Transient congenital hypothyroidism - too short to be transient.

Congenital hypothyroidism (CH) occurs due to thyroid dysgenesis, thyroid ectopy, and dyshormonogenesis. A proportion of CH is transient which might be due to iodine deficiency/excess or maternal antibody-mediated. Certain forms of dyshormonogenetic defects may cause transient hypothyroidism. Here is a report of a neonate with overt clinical and biochemical hypothyroidism, who on evaluation was found to have dyshormonogenesis with a homozygous mutation in dual oxidase 2 (DUOX2) gene. During infancy, she became euthyroid. Severe in utero deficiency of thyroid hormone, very short duration of hypothyroidism and first-reported mutation of the DUOX2 gene in the Indian subcontinent were interesting features in this infant.

Introduction

Congenital hypothyroidism (CH) is estimated to occur in approximately 1 out of 700-2,500 newborns in India.[1] Transient hypothyroidism can occur due to transplacental passage of the maternal thyrotropin (TSH) receptor-blocking antibodies in the autoimmune thyroid disease, neonatal exposure of iodine in the peripartum period, iodine deficiency, maternal antithyroid drug usage, and due to large hemangiomas. Usually, dyshormonogenetic goiter is permanent except for a few genetic defects such as dual oxidase 2 (DUOX2)/dual oxidase maturation factor 2 (DUOXA2). We present an unusual case of this genetic abnormality.

Case Presentation

A neonate was referred to our hospital on day 5 of life for evaluation of CH. Her mother did not have goiter/thyroid disorders and was not on any medications antenatally. She was delivered at term by natural labor and cried immediately after birth (birth weight was 3.15 kg). Routine screening of TSH in the cord blood revealed a value of 36 mIU/L (normal <20), and on retesting venous blood on day 4 of life, TSH was 44 mIU/L (normal <20). Total T4 was 6 mcg/dL (normal 10-16) and total T3 was 60 ng/dL (120-220). The neonatal screen for hearing was normal. Her total bilirubin was 14 mg/dL on day 3 of life for which she received phototherapy for a day following which she was referred for management of hypothyroidism.

On examination at our hospital, her length was 52 cm, weight was 3.2 kg, and the head circumference was of 35 cm. She was having coarse facial features with mild macroglossia and a small umbilical hernia. Ultrasound of the thyroid showed normally placed but mildly enlarged gland. 99mTc pertechnate scan revealed uniform increased uptake in both lobes of the thyroid of 7.8% (normal 1-4%) [Figure 1]. There was a possibility of dyshormonogenesis in the baby and a perchlorate discharge test was required to establish the diagnosis. The perchlorate discharge test was not done in the baby because of non-availability of perchlorate in such a short notice (levothyroxine was started the very next day). Since the possibility of dyshormonogenesis was present in the baby, the parents were counseled for genetic testing. There were no members of the extended family who had any thyroid abnormality. The baby was started on levothyroxine replacement at a dose of 10 mcg/kg/day initially (37.5 mcg for 5 days and 25 mcg for 2 days a week).

Figure 1

Increased radionuclide uptake in thyroid bed

The next-generation sequencing panel included genes of SLC5A5 (NIS), SCL26A4 (PDS), TG, TPO, DUOX2, DUOXA2, and IYD. The coverage was 93.94% for the DUOX2 gene. The results showed a homozygous missense mutation of exon 15 in chromosome 15 of DUOX2 gene—NM_014080.4: c.1709A>T; p.Gln570Leu.

The parents did not consent to confirmation of variants by Sanger sequencing in the baby or testing themselves and their other son for the genetic abnormality. Subsequently, after 1 month, macroglossia and umbilical hernia got reduced in the baby. TSH was suppressed [Table 1], and the dose of levothyroxine was reduced to 5 mcg/kg/day (12.5 mcg for 3 days and 25 mcg for 4 days a week). Her bilirubin was normal. After 2 months (3 months of age), TSH continued to be suppressed [Table 1] and the dose was reduced further to 2 mcg/kg/day (12.5 mcg daily). At 5 months of age, levothyroxine was stopped and at her last follow up at 9 months, the baby was euthyroid without any signs of psychomotor delay or stunting (Crawling forward, sits with her hands free; transfers objects from hand-to-hand; non-specific babbling, responds to name; displays separation anxiety) [Table 1].

Table 1

Evolution of dose of levothyroxine

Age in months	Weight in kg	Length in cm	Head circumference in cm	TSH in mIU/L	Dose of levothyroxine in mcg/kg/day
0.25	3	52	35	44	10
1	4.2			<0.014	5
3	6.1	62	39.5	0.01	2
5	7.1			0.2	stopped
7	8	68		2.3	nil
9	8.8	71	45	1.8	nil

Discussion

Dual oxidase isoenzymes (1 and 2) are calcium-dependent Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases located in the apical membrane of thyrocytes involved in generating hydrogen peroxide (H2O2) for oxidation and organification of iodine into the thyroglobulin. They require maturation factors (DUOXA1 and DUOXA2) for the generation of H2O2. DUOX2 defect-causing CH was first reported in 2002, and since then, an enormous number of cases have been detected.[2] The prevalence of DUOX2-induced CH varies by geographical areas: 35% in Korea, 30-45% in Italy, 43% in Japan, 44% in the Netherlands and 29-83% in China.[3] In two different previous studies from South India, one looking at 45 CH babies and the other at 42 children with childhood hypothyroidism, DUOX2 mutations were not reported.[45] To the best of our knowledge, this seems to be the first report of homozygous mutation of DUOX2 from India.

Data on the natural history of DUOX2 mutations has been accumulating of late. In a cohort of 25 children with biallelic DUOX2 mutations, for a majority of patients, levothyroxine could be reduced by 2-4 years of age and stopped by median 8 years of age. Subsequently, during puberty, none of those with transient CH required thyroxine supplementation.[6] This is the largest cohort of CH due to DUOX2 defect in the world as of date and is from the Japanese ethnicity. The reason for the transient nature of the genetic defect is hypothesized as follows.

In the absence of DUOX2, DUOX1 is expressed one-fifth of that of DUOX2 and is able to generate H2O2. As the requirement of thyroxine reduces with age (from 10-15 mcg/kg/day in infancy to 1.6 mcg/kg/day in adulthood), DUOX1 per se is able to cope with the demand in due course of time.[6] Another factor playing a role in the natural history of DUOX2 is the iodine content of the soil/food. High iodine content in food is considered to render a milder phenotype/transient CH. Low prevalence of iodine deficiency disorders in the district of Ernakulam in Kerala[7] might have also contributed to transient CH in our neonate.

The mutation noted in the proband (p.Gln570Leu) has been reported already.[89] In a study from the UK, this particular mutation occurred frequently in South Asians.[9] With the background allele frequency of 0.01, it was suggested that this may contribute to CH in a wider Asian population. With widespread screening for CH and genetic analysis of many of them, in the future, there might be increased detection from India.

In conclusion, this is a case report of transient CH due to DUOX2 mutation having a severe in utero thyroid hormone deficiency with hypothyroidism lasting only a few months postnatally and recovering spontaneously.

Declaration of patient consent

The author confirms that written consent was obtained from the parents of the baby.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.