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Original Studies |
Center for Endocrinology, Metabolism and Molecular Medicine, Departments of Medicine (H.G.M., G.B.), Pediatrics (B.L.S.), and Preventive Medicine (J.D.), Northwestern University Medical School, Chicago, Illinois 60611
Address all correspondence and requests for reprints to: G. Baumann, M.D., Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611.
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Abstract |
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Stop) in the extracellular domain of the
GHRH-R. This mutation predicts a severely truncated GHRH-R; it is
identical to that recently reported in four patients from two other
families. Inheritance is autosomal recessive (chromosome 7p) with a
high degree of penetrance. Relatives heterozygous for the mutation had
moderately decreased IGF-I levels and slightly blunted GH responses to
GHRH and L-dopa, but they showed only minimal or no height
deficit. This syndrome represents the human homologue of the little (lit/lit) mouse and closely resembles its phenotype. It demonstrates the absolute requirement of GHRH signaling for pituitary GH secretion and postnatal growth in humans, and its relatively minor (but discernible) biological importance in extrapituitary sites. The syndrome is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Its discovery raises the possibility of milder mutations in the GHRH-R gene as potential causes for partial GH insufficiency and idiopathic short stature.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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In 1994, an article appeared in Dawn (a Karachi, Pakistan, newspaper), describing the existence of a cluster of familial severe dwarfism in two remote villages in the lower Indus valley (10). We reasoned that this syndrome may reveal new information on the genetic regulation of growth, and we organized an expedition to investigate the nature and cause of this growth disorder.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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A preliminary visit by one author (H. G. Maheshwari) identified 13 dwarfs in 2 neighboring villages (Umar Burro and Fakirabad), approximately 30 km from Sukkur, in the Province of Sindh, Pakistan. Photographs documented the severity of growth retardation and suggested that dwarfism was proportionate. Two of us (H. G. Maheshwari and G. Baumann) then traveled to Sukkur to obtain precise population, ecological, nutritional, pedigree, clinical, biochemical, and genetic information. A field laboratory was set up in the district hospital. The study plan was approved by the Northwestern University Institutional Review Board, and subjects participating in the study gave informed consent or parental assent.
We conducted extensive interviews to establish family relationships and medical histories. Height was measured using a wall-mounted ruler and a draftsman’s triangle, and weight was determined using a portable scale. Height and weight were compared with the NCHS/CDC reference population (11); head circumference with the standards published by Nellhaus (12); body proportions with those of Wilkins (13), Roche and Malina (14), and Forbes (15); and blood pressure with those of Drizd et al. (16) and Blumenthal et al. (17). Age-adjusted data are expressed as SD scores (SDS). Bone age was determined on wrist radiographs, according to the TW2 method (18). Nutritional status was assessed by nutritional histories and inspection of sc fat deposits. Intellectual function was estimated during conversations with patients and relatives and by judging the appropriateness of school year for age.
Baseline blood samples were obtained after a 12-h fast. The following pituitary function tests were performed: GHRH-1–44 1 µg/kg iv; TRH 7 µg/kg iv; L-dopa 250 mg (9–25 mg/kg) po; clonidine 125 or 250 µg (3.9–6.2 µg/kg) po. An insulin-like growth factor I (IGF-I) generation test was performed by injecting recombinant human GH (hGH; 0.05 mg/kg sc) once daily for 5 days. GHRH and TRH were purchased from Ferring (Lübeck, Germany, and Suffern, NY, respectively). hGH was kindly provided by Eli Lilly & Co., Indianapolis, IN.
Biochemical and hormone assays
Blood was centrifuged and plasma immediately frozen until transported to Chicago on dry ice. Serum SMAC-20 and immunoglobulins were determined by standard procedures; T4, cortisol, aldosterone, testosterone, dehydroepiandrosterone sulfate (DHEA-S), GH, and PRL by RIA; and TSH by immunoradiometric assay. GH was also measured by ultrasensitive chemiluminescent assay (19). Measurements of extracted IGF-I, IGF-II, and IGF-binding proteins 2 and 3 (IGFBP2 and IGFBP3) were performed by Corning-Nichols Laboratories, San Juan Capistrano, CA. GH-binding protein (GHBP) was determined by GH-binding assay (20). Statistical analysis was performed by t test or ANOVA, as appropriate.
Nucleic acid extraction, amplification, and cloning
Genomic DNA and RNA were extracted from peripheral leukocytes in whole blood according to standard procedures. PCR was used to amplify genomic DNA or reversely transcribed complementary DNA of candidate genes. Generally, 30–35 thermal cycles were used, followed by agarose gel purification of amplimers and either direct DNA sequencing or subcloning into pCR II vector.
Linkage analysis
Candidate genes (see below) were probed for linkage to the dwarf phenotype using amplification and size determination of polymorphic chromosomal markers (microsatellites) in the vicinity of the candidate genes, using fluorescent primers and an ABI 373A semiautomatic DNA sequencer with the aid of ABI GeneScan software. Two- and three-point linkage analysis was performed using version 5.0 of the LINKAGE program (21) and version 3.0 of the FASTLINK subroutines (22, 23), as well as by analysis of homozygosity by descent. A fully penetrant autosomal recessive mode of inheritance was assumed, with a disease allele frequency of 0.0001. The allele frequencies of the microsatellites were set to 1/n, where n is the number of alleles observed. However, the robustness of the LOD scores was verified by setting the frequencies to the published values, when available. For the three-point analysis, two of the inbreeding loops had to be omitted because of computational constraints.
DNA sequencing
DNA sequencing was performed using cycle sequencing with AmpliTaq FS, fluorescent dideoxy chain terminators and analysis in a semiautomatic DNA sequencer. Generally, PCR products were directly sequenced; in the case of cloned DNA, at least 6 clones were sequenced to guard against Taq polymerase errors.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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The affected population lives in two neighboring villages in the semiarid, but irrigated lower Indus valley. The population is native Sindhi and Muslim. Occupation consists primarily of farming (dates, rice, livestock) and brick manufacture. There is neither shortage of food nor evidence of malnutrition. We found no infectious, gastrointestinal, or other general medical reasons for growth retardation. Consanguineous marriages are common. Dwarfism emerged recently, with the oldest patient being 28 yr old. Parents of affected subjects reported that pregnancy, birth size, and breast feeding were normal and that growth retardation became apparent during early childhood. There were no unusual illnesses or deaths among affected children. In particular, no symptoms of hypoglycemia could be elicited. Intelligence appeared normal. Puberty in males was reported to occur at about age 16 (a delay of 2–3 yr for the local population standard); in females this information could not be obtained.
Pedigree (Fig. 1
)
The pedigree of the affected kindred shows 7 consanguineous unions (6 first cousin and 1 uncle/niece). Because of the complex intergenerational marriage patterns, we were unable to assign generations. Subjects are therefore numbered consecutively throughout the pedigree. Based on the physical phenotype, we found 16 clearly dwarfed subjects (13 male, 3 female, age range 7–28 yr; black symbols). We were uncertain how to classify 6 subjects (no. 6, 12, 27, 28, 38, and 43) based on phenotype alone, because of their intermediate stature (-2.5 to -4.5 height SDS). Of note is subject no. 12, who is the offspring of two dwarfed parents. He was 25 days old at the time of examination; having been delivered at or near term by cesarean section. His mother had sufficient milk to satisfy his needs.
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Affected patients were short but exhibited normal body proportions
(Fig. 2). There were no dysmorphic
features or deformities. In some (but not all) patients, there was
minimal facial hypoplasia, some had abducted ears, and two (subjects
no. 45 and 46) had a slightly protruberant abdomen. None of the
patients had microphallus. Tanner staging in adolescents confirmed a
pubertal delay of 2–3 yr. Adult male patients had a distinctive,
raspy, high-pitched voice. Anthropometric data are summarized in Table 1. Height, weight, head circumference,
bone age, and blood pressure were significantly below normal, and
waist/hip ratio was above American norms (14, 15). Adult height was
130 ± 10.6 cm for men and 113.5 ± 0.7 cm for women
(mean ± SD). Blood pressure was low, even if
allowance is made for measurements with an adult-size cuff. The newborn
boy born of two dwarfed parents (subject no. 12) showed evidence of
intrauterine growth retardation (hypoplastic adipose tissue and
skeletal muscle, but both testes normal in size and descended). This is
in contrast to the reported normal birth size of affected subjects born
of normal statured parents.
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Biochemical phenotype
Patients and relatives had normal routine blood chemistry and
immunoglobulin levels. Baseline endocrine parameters are shown in Table 2. The patients were euthyroid and had
normal PRL, cortisol, aldosterone, DHEA-S, and
testosterone levels. Abnormalities were confined to the GH-IGF-I axis
and included low IGF-I, IGF-II, and IGFBP3, and elevated IGFBP2 levels.
Basal plasma GH was undetectable in a conventional RIA (<0.3 ng/mL)
but measurable in a chemiluminescent assay. GHBP was in the normal
range.
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). GH remained undetectable by RIA
(<0.3 ng/mL); when measured by the chemiluminescent assay, GH rose
slightly from 0.070 ± 0.054 to 0.107 ± 0.053 ng/mL
(mean ± SD) after GHRH, from 0.150 ± 0.175 to
0.255 ± 0.193 ng/mL after L-dopa, and from 0.073
± 0.052 ng/mL to 0.374 ± 0.406 ng/mL after clonidine. None
of these responses are statistically or clinically significant. The
responses of TSH and PRL to TRH (Fig. 3B) were present but somewhat
blunted [normal range for TSH response, 10–17 µU/mL; for PRL
response, 15–30 ng/mL (Ref. 24 and references cited therein)].
Exogenous GH treatment resulted in a significant rise of serum IGF-I
and IGFBP3 (Fig. 3C), indicating normal tissue responsiveness to
GH.
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Based on the pedigree, clinical and biochemical phenotype, the patients were diagnosed as having isolated GH deficiency on a genetic basis. We first analyzed the GH gene locus by restriction mapping but found no major rearrangement of the GH and placental lactogen genes. Sequencing of the GH-N gene in its entirety showed no mutation, excluding a defective structural GH gene as the basis for the disease.
Linkage analysis for candidate genes
We then considered other candidate genes, which included the
promoter region of the GH-N gene, genes for GHRH, the GHRH-R, Bruton’s
tyrosine kinase (25), Pit-1 (26), and several other less likely
candidates coding for factors involved in the regulation of GH
secretion. The first three candidate genes (deemed most likely to be at
fault) were examined for linkage between dwarfism and chromosomal
markers near the candidate gene. Markers D17S795, D17S784 (near GH
gene), D20S95, D20S27, D20S115, D20S470 (near GHRH gene), D7S493, and
D7S1830 (near GHRH-R gene) were not linked to dwarfism, but D7S1808 and
D7S817 (also near the GHRH-R gene) yielded LOD scores of 3.44 and 6.26
at 
of 0.106 and 0.042, respectively, indicating linkage of the
GHRH-R locus to the dwarf phenotype. Analysis of homozygosity
by descent was consistent with linkage to that locus, though not
statistically proven (P 
0.02 and 0.06 for the
two closest markers).
Amplification and sequencing of the GHRH-R gene
Segments of the GHRH-R gene were PCR-amplified from genomic DNA in
a stepwise fashion based on the known complementary DNA structure (27, 28). We found a G-to-T transversion (GAGTAG) in codon 72 (numbered
from the AUG start codon), corresponding to amino acid residue 50 in
the mature GHRH-R protein (Fig. 4A). This
mutation predicts a translational stop (GluStop), which truncates
the GHRH-R in its extracellular domain (Fig. 5). The resulting GHRH-R protein, if
extant, is predicted to be severely dysfunctional, bearing a disrupted
binding site and lacking all transmembrane helices and intracellular
segments.
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In addition to restriction analysis with BfaI, genotypes
were confirmed by DNA sequencing. The homozygous mutation segregated
100% with the dwarf phenotype, and all obligate heterozygotes were
heterozygous for the mutation (Fig. 1). Thus, the disorder is
transmitted in an autosomal recessive fashion with a high degree of
penetrance. The subjects who were difficult to classify phenotypically
included two homozygous subjects [one adult (no. 6) and one newborn
(no. 12)] and four heterozygotes (no. 27, 28, 38, 43; aged 9–14). Heterozygous phenotype
In an effort to determine whether there is a gene dosage effect in this disease, we carefully examined heterozygotes (n = 22) for subtle abnormalities (data are given as mean ± SD). Adults had no obvious short stature (height SDS, -1.5 ± 0.7) or other distinctive physical characteristics, but children and adolescents were relatively short (height SDS, -2.73 ± 0.94). The average age for male puberty in the affected kindred (with a high prevalence of heterozygous subjects) was reported as age 13; our Tanner staging of 2 heterozygous adolescents was consistent with that timing. When all heterozygous subjects were pooled, their height SDS was -1.89 ± 1.1, whereas that of 5 subjects homozygous for the wild-type allele was -1.51 ± 1.8 (difference not significant). The average height of randomly selected men without known genotype was 172.8 ± 6 cm, which corresponds to a height SDS of -0.6 ± 0.9 [based on recent reports, the growth data of adequately nourished Pakistani children are indistinguishable from American NCHS data (29); this is consistent with our own observations about adult height in the affected region.] Our measurements suggest, but do not prove, a slight growth delay and, perhaps, adult height deficit in the heterozygous state.
In adult heterozygotes, serum IGF-I was 103 ± 53 ng/mL, IGF-II was 395 ± 110 ng/mL, IGFBP3 was 2.8 ± 1.7 µg/mL, IGFBP2 was 389 ± 106 ng/mL, and GHBP was 1.36 ± 0.58 nM (insufficient data are available in wild-type homozygotes for comparison). The mean GH responses to GHRH, L-dopa, and clonidine showed peak levels of 7.1 ± 2.0, 6.6 ± 1.5, and 10.5 ± 5.4 ng/mL, respectively, all except clonidine slightly below the normal range [normal for GHRH, 8–40 ng/mL; for L-dopa, 11–20 ng/mL; and for clonidine, 6.5–10 ng/mL (Ref. 24 and references cited therein)]. The overall data are consistent with a partially blunted GH-IGF axis in heterozygotes.
Chromosomal location of the GHRH-R gene
Multipoint linkage analysis permitted a more precise localization
of the GHRH-R gene than was previously available (30, 31). The gene is
located on the short arm of chromosome 7 (7p14), approximately 2.6
cM telomeric from microsatellite D7S510 (Fig. 6).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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Dwarfism of Sindh represents the human homologue of the little (lit/lit) mouse, first described in 1976 (33). This mouse harbors a missense mutation in the GHRH-R (34, 35), which abolishes ligand binding, causing GHRH resistance, pituitary hypoplasia, isolated GH deficiency, and a dwarf phenotype. Brain weight is decreased by 15–20% (36), a finding consistent with the small head circumference in our patients. Despite the existence of this mouse model, human GHRH resistance was not identified until 1996 (4, 37).
This syndrome demonstrates that in humans, as in mice, GHRH signaling is absolutely required for normal GH production and somatic growth. Because of the complex regulation of GH secretion, which involves GHRH, SRIF, and probably the putative endogenous ligand for the GH-releasing peptide (GHRP) receptor (38), it is difficult to discern their relative contributions to GH secretion in the intact subject. Dwarfism of Sindh clearly identifies GHRH as a critical factor because of its importance for somatotroph development (39, 40), GH synthesis (41), and GH release (42). Nonetheless, a minuscule amount of GH seems to be released with secretagogues, in agreement with data in the little mouse (43, 44).
Several aspects of this syndrome are of interest, and some differ from other forms of GH deficiency. Although growth retardation is severe, there is significant variability in height. In particular, one patient (no. 6) is relatively tall. Head size is significantly smaller than that observed in conventional GH deficiency (45, 46, 47), and there is no facial hypoplasia or frontal bossing. This contributes to the "normal, but miniature adult" aspect of these patients. The asymptomatic low blood pressure is a unique finding. We did not observe significant truncal obesity or microphallus, nor could we elicit a history of hypoglycemia, all well-recognized features of classical GH deficiency (or GH resistance). Absence of these features was also noted by Netchine et al. (9), though Wajnrajch et al. reported frontal bossing and obesity in their patients (7). The blunted PRL and TSH responses [the former also reported by Netchine et al. (9)] are unexpected in classical isolated GH deficiency. They may be related to pituitary hypoplasia or to a specific role of GHRH in maximizing PRL and TSH production. Neither PRL nor TSH insufficiency is clinically apparent in the patients, but the little mouse has some difficulty with lactation (33). It is tempting to attribute these deviations from classical GH deficiency to the absence of direct GHRH effects. Although direct extrapituitary GHRH effects remain poorly characterized, they are plausible in view of the widespread expression of GHRH and the GHRH-R (48). An alternative explanation for unexpected findings, such as hypotension, is consanguinity, affecting loci unrelated to the GHRH-R gene.
Pubertal delay is common in GH deficiency and was also seen in our patients and in a 16-yr-old male reported by Wajnrajch et al. (7). In contrast, the two male patients of Netchine et al. (9) started puberty at age 13, but as pointed out by the authors, they had been treated with GH for several years. It seems likely that pubertal delay is a result of GH deficiency rather than a direct consequence of abnormal GHRH-R function.
Reports of the identical mutation in two other families originating on the Indian subcontinent (7, 9) raises the question of a founder effect. However, there is no known recent connection among the three populations. The Sindhi population that gave rise to our patients has lived in the same area for at least 200 yr; they are not recent immigrants from India. Conversely, the patients reported by Wajnrajch et al. (7) originate from the Bombay area (J.M. Gertner, personal communication), without known ancestry in the Indus valley. The patients reported by Netchine et al. (9) are Tamouleans from Delft, an island between India and Sri Lanka. In addition to their geographic separation, ethnic and linguistic evidence does not suggest a recent relationship among the three families. A historically remote connection, though probable, fails to fully explain why this syndrome was not observed earlier (see below). Therefore, the possibility of an independent occurrence of the same mutation cannot be dismissed, possibly implying a mutational hot spot. This issue may be resolved by haplotype analysis.
A related puzzle is the very recent emergence of this syndrome. Given the long-standing custom of consanguineous unions in this population, the distinctive phenotype, high penetrance, apparent lack of lethality, limited gene pool, and large size of families, it would be expected that the homozygous dwarf phenotype would emerge soon after the occurrence of the mutation. One possible explanation for the dwarfism being limited to the youngest generation is that the mutation is of recent origin. We presently have no evidence to confirm or exclude this hypothesis. Other possibilities include: 1) lack of recognition of dwarfism in earlier generations, which may have been of shorter stature because of nutritional deficiency; 2) mortality of the affected (perhaps of hypoglycemia), in previous generations, during early childhood, at an age when dwarfism is not yet obvious; and 3) suboptimal health and nutrition, leading to fetal death of the affected in earlier generations. None of these explications is entirely satisfactory. Future haplotype analysis, with closely spaced markers surrounding the GHRH-R gene, may provide the answer to when the mutation occurred.
The offspring of two affected parents provides some unique insights. First, the child proves that fertility is possible, in both sexes, in the absence of a GHRH-R. GHRH and its receptor are expressed in testis and ovary (49, 50), but their role in gonadal function is not clear. Our observation shows that the GHRH-R is not critical for fertility (though subfertility cannot be excluded). This is consistent with fertility in the little mouse (33, 34). It has been proposed that the reproductively important GHRH gene product in testis is a peptide distinct from GHRH (the GHRH-related peptide) and that this peptide signals through a receptor distinct from the GHRH-R (51). The second insight results from the phenotype of the newborn (no. 12), which resembles intrauterine growth retardation. This may be a result of maternal size, the conceptus’ genotype, or both. A mismatch between (dwarfed) maternal and (relatively normal) fetal size may have resulted in placental insufficiency. Dwarfed mothers have an increased rate of fetal loss for unknown reasons (52). Alternatively, GHRH-R deficiency in the fetoplacental unit may have played a role, although little is known about expression or function of the GHRH-R in human placenta.
Treatment of this syndrome with GH results in normalization of growth (7, 9), without evidence of significant anti-GH antibody production. This suggests that the small amount of GH produced is sufficient to induce immune tolerance to GH, similar to what has been postulated for isolated GH deficiency type IB (3). A potential alternative for therapy is GHRP, but it is unknown whether GHRP can release GH in the absence of a functional GHRH system. GHRH is known to potentiate GHRP effects (53), but the mechanistic basis of this phenomenon is poorly understood. Therefore, testing GHRH-R-deficient patients with one of the GHRPs will be important for both heuristic and therapeutic reasons. Pituitary (somatotroph) hypoplasia will have to be taken into account in interpreting the response to GHRP.
As a byproduct of linkage analysis, we have refined the localization of the GHRH-R gene on the short arm of chromosome 7. This should facilitate the search for disorders potentially linked to the GHRH-R gene (e.g. short stature, pituitary tumors, and acromegaly). In a recent listing of human genetic diseases, a locus associated with GH-deficient dwarfism is identified on the short arm of chromosome 7 (54). It is likely that the gene in question encodes the GHRH-R.
In summary, we describe, in detail, a cluster of severe familial dwarfism caused by a nonsense mutation in the GHRH-R gene, which, in its homozygous form, causes isolated GH deficiency with some unusual features. This discovery should facilitate the search for milder mutations in the GHRH-R as a potential cause of short stature and should help in the identification of factors responsible for genetic height determination.
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Note Added in Proof |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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Acknowledgments |
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Footnotes |
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2 Amino acid residue no. 50 refers to the mature
protein; it corresponds to residue 72 when the signal peptide is
included.
Received May 19, 1998.
Revised July 17, 1998.
Accepted July 28, 1998.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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