Case report: a Chinese girl like atypical Rubinstein-Taybi syndrome caused by a novel heterozygous mutation of the EP300 gene

Abstract

Background: Rubinstein-Taybi syndrome (RSTS) is an extremely rare autosomal dominant inheritable disorder caused by CREBBP and EP300 mutations, while atypical RSTS harbouring variant from the same genes but not obvious resembling RSTS. There are only a few cases of Menke-Hennekam syndrome (MKHK) with variant of exon 30 or 31 of CREBBP or EP300 gene have been reported that not resembling RSTS recent years. Atypical RSTS cannot be accurately classified as MKHK, nor is it easy to identify the obvious classic characteristics of RSTS. The clinical manifestations and genetic variation of atypical RSTS are not fully understood.

Case presentation: We present a Chinese core family with a girl had recurrent respiratory tract infection and developmental delay. The patient with language and motor mild development retardation, she has slight abnormal facial features, mild hirsutism and post-axial hexadactylia of left foot. Her cisterna magna is enlarged to connect with the fourth ventricle, and the ventricular system is enlarged. She has a malacia beside the posterior horn of the left lateral ventricle. The patient has primary low immunoglobulin G and A, but her level of immunoglobulin M content in blood is normal. The patient harbors a novel heterozygous frameshift variant of c.2499dupG in exon 14 of EP300 gene, that it is proved to de novo origin. The mutation is judged to be a pathogenic mutation, and it has high-grade pathogenic evidence.

Conclusion: The clinical and genetic evaluation of this case corroborates that clinical features caused by c.2499dupG in exon 14 of EP300 are less marked than RSTS2 patient although it is difficult to establish an accurate genotype-phenotype correlation. Our additional case also helps to deepen the clinical and genetic spectrum in this disorder. The case provides a novel mutation of EP300 and enriches the phenotypes related with the gene. We have contributed new variation and disease information for guardians and doctors to broaden the knowledge about EP300-RSTS genotype and phenotype, this may contribute to ameliorate the health management of patients and improve the genetic counseling to the families.

Keywords: Atypical Rubinstein–Taybi syndrome; EP300; Immunodeficiency; Novel mutation.

Fig. 1

Phenotypic features of patient described in this study. a and b The patient 4 years old. Note slightly arched eyebrows and synophridia, a square tip to his nose, normal columella, prominent two front teeth, normal tooth number and absence of characteristic grimace of Rubinstein–Taybi syndrome. c The fine hairs on the front of the ear and on the cheek are hair whorl. d and e The child has heavy fine hair on her back and opisthenar. f Patient has no broad or angulated thumbs, nor broad distal phalanges of the fingers, as seen in patients with Rubinstein–Taybi syndrome. g Girl has a sixth toe of her left foot, that hexadactyly

Fig. 2

Sanger sequencing results of EP300 c.2499dupG mutation in the core family. Sample P denotes the patient, sample F and M denote the father and mother of the patient, respectively

Fig. 3

Distribution of EP300 domains and mutations in our patient (in red arrow) versus in previous patient cohort (in black arrow). Schematic representation of the EP300 protein and functional domains excerpted from http://www.ebi.ac.uk/interpro/ at March 26th 2021. Previous patient cohort refers to the cohort published [, –16]. Previous patients marked by red box accorded with the diagnosis of MKHK, the other previous patients marked by green box accorded with the diagnosis of RSTS