Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Abstract

Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Keywords: Jansen-de Vries syndrome; PPM1D; cyclic vomiting; developmental delay; hypersocial personality.

Figure 1.

Spectrum of variants identified in PPM1D. Variants are identified by position in the amino acid sequence. The number within the circle indicates the case number from this series. All variants fall within exons 5 and 6 of PPM1D, which comprises six exons total.

Figure 2.

Box and whisker plot depicting the Z-score for anthropomorphic measurements at last examination. The line within the box represents the median, with the box boundaries representing the interquartile range and whiskers represent range. Data on height were available for 33 participants, weight for 35, and head circumference for 20.

Figure 3.

(A) In infancy and early childhood, the common facial gestalt is more easily recognizable, particularly the broad forehead and wide mouth with thin upper lip. (B) School age. (C) Adulthood. (D) Familial cases. (E) Hands and feet of affected individuals, illustrating the small size and hypoplastic nails in some.

Figure 3.

(A) In infancy and early childhood, the common facial gestalt is more easily recognizable, particularly the broad forehead and wide mouth with thin upper lip. (B) School age. (C) Adulthood. (D) Familial cases. (E) Hands and feet of affected individuals, illustrating the small size and hypoplastic nails in some.

Figure 3.

(A) In infancy and early childhood, the common facial gestalt is more easily recognizable, particularly the broad forehead and wide mouth with thin upper lip. (B) School age. (C) Adulthood. (D) Familial cases. (E) Hands and feet of affected individuals, illustrating the small size and hypoplastic nails in some.

Figure 3.

(A) In infancy and early childhood, the common facial gestalt is more easily recognizable, particularly the broad forehead and wide mouth with thin upper lip. (B) School age. (C) Adulthood. (D) Familial cases. (E) Hands and feet of affected individuals, illustrating the small size and hypoplastic nails in some.

Figure 4.

Face2Gene facial composite from a cohort of children with Jansen-deVries Syndrome (Cohort 1) compared to controls.

Figure 5.

Frequency of salient features within our cohort and published literature cases. Dark blue bars represent the number cases within our cohort, light blue bars represent cases published in the literature, orange bars represent the number without the feature, and grey bars indicate the number for whom the feature is not reported.