NKX2-1-conditioned disorder — «brain–lung–thyroid» syndrome: results of a multicenter study

Introduction. Brain–lung–thyroid syndrome (BLTS, choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction) is an autosomal dominant disorder associated with mutations of the NKX2-1 gene. A triad of symptoms from three organs (brain, lungs, thyroid gland) is manifested in 50% of patients, in other cases there is an incomplete phenotype of the disease. The most common manifestations are neurological. The aim of the study was to provide genetic, clinical, laboratory, and instrumental characteristics in BLTS patients with a clinical and morphological assessment of the phenotype.

Materials and methods. Ten children from 9 families with identified mutations in the NKX2-1 gene were observed. Methods used: genealogical, Sanger sequencing, clinical and morphological assessment of the phenotype, examination of thyroid hormone levels, CT, MRI of the brain, CT of the chest, lung biopsy.

Results. The article presents the results of molecular genetic analysis, family history, age of manifestation and diagnosis. 9 out of 10 children had damage to the central nervous system, thyroid gland, lungs, and one child had a combination of neurological pathology and hypothyroidism. Neurological pathology was represented by benign hereditary chorea (2 children), delayed motor development (8), muscular hypotension (7), ataxia (5), choreoathetosis (1), clonuses (1), seizures (1), hyperkinesis (3); respiratory — respiratory distress syndrome (RDS) of newborns (6), chronic respiratory failure (5), interstitial lung disease (6), bronchial asthma (1), chronic pneumonitis of infants (1), bronchiectasis (1). There are presented changes in computed tomograms of the lungs and during preforming CT, MRI of the brain. Typical developmental microanomalia included a protruding forehead, a wide tip of the nose, elongated narrow palpebral fissure, deep-set eyes, hypertelorism of the eyes, large rotated low-lying auricles, conical fingers.

Conclusion. A combination of congenital hypothyroidism, neonatal RDS, heart disease, neurological disorders (hypotension, ataxia, delayed motor development, chorea), craniofacial dysmorphia is the basis for a molecular genetic examination to exclude BLTS.

Contribution:
Strelnikova V.A. — text writing, material collection and data processing, review of publications on the topic;
Ovsyannikov D.Yu. — patient management, text writing, material collection and data processing, concept, text editing;
Kondakova O.B. — concept, writing of the text, clinical and morphological assessment of the phenotype of patients, review of publications on the topic;
Kuzenkova L.M. — text editing, patient management, assessment of the neurological status of patients;
Savostyanov K.V. — analysis of the results of molecular genetic diagnostics, concept, text editing;
Gitinov S.A. — patient management, material collection and data processing;
Girutskaya I.V. — patient management, material collection and data processing;
Gorev V.V. — patient consultation, the concept of the article;
Zhestkova M.A. — patient consultation, material collection and data processing, review of publications on the topic;
Kravchenko N.E. — patient consultation, material collection and data processing;
Mamaeva E.A. — evaluation of neuroimaging results, text writing, material collection and data processing;
Mezhinsky S.S. — patient management, material collection and data processing;
Nikolishin A.N. — patient consultation, material collection and data processing;
Orlov A.V. — patient management, material collection and data processing;
Pushkov A.A. — conducting molecular genetic diagnostics, analysis and processing of the results of molecular genetic diagnostics;
Sudakova O.V. — patient management, material collection and data processing;
Suetina O.A. — patient consultation, material collection and data processing;
Tsverava A.G. — patient management, material collection and data processing;
Afukov I.I. — organization of medical care for patients;
Cherkasova S.V. — patient management, text writing, material collection and data processing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare the absence of obvious and potential conflicts of interest in connection with the publication of this article.

Received: February 16, 2024
Accepted: March 15, 2024
Published: April 27, 2023

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