We have investigated the genetic mechanisms leading to hypothyroidism in a child
with CH associated with bilateral choanal atresia, cleft palate, and spiky hair. Direct
sequencing of coding exon of TTF-2 gene from the patient revealed a novel homozygous
missense mutation (c.304C>T; p.R102C) affecting the forkhead DNA binding domain of
TTF-2. Both parents were heterozygous for the mutation but euthyroid with no congenital
anomalies, and the mutation was absent in 100 control chromosomes. The arginine residue
at codon 102 is a highly conserved residue in the forkhead domain family of proteins, and
mutations of the equivalent amino acid in other forkhead proteins [e.g. FOXC1 (R127H),
FOXC2 (R121H), and FOXP2 (R553H)] have been described. Consonant with this, in
vitro studies (performed in University of Cambridge, UK) indicated that the mutation was
highly deleterious, with the p.R102C mutant protein exhibiting negligible DNA binding
and transcriptional activity (Appendix 1). Interestingly, thyroid ultrasonography and CT
examination of the proband indicated thyroid tissue in a eutopic location, although
biochemical measurements and radioisotope scanning show that it is nonfunctional.
Our case represents the third recorded example of a loss-of-function mutation in the
human TTF-2 gene, with the two previously described mutations (A65V and S57N) also
being located within its forkhead, DNA-binding domain (Clifton-Bligh et al., 1998;
Castanet et al., 2002). The A65V mutation was identified in a nonconsanguineous Welsh
family with two male siblings exhibiting CH, cleft palate, choanal atresia, and bifid
epiglottis together with spiky hair, whereas the S57N mutation was reported in two male
siblings of a consanguineous Tunisian kindred exhibiting CH and cleft palate alone. With
both of these TTF-2 mutation cases, 123I scanning and ultrasonography showed complete
athyreosis (Clifton-Bligh et al., 1998; Castanet et al., 2002). In contrast, although the third
case we report here shares some of these features, including severe CH and extrathyroidal
anomalies, imaging indicates the presence of thyroid tissue in a eutopic location. However,
severe biochemical hypothyroidism at birth and also following T4 withdrawal, together
I uptake and very low serum thyroglobulin levels, indicates that the function
of such glandular tissue is markedly compromised.
Mouse models support a critical role for TTF-2 in thyroid and palate organogenesis.
Expression of TTF-2, together with the transcription factors TTF-1 and PAX-8, has been
demonstrated from the onset of formation of the thyroid primordium (embryonic d 8–8.5),
continuing throughout the migration of the thyroid diverticulum (Kimura et al., 1996;
Zannini et a., 1997; Mansouri et al., 1998). TTF-2 is also expressed in craniopharyngeal
ectoderm involved in palate formation and Rathke’s pouch in mouse embryos (Zannini et
a., 1997) and in the outer follicular hair sheath in humans (Sequeira et al., 2003). Targeted
disruption of the murine Titf2 locus results in homozygous null mice with cleft palate and
either complete thyroid agenesis or ectopic sublingual gland development (De Felice et al.,
1998). The two murine phenotypes were seen with equal frequency and may reflect
different developmental manifestations of the disorder. Thus, similar to the murine context,
our human proband illustrates that thyroid morphogenesis can occur in the absence of
TTF-2, albeit with migration of thyroid gland tissue to a eutopic location.
Mutations in TTF-2 and a TTF-1/NKX2.1 mutation (Krude et al., 2002) are the only
known genetic causes of thyroid agenesis. However, involvement of TTF-2 accounts for
only a small minority of CH cases, being a strong consideration only in those with cleft
palate, which is an infrequent association of CH (Olivieri et al., 2002). This case illustrates
further phenotypic heterogeneity associated with human TTF-2 mutations and suggests that
defects in this gene should also be considered in cases of syndromic CH with cleft palate,
but not necessarily complete thyroid agenesis. This variable phenotype may reflect
differential effects of TTF-2 mutations on downstream target genes required for normal
human thyroid organogenesis, migration, and differentiation, and the further identification
of such genes may elucidate these mechanisms and provide novel genetic candidates for
CH and cleft palate.
6.3.1. Mutation Analysis of Butyrylcholinesterase (BChE) Gene
The same CH patient with the TTF2 mutation was referred to our lab a year later
since she experienced prolonged neuromuscular block after an operation and had a marked
decrease in BChE activity compared with her parents and brother. Because BChE is known
to hydrolyze the anesthetic reagents we analyzed its two common variants in the patient
that can be responsible for reduced plasma cholinesterase and prolonged paralysis.
Restriction analysis revealed that the patient, her consanguineous parents and unaffected
brother were negative for these variants. However, the whole BChE gene should be
screened for variants that might be responsible for the plasma cholinesterase deficiency.
To our knowledge this patient was the first case with CH showing the prolonged
neuromuscular block. Patients with CH are candidates for multiple operations due to
midline defects (e.g. cleft palate and choanal atresia) and their responses to muscle
relaxants are not known. Therefore, careful preoperative evaluation and molecular genetic
testing should be performed.
7. CONCLUSION AND FUTURE PROSPECTS
To our knowledge, this is the first study on genetic basis of Rett Syndrome in our
population. Our findings suggest that gene dosage can be a mechanism that leads to this
devastating genetic/epigenetic disease. We have shown the duplication of exons that are
known to be the expressed. As a future prospect, the breakpoints of the duplications,
whether they are tandem repeats, and their effect on MECP2 expression can be
investigated in these patients.
The findings of methylation analyses of hHR23A and hHR23B prompted us to
speculate that the cytosine methylation of putative promoter region may down regulate
transcription of hHR23A and hHR23B genes in tumor tissues. Additional studies can be
performed to investigate the expression pattern of methylated hHR23 genes in fresh or
frozen tumor tissues. Methylation status of hHR23 genes may be tested as a candidate
marker in breast carcinomas upon correlation of promoter methylation with the loss of
expression. Additionally, the body fluids could be investigated for the presence of aberrant
promoter hypermethylation. If the results were concordant between tumor and circulating
DNA methylation, the screening of hHR23 methylation may enhance early detection of
The identification of TTF2 mutation in a CH patient with thyroid tissue suggested
that further phenotypic heterogeneity is associated with human TTF-2 mutations and the
CH patients with thyroid tissue should also be screened for the mutations within the TTF2
gene. Further mutations should be identified and investigated to unravel the functions of
TTF2 in thyroid organogenesis.
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