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Four New Cases of Congenital Secondary Hypothyroidism due to a Splice Site Mutation in the Thyrotropin-ß Gene: Phenotypic Variability and Founder Effect

Children’s Hospital of the Johannes Gutenberg University (G.B., U.M., G.W., J.P.), D-55101 Mainz, Germany; Institut National de la Santé et de la Recherche Médicale U393 (G.B.), Hopital Necker-Enfants Malades, F-75015 Paris, France; Department of Pediatric Endocrinology and Metabolism (A.K.T., N.O.-M., B.Y., G.O.), Cukurova University, Faculty of Medicine, TR-01330 Adana, Turkey; Children’s Hospital Amsterdamer Strasse (E.K.), D-50735 Köln, Germany; Kinderklinik des Allgemeinen Krankenhauses Hagen GmbH (U.A., G.K.), D-58095 Hagen, Germany; Children’s Hospital (R.P.), University of Leipzig, D-04103 Leipzig, Germany; and Departments of Medicine (N.H.S., S.R.) and Pediatrics (S.R.) and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Joachim Pohlenz, M.D., Children’s Hospital, University of Mainz, Langenbeckstrasse 1, Building 109, D-55101 Mainz, Germany. E-mail: pohlenz{at}mail.uni-mainz.de; or pohlenz{at}kinder.klinik.uni-mainz.de.

	Abstract

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Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 G A) in the TSHß gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we detected a very low concentration of authentic, heterodimeric TSH in serum, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping all family members with polymorphic markers at the TSHß locus, we show that the mutation arose on a common ancestral haplotype in three unrelated Turkish families indicating a founder mutation in the Turkish population. These results suggest that this TSHß mutation is among the more common TSHß gene mutations and stress the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal.

	Introduction

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CONGENITAL SECONDARY (CENTRAL) hypothyroidism occurs with a prevalence of approximately 1 in 28,000–45,000 newborns and can be caused by defects in the hypothalamus, pituitary, or TSH molecule (1). Isolated TSH deficiency is diagnosed in children having low serum free T₃ (fT3) and free T₄ (fT4) levels in association with low or even undetectable serum TSH concentrations and no signs of other pituitary hormone deficiencies (2). Because many newborn screening programs for hypothyroidism are based on the detection of elevated TSH levels only (3), isolated TSH deficiency is often not diagnosed in the newborn period but later when patients present with symptoms of hypothyroidism. It has been reported that isolated TSH deficiency can lead to severe growth and mental retardation (4); therefore, an early diagnosis prompting immediate initiation of thyroid hormone replacement therapy is necessary.

The TSHß gene maps to the short arm of chromosome 1 (5). It consists of a 5' untranslated exon and two exons that encode a 138-amino acid chain that is cleaved into a 118-amino acid mature protein. After cloning of the gene in 1988 (6, 7, 8), five different homozygous TSHß mutations leading to congenital secondary hypothyroidism have been identified in the coding region of the gene: G29R (9, 10), C105Vfs114X (11, 12, 13, 14, 15, 16, 17, 18), E12X (19), Q49X (20, 21, 22), and C85R (22). Of these, C105Vfs114X is the most frequently reported mutation in the TSHß gene, accounting for more than half of all published cases to date (17). Whereas the occurrence of this mutation in three German families seems to be due to a founder effect (15), other families do not share a common haplotype, suggesting that codon 105 is a mutational hotspot (17).

We previously identified a sixth homozygous TSHß mutation in a 4-month old girl of Turkish origin (23). The mutation is located in the noncoding region of the gene, affecting the donor splice site of intron 2 (IVS2 + 5 G A). This mutation results in skipping of exon 2 in vitro, predicting a new out-of-frame translational start point and the production of a nonsense protein consisting of only 25 amino acids (23).

Here we report four new cases of congenital secondary hypothyroidism due to the same intronic mutation. We describe a variable phenotype in these children and show that the mutation IVS2 + 5 G A is the result of a founder effect in three Turkish families.

	Subjects and Methods

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Laboratory testing

FT4, fT3, and cortisol were measured by competitive immunoassays using direct chemoluminescent technology (Ciba Corning; Chiron Diagnostics, Basel, Switzerland, and Bayer, Leverkusen, Germany, respectively). TSH and prolactin were measured using a two-site sandwich immunoassay with direct chemoluminescent technology (Chiron Diagnostics and Bayer, respectively). The test for GH was a chemoluminescent enzymatic immunoassay purchased from DPC Biermann (Bad Nauheim, Germany). The glycoprotein hormone -subunit concentration was measured by RIA (Nichols Institute, San Juan Capistrano, CA)

For pituitary function testing, GH, cortisol, ACTH, and TSH concentrations were measured before and 15, 30, 45, 60, and 90 min after administration of clonidine, TRH, and CRH.

Finally, we measured TSH in the serum of patient 1 also by chemiluminescence, using two monoclonal antibodies in the Elecsys automated system (Hitachi Roche Molecular Biochemicals, Mannheim, Germany). One monoclonal antibody was directed to the ß- and the other to the -subunit, thus detecting only the intact, heterodimeric TSH molecule. TSH was measured undiluted and in two dilutions with a serum that in the same assay had a very low but still detectable TSH level. The detection limit was 0.002 µU/ml (to convert to SI units multiply metric units by 1 to equal micrograms per liter), and the coefficients of variation were 10.2% at 0.037 mU/liter, 17.6% at 0.019 mU/liter, and 26.8% at 0.0095 µU/ml. TSH was also measured by an equally sensitive immunoassay (Corning/Nichols Diagnostics, San Juan Capistrano, CA). Serum TSH was measured after filtration through a Quick Spin Sephadex G50 column (Roche Molecular Biochemicals) modified to contain 1.5 ml rather than 0.8 ml.

Sequence analysis and MslI digestion

After all investigated individuals gave informed consent for participation in this study, we extracted genomic DNA from blood leukocytes using standard techniques. For the analysis of the TSHß-subunit gene, the coding exons (exons 2 and 3) including the surrounding intronic sequences were amplified by PCR as described previously (12). PCR products were purified and sequenced directly in both directions using an automated sequencing system (A377, Applied Biosystems, Weiterstadt, Germany).

PCR primers specific for exon 2 and parts of the surrounding intronic sequences amplify a 455-bp fragment from the wild-type template, which contains two MslI restriction sites. Restriction enzyme digestion with MslI was performed as recommended by the manufacturer (New England Biolabs, Schwalbach, Germany). After digestion, PCR products were electrophoresed on a 10% polyacryl amide gel, stained with ethidium bromide, and visualized under UV light.

Haplotype analysis

For haplotype analysis, we genotyped three highly polymorphic dinucleotide repeat microsatellite markers: D1S2881, D1S250, and D1S2852 (in the order from telomere to centromere) (24) as well as two single nucleotide polymorphisms (SNPs): SigP A14T and rs6330, described previously (15, 23). Physical positions of markers are given according to the draft sequence of the human genome (July 2003 freeze; www.genome.ucsc.edu). Alleles were given numbers based on the relative length of the amplified DNA fragments.

The study was approved by the respective institutional review boards and performed according to the Declaration of Helsinki.

	Case Reports

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Patient 1 (family A)

The propositus (A III-1, Fig. 1) is the first child born to healthy parents who are first-degree cousins. Delivery at 37 wk of gestation was by forceps due to facial presentation and fetal distress. Birth weight was 2750 g (10th to 25th centile) and length 46 cm (third to 10th centile). The APGAR score was 5/6/7 at 1, 5, and 10 min, respectively. Because of respiratory distress, the male baby required mechanical ventilation for 3 d. Physical examination was normal without signs of hypothyroidism. However, because of muscular hypotonia, difficulty in maintaining body temperature, and icterus neonatorum with a maximum total bilirubin of 17.2 mg/dl (to convert to SI units multiply metric units by 17.1 to equal micromoles per liter) at age 5 d, we suspected congenital hypothyroidism (CH), although the newborn TSH screening test gave a normal result (TSH < 15 µU/ml).

View larger version (27K): [in this window] [in a new window]   FIG. 1. Detection of the TSHß gene mutation IVS2 + 5 G A in families A and B. Pedigree of families A and B and polyacryl amide gels showing the results of restriction enzyme analysis. In a wild-type individual (WT), the PCR product is cut into three fragments of 255, 186, and 14 bp after digestion with MslI. The mutation IVS2 + 5 G A abolishes one of the MslI recognition sites, yielding only two fragments of 441 and 14 bp in homozygotes (A III-1, B II-1, B II-3, and B II-4), whereas heterozygous individuals have four bands (441, 255, 186, 14 bp). Note that the 14-bp band cannot be detected. MW marker, Molecular-weight marker.

To rule out multiple pituitary hormone deficiencies, we performed additional hormone tests. Serum prolactin was normal and stimulation with CRH revealed normal increases of serum cortisol and ACTH (data not shown). GH increase after clonidine stimulation was weak from 6.4 ng/ml at 0 min, maximum GH concentration 8.9 ng/ml at 45 min (to convert to SI units multiply metric units by 1.0 to equal micrograms per liter). However, normal spontaneous growth and normal serum IGF-I concentrations excluded GH deficiency (data not shown). The subnormal GH values post clonidine are best explained by hypothyroidism, which was not fully corrected at the time of testing. Cranial magnetic resonance imaging at 6 wk of age was unremarkable.

In summary, these results confirmed that the child had congenital secondary hypothyroidism due to isolated TSH deficiency (Table 1).

View this table: [in this window] [in a new window]   TABLE 1. Phenotype of the so-far-known individuals being homozygous for IVS2 + 5 GA

The propositus’ parents were clinically unaffected. Their thyroid function tests showed normal levels of TSH, fT3, and fT4 (data not shown).

Patients 2, 3, and 4 (family B)

The three children (B II-1, B II-3, B II-4, Fig. 1), two boys and a girl, were born to healthy parents who are first-degree cousins. Their mother’s height is 148 cm and their father’s height was 152 cm. A fourth child (B II-2) is healthy and euthyroid. The family lives in a remote region with difficult access to medical care.

When patients 2, 3, and 4 were born, routine TSH neonatal screening was not established in Turkey (25). All three presented later with short stature and mental retardation. At diagnosis, their respective height ranged from –6 to –8 SD scores (SDS) for age and gender. Based on low serum T₄ concentrations in combination with low to low normal TSH values (Table 1), secondary hypothyroidism was diagnosed. Additional hormone tests were performed in patient 2. The diagnosis of secondary hypothyroidism was confirmed by the absence of an increase in TSH after TRH administration (Table 1). Based on a maximum GH response to clonidine of 14.2 µg/liter, GH deficiency as well as multiple pituitary hormone deficiency (normal prolactin and cortisol levels in stimulation tests) was excluded. No pituitary pathology was seen on cranial magnetic resonance imaging.

After diagnosis, T₄ treatment was immediately started in the three siblings. This led to a dramatic growth acceleration. Indeed, growth velocity was between 11.3 and 14 cm in the first year after T₄ treatment had been initiated in the three siblings. Most interestingly, patient 4’s height passed from –8 SDS at 2 yr and 2 months to –3.3 SDS at 7 yr and 3 months of age. Patient 2, who is currently 17 yr old and whose epiphyses are still open, is expected to reach his target height.

However, there persists a moderate degree of mental retardation in the three children.

Patient 5 (family C)

Patient 5 has been previously reported in detail (23) (see Table 1).

Families A, B, and C originate from different parts of Turkey. Family B is ethnically Kurdish.

	Results

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Phenotypic variability of IVS2 + 5 G A-associated hypothyroidism

Table 1 summarizes the clinical data of the four children reported here with congenital secondary hypothyroidism and the previously reported case with an intronic TSHß gene mutation. All children have been born to consanguineous parents originating from different parts of Turkey. Parents and clinically unaffected siblings were euthyroid. Common features in the affected children included a normal newborn TSH screening (when available), reduced or absent TSH response to TRH, retarded bone age, and normally positioned thyroid gland of normal volume. All these features are consistent with the diagnosis of secondary hypothyroidism. Interestingly, serum TSH was low but still detectable in affected children and even in the low normal range in patient 4.

On the other hand, the clinical presentation and the ages at diagnosis varied widely among the affected children. The main symptoms prompting the diagnosis of hypothyroidism included muscular hypotonia in the newborn period and growth and mental retardation in older children (Table 1).

Mutation identification

Direct sequencing of the TSHß gene from genomic DNA revealed a homozygous G-to-A transition at position +5 of the intron 2 donor splice site (IVS2 + 5 G A) in patients 1–4 from families A and B. The parents were heterozygous for the mutation, and the unaffected sibling in family B was homozygous for the wild-type allele. Because the mutation abolishes a restriction site for MslI, we used this restriction enzyme to confirm homozygosity for the mutation in the affected children and genotyped other family members and control subjects. Figure 1 shows the results for families A and B. We detected the same mutation IVS2 + 5 G A in the affected child of family C (patient 5) earlier (23) and did not find it in 50 normal Turkish controls.

Haplotype analysis

To investigate whether a common ancestral chromosome accounted for the occurrence of the same mutation in the five affected children, we constructed mutation-associated haplotypes by genotyping all family members for three microsatellite and two SNP markers. Comparison of the results showed that all affected individuals (families A, B, and C) shared a common haplotype, spanning a region of 1.1 megabases that includes the TSHß gene (Fig. 2).

View larger version (32K): [in this window] [in a new window]   FIG. 2. Haplotype analysis. Parts of the pedigrees of families A, B, and C showing the haplotypes for microsatellite and SNP markers straddling the TSHß locus in relation to the mutation (Mut = IVS2 + 5 G A; small letters). The order (from telomere to centromere) and physical positions of the markers (in Mb from the short-arm telomere) are shown on the left. Haplotypes are aligned with each individual symbol. Individuals homozygous for the mutant allele are clinically affected and represented by filled symbols, whereas unaffected heterozygous individuals have one wild-type allele (half-filled symbols). Homozygous unaffected individuals have open symbols. Haplotypes associated with the mutation are represented by black bars. All different wild-type alleles are shaded differently. The alleles of family B’s deceased father were deduced from those of the other family members and are shown in brackets.

We have previously shown that the IVS2 + 5 G A mutation induces aberrant splicing in vitro leading to skipping of exon 2 and a predicted nonsense protein (23). Surprisingly, TSH was detected in the serum of patient 1 (0.23 µU/ml before treatment). This prompted us to remeasure the circulating TSH concentration in another sample (obtained after institution of hormone replacement therapy), using two different sets of two monoclonal antibodies detecting only the intact TSH molecule (see Subjects and Methods). Immunoreactive TSH was present in the patient’s serum at a concentration of 0.047 and 0.043 µU/ml (Elecsys and Corning/Nichols, respectively). Interference from endogenous antibodies to TSH was excluded by the recovery of added TSH standard to the patient’s serum. Filtration of the serum through a Sephadex G50 column, which excludes molecules greater than 20 kDa, recovered 68% of the immunoreactive TSH contained in the patient’s sample. This was almost identical with the 72% recovery of TSH from the serum of a normal subject, similarly treated, and containing 0.040 µU/ml TSH before filtration. The glycoprotein hormone -subunit concentration in the same patient’s sample was 3.6 ng/ml (normal < 0.1 ng/ml; to convert to SI units multiply metric units by 1.0 to equal micrograms per liter). More importantly, when serially diluted using a human serum with a suppressed TSH of 0.002 µU/ml, measured values were in agreement with those of the diluted authentic human TSH standard (Fig. 3).

View larger version (13K): [in this window] [in a new window]   FIG. 3. Authenticity of TSH in patient serum. Serum from patient 1 (A III-1) was serially diluted with serum from a normal individual whose TSH was partially suppressed by the administration of thyroid hormone. Measured (observed) values are plotted against the expected values calculated from TSH concentrations measured in the original samples. The concordance, in parallel with the TSH standard, indicates that the patient serum contained authentic dimeric TSH. Bars show ±1 SD of eight determinations at the indicated mean TSH concentrations. Coefficients of variation are given in Subjects and Methods.

	Discussion

Top Abstract Introduction Subjects and Methods Case Reports Results Discussion References

Of the so-far-identified TSHß gene mutations, three (G29R, C105Vfs114X, and Q49X) have each been detected in more than one unrelated family (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22). Because all these cases escape detection by TSH-based newborn screening programs, it is of clinical and public health interest to know whether these mutations are independently recurrent mutations or whether they are due to a founder effect. Indeed, recurrent mutations would argue in favor of a combined TSH-T₄ screening, whereas heterozygote detection in affected families and early thyroid function testing in newborns are the methods of choice in the case of founder mutations.

To discriminate between a de novo recurrence of the IVS2 + 5 G A mutation and a founder effect, we genotyped a dense set of microsatellite and SNP markers. Because affected children from all three families shared a common haplotype at the TSHß locus, it is very likely that these families have a common ancestor. We therefore suggest that IVS2 + 5 G A is a founder mutation in the Turkish population.

The IVS2 + 5 G A mutation results in phenotypes differing in severity: whereas the patient we described previously (23) was diagnosed when psychomotor retardation and failure to thrive became apparent at the age of 4 months, the patients reported here were diagnosed to be hypothyroid at ages 25 d to 11 yr. The severity of hypothyroidism differs also in patients with the C105Vfs114X mutation, who were brought to medical attention because of symptoms consistent with CH at ages 2 wk (13) to 5 months (12). Thus, it appears that the same mutation can lead to clinically milder or severe forms of hypothyroidism and that there is no tight genotype-phenotype correlation in these TSHß gene mutations. Whether other genetic or environmental factors affect the phenotype in TSH deficiency remains to be investigated. One explanation might be that the constitutive activity of the TSH receptor, which leads to thyroid hormone synthesis even in the absence of biologically active TSH (26), varies in different individuals.

In addition, when investigated in one patient, TSH was detectable using two assays that require an /ß TSH dimer. This is surprising because the predicted mutant transcript results in a nonsense TSH molecule that lacks the entire region required for heterodimerization with the -subunit. However, we demonstrate that the measured protein was intact TSH. This finding indicates that the mutant gene partially escapes the aberrant splicing, yielding a small amount of normal transcript and protein. The small increase in TSH following the administration of TRH in patient 1 and the detection of low amounts of TSH in the other cases (patient 4 having even a low normal TSH) support our interpretation. Nevertheless, in all cases, the amount of TSH was too low to produce a significant biological effect. As previously reported in subjects with loss-of-function mutations in the TSHß gene (18, 21), the concentration of the glycoprotein -subunit in serum was elevated.

In conclusion, we report four new cases with secondary hypothyroidism due to a homozygous splice site mutation in the TSHß gene. All children with this mutation share a common haplotype at the TSHß locus. Therefore, a founder effect could explain the recurrence of this TSHß gene mutation. We suggest that every child with congenital secondary hypothyroidism should be analyzed for TSHß gene mutations and that such children originating from Turkey should be investigated for IVS2 + 5 G A. Even a normal newborn TSH screening and the presence of low detectable TSH serum levels cannot rule out a defect in the TSH molecule.

	Acknowledgments

 
We thank all family members and probands for participating in the study, Alexandra Dumitrescu (University of Chicago) for helpful advice, and Laurence Colleaux (Institut National de la Santé et de la Recherche Médicale U393, Paris, France) for generous support.

	Footnotes

 
This work was supported in part by the University of Mainz-MAIFOR (to J.P.) and by Grants DK 00055 and 15070 from the National Institutes of Health (to S.R.). G.B. was supported by an Institut National de la Santé et de la Recherche Médicale fellowship (poste vert).

Abbreviations: CH, Congenital hypothyroidism; fT3, free T₃; fT4, free T₄; SDS, SD scores; SNP, single nucleotide polymorphism.

Received March 15, 2004.

Accepted April 29, 2004.

	References

Top Abstract Introduction Subjects and Methods Case Reports Results Discussion References

 

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