deficiencies (48). One series examining 10 kindreds and 21 sporadic cases of combined pituitary hormone deficiencies from eight different countries found a PROP-1 mutation (301 del AG) in 55% of the PROP-1 alleles from affected families and in 12% of the alleles from sporadic cases (31). The hormonal deficiencies include not only the expected growth hormone, TSH, and prolactin deficiencies, but also gonadotropin deficiency in a number of cases. This finding in humans is surprising because the Ames mouse does not manifest gonadotropin deficiency.
Pit-1 mutations resulting in GHAD were first described in two dwarf mouse mutants (49). These mice have growth failure with intact GH genes (50). Snell mice have a homozygous missense mutation within the POU-HD, which produces a substitution of an invariably conserved tryptophan (Trp261^Cys) (49). Jackson mice have homozygous rearrangements in the pit-1 gene with a 4kb DNA segment insertion. Both strains of mice have profound pituitary hypoplasia, and lack somatotrophs, lactotrophs, and thyrotrophs.
In 1992, the first pit-1 mutations that produce pituitary hormone deficiencies in human beings were described (51,52). Since the original descriptions, sporadic, autosomal recessive, and autosomal dominant mutations of pit-1 have been reported. As of this writing, eight different pit-1 mutations have been found associated with GH, prolactin, and TSH deficiency. Six of these are recessive; two are dominant-negative mutations. In 1992, Tatsumi et al. described a Japanese girl who had growth failure and severe congenital central hypothyroidism (51). They found a homozygous missense transition (C^T) that converted Arg172 to a termination codon, producing a truncated pit-1 protein without a POU-homeodomain. The next homozygous pit-1 mutation to be described was an Arg143^Gln mutation (the result of an A^G missense mutation) in a Japanese girl with complete growth hormone, prolactin, and TSH deficiency (53). Another pit-1 missense mutation (Ala158^Pro) has been identified in two Dutch families (54,55). This mutationresults in a pit-1 protein that cannot activate expression of growth hormone and prolactin genes (55). Irie et al. (1995) reported a homozygous Glu250^Stop mutation that results in the loss of the third helix of the POU-HD and clinical GHD (56). Other recessive mutations identified to date are Phe135^Cys and Pro239^Ser (57,58).
Other pit-1 deficiencies are inherited in an autosomal dominant manner. Codon 271 appears to be a hot spot for these mutations (59). A heterozygous C ^T mutation resultsin an Arg271^Trp pit-1 change in patients with GH, prolactin, and eventual TSH deficiency (52,53,59). This may produce a dominant-negative effect via the resultant mutant POU protein that both binds DNA and inhibits transcription (52).
Okamoto et al. (1994) performed a pedigree analysis of multiple members of a family with an Arg271^Trp pit-1 mutation and found the same heterozygous gene mutation in clinically unaffected family members as in the proband who had GH and prolactin deficiency (60). They found monoallelic pit-1 transcription (normal gene only, without mutant gene expression) in the unaffected father, aunts, and grandmother of their index case and skewed biallelic pit-1 expression (normal > mutant gene) in the patient. They speculated that phenotypic expression of the pit-1 abnormality was secondary to genomic imprinting that caused biallelic expression in the affected patient. The mutant pit-1 protein exerts a dominant-negative effect on the normal pit-1 protein, thereby neutralizing its activity.
Ohta et al. have described a second heterozygous pit-1 mutation (Leu24^Pro) in a child with GH and prolactin deficiency (53). This mutation is located in the transcriptional activation domain ofpit-1 and is also assumed to have a dominant-negative effect, although its DNA-binding and transcriptional activation properties have not yet been elucidated.
GH-1 Gene Deletions. Some patients with GHAD have complete GHD caused by deletions of the entire GH-1 gene. These children have the most severe form of inherited GHD. In 1970, Illig et al. identified six patients receiving human pituitary GH therapy who demonstrated growth retardation in infancy with subsequent severe dwarfism, a characteristic facies, and a strong anabolic response to exogenous GH (61). Four of these six children were related to each other. Illig named the syndrome "type A" after the first initial of the family's surname (62). With GH treatment, these children developed high titers of GH antibodies and resultant growth inhibition. Illig hypothesized that these patients became resistant to exogenous GH because their immune systems did not recognize GH as a homologous hormone molecule (61,63). In 1981, Phillips et al. were the first to describe mutations of the GH-1 gene when they studied these children and found that they had deletions of 6.7 kb of DNA that normally contains the GH-1 gene (64).
It is now accepted that heterogeneous deletions of both alleles encoding the GH-1 gene ranging from 6.7 to 45 kb produce complete absence of GH (65,66). The most prevalent mutation is the 6.7 kb deletion. The deletions appear to arise from unequal recombination events owing to meiotic misalignment of wild-type chromosomes. The GH-1 gene is predisposed to such mutations because it is flanked by long stretches of highly homologous DNA (67,68). Phenotypic heterogeneity is most often found in cases with small gene deletions, but can also be seen in some children with the largest (45-kb) deletions (69).
The prevalence of complete GHD varies between populations; it appears overall that 13-15% of patients with severe GHD (height <-4.5 SD for age and sex) have GH-1 gene deletions (70). Parks et al. reported that 5 of 13 Oriental Jewish patients with height <-4 SD for age and sex had a GH-1 gene deletion (71). Mullis et al. examined 78 children with severe GHD from inbred populations of Northern-European, Turkish, and Mediterranean ancestry and found that 10 of them had GH-1 gene deletions (3). Eight of the 10 had deletions spanning 6.7 kb; two had 7.6 kb deletions. Five of the ten developed antibodies to GH replacement.
Interestingly, despite their total lack of GH production, patients with complete GH gene deletions do not always develop GH antibodies when treated with exogenous GH. Phillips has reported that 82% (14/17) of the patients he examined with GH-1 deletions developed antibodies during replacement therapy (72). Differential antibody formation appears to be partially explained by the molecular heterogeneity of gene deletions; but individuals within families who share apparently identical deletions can also have discordant antibody formation (62,73). These antibodies may prevent patients from responding to GH treatment, resulting in a type of GH insensitivity, but growth in children being treated with GH can also be variable even in the face of antibodies. Rivarola et al. described formation of high antibody titers and consequent growth arrest in a child receiving GH whose sibling had similar antibody titers during GH treatment but continued to grow (74). This variable clinical response to GH replacement might be due to factors other than molecular heterogeneity in the gene deletions, including individual responses to different synthetic GH preparations, specific HLA groups, unique immune antibody formation, or production of antibodies with different GH neutralizing capacities (75).
Until recently, unresponsiveness to GH treatment due to antibody formation left no therapeutic alternatives and resulted in extreme adult short stature. Children who develop an immune response to GH therapy that interferes with therapeutic efficacy are candidates for treatment with synthetic IGF-I, although it is not readily available (76).
Multiple GH Family Gene Deletions. There have been two reports of GH-1 deficiency in combination with other GH family gene deletions (77,78). Goossens et al. found siblings who were homozygous for a 40 kb deletion that eliminated GH-1, GH-2, CS-A, and CS-B genes, leaving only CS-L (77). Akinci et al. described a consanguineous Turkish family with children homozygous for a 45 kb deletion encompassing a different four genes (GH-1, CS-L, CS-A, and GH-2) (78). The children with these deletions had normal birth weights, but demonstrated subsequent severe growth retardation and hypoglyce-mia. Their mother, who was heterozygous for the mutation, had normal postpartum lactation. This suggests that placental expression of CS-L or CS-B alone may be sufficient to sustain a normal pregnancy and prenatal growth, supporting the concept of significant duplication in function of these five genes.
HCS Deficiency (CS-A and CS-B Gene Mutations). Nielsen et al. first detected antenatal hCS deficiency in otherwise normal appearing pregnancies in 1979 during prenatal screening of hCS levels in maternal serum (79). HCS does not appear to be essential for maintenance of pregnancy, fetal growth, or lactation. Some cases of hCS deficiency are total; others are partial. They produce abnormal biochemical phenotypes (with altered maternal IGF-I levels) but no overt disease. In cases of partial hCS deficiency, the amount of hCS produced by the placenta appears to be directly proportional to the number of normal CS-A or CS-B genes (80).
HCS deficiency results from deletions in the GH and CS gene cluster. Wurzel et al. were the first to describe such a gene mutation when they described a homozygous CSA, GH-2, and CS-B gene deletion responsible for Nielsen's index case of hCS deficiency (81). Both parents and two of the proband's three siblings were heterozygous for the deletion. Since no deletion that encompasses the entire five gene cluster has been reported, it remains possible that any one ofthe five genes can produce a peptide that performs the essential functions of any missing peptides in utero. This is in contrast to the situation postnatally, when, because the placental genes are no longer expressed, mutations in GH-1 alone produce an abnormal phenotype.
GH Gene Mutations. Partial GHD is attributed to mutations in GH-1, which produce a GH molecule that retains some biologic function. Clinically, these individuals are less severely affected than those with GH-1 gene deletions and complete GHD (70). Patients with partial GHD have low, but detectable levels of GH on provocative stimulation testing. Growth retardation usually has its onset within the first two years of life (82). Children respond well to treatment with GH without developing antibodies. The reported mutations can be autosomal recessive or autosomal dominant.
Cogan et al. described autosomal recessive inheritance of a GHAD when they found a homozygous splice site G^C transversion in intron IV of the GH-1 gene in a con sanguineous Saudi Arabian family (83). This mutation appears to cause a splice deletion of half of exon IV as well as a frameshift within exon V. Amino acid sequences derived from exons IV and V appear to play an important role in targeting the GH peptide into secretory granules. These investigators later identified a G^T transversion at the same location in another family (70). A deletion/frameshift mutation in exon III has also been described in a patient (84). Homozygous nonsense, splicing, and frame-shift mutations can also eliminate biologically active endogenous GH synthesis (85,86).
Cogan et al. have studied a Turkish family with autosomal dominant partial GHD (83); affected members have a heterozygous T^C transition of a GH-1 intron III donor splice site, which causes skipping of exon III. In 1995, Binder and Ranke demonstrated a de novo G^C splice site mutation of the GH-1 gene that also produced transcriptional exon III skipping and a 17.5 kDa GH protein (82).
In these individuals, presence of one normal GH-1 allele does not compensate for the presence of the abnormal allele. Mutations appear to produce autosomal dominant expression in a dominant-negative manner (87,88). Their adverse effects result from abnormal allele interference in any step from GH transcription to mRNA splicing, translation, and modification to post-translational protein handling. The degree of growth impairment varies greatly between kindreds and even between affected individuals within the same family.
Binder et al. examined relative expression of mutant and normal GH-1 allele expression in an individual with autosomal dominant partial GH deficiency and found equivalent amounts of mRNA with and without exon III in peripheral lymphocytes (88). This suggests that the molecular defect does not interfere with mRNA production but instead involves subsequent translation, processing, storage, or secretion. Binder et al. also found identical levels of GH secreted by proband and control lymphocytes, suggesting that the defect is pituitaryspecific. They theorized that these dominant-negative mutations involve pituitary-specific GH dimer formation or GH aggregation within pituitary cell secretory granules (83,88).
Bioinactive GH. Laron et al. described three siblings with clinical features of GH deficiency but with high serum concentrations of immunoreactive GH (89). These children appeared to have growth hormone insensitivity (GHI). Laron et al. initially theorized that most cases of GHI would result from a defect in GH synthesis that produced a GH molecule that was immunoreactive but without biologic activity (90). Recently however, most cases of Laron syndrome have been found to result from growth hormone receptor (GHR) mutations. It took nearly thirty years for the first proven case of bioinactive GH to be described.
In 1996, Takahashi et al. described a child with severe growth retardation and high serum GH levels, elevated GHBP, low IGF-1 levels, and increased GH levels after provocative testing (91). The patient had responded well to exogenous GH therapy. GH-1 sequencing revealed that the child had an Arg77^Cys mutation. This mutation was inherited from his unaffected father, who produced only wild-type GH. The son was found to express both mutant and wild-type GH. When compared to wild-type GH, the mutant GH had a higher affinity for GHBP, less phosphorylating activity, and an inhibitory or dominant-negative effect on wild-type GH activity. Takahashi et al. have theorized that the cysteine in place of arginine may change the GH molecule configuration by forming a new disulfide bond, resulting in lower bioactivity. A second GH mutation (Aspm^Gly) resulting in a biologically inactive GH was reported by the same group in 1997 (92). This mutant GH is believed to prevent GH receptor dimerization.
Interstitial Xq13.3-Xq21.1 deletions or microduplications of certain Xq regions result in X-linked recessive GH deficiency (93). The phenotype for affected boys is variable. Patients may also have hypogammaglobulinemia, suggesting a contiguous Xq21.3-Xq22 deletion (94). The growth hormone deficiency of Thode-Leonard syndrome (marked short stature, severe mental retardation, unusual facies) has also been shown to be linked to X-chromosome mutations. In 1992, Yokoyama et al. reported growth hormone deficiency and the empty sella syndrome in a child with Thode-Leonard who had a tandem microduplication of Xq13.3^q21.2 (95).
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