Pitt-Hopkins-Like Syndrome 2

A number sign (#) is used with this entry because Pitt-Hopkins-like syndrome-2 (PTHSL2) is caused by compound heterozygous mutation in the NRXN1 gene (600565) on chromosome 2p16.

Clinical Features

Zweier et al. (2009) reported an 18-year-old girl with a mental retardation syndrome resembling Pitt-Hopkins syndrome (PTHS; 610954). She had normal growth parameters but severe mental retardation, acquired walking at age 2 years, and showed developmental regression after the first years. She also had hyperbreathing and autistic behavior. Seizures were not present, and brain MRI was normal. Other features included decreased reflexes in the upper extremities, constipation, and mild facial dysmorphism, including broad mouth, strabismus, and protruding tongue with drooling.

Harrison et al. (2011) reported 2 sisters, born of unrelated Caucasian parents, with a severe mental retardation syndrome characterized by onset of epileptic encephalopathy at age 4 and 6 months, respectively, with loss of early developmental skills. Both had hypotonia and poor feeding in early infancy. The older sister began to walk with a wide-based unsteady gait at age 5 years, whereas the younger sister never learned to walk. At age 16 years, the older sister had a complex seizure disorder with drop attacks, tonic-clonic seizures, atypical absences, and myoclonic jerks. Development was very slow, with occasional episodes of regression associated with an increase of seizures. She had very limited speech and several behavioral abnormalities, including self-harm and repetitive movements. At age 11 years, the younger sister had severe myoclonic epilepsy with occasional atypical absences, and slow developmental progress without episodes of regression. The older sister had episodes of hyperventilation, and the younger had breath-holding spells. Other features in both girls included an abnormal sleep-wake cycle, stereotyped behavior, gastroesophageal reflux with poor growth, constipation, early-onset puberty, pulmonary stenosis, and scoliosis. Brain MRI was normal in the older sister.

Molecular Genetics

In a girl with Pitt-Hopkins-like syndrome-2, Zweier et al. (2009) identified compound heterozygosity for 2 mutations in the NRXN1 gene (600565.0001 and 600565.0002).

In 2 sisters with a severe early-onset mental retardation syndrome with severe epilepsy, Harrison et al. (2011) identified compound heterozygous deletions on chromosome 2p16.3, exclusively affecting the NRXN1 gene (600565.0004 and 600565.0005). Each deletion was inherited from an unaffected parent. In addition, both girls had a heterozygous paternally inherited 742-kb duplication at chromosome 5q35.1 including 4 genes, which was thought to be a coincidental finding.