Braddock–Carey syndrome: A 21q22 contiguous gene syndrome encompassing RUNX1

Abstract

In 1994, Braddock and Carey first reported two unrelated girls with a new multiple malformation syndrome. The primary features included Pierre Robin sequence, persistent neonatalonset thrombocytopenia, agenesis of the corpus callosum, a distinctive facies, enamel hypoplasia, and severe developmental delay. Since that time, there have been multiple other reported patients with a similar phenotype. In addition, several reports of thrombocytopenia and developmental delay have been documented in association with deletions in the Down syndrome critical region at 21q22. The similarity of the reported cases with deletions involving 21q22 with the clinical presentation of the two patients with Braddock-Carey syndrome resulted in a reinvestigation of the genetic etiology of these two patients 20 years after the original study. This investigation provides evidence that the etiology of this and other "Fanconi-like" disorders represent a newly recognized contiguous gene deletion syndrome involving 21q22 and specifically, the RUNX1 gene.

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

“…It has to be kept in mind that the symptoms may be mild, that hematological neoplasms may present as MDS, AML or T-cell leukemias, and that onset of overt leukemia can be from childhood to adulthood [8]. In case there is a family history of MDS, early onset cancer or a personal history of bleeding tendency, immune deficiency, dysmorphic features and/or intellectual deficits, persons at risk should be transferred to genetic counselling [9,10].…”

“…Deletions of large proportions of the long arm of chromosome 21 cause a contiguous gene syndrome with various clinical signs, e.g. dysmorphisms, mental retardation, thrombocytopenia and increased risk to develop leukemia [9,10]. Under diagnostic conditions, these large frequently de novo deletions can most reliably be detected by arrayCGH/ SNP arrays [8,10,15,40].…”

“…It has to be kept in mind that the symptoms may be mild, that hematological neoplasms may present as MDS, AML or T-cell leukemias, and that onset of overt leukemia can be from childhood to adulthood [8]. In case there is a family history of MDS, early onset cancer or a personal history of bleeding tendency, immune deficiency, dysmorphic features and/or intellectual deficits, persons at risk should be transferred to genetic counselling [9,10].Comprehensive genetic evaluation and counseling involves a thorough review of an individual's personal medical and family history, including review of somatic cytogenetic and molecular test results and review of medical diagnoses in family members [11]. In case transplantation from a HLA-matched sibling donor is planned, germline RUNX1 mutation analysis has to be discussed.…”

Lethal renal anomalies in a fetus with 21q22.11‐q22.12 deletion

“…Fourteen overall OMIM genes were included in the smallest region of overlap among patients with 21q22 deletions. Coordinates were converted across all patients to a common genome build (GRCh37/hg19) [Color figure can be viewed at wileyonlinelibrary.com] (Braddock et al, 2016;Carrascosa-Romero et al, 2013;Marden & Walker, 1966;Yang et al, 2019). Our patient had brain malformations, heart defects and kidney anomalies, which are seen in all these conditions, in addition to other patients with 21q22.11-22.12 deletions (Carrascosa-Romero et al, 2013;Izumi, Brooks, Feret, & Zackai, 2012).…”

Jacobsen syndrome, Braddock–Carey syndrome, and Beyond: Reflections on intellectual disability accompanied with thrombocytopenia

“…Another 20 years elapsed after their first description of Braddock–Carey syndrome until the advent of microarray chromosomal testing, which led to the definition of this syndrome as a microdeletion syndrome at 21q22. Haploinsufficiency of RUNX1 was considered as the cause of the thrombocytopenia [Braddock et al, ; Izumi et al, ].…”