Congenital Hypothyroidism Due to Thyroid Agenesis

AUTHORS:
Arooj Fatima Chaudhry¹ • Halina Aniol, MD² • Cameron Joseph Shegos¹

AFFILIATIONS:
¹Saint James School of Medicine, Anguilla
²AMITA Health Resurrection Medical Center Chicago, Illinois

CITATION:
Chaudhry AF, Aniol H, Shegos CJ. Congenital hypothyroidism due to thyroid agenesis. Consultant. 2020;60(10):25-27. doi:10.25270/con.2020.05.00011
Received January 21, 2020. Accepted April 30, 2020.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Halina Aniol, MD, Chicago Pediatric and Neonatology Center, 7447 W Talcott Ave, Ste 561, Chicago, IL 60631 (chicagopediatric@gmail.com)

A 10-day old neonate presented to the clinic with her parents, who expressed concern over the girl’s worsening yellow skin discoloration, poor weight gain, and elevated bilirubin levels that had been detected at birth prior to hospital discharge.

History. The patient’s medical history was significant for neonatal jaundice with elevated total bilirubin levels, as well as a benign grade 2/6 systolic murmur at the fourth intercostal space. The pregnancy had been uncomplicated, and the patient had been born at term at 39 weeks of gestation via spontaneous vaginal delivery. Her birth weight was 3.2 kg. The mother had tested positive for group B streptococcus vaginitis, which then had been treated appropriately with antibiotics prenatally. Hepatitis B vaccination had been given soon after birth, and the patient and mother had been sent home on the child’s second day of life, with mild jaundice noted.

The parents reported that the patient had been breastfeeding approximately 20 minutes per breast every 2 hours without any complications and had been taking vitamin D supplementation, 400 IU daily. Wet diapers were changed 8 times a day and stooled diapers a few times a day. They reported that the neonate sleeps the entirety of the day, waking only to feed. The patients had no known allergies. The family history was noncontributory.

Physical examination. At presentation, the patient’s vital signs were stable, with a blood pressure of 71/39 mm Hg, a pulse of 120 beats/min, a temperature of 36.7 °C, and respiratory rate of 36 breaths/min. Head circumference was 34 cm (75th percentile), length was 51 cm (75th percentile), and weight was 3.1 kg (25th percentile).

Red reflexes were noted in both eyes, with normal sclera. The anterior and posterior fontanelles were noted to be soft, open, and flat, but no other cranial deformities or facial anomalies were present. The neck was supple with no masses. Upon auscultation of the heart, a systolic murmur could be heard in the fourth intercostal space, left of the sternum. The lungs were clear to auscultation, with no wheezing, rales, stridor, or signs of respiratory distress. The abdomen was soft, with no masses, and there was a patent umbilical stump. The genitalia appeared normal. The patient had normal range of motion of the extremities. Barlow and Ortolani maneuvers were negative for hip dysplasia. The girl’s skin was warm to the touch and jaundiced (Figure). The rest of the physical examination findings were unremarkable.

Figure. The patient’s skin showing jaundice at presentation.

Diagnostic tests. Thyroid screening tests collected within 24 hours after birth disclosed a thyrotropin level greater than 621.6 mIU/L (reference range, 0.72-11 mIU/L) and a total thyroxine (T₄) level of 2.2 µg/dL (reference range, 5.41-17.0 µg/dL). Additionally, upon discharge the total bilirubin level was 6.1 mg/dL (reference range, 0.3-0.9 mg/dL), and the direct bilirubin level was 0.48 mg/dL (reference range, 0.03-0.18 mg/dL). At 10 days of age, the total bilirubin level was 13.4 mg/dL, and the direct bilirubin level was 0.77 mg/dL.

Results of follow-up endocrinology screening tests were as follows: thyrotropin, 789.8 mIU/L; total triiodothyronine (T₃), 0.9 pg/mL (reference range, 1.95-6.04 pg/mL); and T₄, 0.9 µg/dL. Technetium Tc 99m pertechnetate scans revealed that no thyroid was present.

Treatment. The patient was administered 37.5 µg levothyroxine orally (the standard dose for patients younger than 3 months of age is 10-15 µg/kg/d), and the parents were instructed to administer half of a 75-µg tablet (37.5 µg) by mouth daily, crushed with water or milk, on an empty stomach. A treatment plan was discussed with the neonate’s family and put in place for appropriate follow-up visits. The treatment plan included educating the patient’s family on lifelong administration of levothyroxine, increasing doses of which would be required with the patient’s increasing age. Frequent monitoring with laboratory tests was also discussed, as were the consequences of a lack of adherence to the medication regimen, such as lower neurocognitive function and hypothyroidism. After her condition had stabilized, the patient was sent home with a follow-up appointment to be scheduled for within the next 3 months.

Discussion. Congenital hypothyroidism (CH) is a neonatal condition in which there is insufficient production of thyroid hormones. CH is the most commonly detected endocrine abnormality on newborn screening, with an incidence of approximately 1 reported case in every 2000 to 4000 births.¹ CH can occur as a result of iodine deficiency, an anatomic defect of the thyroid, or an inborn error of thyroid metabolism.²

Manifestations of CH can be very subtle. When apparent, symptoms include difficulty in feeding, sleep disturbances, decreased activity, prolonged jaundice, constipation, mottled skin, patent posterior fontanelles, distended abdomen with umbilical hernia, a protruding tongue, delayed skeletal maturation for gestational age, and most concerning, restricted neurocognitive development.²

Although approximately 85% of CH cases are sporadic,³ some cases are linked with the autosomal recessive inheritance pattern—that is, both parents carry a copy of the mutated gene, but they themselves do not show signs of the disease. When CH occurs because of mutations in the thyroid stimulating hormone receptor gene (TSHR), the dual oxidase 2 gene (DUOX2), or the paired box 8 gene (PAX8), it is associated with an autosomal dominant inheritance pattern.⁴ Other mutations may arise de novo throughout embryonic development.

The introduction of CH screening at birth has allowed early disease detection and therapeutic management by measuring the levels of thyrotropin and T₄ to assess organ function. Screening for thyrotropin is more specific in the diagnosis of CH, with a sensitivity of 97.5% and specificity of 99%, whereas T₄ is more sensitive in detecting rare hypothalamic pituitary hypothyroidism.⁵ The three possible screening strategies for CH are primary thyrotropin measurement with backup T₄ determination in infants with high thyrotropin levels; primary T₄ measurement with backup thyrotropin assessment in infants with low T₄ levels; and simultaneous measurement of T₄ and thyrotropin levels.⁶ Each method has its own limitations; however, in order to insure optimal screening, initial T₄ levels backed with thyrotropin readings detect not only primary hypothyroidism, but also thyroxine-binding globulin deficiency and central hypothyroidism, whereas the other two methods do not.⁶ Ideally, blood samples should be drawn 3 to 5 days after birth to minimize false-positive results due to the physiological rise in the thyrotropin level at 1 to 2 days of life, or the delayed surge in premature infants with very low body weight.⁵ It is important to note, however, that early discharge of postpartum mothers in most medical centers has shifted the collection timeline forward to just after 24 hours following birth, resulting in an increase in false-positive thyrotropin measurements from a ratio of 3 to 1 to 5 to 1.⁵

Newborn screening of thyrotropin and T₄ levels helps to establish a defect in thyroid hormone production, but the underlying etiology still remains unknown. Therefore, other diagnostic studies, including thyroid ultrasonography (TUS), thyroid scintigraphy (TS), serum thyroglobulin measurement, and measurement of urine iodine, can be used to determine the cause of CH.⁷ Typically, TUS is the initial choice, given its limited preparation needs and having no radiation burden; however, patients presenting with significantly elevated thyrotropin levels, such as children hospitalized for confirmatory blood testing, are candidates for TS with either sodium iodide I 123 or technetium Tc 99m pertechnetate.⁸ TS provides functional imaging and aids in the diagnosis thyroid dysgenesis or thyroid aplasia.^7,8 Hyperbilirubinemia (direct or indirect) is an isolated finding that has long been associated with CH, but the underlying case has not been identified.⁹

Replacement therapy with levothyroxine (the synthetic form of T₄) is the mainstay treatment for CH.^2-9 Although T₃ is the biologically active form of the hormone, the brain primarily uses the deiodinated form of T₃ converted from T₄.⁷ Therefore, directly replacing T₃ will have little effect on stabilizing normal neurodevelopment.⁷ Combination treatment with both T₄ and T₃ has not shown any extra benefit than T₄ alone in terms of neurodevelopment.¹⁰ In order to preserve normal neurodevelopment, treatment must be initiated within the first 2 weeks of life.¹⁰ A week’s delay in normalizing T₄ levels can lead to a lower IQ scores.⁷ Additionally, initiating high-dose therapy greater than 10 µg/kg has shown to improve cognitive development and IQ scores.¹¹ Therefore, both time and dose are critically important when initiating treatment in CH. The therapeutic target goals as outlined by the American Academy of Pediatrics include a serum FT₄ level and total T₄ level kept in the upper range of normal during the first year of life, and a thyrotropin level kept under 5 mIU/L.¹² With regard to hyperbilirubinemia and jaundice, normalizing thyrotropin and T₄ levels will correct abnormal bilirubin levels; however, direct association between the two has yet to be identified.⁹

The typical levothyroxine dose for infants younger than 3 months of age is 10-15 µg/kg/d.¹³ Levothyroxine is mainly absorbed in the small intestines; however, factors including gastric pH and food can impair drug absorption.¹³ When levothyroxine is taken with food, its bioavailability drops from 79% to 64%.¹⁴ Additionally, foods including soybeans and grapefruit can further limit drug concentrations and should be avoided.¹³ Traditionally, liquid formulations and compounding recipes of levothyroxine have been avoided in the United States for the management of CH due to concerns about stable drug concentrations during a critical time in brain development.¹⁵ For this reason, in order to ensure the best and stable therapeutic effects of levothyroxine, patients with CH should take a tablet-form, crushed in breast milk, non–soy-based formula, or water on an empty stomach approximately 30 to 60 minutes before a meal.

In an effort to increase prompt diagnosis of CH, many states have implemented screening. It is important to keep in mind that every state follows different screening protocols from one of the three screening strategies described above. Relevant to our case, Illinois screens for the initial thyrotropin level, backed with T₄ when the thyrotropin level is abnormal.¹⁶ Illinois began screening for CH in 1979, and as a result of this screening program, 60 to 70 new cases are diagnosed annually in the state.¹⁶ Efficient screening is able to catch and slow the progression of lifelong adverse effects, which include intellectual disability and an increased risk of cretinism, which is characterized by physical and neurocognitive disability due to deficiency of iodine or of thyroid hormones.¹⁶

Despite the development of newborn screening methods for CH, 8% to 10% of cases are still undiagnosed.¹⁷ For this reason, it is crucial for parents and clinicians to be alert for any possible signs and symptoms of hypothyroidism. Similar to our patient’s case, various reports have found an association of CH with other malformations such as heart defects.²

Management of CH involves adherence with daily medication regimens and regular follow-up visits with medical specialists as appropriate.¹⁶ Newborn screening is crucially important in early disease detection and in the prevention of lifelong neurocognitive deficiencies.

REFERENCES:

1. McGrath N, Hawkes CP, McDonnell CM, et al. Incidence of congenital hypothyroidism over 37 years in Ireland. Pediatrics. 2018;142(4):e20181199. doi:10.1542/peds.2018-1199
2. Daniel MS, Postellon DC. Congenital hypothyroidism. Medscape. Updated October 14, 2017. Accessed May 7, 2020. https://emedicine.medscape.com/article/919758-overview
3. Castanet M, Lyonnet S, Bonaïti-Pellié C, Polak M, Czernichow P, Léger J. Familial forms of thyroid dysgenesis among infants with congenital hypothyroidism. N Engl J Med. 2000;343(6):441‐442. doi:10.1056/NEJM200008103430614
4. Congenital hypothyroidism. Genetics Home Reference. Reviewed September 2015. Accessed May 7, 2020. https://ghr.nlm.nih.gov/condition/congenital-hypothyroidism
5. Büyükgebiz A. Newborn screening for congenital hypothyroidism. J Clin Res Pediatr Endocrinol. 2013;5(suppl 1):8‐12. doi:10.4274/jcrpe.845
6. Smith L. Updated AAP guidelines on newborn screening and therapy for congenital hypothyroidism. Am Fam Physician. 2007;76(3):439-444. Accessed May 7, 2020. https://www.aafp.org/afp/2007/0801/p439.html
7. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010;5:17. doi:10.1186/1750-1172-5-17
8. Volkan-Salancı B, Kıratlı PÖ. Nuclear medicine in thyroid diseases in pediatric and adolescent patients. Mol Imaging Radionucl Ther. 2015;24(2):47‐59. doi:10.4274/mirt.76476
9. Ahmad N, Irfan A, Al Saedi SA. Congenital hypothyroidism: screening, diagnosis, management, and outcome. J Clin Neonatol. 2017;6(2):64-70. doi:10.4103/jcn.JCN_5_17
10. Mantri R, Bavdekar SB, Save SU. Congenital hypothyroidism: an unusual combination of biochemical abnormalities. Case Rep Pediatr. 2016;2016:2678578. doi:10.1155/2016/2678578
11. Aleksander PE, Brückner-Spieler M, Stoehr AM, et al. Mean high-dose l-thyroxine treatment is efficient and safe to achieve a normal IQ in young adult patients with congenital hypothyroidism. J Clin Endocrinol Metab. 2018;103(4):1459‐1469. doi:10.1210/jc.2017-01937
12. Selva KA, Mandel SH, Rien L, et al. Initial treatment dose of L-thyroxine in congenital hypothyroidism. J Pediatr. 2002;141(6):786‐792. doi:10.1067/mpd.2002.128887
13. Colucci P, Yue CS, Ducharme M, Benvenga S. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Eur Endocrinol. 2013;9(1):40‐47. doi:10.17925/EE.2013.09.01.40
14. Wenzel KW, Kirschsieper HE. Aspects of the absorption of oral L-thyroxine in normal man. Metabolism. 1977;26(1):1‐8. doi:10.1016/0026-0495(77)90121-4
15. Wassner AJ, Brown RS. Hypothyroidism in the newborn period. Curr Opin Endocrinol Diabetes Obes. 2013;20(5):449‐454. doi:10.1097/01.med.0000433063.78799.c2
16. Congenital hypothyroidism: information for physicians and other health care professionals. Illinois Department of Public Health. Published October 2017. Accessed May 7, 2020. http://www.dph.illinois.gov/sites/default/files/publications/Congenital%20Hypothyroidism%202012.pdf
17. Fisher DA. Effectiveness of newborn screening programs for congenital hypothyroidism: prevalence of missed cases. Pediatr Clin North Am. 1987;34(4):881‐890. doi:10.1016/s0031-3955(16)36292-7