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Defective thyroglobulin synthesis causing fetal goiter: intra- uterine
diagnosis and intra-amniotic treatment with L-T4
was reported by Tomimori and collaborators (Sào Paulo,
Brazil). This group presents a case of fetal goiter diagnosed in a 27-y-old
pregnant female referred to the Hospital das Clinicas at 26 weeks of gestation.
A large homogeneous mass was previously identified in the anterior portion
of the fetal neck, by echography, suggestive of fetal goiter. The mother
previously gave birth (6 years ago) to a child with neonatal goitrous hypothyroidism,
subsequently treated with progressive higher doses of L-T4
to a daily dose of L-T4 (100 µg q.d.). The goiter
reduced in size but it remained present. The mother is a second cousin
of the father and there is another child (a nephew) with congenital goitrous
hypothyroidism. Maternal serum thyroid function tests were normal with
a borderline low free T4 (0.8 ng/dL). There were no
anti-TPO, or anti-Tg and TRAb autoantibodies. A cordocentesis was performed
at 27 weeks confirming fetal hypothyroidism with TSH of 61.5 µU/mL.
Total T3: 34 ng/dL, Total T4:
3.0 µg/dL and serum Tg: 1.3 µg/mL. As the eldest sibling has
also a goiter and a very low serum Tg level (<0.5 ng/mL) a provisional
diagnosis of congenital goiter with defective Tg synthesis and secretion
was made. At 28 weeks gestation an intra-amniotic injection of L-Thyroxine
(400 µg) was given. The fetal goiter initially with 12.5 cm of circumference
(estimated weight: 9.2 g) decreased to 10.8 cm after 4 weeks. This case
and previously reported cases demonstrate that congenital goitrous hypothyroidism
can be treated anti-natally treatment with L-T4, following
diagnosis.
A Pit-1 gene mutation was described in a patient with growth retardation by Martinelli and co-authors (Curitiba, PR, Brazil). They describe a case of a 38-year-old woman, born to onsanguineous parents being the only one affected of the couple's 12 children, presenting with growth failure (very short stature) and hypothyroidism. Growth failure was noted from early infancy but hypothyroidism was only apparent from adolescence. She had almost undetectable GH and PRL levels and an inappropriate low TSH for very low levels of T3 and T4, at baseline and after TRH stimulation. The remaining pituitary functions were normal. The pituitary gland was hypoplastic at MRI. Amplification of genomic DNA and subsequent sequencing (PCR) of the fifth and sixth exons of the Pit-1 gene ("hot spot") allowed identification of a point mutation in exon 6, monoallelic, a T to G substitution that changed amino acid 271 from Arg to Trp. This was the first description of such a mutation in Brazil. It is suggested that the diagnosis may be overlooked in some children with complete GH deficiency because thyrotrophy function may be maintained for a while. Molecular analysis of mutated thyroid peroxidase gene in patients with congenital goitrous hypothyroidism was reported by Rego and co-authors (from Sào Paulo, Brazil). One of the most frequently occurring hereditary inborn errors in thyroid hormonogenesis is the iodide organification defect (IOD) resulting from inactive mutated thyroid peroxidase (TPO). The TPO genes of 14 patients with IOD were screened for mutations in seven unrelated families. Twenty six relatives were also studied. Northern blot of the mRNA extracted from thyroid tissues showed the expression of a normal size TPO mRNA. Denaturing gradient gel electrophoresis (DGGE) of the PCR amplified genomic DNA fragments identified the presence of mutations in exon 8 in three families and in exon 14 in two kindreds. The mutation in exon 8 resulted from a GGCC duplication at position 1277 in both TPO alleles, conducting to a frameshift with a termination signal in exon 9. TPO activity was not detectable. No signal of an immunoreactive TPO protein was observed at immunohistochemical studies. It is possible that some alternatively spliced TPO mRNA missing part of exons 8 and 9 may be expressed. The mutation in exon 14 resulted from an insertion of one extra single nucleotide (C) in a stretch of seven Cs (position 2505-2511). The insertion causes a frameshift and runs in a termination signal after 72 aa in exon 16. TPO derived from this allele will be truncated missing the membrane spanning region replaced by a piece of nonsense protein. Immunohistochemical studies indicated a faint signal of immunoreactive protein. The fact that these mutations cosegregate with IOD in unrelated families strongly indicates that they are the cause of inactive TPO in the affected patients. Mutations in exon 8 will markedly affect the functional part of the translated mutated protein generating a severely affected phenotype. By contrast, mutations in exon 14 will probably lead to some TPO activity "in vivo" that will provide a limited synthesis of T3 and T4, resulting in a less affected phenotype. |
