Nkx2-1-Related Disorders

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2021-01-18

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Summary

Clinical characteristics.

NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses 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 persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only.

Diagnosis/testing.

The diagnosis of an NKX2-1-related disorder is established in a proband by identification of a heterozygous pathogenic variant in NKX2-1.

Management.

Treatment of manifestations: Tetrabenazine in low doses reduces chorea. Levodopa has been reported to improve chorea in four children with substantial improvement in gait symptoms (falls); it can be considered as second line therapy for the treatment of chorea and as first line therapy in children with gait impairment. Pulmonary manifestations are treated in the usual manner for asthma and interstitial lung disease; hypothyroidism is treated with thyroid replacement therapy.

Surveillance:

For individuals with no or minimal neurologic manifestations: Annual neurologic evaluation.
For individuals with no or minimal pulmonary manifestations, starting at the time of diagnosis: Annual pulmonary function tests and chest x-ray or CT scan of the chest to screen for pulmonary malignancy.
For individuals with no or minimal manifestations of thyroid disease, starting at the time of diagnosis: Annual serum thyroid-stimulating hormone and physical examination (including thyroid palpation) to screen for thyroid cancer.

Evaluation of relatives at risk:

In a family in which the NKX2-1 pathogenic variant has been identified, testing of at-risk relatives prenatally or as soon as possible after birth allows early identification of infants at high risk for congenital hypothyroidism and pulmonary disease to permit early diagnosis and management, particularly to prevent the neurodevelopmental consequences of untreated hypothyroidism.
In a family with benign hereditary chorea or brain-lung-thyroid syndrome in which a pathogenic variant has not been identified, assessing thyroid function of at-risk infants as soon as possible after birth allows early identification and management of congenital hypothyroidism.

Pregnancy management: Prior to pregnancy or early in gestation, it is recommended that a woman work with her physician to determine the safety for the fetus of the use of any medication she is taking for chorea.

Genetic counseling.

NKX2-1-related disorders are inherited in an autosomal dominant manner. Most individuals with an NKX2-1-related disorder have an affected parent. Each child of an individual with an NKX2-1-related disorder has a 50% chance of inheriting the pathogenic variant. Once the NKX2-1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk is a possible option.

Diagnosis

NKX2-1-related disorders include: benign hereditary chorea (BHC); and choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome).

No formal clinical diagnostic criteria have been published for NKX2-1-related disorders.

Suggestive Findings

NKX2-1-related disorders should be suspected in individuals with EITHER of the following:

Childhood-onset non-progressive chorea that may or may not be associated with congenital hypothyroidism or respiratory distress syndrome
A history of congenital hypothyroidism and (later) development of neurologic findings and/or respiratory dysfunction

Establishing the Diagnosis

The diagnosis of an NKX2-1-related disorder is established in a proband with suggestive findings and identification of a heterozygous pathogenic variant in NKX2-1 by molecular genetic testing [Inzelberg et al 2011] (see Table 1).

Molecular genetic testing approaches can include single-gene testing, chromosomal microarray analysis (CMA), use of a multigene panel, and more comprehensive genomic testing:

Single-gene testing. Sequence analysis of NKX2-1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
Chromosomal microarray analysis (CMA) – if not already performed – may be obtained to detect genome-wide deletions/duplications (including NKX2-1). See Table 1, footnote 9.
A multigene panel that includes NKX2-1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing, whole mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes NKX2-1) fails to confirm a diagnosis in an individual with features of an NKX2-1-related disorder. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in NKX2-1-Related Disorders

Gene ¹	Method	Proportion of Probands/Families with a Pathogenic Variant ² Detectable by Method
Gene ¹	Method	Probands	Families
NKX2-1	Sequence analysis ³	81% (100/122)	76% (55/72)
	Deletion/duplication analysis ⁴	14% (17/122)	24% (13/72) ^5, 6, 7
	CMA ⁷	3% (4/122) ⁶	6% (4/72)

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: Partial-, whole-, and contiguous-gene (some including PAX9) deletions have been reported [Devos et al 2006]; see Table A, HGMD.
6.: Probands with complete or partial brain-lung-thyroid syndrome [Teissier et al 2012]
7.: One individual with findings similar to the NKX2-1-related disorders (choreiform movements, neonatal respiratory distress, and hypothyroidism) had a 3.5-Mb contiguous-gene deletion (14q13.3) adjacent to but not interrupting NKX2-1 [Barnett et al 2012]. The authors emphasize the consideration of CMA analysis in probands with features of this condition in whom sequence analysis or NKX2-1-targeted copy number analysis do not reveal a pathogenic variant. See Molecular Genetics.

Clinical Characteristics

Clinical Description

The clinical manifestations of NKX2-1-related disorders range from benign hereditary chorea (BHC) to congenital hypothyroidism to neonatal respiratory distress or any combination of brain, thyroid, and lung development. When all three organ systems are involved, this is also known as "brain-lung-thyroid syndrome" (see Figure 1).

Figure 1.

Phenotypic spectrum of NKX2-1-related disorders NKX2-1-related disorders may manifest as abnormalities in a single organ system or as any combination of brain, thyroid, and lung involvement. "Brain-lung-thyroid syndrome" refers to involvement of all three (more...)

In a review of 46 affected individuals Carré et al [2009] found that 50% had the full brain-lung-thyroid syndrome, 30% had involvement of only brain and thyroid, and 13% had isolated chorea only.

The prevalence of chorea in the NKX2-1-related disorders is unknown. In one study all 28 affected individuals from 13 families with a heterozygous NKX2-1 pathogenic variant had chorea and hypotonia [Gras et al 2012]. However, in a retrospective study of 21 individuals with an NKX2-1-related disorder presenting with pulmonary dysfunction, at least two unrelated individuals and three members of one family did not manifest neurologic symptoms [Hamvas et al 2013].

Neurologic

Chorea, an involuntary, random, irregular, jerk-like, and continuous movement, is a classic early finding in BHC and other NKX2-1-related disorders. The onset of chorea generally occurs in one of the following time periods:

Early infancy
Approximately age one year (most common) [Kleiner-Fisman et al 2003]
Late childhood or adolescence

Chorea progresses into the second decade, after which it remains static or may even spontaneously remit [Kleiner-Fisman et al 2003].

Chorea typically involves all body regions (i.e., face, tongue, neck, trunk, and limbs) and may be associated with motor and gait delay, possibly secondary to the choreiform movements. The movements are jerk-like and move randomly from one body part to another; they often worsen with stress, and may disappear with sleep. Children with BHC may fall frequently and are often described as clumsy [Kleiner-Fisman et al 2003]. Although affected children may be delayed in walking, persistent gait impairment is rare [McMichael et al 2013]. Rosati et al [2015] describes two unrelated children presenting with spontaneous falls without loss of consciousness preceding the development of chorea.

Other neurologic manifestations

Intention tremor [Pincus & Chutorian 1967]
Dysarthria [Schady & Meara 1988]
Facial apraxia [Suchowersky et al 1986]
Sensorineural hearing loss [Damasio et al 1977]
Hypotonia, incoordination, and motor developmental delay [Doyle et al 2004, Veneziano et al 2014]
Myoclonus, dystonia, and/or ataxia [Breedveld et al 2002, Peall et al 2014, de Gusmao et al 2015]

In one report, two sibs initially diagnosed with ataxic dyskinetic cerebral palsy were later found to have an NKX2-1 pathogenic variant [McMichael et al 2013].

Neuropsychiatric symptoms including attention deficit and hyperactivity have been reported [Gras et al 2012]. Although psychiatric features are rare in this group of disorders, Glik et al [2008] described an individual with an NKX2-1 pathogenic variant and psychosis diagnosed as schizophrenia. Subsequently, Salvatore et al [2010] reported an individual with postpartum psychosis. Additionally, Peall et al [2014] reported a single case of severe obsessive-compulsive disorder.

Neuroimaging has in rare cases identified structural brain abnormalities including abnormal sella turcica [Krude et al 2002], agenesis of the corpus callosum [Carré et al 2009], and cavum septum pellucidum and microcephaly [Iwatani et al 2000]. Hypoplastic pallidum and lack of differentiation of medial and lateral components was reported in a single individual, and bilateral pallidal signal hyperintensities on T₂-weighted MRI images were described in another individual [Kleiner-Fisman & Lang 2007]. An expanding pituitary cyst was reported in two related individuals a novel NKX2-1 pathogenic variant [Veneziano et al 2014].

Single-photon emission computed tomography (ECD-SPECT) has demonstrated reduced cerebral blood flow to bilateral basal ganglia, more specifically to the caudate [Uematsu et al 2012].

Subtle abnormalities in presynaptic dopamine transporter function utilizing positron emission tomography (PET) imaging have been reported [Konishi et al 2013].

Neuropathology. Autopsies of two individuals with a genetically confirmed NKX2-1-related disorder did not identify gross or microscopic abnormalities of the brain, but rather reduced numbers of striatal and neocortical interneurons consistent with a defect in neuronal migration, supporting the theory that these disorders are related to abnormalities in brain development rather than neurodegeneration [Kleiner-Fisman et al 2003].

Pulmonary

Pulmonary dysfunction is the second most common manifestation of NKX2-1-related disorders. In a meta-analysis of 29 published cases of NKX2-1-related disorders, up to 49% (61/124) had pulmonary manifestations of varying severity [Gras et al 2012].

Clinical presentation and course vary.

Respiratory distress syndrome with or without pulmonary hypertension is most common in the neonatal period.
Neuroendocrine cell hyperplasia, a distinct form of childhood interstitial lung disease (ILD), can be present in infancy; it typically improves with age [Young et al 2013].
ILD can occur between ages four months and seven years.
Pulmonary fibrosis can occur in older individuals [Hamvas et al 2013].

The highest risk for respiratory distress is in the neonatal period. Affected infants often require mechanical ventilation [Carré et al 2009]. Although usually not fatal, NKX2-1-related disorders resulted in death from respiratory failure in three infants in the immediate postnatal period [Maquet et al 2009, Kleinlein et al 2011, Gillett et al 2013].

As a result of the pulmonary involvement, individuals with an NKX2-1-related disorder are at increased risk for recurrent pulmonary infections and chronic interstitial lung disease [Carré et al 2009, Inzelberg et al 2011] because of abnormal surfactant production [Peca et al 2011]. Respiratory failure (which most commonly occurs in neonates) has been reported in adults [Maquet et al 2009, Kleinlein et al 2011, Gillett et al 2013].

In one restrospective study of individuals with known pulmonary dysfuction and an NKX2-1 pathogenic variant, histologic abnormalities included interstitial widening and pneumocyte hyperplasia, desquamative interstitial pneumonia, accumulation of foamy alveolar macrophages, and pulmonary alveolar proteinosis [Hamvas et al 2013].

Pulmonary carcinoma. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1 related disorder [Fernandez et al 2001, Willemsen et al 2005, Glik et al 2008]. The role of somatic NKX2-1 expression is being investigated in pulmonary adenocarcinoma [Chen et al 2015] and non-small cell lung cancer [Inoue et al 2015]. However, the influence of germline variants in individuals with NKX2-1-related genetic disorders has not been established in these malignancies.

Thyroid

Thyroid dysfunction, which results from dysmorphogenesis, can present as congenital hypothyroidism, reduced or absent production of thyroid hormone, or compensated hypothyroidism (i.e., low to normal thyroid hormone production with elevated thyroid-stimulating hormone) [Moya et al 2006, Montanelli & Tonacchera 2010, Gras et al 2012]. Of note, thyroid dysmorphogenesis can manifest structurally as thyroid hypoplasia or hemi-agenesis (11/31) and complete absence of the thyroid (3/31) [Carré et al 2009].

Thyroid dysfunction varies between individuals with an NKX2-1-related disorder and within families with multiple affected individuals. In a meta-analysis of 46 individuals reported with an NKX2-1-related disorder, 40 had documented overt or subclinical hypothyroidism; only six had normal thyroid function [Carré et al 2009].

Currently most industrialized nations conduct newborn screening for hypothyroidism including testing levels of thyroid-stimulating hormone with or without testing levels of thyroxine (T₄). With immediate implementation of thyroid replacement therapy in the neonatal period, the neurodevelopmental complications associated specifically with congenital hypothyroidism can be avoided (see Management).

One should consider the diagnosis of NKX2-1-related disorders in a child born with congenital hypothyroidism with or without other neurologic or pulmonary manifestations, as the clinical manifestations can vary even within the same family.

Papillary thyroid cancer. In a Japanese study a weak association between sporadic papillary thyroid cancer and pathogenic variants in NKX2-1 was observed. However, it is well known that the Japanese are at increased risk for papillary thyroid cancer compared to other populations as a result of increased dietary consumption of iodine and radiation exposure [Matsuse et al 2011]. Ngan et al [2009] reported a significant association with multinodular goiter and papillary thyroid cancer in Chinese persons with germline NKX2-1 pathogenic variants [Ngan et al 2009]. Furthermore, preliminary evidence suggests that individuals with a germline NKX2-1 pathogenic variant may have a more aggressive clinical course [Ngan et al 2009, Jendrzejewski et al 2016].

Prognosis and Progression

Life expectancy in persons with NKX2-1-related disorders is normal [Fernandez et al 2001].

A retrospective study describing 28 persons with 13 novel NKX2-1 pathogenic variants over a mean duration of 24.5 years reports a homogeneous progression of neurologic symptoms. Hypotonia is present in the first year of life with or without delays in motor milestones and early chorea. Chorea improves up until puberty through early adulthood. Chorea is mild and stabilizes in adulthood and in some cases may resolve in adulthood [Gras et al 2012].

There is limited information on long-term follow up of pulmonary and thyroid manifestations of this disorder. Symptom progression is rare and may even improve in adulthood [Gras et al 2012]. Those with lung involvement are at risk for respiratory failure in early infancy and recurrent infections and asthma throughout life. Compensated hypothyroidism is well tolerated by persons with an NKX2-1-related disorder.

Rare Findings Reported

Leukemia was reported in two individuals from two different families who were heterozygous for an NKX2-1 germline pathogenic variant [Kleiner-Fisman et al 2003, Asmus et al 2005].

Other findings in NKX2-1-related disorders described in individual cases:

Hypodontia [Devos et al 2006, Guala et al 2008]
Genitourinary abnormalities:
- Hypospadias [Burns et al 1976]
- Vesicoureteral reflux [Ferrara et al 2008, Salvatore et al 2010]
- Megacystis [Ferrara et al 2008, Salvatore et al 2010]
Cardiac abnormalities:
- Patent foramen ovale [Ferrara et al 2008, Salvatore et al 2010]
- Cardiac malformations (ventricular or atrial septal defects) [Thorwarth et al 2014]
Short stature with webbed neck [Glik et al 2008, Thorwarth et al 2014]

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed as manifestations of NKX2-1-related disorders vary among individuals with the same NKX2-1 pathogenic variant even within the same family.

In general, the severity of the phenotype associated with a heterozygous NKX2-1 pathogenic variant depends on the type of variant (missense or nonsense), deletion size, or location within functional domains of NKX2-1 [Inzelberg et al 2011].

Larger (exon or whole-gene) deletions have been reported in infants with respiratory distress, congenital hypothyroidism, delayed achievement of motor milestones, and ataxia [McMichael et al 2013], including individuals with a contiguous deletion of NKX2-1 and PAX9 [Devos et al 2006]. Missense variants resulting in protein truncation have been related to milder phenotypes, though a systematic analysis of published cases revealed no clear correlation between variant type and protein functionality [Gras et al 2012, Monti et al 2015].

Penetrance

No studies have evaluated the penetrance of NKX2-1 pathogenic variants though observational case reports of families suggest a variable penetrance.

Nomenclature

Before its molecular basis was known, the disorder now known to be caused by a heterozygous pathogenic variant in NKX2-1 [Inzelberg et al 2011] was referred to as benign hereditary chorea (BHC) based on the original description of non-progressive, familial chorea in a five-generation African American family from rural Mississippi [Haerer et al 1967]. The broad phenotypic spectrum associated with pathogenic variants in NKX2-1 (including BHC and a variable combination of lung, thyroid, and neurologic abnormalities) identified in these studies led Willemsen et al [2005] to coin the term brain-lung-thyroid syndrome. In light of the varied manifestations of heterozygous mutation of NKX2-1, the authors suggest that these disorders be referred to as NKX2-1-related disorders.

Of note, NKX2-1 was previously known as TITF-1; thus, the early literature describing the molecular basis of this disorder uses this gene designation [Breedveld et al 2002, Kleiner-Fisman et al 2003, Costa et al 2005, Devos et al 2006, Kleiner-Fisman & Lang 2007, Glik et al 2008].

Prevalence

A prevalence of 1:500,000 was suggested by Harper [1978] in a study of individuals with clinically diagnosed benign hereditary chorea (BHC). However, the study was performed before the molecular basis of BHC was known; thus, it is unclear if all individuals included in the study had an NKX2-1 pathogenic variant. Additionally, persons with mild chorea and individuals without chorea as a presenting symptom were not included in the study [Kleiner-Fisman et al 2003].

NKX2-1-related disorders have primarily been described in Western European, Mediterranean, African American, and Japanese populations [Veneziano et al 2014].

Differential Diagnosis

Table 2.

Differential Diagnosis for NKX2-1-Related Disorders

Clinical Feature	NKX2-1-Related Disorders	Differential Diagnosis
Chorea ¹	Primarily characterized by infantile or early-childhood onset of a non-progressive chorea w/good prognosis	Physiologic chorea of infancy Chorea minima Idiopathic chorea Bucco-oro-lingual dyskinesias
	Less commonly present w/adult-onset AD benign chorea w/out dementia	Benign hereditary chorea type 2 ²
	Can be differentiated from chorea assoc w/generally progressive cognitive/neurologic dysfunction	Developmental choreas Hereditary choreas ³ ADCY5-associated disease ⁴ Neurometabolic disorders ⁵ Drug & toxin-related chorea ⁶ Metabolic & endocrine disorders ⁷ Infection & post-infection-related disorders ⁸ Immunologic-related chorea ⁹ Vascular-related chorea ¹⁰ Tumor-related chorea Trauma-related chorea Miscellaneous causes of chorea ¹¹
Congenital hypothyroidism ¹²	Congenital hypothyroidism similar to idiopathic congenital hypothyroidism	Thyroid dysgenesis (aplasia, hypoplasia, or ectopic thyroid gland) Inborn errors of thyroxine synthesis ¹³ Hypopituitarism Iodine deficiency Panhypopituitarism Maternal antibody-mediated congenital hypothyroidism
Respiratory insufficiency ¹⁴	Neonatal pulmonary hypertension is a characteristic form of respiratory distress.	Respiratory distress syndrome (hyaline membrane disease) Meconium aspiration syndromes Persistent pulmonary hypertension Pneumothorax Transient tachypnea of the newborn Polycythemia Non-pulmonary causes ¹⁵

: AD = autosomal dominant
1.: Some individuals initially diagnosed with BHC are later found to have some other diagnosis, such as myoclonic dystonia, hereditary essential myoclonus, tics, and Huntington disease [Schrag et al 2000]. Huntington disease, an autosomal dominant genetic disorder characterized by chorea, typically presents later in life and is a progressive neurodegenerative disorder associated with dementia.
2.: Shimohata et al [2007]
3.: Neuroacanthocytosis, tuberous sclerosis complex, neurodegeneration with brain iron accumulation (NBIA), infantile bilateral striatal necrosis, Wilson disease, neuroferritinopathy
4.: Chang et al [2016]; see ADCY5-Related Dyskinesia.
5.: Lesch-Nyhan syndrome, lysosomal storage disorders, amino acid deficiency disorders, Leigh disease
6.: Neuroleptic exposure, anoxia, cerebral palsy (anoxia), carbon monoxide, heavy metal poisoning
7.: Hypo/hyperglycemia (non-ketotic), hyper/hypothyroidism, renal failure, nutritional
8.: Sydenham chorea, other infectious and post-infectious encephalitis (Lyme disease, mycoplasma)
9.: Acute disseminated encephalomyelitis (ADEM), acquired immunodeficiency syndrome (AIDS)
10.: Infarction or hemorrhage, arteriovenous malformation, antiphospholipid syndrome, following cardiac surgery with hypothermia and extracorporeal circulation in children (i.e., CHAP [choreoathetosis and orofacial dyskinesia, hypotonia, and pseudobulbar signs] syndrome)
11.: Kernicterus, sarcoidosis, multiple sclerosis, mitochondrial disorders, paroxysmal dyskinesias (kinesigenic dyskinesia; nonkinesigenic dyskinesia), familial dyskinesia
12.: Screening for congenital hypothyroidism is performed by checking serum thyroid stimulating hormone (TSH) and thyroxine levels (T₄). NKX2-1 disorders are associated with primary hypothyroidism with elevated serum TSH and low free T₄. Additional testing with thyroid ultrasound, radionucleotide uptake scan, serum thyroglobulin, urinary iodine, and maternal TSH-receptor blocking antibodies (TRB-Ab) can be obtained based on clinical suspicion and family history. Central hypothyroidism is associated with normal to low TSH with low free T₄. This condition is often associated with abnormalities in other pituitary hormone levels such as adrenocorticotropic hormone (ACTH), gonadotropins, growth hormones, and prolactin.
13.: Thyroid peroxidase defects, thyroxine-binding globulin deficiency (OMIM 314200)
14.: The etiology of respiratory distress syndrome is determined by perinatal risk factors such as gestational age, method of delivery, risk of infection, and associated complications such as presence of meconium in amniotic fluid or exposure to bacterial infections in the perinatal period. Chest radiograph can aid in determining the presence of a pneumothorax and other structural abnormalities in the chest.
15.: Diaphragmatic hernia, tracheoesophageal fistula

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an NKX2-1-related disorder, the following evaluations are recommended:

For benign hereditary chorea*

Consultation with a clinical geneticist and/or genetic counselor

For brain-lung-thyroid syndrome (choreoathetosis*, congenital hypothyroidism, and neonatal respiratory distress)

Lung
- Pulmonary function testing, if not performed at the time of diagnosis
- Pulmonary consultation for further evaluation and treatment of pulmonary dysfunction
- Screening for pulmonary malignancy with chest x-ray or CT scan of the chest
Thyroid
- Thyroid function testing (TSH, T₃, T₄) for evaluation of possible hypothyroidism, if not performed at the time of diagnosis
- Endocrinology consultation for further evaluation and treatment of thyroid abnormalities
- Consider evaluation for thyroid malignancy by physical examination that includes thyroid palpation.
Consultation with a clinical geneticist and/or genetic counselor

*Note that brain MRI is typically obtained as part of the diagnostic evaluation.

Treatment of Manifestations

A multidisciplinary approach to the management of individuals with NKX2-1-related disorders is recommended.

Chorea. Tetrabenazine, which has been reported to reduce chorea in low doses [Jankovic 2009, Salvatore et al 2010, Jankovic & Clarence-Smith 2011, Gras et al 2012, Jimenez-Shahed & Jankovic 2013], is a first-line treatment for chorea. Starting at low doses and gradually increasing to the dose most effective in controlling symptoms is recommended.

Children: 0.5 mg/kg/day starting dose divided into 2-3 doses
Adults: 37.5 mg/day starting dose divided in 2-3 doses

Levodopa therapy has been reported to improve chorea in four children and can be considered as second-line therapy for the treatment of chorea [Asmus et al 2005, Rosati et al 2015]. Rosati et al [2015] and Asmus et al [2005] noted a dramatic and substantial improvement in gait symptoms (specifically falls) in the same four children with levodopa therapy; this medication can be used as first-line therapy in children with gait impairment.

Of note:

Although Devos et al [2006] found a beneficial effect of methylphenidate on chorea in one patient, methylphenidate is not recommended as first-line therapy for the treatment of chorea.
Although Glik et al [2008] reported amelioration of choreic movements in an individual with benign hereditary chorea treated with olanzapine for psychosis, dopamine receptor blockers are not recommended as first-line therapy for the treatment of chorea.

Other neurologic manifestations. Gross motor and gait abnormalities can occur during early development [Harper 1978]; physical therapy is recommended to address delays in motor and gait development identified in childhood.

Pulmonary dysfunction. Treat asthma and interstitial lung disease as needed.

Hypothyroidism. Thyroid hormone replacement therapy is recommended.

Prevention of Primary Manifestations

Neonatal screening for thyroid-stimulating hormone, thyroxine (T₄) levels with appropriate thyroid replacement can prevent systemic sequelae of congenital hypothyroidism.

Prevention of Secondary Complications

Screening and treatment of hypothyroidism can prevent the systematic sequelae of congenital hypothyroidism.

Early and aggressive medical intervention for respiratory infections and asthma can prevent respiratory distress, intubation and/or death.

Early intervention for motor development delays with physical therapy and/or medication for the treatment of chorea can improve function.

Annual screening for pulmonary and thyroid cancer can reduce morbidity and mortality associated with malignancy with NKX2-1 related disorders.

Surveillance

The following are appropriate:

For individuals with no neurologic manifestations or minimal symptoms: annual neurologic evaluation
For individuals with no pulmonary manifestations or minimal symptoms: annual evaluation starting at the time of diagnosis for pulmonary dysfunction (pulmonary function tests) and pulmonary malignancy with chest x-ray or CT scan of the chest
For individuals with no manifestations of thyroid disease or minimal symptoms: annual evaluation starting at the time of diagnosis for thyroid dysfunction (serum concentration of thyroid stimulating hormone) and for thyroid cancer (physical examination that includes thyroid palpation)

Agents/Circumstances to Avoid

No agents or circumstances are known to trigger or exacerbate NKX2-1-related disorders.

Evaluation of Relatives at Risk

Evaluation of at-risk relatives prenatally or as soon as possible after birth enables early identification of infants at high risk for congenital hypothyroidism and pulmonary disease, permitting early diagnosis and management, and particularly, prevention of the neurodevelopmental consequences of untreated hypothyroidism.

Evaluations can include:

Molecular genetic testing if the NKX2-1 pathogenic variant in the family is known;
If a pathogenic variant has not been identified, assessment of thyroid function in a family with benign hereditary chorea or brain-lung-thyroid syndrome.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no known increased risk during pregnancy for a woman with an NKX2-1-related disorder.

Prior to pregnancy or early in gestation, it is recommended that a woman work with her physician to determine the safety for the fetus of the use of any medication she is taking for chorea.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.