month. GH treatment was stopped at 14.8 yr when her height was 166.8 cm (+0.8 SD score), bone age was 13 yr, breast stage was Tanner IV, and pubic hair stage was Tanner III. At 15.5 yr, she complained of lethargy and somnolence and was treated with cortisone acetate (9 mg/m2·day). Her younger sister and nonconsanguineous parents were of normal height.
Patient 2 was also screened for the PROP1 2-bp deletion by Cogan et al. (subject 1 in Ref. 13), but only minimal clinical data were reported. On first examination, she was a 12.3-yr-old prepubertal Caucasian girl with a height of 107 cm (-5.5 SD score), a weight of 21.3 kg (-2 SD score), and a bone age of 7.8 yr. She was born weighing 2500 g after an uncomplicated term pregnancy with cephalic presentation. According to her mother, growth had slowed at age 5 yr. The diagnosis of CPHD was made, and she was treated with L-T4 (6 µg/kg·day). She did not receive GH therapy due to social problems. At 21.1 yr of age, her height was 131.8 cm (-5 SD score), her weight was 34.8 kg (-2.6 SD score), and her bone age was 13 yr. She had no breast or pubic hair development, and she was treated with conjugated estrogens (0.3–0.625 mg/day) continuously, in combination with medroxyprogesterone acetate (5 mg/day) for 11 days each month. Her father, mother, and six siblings were of normal height. Her parents are first cousins and referred a first cousin, also offspring of a consanguineous marriage, and two grandaunts with dwarfism and sexual infantilism.
Heights were measured with a stadiometer, and height SD values were calculated using British reference standards (11). Bone age was determined by the standards of Greulich and Pyle, and pubertal development was rated using Tanner stages.
Hormonal assays
Basal T3, T4, insulin-like growth factor
I, and estradiol levels were measured. All patients underwent a
combined pituitary stimulation test (0.1 U/kg insulin, 200 µg TRH,
and 100 µg GnRH, iv); glucose, GH, cortisol TSH, PRL, LH, and FSH
were measured in the basal state and 15, 30, 45, 60, and 90 min after
stimulation. GH was also measured 0, 60, 90, and 120 min after
clonidine stimulation (0.1 mg/m2, orally) in patient 1 and
60, 90, and 120 min after L-DOPA stimulation (10 mg/kg,
orally) in patient 2. GH was measured by RIA and immunofluorimetric
assay (Wallac, Turku, Finland), with interassay coefficients of
variation below 6%. TSH was measured by RIA and enzyme immunoassay
with interassay coefficients of variation below 8%. Normal values for
the combined test were established in 20 children with short stature
who had a normal rise in GH (Table 1
).
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Sella turcica x-ray was obtained from lateral radiographs of the skull. MR scans were performed in a 1.5 Tesla unit (GE, Sigma, Milwaukee, WI) using T1 weighted sagittal and coronal scans with TR:350 ms and TE:20 ms. The coronal images were obtained using 3.0-mm slices with a 10% gap before and after administration of 5 mL paramagnetic contrast. We used a 18-cm field of view for the sagittal images. The maximal height of the pituitary gland was measured perpendicular to the sella turcica and compared to that in normal controls (12).
DNA analysis
Genomic DNA was isolated from peripheral blood by standard
methods. Exon 2 of the PROP1 of each affected patient was amplified by
the PCR, using a set of flanking intronic primers. The primer sequence
and protocol were provided by Dr. Milton R. Brown. Amplification was
carried out in a 50-µL reaction, using 1 or 2 µL (200 ng) genomic
DNA, 10 mmol/L Tris-HCl (pH 8.3), 1.5 mmol/L MgCl2, 25
mmol/L KCl, 0.2 mmol/L of each deoxy-NTP, 15 pmol of each primer, and
1.25 U of Taq polymerase (Pharmacia Biotech,
Uppsala, Sweden). The reaction product was run on a 2% agarose gel and
stained with ethidium bromide. The previously described 2-bp deletion
(A301,G302) of the PROP1 gene introduces a restriction site for the
enzyme BcgI and was screened in the two patients. Ten
microliters of each PCR product of exon 2 were digested with 6 U
BcgI (New England Biolabs, Inc., Beverly, MA)
and 20 µmol/L S-adenosyl-methionine for 4 h at 37 C,
followed by 20 min at 65 C. The digestion products were electrophoresed
through a 3% low melting temperature agarose gel (NuSieve GTG agarose,
FMC BioProducts, Rockland, ME) and visualized with ethidium bromide.
Symmetric PCR products were purified by enzymatic pretreatment with 10
U exonuclease I and 2 U shrimp alkaline phosphatase (Amersham
Science, U.S. Biochemical Corp., Cleveland, OH). The
flanking primers for exon 2 were used for sequencing by the dideoxy
nucleotide chain termination method (Sequenase version 2.0 DNA
polymerase, Amersham, U.S. Biochemical Corp.)
in the presence of [
-35S]deoxy-ATP. The reaction
products were run on a 6% polyacrylamide gel.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In patient 1 at 6.8 yr of age, serum GH failed to reach normal
levels after stimulation by hypoglycemia (Table 1
) or clonidine (GH,
3
2 ng/mL); basal TSH and PRL levels were normal, with a
blunted response to combined TRH and hypoglycemia stimulation (Table 1). Baseline gonadotropin levels were in the prepubertal range and
presented no response to GnRH stimulation at 6.8 yr or 15.2 yr of age
(Table 1). At 12.4 yr of age (bone age, 10.5 yr), the patient was
prepubertal, and a new GnRH stimulation test did not evoke a rise in LH
or FSH levels (data not shown). Basal cortisol levels were high normal
at 6.8 yr, but had declined at 15.2 yr with a subnormal response to
hypoglycemia (Table 1).
In patient 2 at 12.3 yr, serum GH remained low after stimulation by
hypoglycemia (Table 1) and L-DOPA (GH, 0.1<0.1
ng/mL); basal TSH and PRL were normal, with blunted responses to
combined TRH and hypoglycemia stimulation (Table 1). Baseline
gonadotropin levels were normal for prepubertal age and presented no
response to GnRH stimulation at 12.3 yr, 21.1 yr (data not shown), and
28.4 yr of age (Table 1). At 28.4 yr (bone age, 15 yr), another
combined pituitary stimulation test revealed low basal PRL levels and
normal cortisol levels, without any other changes in relation to the
previous test (Table 1).
Skull x-ray and pituitary MRI
Patient 1 was submitted to sella turcica x-ray and to MRI of
hypothalamic-pituitary region twice. At 8.8 yr, a skull x-ray revealed
a spherical large sella, with no erosion of the posterior clinoids
(Fig. 1). MRI showed an enlarged anterior
pituitary lobe (height of 8 mm vs. 4.5 ± 0.6 mm in
age-matched controls) and hyperintense T1 weighted image at coronal and
sagittal views (Fig. 2). MRI repeated at
15 yr revealed a marked reduction of pituitary height (2 mm
vs. 5.3 ± 0.8 mm in controls; Fig. 2).
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) associated with a
pituitary gland of reduced size (5 mm vs. 6.1 ± 0.3 mm
of height in age-matched controls) with normal intensity. In both patients, MRI showed a normal stalk and a normally located posterior pituitary lobe.
Genomic analysis of the PROP1 gene
A fragment containing exon 2 of the PROP1 gene was successfully
amplified by PCR and exhibited the expected size (
365 bp) on agarose
gel. The PCR product was entirely cleaved with BcgI in three
fragments of 235, 96, and 32 bp in the two patients. The mother and one
sister of patient 2 had the 365-bp fragment in addition to the 235- and
96-bp fragments, indicating that they were heterozygous for this
mutation. Direct sequencing of the fragment containing exon 2 confirmed
the homozygous A301,G302 deletion in patients 1 and 2.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Heterozygous dominant, homozygous recessive, or compound heterozygous mutations at different sites of the Pit-1 gene were found in patients with CPHD. All had GH, PRL, and, eventually, TSH deficiencies. In contrast to patients with Pit-1 deficiency, those subjects with PROP1 mutations cannot produce LH or FSH at a sufficient level and do not enter puberty spontaneously (9).
Wu et al. identified 4 families in which CPHD was caused by homozygosity (delA301,G302 or R120C) or compound heterozygosity (delA301,G302/F117I) for inactivating mutations of the PROP1 gene (9). The A301,G302 2-bp deletion in the PROP1 gene leads to a frame shift in the coding sequence starting at codon 101 and premature termination at codon 109. Wu et al. demonstrated that constructs with A301,G302 deletion failed to bind to DNA and to activate a reporter gene, whereas those with the F117I and R120C substitutions bound DNA with greatly reduced affinity and activated the reporter with significantly reduced efficiency (9). Fofanova et al. identified the same 2-bp deletion (A301,G302) in the PROP1 gene of 3 patients from 2 Russian families with CPHD and termed it 296delGA (10). The precise location of the 2-bp GA or AG deletions in the 295-CGAGAGAGTC-304 sequences is unknown. Any combination of GA or AG deletion will behave as a deletion of A301,G302 and lead to the same frame shift after codon 101. Fofanova et al. also identified compound heterozygosity for A301,G302 and 149delGA in exon 2 of PROP1 gene in 5 additional Russian children with CPHD belonging to 4 different families (10). The 149delGA leads to a frame shift after amino acid 50 and results in a stop codon at position 109. The A301,G302 deletion creates a BcgI restriction endonuclease site that can be used to screen patients with CPHD for this mutation. Using this screening procedure, Cogan et al. identified a homozygous A301,G302 deletion in PROP1 gene in 5 of 10 familial and 2 of 21 sporadic cases of CPHD (13). The 2 patients reported here were detected after amplification of exon 2 of the PROP1 gene by PCR followed by digestion with BcgI.
In a recent review, pituitary size was small in 9 and normal in 6 patients with Pit-1 deficiency (7). There was also a suggestive association of smaller pituitary size and later age when the image study was performed.
Information regarding pituitary size in patients with PROP1 mutations is scarce. Wu et al. reported a hypocellular pituitary at MRI in one patient with compound heterozygosity (delA301,G302/F117I) for the PROP1 gene (9). Most patients with hypopituitarism have normal or small sella turcica (14). In contrast, Parks et al. in 1978 reported three siblings with CPHD with large sella turcica (>3.7 SD score above the mean for chronological and height ages) (15). Recently, Parks et al. detected the A301,G302 deletion in one allele and presumed a loss of function mutation in the other allele of the PROP1 gene in these patients (16). In three siblings from another Brazilian family and in patients from Jamaica with CPHD, Parks et al. identified a homozygous A301,G302 deletion in the PROP1 gene (16). Definite enlargement of the anterior pituitary occurred in all but the youngest Brazilian patient. Two patients had suprasellar extension, and one patient from Jamaica had removal of the mass, and histopathology disclosed amorphous material with occasional fibroblastic cells, but no recognizable cell types. An enlarged pituitary gland with hyperintense signal at MRI, as found in our patient 1, could reflect an elevated protein content and correspond to the same amorphous material described in the Jamaican patient. A marked reduction of the anterior pituitary lobe suggests that a reabsorbtive process could occur in the evolution of patients with PROP1 2-bp deletions. Our patients had an intact stalk and normal posterior pituitary lobe, in accordance with PROP1 being expressed only in the anterior pituitary.
Both patients had GH, TSH, PRL, LH, and FSH deficiencies. Interestingly, patient 1 had high normal basal cortisol levels. Elevated cortisol levels without signs of Cushing’s syndrome were also described in patients with Pit-1 deficiency (7), but the underlying mechanism remains to be established. Patient 1 had a decline in basal cortisol levels and a subnormal response to hypoglycemia when retested at age 15 yr. Partial ACTH deficiency developed eventually in two of the nine patients with PROP1 deficiency reported by Parks et al. (16), suggesting that acquired cortisol deficiency may occur in patients with PROP1 deficiency. Cortisol deficiency is absent or develops later in some patients with PROP1 mutations, suggesting a different mechanism for this deficiency.
We conclude that pituitary morphology can change during the follow-up of patients with PROP1 gene mutation, and that hormonal deficiencies could include the adrenal axis.
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Acknowledgments |
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Footnotes |
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Received September 22, 1998.
Revised November 24, 1998.
Accepted December 2, 1998.
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