Choreoathetosis And Congenital Hypothyroidism With Or Without Pulmonary Dysfunction

A number sign (#) is used with this entry because choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) is caused by heterozygous mutation in the NKX2-1 gene (600635) on chromosome 14q13.

See also benign hereditary chorea (118700), an allelic disorder with less severe manifestations.

Description

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).

Clinical Features

Pohlenz et al. (2002) described a boy with neonatal respiratory distress requiring mechanical ventilation and mildly increased serum thyrotropin (TSH; 188540) with normal serum thyroxine. He was hypotonic, showed delayed development, and staggering gait later in childhood. By age 4.5 years, he had choreiform hyperkinesia. Brain MRI was normal.

Krude et al. (2002) described 5 patients with variable degrees of congenital hypothyroidism with choreoathetosis, muscular hypotonia, and neonatal respiratory distress with recurrent pulmonary infections. Three patients had hypoplasia of the thyroid gland on imaging and 1 had thyroid gland agenesis apparent in the neonatal period. All had increased serum TSH and decreased thyroxin. Four patients aged 3 to 16 years had severe choreoathetosis and 1 showed muscle hypotonia at age 1.5 years. In 1 of the patients, cytogenetic studies identified an interstitial deletion of chromosomal region 14q11.2-q13.3, including the TITF1 locus. Krude et al. (2002) concluded that the neurologic dysfunction in these patients was most likely related to TITF1 gene deficiency in the thyroid and brain rather than to the consequence of hypothyroidism since all patients were adequately treated with thyroxine.

Asmus et al. (2005) reported a German family in which a mother and 3 of her children, all born of different fathers, had congenital hypothyroidism, neonatal respiratory distress, and choreoathetosis. The proband was born prematurely at 31 weeks' gestation and developed pneumonia and apneic episodes at birth. She had a small thyroid gland, increased serum TSH, and delayed motor development. At age 48 months, she was unable to walk unassisted for more than a few steps because of marked muscular hypotonia, hyperextendable knee joints, and muscular atrophy of the lower limbs. She also had rapid choreatic and athetotic movements of the limbs and trunk. Her 2 affected half sibs had respiratory insufficiency at birth, pneumonia, congenital hypothyroidism necessitating thyroxine replacement, muscular hypotonia and choreoathetotic movements developing within the first 2 years of life. All children showed delayed motor development and ataxia and cerebellar symptoms. The mother had hypothyroidism, ataxic gait, and choreoathetosis; information about her neonatal respiratory function was not available. Two of the affected children had a favorable response to levodopa treatment.

Doyle et al. (2004) reported a 3-generation family in which 4 members had congenital hypothyroidism, neonatal respiratory distress, and ataxia. The probands, who were maternal half sibs, both had neonatal respiratory distress requiring prolonged mechanical ventilation and compensated hypothyroidism with increased serum TSH and normal T4. Both showed a normal thyroid gland on ultrasound. During infancy, each child showed global developmental delay and later developed ataxia, choreoathetosis, and dysarthria. The mother had required mechanical ventilation as a neonate, had delayed motor development, and was diagnosed with hypothyroidism at age 18 years. She demonstrated ataxia and dysarthria. The maternal grandmother had a twin who died at birth of respiratory distress. The grandmother had pneumonia as a child, fell frequently, had dysarthria, and was diagnosed with hypothyroidism at age 52 years.

Carre et al. (2009) reported that the clinical spectrum of 46 patients from 28 families with NKX2-1 mutations. Half of the patients developed the complete triad of brain-lung-thyroid syndrome, whereas 14 (30%) of 46 had brain and thyroid disease, 6 (13%) of 46 had chorea only, and 3 (7%) of 46 had no neurologic signs with lung and thyroid disease or thyroid disease only. Thyroid morphology was normal in 17 (55%) of 31 patients by ultrasound or scintigraphy. In 28 patients with documented peripheral thyroid hormone values, compensated hypothyroidism was more prevalent than overt hypothyroidism (61% vs 39%). Lung disease occurred in 25 (54%) of 46 patients, with infant respiratory distress syndrome present at term in 19 (76%) patients and recurrent pulmonary infections in 6 (24%). On follow-up, 5 (20%) of 25 developed severe chronic interstitial lung disease, and 4 (16%) of 25 died from respiratory failure or infant respiratory distress syndrome.

Thorwarth et al. (2014) identified 25 unrelated patients with NKX2-1 mutations (17) or deletions involving the NKX2-1 gene (8). All patients had muscular hypotonia in infancy followed by choreoathetosis and other movement abnormalities, including ataxia in 7, and dystonia in 6. Dysarthria was present in 23 patients. All but 2 patients had thyroid defects, including congenital hypothyroidism (11), hyperthyrotropinemia (12), and thyroid dysgenesis (14). The lungs were affected in 22 patients; 13 had neonatal respiratory distress and 15 had recurrent respiratory infections. Some family members reportedly had asthma. Several patients showed symptoms of possible hypothalamic dysfunction, such as unexplained fever and disturbed hunger, thirst, or sleep. Seven patients had congenital cardiac septal defects that did not require surgery. All but 2 of 17 patients with point mutations had truncating mutations. Two additional patients with a similar phenotype had deletions that excluded the NKX2-1 gene, but affected the neighboring MBIP gene (609431), which was shown to have a similar expression pattern as NKX2-1 in mouse embryonic brain, thyroid, and lung. However, direct sequencing of the MBIP gene did not identify mutations in 79 other patients.

Molecular Genetics

Devriendt et al. (1998) identified deletion of the TITF1 gene in an infant with neonatal thyroid dysfunction, respiratory failure, hypotonia, and ataxia. Iwatani et al. (2000) reported deletion of the TITF1 gene in 2 sibs with hypothyroidism and respiratory failure.

In 5 unrelated patients with choreoathetosis, hypothyroidism, and respiratory distress, Krude et al. (2002) identified 4 different mutations in the TITF1 gene (see, e.g., 600635.0005 and 600635.0006) and 1 deletion of the TITF1 gene.

Pohlenz et al. (2002) identified a 1-bp insertion in the TITF1 gene (600635.0010) in a boy with choreoathetosis, hypothyroidism, and neonatal respiratory distress.

Doyle et al. (2004) identified a heterozygous mutation in the TITF1 gene (376-2A-G; 600635.0011) in 4 affected members of a family with autosomal dominant inheritance of this disorder.

In 4 affected members of a German family with congenital hypothyroidism, neonatal respiratory distress, and choreoathetosis, Asmus et al. (2005) identified a heterozygous mutation in the TITF1 gene (600635.0008).