Figure 1
Diagram of the “Classical” Features of Benign Hereditary Chorea and Expanding Clinical Phenotype. Each ring, brain (red), lung (green), and thyroid (blue), represents a body system involved in the classical brain–lung–thyroid triad. The most common clinical features are listed within each ring. Other clinical features increasingly recognized in association with NKX2.1 mutations are listed outside the rings. ADHD, Attention Deficit Hyperactivity Disorder; Brain–Lung–Thyroid, Overlapping clinical phenotypes involving the complete brain–lung–thyroid clinical spectrum; OCD, Obsessive–Compulsive Disorder.
Figure 2
Schematic Representation of NKX2.1 Missense, Frameshift, and Stop Codon Mutations Reported in the Published Literature to Date. Different reported NKX2.1 mutations are represented, and nucleotide changes and protein changes are displayed. Stop codon mutations (green) and splice-site mutations (purple) are located below the gene. Missense mutations (orange) and frameshift mutations (blue) are located above the gene.
Table 1
Genotype and Clinical Phenotype of Reported Whole Gene Deletions Involving NKX2.1
| Authors | Year of Publication | Deletion size and Chromosomal Location* | Genes Involved1 | Organ Involvement | Additional Clinical Characteristics | ||
|---|---|---|---|---|---|---|---|
| Brain | Lung | Thyroid | |||||
| Devriendt et al.30 | 1998 | <13cM deletion involving 14q13-q21 | NKX2.1, PAX9 | Hypotonia, truncal ataxia, motor DD | RDS, mechanical ventilation | Congenital hypothyroidism | Nil observed |
| Iwatani et al. (1)62 | 2000 | 14q12-q13.3 | NKX2.1, PAX9 | Motor DD | Bronchiolitis, recurrent RTI, RDS | Congenital hypothyroidism | Feeding difficulties, failure to thrive, microcephaly, hearing loss, cognitive impairment, dysmorphic facial features (e.g. hypertelorism, high arched palate), lower limb contractures |
| Iwatani et al. (2)62 | 2000 | 14q12-q13.3 | NKX2.1, PAX9 | Motor DD | Died of respiratory failure aged 3 years | Nil observed | Feeding difficulties, failure to thrive, microcephaly, hearing loss, cognitive impairment |
| Breedveld et al.9 | 2002 | 1.2Mb | NKX2.1, MBIP, NKX2.8, PAX9, SLC25A21 | Chorea | Nil observed | Nil observed | Nil observed |
| Krude et al.10 | 2002 | 14q11.2-q13.3 | NKX2.1 | Severe choreoathetosis | RDS, recurrent RTI | Thyroid hypoplasia | Nil observed |
| Devos et al. (1)34 | 2006 | 0.9Mb | NKX2.1, MBIP, NKX2.8, PAX9, SLC25A21, MIPOL1 | Chorea, hypotonia | Nil observed | Hypothyroidism | Diarrhea |
| Devos et al. (2)34 | 2006 | 0.9Mb | NKX2.1, MBIP, NKX2.8, PAX9, SLC25A21, MIPOL1 | Chorea, motor DD, hypotonia, cerebellar signs | Interstitial pneumonia | Hypothyroidism | Diarrhea, malabsorption, osteoporosis, hypoparathyroidism, dry eyes |
| Devos et al. (3)34 | 2006 | 0.9Mb | NKX2.1, MBIP, NKX2.8, PAX9, SLC25A21, MIPOL1 | Chorea, motor DD, hypotonia, cerebellar signs | Interstitial pneumonia | Hypothyroidism | Diarrhea, malabsorption, osteoporosis, dry eyes |
| Carre et al.15 | 2009 | 14q13 | NKX2.1 | Ataxia, motor DD | RDS, mechanical ventilation, Recurrent RTI | Congenital hypothyroidism | Mental retardation, impaired saccadic eye movements, absent corpus callosum |
| Accornero et al.63 | 2010 | 1.2Mb | NKX2.1, MBIP, NKX2.8, PAX9, SLC25A1 | Chorea | Nil observed | Subclinical hypothyroidism | Duplication of pituitary stalk |
| Uematsu et al.64 | 2012 | 2.6Mb deletion involving 14q12-q13 | NKX2.1 | Motor DD, choreoathetosis | Recurrent RTI | Nil observed | Bilateral reduced cerebral blood flow in basal ganglia (especially caudate nucleus) on ECD-SPECT imaging |
| Gras et al. (1)13 | 2012 | 13.8Mb deletion involving 14q13.2-q22.1 | NKX2.1, MBIP, PAX9, SLC25A21, MPOL1, FOXA1, SEC23A, GEMIN2, TRAPPC6B, CTAGE5, FBXO33, LRFN5, FSCB, C14orf28, KLHL28, FAM179B, PRPF39, FKBP3, FANCM, MDGA2 | Chorea, hypotonia | Nil observed | Nil observed | Nil observed |
| Gras et al. (2)13 | 2012 | 6.2-Mb deletion involving 14q13.2-q21.2 | NKX2.1, MBIP, PAX9, SLC25A21, MPOL1, FOXA1, SEC23A, GEMIN2, TRAPPC6B, CTAGE5, FBXO33 | Chorea, hypotonia | Nil observed | Hypothyroidism | Learning difficulties, ADHD |
| Gras et al. (3)13 | 2012 | 0.3-Mb deletion involving 14q13.3 | NKX2.1, MBIP, PAX9 | Chorea | Nil observed | Hypothyroidism | Learning difficulties, ADHD |
| Dale et al.65 | 2012 | 3.27-Mb deletion(Chr 14:35,327,739-38,602,335) | NKX2.1, PAX9, MIPOL1, SEC23A | Motor DD, gait disturbance | Nil observed | Nil observed | Mild intellectual disability, ligament laxity, oligodontia |
| Teissier et al.66 | 2012 | 14q13.3 | NKX2.1 | Chorea, dystonia, gait disturbance | COPD | Congenital hypothyroidism | Nil observed |
| Teissier et al.66 | 2012 | 14q13.3 | NKX2.1 | Chorea, hypotonia, ataxia | Nil observed | Congenital hypothyroidism | Dysmorphic features: hexadactyly, arched palate |
| Hamvas et al. (1)67 | 2013 | 14q13.1-q21.1 | NKX2.1 | Hypotonia, motor DD, ataxia | Hypoxia, recurrent RTI, pneumathoraces | Hypothyroidism | Absent corpus callosum |
| Hamvas et al. (2)67 | 2013 | 14q13.3 | NKX2.1 | Ataxia, motor DD | Recurrent infections | Hypothyroidism | Behavioral difficulties |
| Hamvas et al. (3)67 | 2013 | 14q13.3-q21.1 | NKX2.1 | Hypotonia, DD, ataxia | RDS, PH, RTI, oxygen therapy | Congenital hypothyroidism | Language delay |
| Hamvas et al. (4)67 | 2013 | 14q13.3-q21.1 | NKX2.1 | Hypotonia, developmental delay | RDS, PH | Congenital hypothyroidism | Microcephaly, language delay |
| Hamvas et al. (5)67 | 2013 | Deletion of exons 1 & 2 | NKX2.1 | Hypotonia, motor DD, ataxia | Severe RDS | Congenital hypothyroidism | Language delay |
| Peall et al. (1)14 | 2014 | 0.36Mb deletion(Chr14:36,924,171-37,283,221) | SFTA3, NKX2.1, BX161496, NKX2.8, PAX9, SLC25A21 | Hypotonia, dystonia, motor DD | Nil observed | Nil observed | Nil observed |
| Peall et al. (2)14 | 2014 | 4.7Mb deletion(Chr14:35,581,654-40,301,792) | RALGAPAI, BRMS1L, MBIP, SFTA3, NKX2.1, NKX2.8, PAX9, SLC25A21, MIPOL1, TTC6, SSTR1, CLEC14A, SEC23A, GEMIN2, TRAPPC6B, MIA2, CTAGE5, FBX033 | Hypotonia, motor DD | Recurrent RTI | Congenital hypothyroidism | Growth hormone deficiency, visual impairment |
ADHD, Attention Deficit Hyperactivity Disorder; COPD, Chronic Obstructive Pulmonary Disease; DD, Developmental delay; ECD-SPECT, Ethyl Cysteinate Dimer-Single-photon Emission Computed Tomography; PH, Pulmonary Hypertension; RDS, Respiratory Distress Syndrome; RTI, Respiratory Tract Infections.