Primrose syndrome: Characterization of the phenotype in 42 patients

Abstract

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.

Keywords: ZBTB20; Primrose syndrome; alpha-fetoprotein; ectopic calcifications; overgrowth.

FIGURE 1

Features from selected individuals with Primrose syndrome. (A) Faces from youngest to oldest at age 1.5 years (A), 2.5 years (B), 3 years (C), 4 years (D), 4 years (E), 5 years (F), 6 years (G), 8 years (H), 9 years (I), 11 years (J), 12 years (K), 13 years (L), 18 years (M), 31 years (N), 33 years (O), and 53 years (P). The patient identification number is indicated underneath the panels. (B) Other clinical features include alobar calcified ear (1), calcified ear on X‐ray (2), incomplete extension of fingers and small nails (3), joint hypermobility (4), distal muscle wasting in an adult (5), markedly small and thin nails (6), and malformed callosal body (7) [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Changes with age of cognition, muscle wasting, and serum alpha‐fetoprotein (AFP) in individuals with Primrose syndrome. A, Cognition. No evident correlation. B, Muscle wasting; data are presented based on age of first appearance. Increase with age evident. C, AFP serum levels. Each symbol represents a single individual; course over time in single patients is depicted if available. Elevated levels in almost every individual; no clear change with age in a single individual

FIGURE 3

Schematic overview of the ZBTB gene and localization of mutations. It is noteworthy that patient carrying p.Gln209Arg mutation showed no macrocephaly and no ID. Autism and self‐injurious behavior were recorded [Colour figure can be viewed at wileyonlinelibrary.com]