Pierpont Syndrome

A number sign (#) is used with this entry because of evidence that Pierpont syndrome (PRPTS) is caused by heterozygous mutation in the TBL1XR1 gene (608628) on chromosome 3q26.

Description

Pierpont syndrome is a multiple congenital anomaly syndrome associated with learning disability. Key features include distinctive facial characteristics, especially when smiling, plantar fat pads, and other limb anomalies (summary by Burkitt Wright et al., 2011).

Clinical Features

Pierpont et al. (1998) suggested that 2 unrelated boys had a previously undescribed disorder characterized by global developmental delay and a phenotype of microcephaly, midface hypoplasia, enlarged fleshy ears, depressed nasal bridge, anteverted nostrils, central palatal ridge, and high forehead. Bilateral congenital fat pads were present anteromedial to the heels. Fetal finger and toe pads were also present, and palmar and plantar grooves were deeper than normal with 'pillowing' of the areas between the grooves. Congenital fatty heel pads, which have been described as an isolated clinical finding (Livingstone and Burd, 1995), are rare.

Oudesluijs et al. (2005) reported a 2.5-year-old boy with axial hypotonia in the first few months of life, prolonged feeding problems, moderate developmental delay, no speech development, deep palmar and plantar grooves, and fat pads at the anteromedial aspect of the heels. Examination at 7 months of age revealed a distinct facial phenotype, with high forehead, high anterior hairline, mild midface hypoplasia, markedly narrow and upwardly slanting palpebral fissures, broad nasal ridge and tip, broad philtrum, bowed upper lip with 'pouting' and hypotonic lower lip, full cheeks, and flat occiput. His neck was short, internipple distance was large, and areolas were small. His penis was small with slightly underdeveloped scrotum. There was excessive skin over the hands and feet, causing them to have a puffy appearance, and on the palms and soles there was pillowing of the areas between the grooves. At 2.5 years of age, the patient had no speech development and could not crawl; he could roll over and sit independently, however, and he moved around by shuffling on his back. Facial features were essentially unchanged, although there was now evidence of widely spaced teeth, with a broad right upper incisor and an irregular edge to all incisors. Oudesluijs et al. (2005) stated that this patient had a phenotype 'almost identical' to that of the 2 boys reported by Pierpont et al. (1998), and proposed the designation 'Pierpont syndrome' for the condition.

Burkitt Wright et al. (2011) provided follow-up on the 3 previously described patients with Pierpont syndrome and reported 7 additional patients with a similar phenotype, including 1 girl and a pair of monozygotic twin boys. The new patients were ascertained by the presence of fat pads anteromedial to their heels, fetal digital pads, learning disability, and characteristic facial dysmorphism. Burkitt Wright et al. (2011) noted that the narrow palpebral fissures took on a distinctive crescent moon shape when smiling due to the fullness of the cheeks in these patients.

Heinen et al. (2016) reported 2 patients with Pierpont syndrome. Both had severely delayed psychomotor development with lack of speech and significant hypotonia in infancy. They had poor overall growth and unusual facial features, including high anterior hairline, narrow palpebral fissures, microcornea, flat cheek bones, broad nasal ridge and tip, smooth philtrum, thin upper vermilion, large ears, and widely spaced teeth. Other features included scoliosis, short fingers and toes, and marked finger and toe pads as well as subcalcaneal fat pads. One patient had hearing loss.

Kahlert et al. (2017) reported a male child with typical features of Pierpont syndrome, including developmental delay, distinctive facial dysmorphic features, dystrophy, and abnormal fat distribution in the feet. In addition, the child had microphthalmia, pendular nystagmus, cryptorchidism, dermal sinus, and peripheral joint laxity.

Lemattre et al. (2018) reported 2 unrelated patients with Pierpont syndrome. Both had typical facial features, growth restriction, and severely impaired intellectual development. One patient had a Chiari malformation, and the other had a gyration disorder with myelination delay. The characteristic palmar and plantar grooves seen in other patients with PRPTS were less prominent in these patients.

Inheritance

Pierpont syndrome is an autosomal dominant disorder (Heinen et al., 2016).

Oudesluijs et al. (2005) stated that the advanced paternal age in the cases described by Pierpont et al. (1998) was suggestive of an autosomal dominant spontaneous mutation; however, the fact that all 3 reported patients were boys was also in keeping with X-linked recessive inheritance.

Burkitt Wright et al. (2011) noted that their identification of a female patient with Pierpont syndrome made X-linked recessive inheritance less likely.

Molecular Genetics

In 6 unrelated patients with Pierpont syndrome, including the 2 unrelated patients originally reported by Pierpont et al. (1998) and the patient reported by Oudesluijs et al. (2005), Heinen et al. (2016) identified the same de novo heterozygous missense mutation in the TBL1XR1 gene (Y446C; 608628.0005). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutant protein assembled correctly into its complex, but further functional studies were not performed.

In a male child with Pierpont syndrome, Kahlert et al. (2017) identified heterozygosity for the same missense mutation (Y466C) in the TBL1XR1 gene that was identified by Heinen et al. (2016).

By whole-exome sequencing in 2 unrelated patients with Pierpont syndrome, Lemattre et al. (2018) identified novel de novo heterozygous missense mutations in the TBL1XR1 gene. One mutation (Y446H; 608628.0006) occurred at the same amino acid as the recurrent mutation previously identified in patients with Pierpont syndrome (Y446C); the other mutation (C325Y; 608628.0007) occurred in the same area of the protein, at the inner surface of the WD40 ring.

Cytogenetics

In a 2.5-year-old boy with Pierpont syndrome, Oudesluijs et al. (2005) performed whole-genome microarray CGH but did not identify any abnormalities.

In 7 patients with Pierpont syndrome, Burkitt Wright et al. (2011) performed routine karyotyping but did not find any abnormalities. Genomewide copy number analysis by SNP array in the 2 boys originally reported by Pierpont et al. (1998), the boy previously studied by Oudesluijs et al. (2005), and 3 additional patients with Pierpont syndrome revealed a 3.17-Mb deletion at chromosome 10q21.3 in 1 of 2 monozygotic twin boys. FISH analysis revealed that the deletion occurred on the maternal allele and was present in his affected twin brother.