Turnpenny-Fry Syndrome

A number sign (#) is used with this entry because of evidence that Turnpenny-Fry syndrome (TPFS) is caused by heterozygous mutation in the PCGF2 gene (600346) on chromosome 17q12.

Description

Turnpenny-Fry syndrome (TPFS) is characterized by developmental delay, impaired intellectual development, impaired growth, and recognizable facial features that include frontal bossing, sparse hair, malar hypoplasia, small palpebral fissures and oral stoma, and dysplastic 'satyr' ears. Other common findings include feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations (Turnpenny et al., 2018).

Clinical Features

The Deciphering Developmental Disorders Study (2015) described 2 unrelated patients with impaired intellectual development who shared the same heterozygous missense mutation in the PCGF2 gene (see MOLECULAR GENETICS). The first patient was a girl who had specific learning disability, long face, mandibular prognathism, microtia, downslanting palpebral fissures, joint hypermobility, and constipation. The second patient was a boy with specific learning disability, drooling, macrocephaly, abnormality of the palpebral fissures and outer ear, hypoplasia of primary teeth, mild short stature, scoliosis, short tapering fingers, and pigmented nevi. The authors noted that the patients had a strikingly similar facial appearance.

Turnpenny et al. (2018) studied 13 patients from 12 unrelated families with similar distinctive facial features, impaired intellectual development of variable severity, and impaired growth, including the 2 patients previously reported by the Deciphering Developmental Disorders Study (2015). Consistent facial features included broad forehead with frontal bossing, sparse and slow-growing hair in the temporal and frontal areas, periorbital fullness, and malar hypoplasia. In addition, patients exhibited small low-set dysplastic ('satyr') ears, mild facial hypotonia with open-mouth posture and drooling, short palpebral fissures, prominent nasal tip, small oral aperture, and mandibular prognathism. All patients had birthweights below the mean for gestational age, and feeding difficulties and gastroesophageal reflux were common in early childhood, as was severe chronic constipation. Cardiovascular anomalies included dilation of the aortic root and ascending aorta and tortuosity of the internal carotid, vertebral, and retinal arteries. Skeletal anomalies were variable, including vertebral anomalies and scoliosis, pectus deformities, and minor digital anomalies. Head size was variable, with some patients showing relative macrocephaly and others showing microcephaly. All patients had impaired intellectual development and/or developmental delay; most showed delayed speech, with absent speech in 3 patients at 21, 9, and 2.5 years of age. MRI abnormalities included patchy to confluent white matter changes, mild ventricular dilation, and polymicrogyria.

Molecular Genetics

From a cohort of 1,133 children with developmental disorders, the Deciphering Developmental Disorders Study (2015) identified 2 unrelated children with specific learning disabilities and dysmorphic features who were heterozygous for the same missense mutation in the PCGF2 gene (P65L; 600346.0001), which occurred de novo in both patients.

In 9 unrelated children with Turnpenny-Fry syndrome, Turnpenny et al. (2018) identified heterozygosity for the P65L mutation in the PCGF2 gene. In addition, 2 monozygotic twin sisters with TPFS were heterozygous for a P65S mutation in PCGF2 (600346.0002). The mutations arose de novo in all patients except 1, in which the P65L mutation was inherited from an asymptomatic mosaic mother.