Exp Clin Endocrinol Diabetes 2018; 126(02): 85-90
DOI: 10.1055/s-0043-119875
© Georg Thieme Verlag KG Stuttgart · New York

Novel Mutations in the NKX2.1 gene and the PAX8 gene in a Boy with Brain-Lung-Thyroid Syndrome

Pia Hermanns
1   Department of Pediatrics, Johannes Gutenberg University Medical School, Mainz, Germany
Małgorzata Kumorowicz-Czoch
2   Department of Pediatric and Adolescent Endocrinology, Chair of Pediatrics, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Cracow, Poland
3   Private Pediatrics and Pediatric Endocrinology Practise, Cracow, Poland
Helmut Grasberger
4   Department of Medicine, University of Michigan, Ann Arbor, MI, USA
Samuel Refetoff
5   Departments of Medicine, Departments of Medicine and Pediatrics, The University of Chicago, Chicago, IL, USA
6   Departments of Medicine and Genetics, The University of Chicago, Chicago, IL, USA
Joachim Pohlenz
1   Department of Pediatrics, Johannes Gutenberg University Medical School, Mainz, Germany
› Author Affiliations
Further Information

Publication History

received     11 July 2017
first decision 07 September 2017

accepted      15 September 2017

Publication Date:
27 September 2017 (online)


Objective To elucidate the molecular mechanism which causes thyroid dysgenesis (TD) in a boy with brain-lung-thyroid syndrome.

Design, patients, measurements We describe a patient with TD, respiratory disease and cerebral palsy who is heterozygous for mutations in two different genes, the PAX8 (p.E234K) and the NKX2.1 (p.A329GfsX108). In vitro studies were performed to functionally characterize these mutations. Congenital hypothyroidism (CH) was identified by neonatal screening associated with a hypoplastic thyroid gland. Postpartum he developed a brain-lung-thyroid syndrome with severe respiratory failure, symptomatic epilepsy and a considerable psychomotor retardation. The DNA-binding capability and the transcriptional activity of the two mutated transcription factors were investigated in vitro.

Results The NKX2.1 mutation did not show any transcriptional activity and had almost no DNA-binding. The PAX8 mutation was normally located to the nucleus and showed a normal transactivation and a normal binding to the known downstream targets.

Conclusions The molecular defect explaining the phenotype of brain-lung-thyroid syndrome was identified. To what extent the PAX8 mutation contributes to the phenotype needs to be further investigated. We recommend to screen patients with CH and TD for mutations in all known TD candidate genes.