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Brain-lung-thyroid syndrome(CAHTP)

MedGen UID:
369694
Concept ID:
C1970269
Disease or Syndrome
Synonyms: CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION; Choreoathetosis, hypothyroidism, and neonatal respiratory distress
SNOMED CT: Choreoathetosis with congenital hypothyroidism and neonatal respiratory distress syndrome (719098007); Brain lung thyroid syndrome (719098007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): NKX2-1 (14q13.3)
 
Monarch Initiative: MONDO:0012593
OMIM®: 610978
Orphanet: ORPHA209905

Disease characteristics

Excerpted from the GeneReview: NKX2-1-Related Disorders
NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark feature of NKX2-1-related disorders, may or may not be associated with pulmonary disease or congenital hypothyroidism. Age of onset of chorea varies from early infancy (most commonly) to late childhood or adolescence and may progress into the second decade, after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older individuals. The risk for pulmonary carcinoma is increased in young adults with NKX2-1-related disorders. Thyroid dysfunction, occurring as a result of thyroid dysgenesis, can present as congenital or compensated hypothyroidism. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had brain and thyroid involvement only, and 13% had chorea only. [from GeneReviews]
Authors:
Neepa Jayant Patel  |  Joseph Jankovic   view full author information

Additional descriptions

From OMIM
Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) is an autosomal dominant disorder characterized by onset of this triad of features in infancy. Movement abnormalities begin with muscular hypotonia followed by the development of chorea, athetosis, dystonia, ataxia, and dysarthria. Some patients show neonatal respiratory distress and developmental delay. The phenotype is variable both between and within families (summary by Thorwarth et al., 2014).  http://www.omim.org/entry/610978
From MedlinePlus Genetics
Thyroid problems are the next most common feature of brain-lung-thyroid syndrome. The thyroid gland makes hormones that help regulate a wide variety of critical body functions, including growth, brain development, and the rate of chemical reactions in the body (metabolism). Many affected individuals have reduced thyroid function from birth (congenital hypothyroidism), resulting in lower-than-normal levels of thyroid hormones. Others have a milder condition called compensated or subclinical hypothyroidism, in which thyroid hormone levels are within the normal range, even though the thyroid is not functioning properly. While most people with brain-lung-thyroid syndrome have a normal-sized thyroid, the gland is reduced in size (hypoplastic) or absent (aplastic) in some affected individuals. Although a shortage of thyroid hormones can cause intellectual disability and other neurological problems, it is unclear whether such issues in individuals with brain-lung-thyroid syndrome are due to hypothyroidism or to the brain abnormalities related to the condition.

Nearly everyone with brain-lung-thyroid syndrome has brain-related movement abnormalities. Benign hereditary chorea is the most common feature of the syndrome. This feature is associated with involuntary jerking movements (chorea) of the face, torso, and limbs; writhing movements (athetosis) of the limbs; and other movement problems. Individuals with brain-lung-thyroid syndrome can have other abnormalities, such as difficulty coordinating movements (ataxia), muscle twitches (myoclonus), and involuntary muscle contractions that result in twisting and repetitive movements (dystonia). The movement problems typically begin around age 1, although they can begin in early infancy or later in life, and are often preceded by weak muscle tone (hypotonia). They can delay the development of walking. The movement problems usually remain stable and can improve over time. Some affected individuals also have learning difficulties or intellectual disability.

Lung problems are common in brain-lung-thyroid syndrome. Some affected newborns have respiratory distress syndrome, which causes extreme difficulty breathing and can be life-threatening. Other affected individuals develop widespread lung damage (interstitial lung disease) or scarring in the lungs (pulmonary fibrosis), both of which can also lead to breathing problems. Recurrent lung infections, which can be life-threatening, also occur in people with brain-lung-thyroid syndrome. People with brain-lung-thyroid syndrome have a higher risk of developing lung cancer than do people in the general population.

Brain-lung-thyroid syndrome is a group of conditions that affect the brain, lungs, and thyroid gland (a butterfly-shaped gland in the lower neck). Brain-lung-thyroid syndrome historically included problems with all three organs, although the designation now encompasses a combination of brain, lung, and thyroid problems. About 50 percent of affected individuals have problems with all three organs, about 30 percent have brain and thyroid problems, and about 10 percent have brain and lung problems. The brain alone is affected in 10 to 20 percent of people with the condition. Such cases are sometimes called isolated benign hereditary chorea.  https://medlineplus.gov/genetics/condition/brain-lung-thyroid-syndrome

Clinical features

From HPO
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Cholesteatoma
MedGen UID:
3043
Concept ID:
C0008373
Disease or Syndrome
Cholesteatoma is a benign but potentially destructive growth consisting of keratinizing epithelium located in the middle ear and/or mastoid process. In cholesteatoma, a skin cyst grows into the middle ear and mastoid. The cyst is not cancerous but can erode tissue and cause destruction of the ear.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Sleep abnormality
MedGen UID:
52372
Concept ID:
C0037317
Finding
An abnormal pattern in the quality, quantity, or characteristics of sleep.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Broad-based gait
MedGen UID:
167799
Concept ID:
C0856863
Finding
An abnormal gait pattern in which persons stand and walk with their feet spaced widely apart. This is often a component of cerebellar ataxia.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Gonadotropin deficiency
MedGen UID:
1632671
Concept ID:
C4552011
Disease or Syndrome
A reduced ability to secrete gonadotropins, which are protein hormones secreted by gonadotrope cells of the anterior pituitary gland, including the hormones follitropin (FSH) and luteinizing hormone (LH).
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Atelectasis
MedGen UID:
13946
Concept ID:
C0004144
Pathologic Function
Collapse of part of a lung associated with absence of inflation (air) of that part.
Cough
MedGen UID:
41325
Concept ID:
C0010200
Sign or Symptom
A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation.
Pulmonary fibrosis
MedGen UID:
11028
Concept ID:
C0034069
Disease or Syndrome
Replacement of normal lung tissues by fibroblasts and collagen.
Crackles
MedGen UID:
11118
Concept ID:
C0034642
Finding
Crackles are discontinuous, explosive, and nonmusical adventitious lung sounds normally heard in inspiration and sometimes during expiration. Crackles are usually classified as fine and coarse crackles based on their duration, loudness, pitch, timing in the respiratory cycle, and relationship to coughing and changing body position.
Wheezing
MedGen UID:
21917
Concept ID:
C0043144
Sign or Symptom
A high-pitched whistling sound associated with labored breathing.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Pulmonary infiltrates
MedGen UID:
116009
Concept ID:
C0235896
Finding
A finding indicating the presence of an inflammatory or neoplastic cellular infiltrate in the lung parenchyma.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Hypoxemia
MedGen UID:
152145
Concept ID:
C0700292
Finding
An abnormally low level of blood oxygen.
Restrictive ventilatory defect
MedGen UID:
478856
Concept ID:
C3277226
Finding
A functional defect characterized by reduced total lung capacity (TLC) not associated with abnormalities of expiratory airflow or airway resistance. Spirometrically, a restrictive defect is defined as FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) less than 80 per cent. Restrictive lung disease may be caused by alterations in lung parenchyma or because of a disease of the pleura, chest wall, or neuromuscular apparatus.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Oxygen desaturation on exertion
MedGen UID:
894519
Concept ID:
C4280731
Finding
Oxygen saturation less than 95% on exertion or arterial partial pressure of oxygen falling by more than 1kPa.
Neonatal respiratory distress
MedGen UID:
924182
Concept ID:
C4281993
Finding
Respiratory difficulty as newborn.
Cystic pattern on pulmonary HRCT
MedGen UID:
1374982
Concept ID:
C4476752
Finding
On pulmonary high-resolution computed tomography, the cystic pattern is composed by well-defined, round and circumscribed air-containing parenchymal spaces with a well-defined wall and interface with normal lung. The wall of the cysts may be uniform or varied in thickness, but usually is thin (less than 2 mm) and occurs without associated emphysema.
Parenchymal consolidation
MedGen UID:
1687071
Concept ID:
C5139174
Finding
Consolidation refers to an exudate or other product of disease that replaces alveolar air, rendering the lung solid (as in infective pneumonia).
Elevated bronchoalveolar lavage fluid lymphocyte proportion
MedGen UID:
1713125
Concept ID:
C5397968
Finding
Usually, Lymphoycytes make up less than 15% of all cells found in the bronchoalveloar lavage fluid. This elevated cell proportion can be induced by virus or drugs, or is associated with specific diseases.
Elevated bronchoalveolar lavage fluid neutrophil proportion
MedGen UID:
1710230
Concept ID:
C5397969
Finding
Usually, Neutrophils make up less than 3% of all cells found in the broncho-alveloar lavage fluid. In children, standard value of neutrophils is higher depending on their age (children under the age of 5 show a maximum value of 10%). This elevated cell proportion is a sign for acute and chronic infections (HP:0012387, HP:0006538) and can be associated to specific diseases.
Ground-glass opacification
MedGen UID:
1779663
Concept ID:
C5539411
Finding
On chest radiographs, ground-glass opacity appears as an area of hazy increased lung opacity, usually extensive, within which margins of pulmonary vessels may be indistinct. On CT scans, it appears as hazy increased opacity of lung, with preservation of bronchial and vascular margins. It is caused by partial filling of airspaces, interstitial thickening (due to fluid, cells, and/or fibrosis), partial collapse of alveoli, increased capillary blood volume, or a combination of these, the common factor being the partial displacement of air. Ground-glass opacity is less opaque than consolidation, in which bronchovascular margins are obscured.
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
Asthma is characterized by increased responsiveness of the tracheobronchial tree to multiple stimuli, leading to narrowing of the air passages with resultant dyspnea, cough, and wheezing.
Congenital hypothyroidism
MedGen UID:
41344
Concept ID:
C0010308
Disease or Syndrome
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.\n\nSigns and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.\n\nCongenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.\n\nCongenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Compensated hypothyroidism
MedGen UID:
473011
Concept ID:
C0271790
Disease or Syndrome
Condition associated with a raised serum concentration of thyroid stimulating hormone (TSH) but a normal serum free thyroxine (FT4).
Elevated circulating thyroid-stimulating hormone concentration
MedGen UID:
108325
Concept ID:
C0586553
Finding
Increased concentration of thyroid-stimulating hormone (TSH) in the blood circulation.
Decreased response to growth hormone stimulation test
MedGen UID:
1784655
Concept ID:
C5539399
Finding
Insufficient responses to growth hormone (GH) provocation tests. GH deficiency is defined as a serum peak GH concentration less than 10 ng/mL on provocation with a combination of at least two separate stimulation tests.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVBrain-lung-thyroid syndrome
Follow this link to review classifications for Brain-lung-thyroid syndrome in Orphanet.

Professional guidelines

PubMed

Nou-Fontanet L, Nguyen QTR, Bachoud-Levi AC, Reinhard C; Chorea & Huntington Disease Group ERN-RND, Ortigoza-Escobar JD
Eur J Paediatr Neurol 2024 Jul;51:110-117. Epub 2024 Jun 19 doi: 10.1016/j.ejpn.2024.06.007. PMID: 38917695

Recent clinical studies

Etiology

Moya CM, Zaballos MA, Garzón L, Luna C, Simón R, Yaffe MB, Gallego E, Santisteban P, Moreno JC
J Clin Endocrinol Metab 2018 Mar 1;103(3):839-852. doi: 10.1210/jc.2017-01241. PMID: 29294041
Nattes E, Lejeune S, Carsin A, Borie R, Gibertini I, Balinotti J, Nathan N, Marchand-Adam S, Thumerelle C, Fauroux B, Bosdure E, Houdouin V, Delestrain C, Louha M, Couderc R, De Becdelievre A, Fanen P, Funalot B, Crestani B, Deschildre A, Dubus JC, Epaud R
Respir Med 2017 Aug;129:16-23. Epub 2017 May 26 doi: 10.1016/j.rmed.2017.05.014. PMID: 28732825
Peall KJ, Lumsden D, Kneen R, Madhu R, Peake D, Gibbon F, Lewis H, Hedderly T, Meyer E, Robb SA, Lynch B, King MD, Lin JP, Morris HR, Jungbluth H, Kurian MA
Dev Med Child Neurol 2014 Jul;56(7):642-8. Epub 2013 Oct 31 doi: 10.1111/dmcn.12323. PMID: 24171694
Carré A, Szinnai G, Castanet M, Sura-Trueba S, Tron E, Broutin-L'Hermite I, Barat P, Goizet C, Lacombe D, Moutard ML, Raybaud C, Raynaud-Ravni C, Romana S, Ythier H, Léger J, Polak M
Hum Mol Genet 2009 Jun 15;18(12):2266-76. Epub 2009 Mar 31 doi: 10.1093/hmg/ddp162. PMID: 19336474

Diagnosis

Magrinelli F, Rocca C, Simone R, Zenezini Chiozzi R, Jaunmuktane Z, Mencacci NE, Tinazzi M, Jayawant S, Nemeth AH, Demidov G, Houlden H, Bhatia KP
Mov Disord 2023 Feb;38(2):347-353. Epub 2022 Nov 23 doi: 10.1002/mds.29280. PMID: 36420574
Liang R, Ou S, Ding Y, Liu C
Zhong Nan Da Xue Xue Bao Yi Xue Ban 2022 Mar 28;47(3):396-400. doi: 10.11817/j.issn.1672-7347.2022.200998. PMID: 35545334Free PMC Article
Ediger K, Hicks A, Siriwardena K, Joynt C
BMJ Case Rep 2021 Mar 31;14(3) doi: 10.1136/bcr-2020-241032. PMID: 33789861Free PMC Article
Nattes E, Lejeune S, Carsin A, Borie R, Gibertini I, Balinotti J, Nathan N, Marchand-Adam S, Thumerelle C, Fauroux B, Bosdure E, Houdouin V, Delestrain C, Louha M, Couderc R, De Becdelievre A, Fanen P, Funalot B, Crestani B, Deschildre A, Dubus JC, Epaud R
Respir Med 2017 Aug;129:16-23. Epub 2017 May 26 doi: 10.1016/j.rmed.2017.05.014. PMID: 28732825
Uematsu M, Haginoya K, Kikuchi A, Nakayama T, Kakisaka Y, Numata Y, Kobayashi T, Hino-Fukuyo N, Fujiwara I, Kure S
J Neurol Sci 2012 Apr 15;315(1-2):77-81. Epub 2011 Dec 12 doi: 10.1016/j.jns.2011.11.025. PMID: 22166853

Therapy

Nattes E, Lejeune S, Carsin A, Borie R, Gibertini I, Balinotti J, Nathan N, Marchand-Adam S, Thumerelle C, Fauroux B, Bosdure E, Houdouin V, Delestrain C, Louha M, Couderc R, De Becdelievre A, Fanen P, Funalot B, Crestani B, Deschildre A, Dubus JC, Epaud R
Respir Med 2017 Aug;129:16-23. Epub 2017 May 26 doi: 10.1016/j.rmed.2017.05.014. PMID: 28732825

Prognosis

Soreze Y, Nathan N, Jegard J, Hervieux E, Clermidi P, Sileo C, Louvrier C, Legendre M, Coulomb L'Herminé A
Neonatology 2024;121(1):133-136. Epub 2023 Nov 30 doi: 10.1159/000534076. PMID: 38035569
Ediger K, Hicks A, Siriwardena K, Joynt C
BMJ Case Rep 2021 Mar 31;14(3) doi: 10.1136/bcr-2020-241032. PMID: 33789861Free PMC Article
LeMoine BD, Browne LP, Liptzin DR, Deterding RR, Galambos C, Weinman JP
Pediatr Radiol 2019 Jun;49(7):869-875. Epub 2019 Mar 30 doi: 10.1007/s00247-019-04388-3. PMID: 30927038
Moya CM, Zaballos MA, Garzón L, Luna C, Simón R, Yaffe MB, Gallego E, Santisteban P, Moreno JC
J Clin Endocrinol Metab 2018 Mar 1;103(3):839-852. doi: 10.1210/jc.2017-01241. PMID: 29294041
Nattes E, Lejeune S, Carsin A, Borie R, Gibertini I, Balinotti J, Nathan N, Marchand-Adam S, Thumerelle C, Fauroux B, Bosdure E, Houdouin V, Delestrain C, Louha M, Couderc R, De Becdelievre A, Fanen P, Funalot B, Crestani B, Deschildre A, Dubus JC, Epaud R
Respir Med 2017 Aug;129:16-23. Epub 2017 May 26 doi: 10.1016/j.rmed.2017.05.014. PMID: 28732825

Clinical prediction guides

Skwara J, Nowicki M, Sharif L, Milanowski Ł, Dulski J, Elert-Dobkowska E, Skrzypek K, Hoffman-Zacharska D, Koziorowski D, Sławek J
J Neural Transm (Vienna) 2024 Sep;131(9):1013-1024. Epub 2024 Jun 25 doi: 10.1007/s00702-024-02800-3. PMID: 38916623Free PMC Article
Soreze Y, Nathan N, Jegard J, Hervieux E, Clermidi P, Sileo C, Louvrier C, Legendre M, Coulomb L'Herminé A
Neonatology 2024;121(1):133-136. Epub 2023 Nov 30 doi: 10.1159/000534076. PMID: 38035569
Invernizzi F, Zorzi G, Legati A, Coppola G, D'Adamo P, Nardocci N, Garavaglia B, Ghezzi D
Eur J Med Genet 2018 Oct;61(10):581-584. Epub 2018 Apr 3 doi: 10.1016/j.ejmg.2018.03.011. PMID: 29621620
Shetty VB, Kiraly-Borri C, Lamont P, Bikker H, Choong CS
J Pediatr Endocrinol Metab 2014 Mar;27(3-4):373-8. doi: 10.1515/jpem-2013-0109. PMID: 24129101
Uematsu M, Haginoya K, Kikuchi A, Nakayama T, Kakisaka Y, Numata Y, Kobayashi T, Hino-Fukuyo N, Fujiwara I, Kure S
J Neurol Sci 2012 Apr 15;315(1-2):77-81. Epub 2011 Dec 12 doi: 10.1016/j.jns.2011.11.025. PMID: 22166853

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