Vertical Transmission of Hypopituitarism: Critical Importance of Appropriate Interpretation of Thyroid Function Tests and Levothyroxine Therapy During Pregnancy

Abstract

Background: Typically, newborns with congenital hypothyroidism are asymptomatic at birth, having been exposed to euthyroid mothers. However, hypopituitarism may be associated with central hypothyroidism, preserved fertility, and autosomal dominant inheritance, requiring increased attention to thyroid management during pregnancy. Patient Findings: A woman with a history of growth hormone deficiency and central hypothyroidism gave birth to a term male neonate appropriate for gestational age. Due to low thyrotropin (TSH) in the second trimester, the levothyroxine dose was decreased by the obstetrician, and free T4 was low throughout the latter half of pregnancy. The neonatal laboratory evaluation showed central hypothyroidism with a low T4 of 2.1 lg/dL (4.5-11.5) and an inappropriately normal TSH of 0.98 uIU/mL (0.5-4.5); undetectable growth hormone, IGF-I, and IGFBP3; a normal cortisol level; and a normal gonadotropin surge. After initiation of levothyroxine in the first week, both tone and feeding tolerance improved. However, the patient was found to have hearing loss, gross motor delay, and speech delay. Summary: In this report, we review a case of vertical transmission of a dominant negative POU1F1 mutation in which fetal abnormalities due to the hypothyroxinemic state during gestation may have been exacerbated by a decrease in the mother's levothyroxine dose based on a low TSH in early gestation. Both mother and fetus were unable to synthesize sufficient thyroid hormone, which may be responsible for the patient's clinical presentation. Conclusion: This case underscores several important points in the management of women with hypopituitarism. First, it is important that patients and clinicians are both aware of the differences in etiology, as well as appropriate screening and treatment, of primary versus central hypothyroidism. Second, it is necessary to monitor the thyroid hormone status closely during pregnancy to prevent fetal sequelae of maternal hypothyroidism. Third, genetic screening of patients with combined pituitary hormone deficiency is necessary, so that prenatal genetic counseling may be an option for expecting parents.

Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era

“…The POU1F1 missense p.R271W acts as a dominant inhibitor of transcription resulting in CPHD (142). A few p.R271W cases exhibit cognitive impairment or hearing impairment, which may be due to hypothyroidism during pregnancy when the mother carries the same variant (143). Approximately half of the p.R271W variants are fully penetrant.…”

Central Hypothyroidism in Children

“…They may develop gestational hypothyroxinemia, which can be missed by routine TSH evaluation of the thyroid axis during pregnancy. This 'unnoticed' low T 4 in the mother can aggravate the hypothyroid state of the fetus who may well have inherited the genetic defect from the mother, overall resulting in short supplies of thyroid hormone to support normal fetal brain development, leading to severe CH with the consequences of gross motor and speech delay [90].…”

Genetic variation in thyroid folliculogenesis influences susceptibility to hypothyroidism-induced hearing impairment

“…Women with hypothyroidism need increased thyroid hormone replacement to meet the increased demands of pregnancy. Failure to manage this properly can have lasting effects on the child’s hearing, which has been observed in the case of POU1F1 p.R271W mutation (Cuevas et al 2005; Haddow et al 1999; Lavado-Autric et al 2003; Pine-Twaddell et al 2013). Our study has identified candidate genes and pathways that could contribute to human variation in susceptibility to hypothyroidism-induced hearing impairment and neurological deficits.…”