Clinical Characteristics

The following description of the broad clinical spectrum is based on the paper: Turnpenny et al., Am. J. Hum Genet 2018.

Growth parameters
Birth weight is usually below average for gestational age. Intrauterine growth retardation (IUGR) can be present. Weight during childhood tends to remain low. Feeding difficulties and gastroesophageal reflux are common problems in infancy. Height tends to be below average but within the normal range. The effects on head size can be variable. Affected individuals can have a relatively large or small head.

Neurological features
Individuals with TPFS have developmental delay and intellectual disability (ID). The level of ID can range from mild to severe. Most individuals have difficulties with verbal communication. Low muscle tone is common and contributes to delay in motor development (sitting ~12 months, walking 2-4 years). Two individuals have had a history of seizures but these were not a major problem.

Structural anomalies of the central nervous system can be present, including mild enlargement of the lateral ventricles, polymicrogyria, and patchy white matter changes. One individual had mild cerebellar vermis hypoplasia. MR angiography in three individuals showed a variable degree of tortuosity and ectasia of the intra- and extracranial blood vessels.

Neuropsychological disorders
Individuals with TPFS are often communicative and attentive. However, some affected individuals have been noted to have behavioural difficulties such as shyness, anxiety, autistic traits or attention deficit hyperactivity disorder.

Facial dysmorphism
Individuals with TPFS have characteristic facial features. Consistent facial features include a broad forehead with frontal bossing; sparse, slow growing hair particularly at the front and side of the head; fullness around the eyes; flat cheek bones; small eye fissures and mouth; and unusual ‘satyr’-like ears. Low facial muscle tone may impair speech and lead to drooling. A prominent nasal tip and chin are common in older individuals. The combination of large forehead, prominent jaw and open mouth makes the face appear long. Dental malocclusion is common.

Visual and hearing impairments
Hearing impairment (usually conductive) is common in TPFS. No serious vision problems have been reported although a couple of affected individuals were noted to have transient corneal opacities/clouding as young children.

Musculoskeletal anomalies
Minor skeletal anomalies can be a feature of TPFS. These have included subtle spinal anomalies (e.g. hypoplasia of a vertebral body or truncated sacrum). Kyphosis and/or scoliosis, pectus deformities and minor digital anomalies have also been seen.

Cardiovascular defects
The heart anomalies in our series mainly included patent ductus arteriosus (PDA), atrial septal defect (ASD), and dilatation of the ascending aorta. One individual had prolapse of both mitral and tricuspid valves with some regurgitation. One individual had an episode of supraventricular tachycardia. No arterial aneurysms or dissections were reported in the subjects. The oldest individual in our series had a severely dilated aortic root at the age of 21 years. No arterial aneurysms or dissections have been reported.

Renal and urogenital anomalies
Two affected males required orchidopexy for undescended testicle(s). One individual had a duplicated renal collecting system.

Skin involvement
Haemangiomas were noted in infancy in two individuals. Pigmented nevi have been noted on the skin and scalp of some affected individuals.

Constipation has been reported in several individuals and can be severe. Obstructive sleep apnoea has occasionally been reported (possibly due to large tonsils). Two individuals have been found to have a small diaphragmatic hernia of the Morgagni type.