Abstract
Background & Aim: Biallelic thyroglobulin (TG) gene variants
can cause congenital hypothyroidism (CH), usually presenting
with neonatal goiter and permanent in duration. In cases where
biallelic truncating TG variants are present, serum TG levels are
undetectable, while monoallelic or biallelic missense mutations
manifest with circulating TG. Here, we present a case of transient
CH resulting from TG deficiency, stemming from compound heterozygosity
for a missense and a splice site mutation.
Case Presentation: The infant, delivered vaginally at term,
underwent regular fetal ultrasound scans, which had been normal.
Throughout the pregnancy, his mother did not take iodine-containing
vitamins. Both parents, of white descent, were healthy and
non-consanguineous. At birth, the boy weighed 3640g (0 SDS),
measured 53cm (+1.1 SDS), and had a head circumference of 36cm
(+0.6 SDS). Upon examination, a goiter and respiratory distress
were noted. Serum thyroid-stimulating hormone (TSH) levels
measured at 72h were elevated (57mIU/L; 0.7-15.2mIU/L), while
free thyroxine (fT4) levels were reduced (5.35 pmol/L;
11.0-32.0pmol/L), and TG levels were elevated (164ng/mL; 3.5-
77ng/mL). Ultrasound imaging revealed an enlarged, homogenous,
hyporeflective thyroid, with MRI documenting posterior
expansion of the thyroid. A targeted CH gene panel analysis,
including classical dyshormonogenesis genes, identified a previously
reported, likely pathogenic missense variant
NM_003235.5(TG):c.113G>A, p.(Arg38Lys) and a splice site variant
of unknown significance NM_003235.5(TG):c.3634+5G>T,
p.?. Each parent carried one of the variants. Treatment with thyroxin
was started at 37.5 μg on day 3, resulting in rapid normalization
of TSH and fT4 by day 5. TSH levels remained below 10mIU/L
during subsequent months of treatment. At 3.5 years old, thyroxine
was discontinued when the child was receiving a dose of 25μg
(= 1.9μg/kg/day). Over the next two years, normal growth in length
and weight, as well as stable thyroid function tests, were observed,
albeit with a consistently slightly enlarged thyroid.
Conclusion: We report the first case in Europe of a newborn
with compound heterozygosity for causal TG variants associated
with a transient goitrous CH. We hypothesize that in newborns
with at least one missense TG mutation, resulting in detectable TG
levels, there may be only a transient insufficiency in thyroid hormone
synthesis during the first months of life, particularly when
there is an increased thyroxine demand and/or maternal iodine
levels are low. We advocate for a reassessment of thyroid function
in newborns carrying compound heterozygous TG variants.
can cause congenital hypothyroidism (CH), usually presenting
with neonatal goiter and permanent in duration. In cases where
biallelic truncating TG variants are present, serum TG levels are
undetectable, while monoallelic or biallelic missense mutations
manifest with circulating TG. Here, we present a case of transient
CH resulting from TG deficiency, stemming from compound heterozygosity
for a missense and a splice site mutation.
Case Presentation: The infant, delivered vaginally at term,
underwent regular fetal ultrasound scans, which had been normal.
Throughout the pregnancy, his mother did not take iodine-containing
vitamins. Both parents, of white descent, were healthy and
non-consanguineous. At birth, the boy weighed 3640g (0 SDS),
measured 53cm (+1.1 SDS), and had a head circumference of 36cm
(+0.6 SDS). Upon examination, a goiter and respiratory distress
were noted. Serum thyroid-stimulating hormone (TSH) levels
measured at 72h were elevated (57mIU/L; 0.7-15.2mIU/L), while
free thyroxine (fT4) levels were reduced (5.35 pmol/L;
11.0-32.0pmol/L), and TG levels were elevated (164ng/mL; 3.5-
77ng/mL). Ultrasound imaging revealed an enlarged, homogenous,
hyporeflective thyroid, with MRI documenting posterior
expansion of the thyroid. A targeted CH gene panel analysis,
including classical dyshormonogenesis genes, identified a previously
reported, likely pathogenic missense variant
NM_003235.5(TG):c.113G>A, p.(Arg38Lys) and a splice site variant
of unknown significance NM_003235.5(TG):c.3634+5G>T,
p.?. Each parent carried one of the variants. Treatment with thyroxin
was started at 37.5 μg on day 3, resulting in rapid normalization
of TSH and fT4 by day 5. TSH levels remained below 10mIU/L
during subsequent months of treatment. At 3.5 years old, thyroxine
was discontinued when the child was receiving a dose of 25μg
(= 1.9μg/kg/day). Over the next two years, normal growth in length
and weight, as well as stable thyroid function tests, were observed,
albeit with a consistently slightly enlarged thyroid.
Conclusion: We report the first case in Europe of a newborn
with compound heterozygosity for causal TG variants associated
with a transient goitrous CH. We hypothesize that in newborns
with at least one missense TG mutation, resulting in detectable TG
levels, there may be only a transient insufficiency in thyroid hormone
synthesis during the first months of life, particularly when
there is an increased thyroxine demand and/or maternal iodine
levels are low. We advocate for a reassessment of thyroid function
in newborns carrying compound heterozygous TG variants.
| Original language | English |
|---|---|
| Pages | 205 |
| Number of pages <span style="color:red"p> <font size="1.5"> ✽ </span> </font> | 205 |
| Publication status | Published - 16 Nov 2024 |
| Event | 62nd Annual Meeting of the European Society for Pediatric Endocrinology (ESPE) - Liverpool , Liverpool, United Kingdom Duration: 16 Nov 2024 → 18 Nov 2024 https://www.eurospe.org/event/62nd-espe-meeting/ |
Conference
| Conference | 62nd Annual Meeting of the European Society for Pediatric Endocrinology (ESPE) |
|---|---|
| Country/Territory | United Kingdom |
| City | Liverpool |
| Period | 16/11/24 → 18/11/24 |
| Internet address |