Abstract | November 8, 2021

A MAP3K7 Molecular Variant Presents a Diagnostic Dilemma Due to Phenotypic Heterogeneity

Presenting Author: Arianna Lanpher, BA, Medical Student, 4th Year, Alabama College of Osteopathic Medicine, Dothan, AL, Anniston, AL

Coauthors: Arianna Lanpher, BA Medical Student, 4th Year, ACOM, AL; Caroline Clark, BS, Medical Student, 4th Year, ACOM, Dothan, AL; Anna Crowley, BS, Medical Student, 4th Year, ACOM, Dothan, AL; Lewis Doggett, MD, Pediatrics, Regional Medical Center, Anniston, AL; Anna Hurst, MD, MS, Assistant Professor in the Department of Genetics at the University of Alabama Birmingham, Birmingham, AL.

Learning Objectives

  1. Describe a de novo MAP3K7 heterozygous likely pathogenic missense variant. 
  2. Examine diagnostic dilemmas when encountering rare genetic variants. 

Introduction: We present an infant with cardiomyopathy and skeletal dysplasia found to have a MAP3K7 likely pathogenic variant. MAP3K7 can cause two disorders — Frontometaphyseal Dysplasia 2 (FMD2) due to gain-of-function and Cardiospondylocarpofacial syndrome (CSCFS) due to loss-of-function. Both are rare conditions with a prevalence of less than 1/1,000,000 and have skeletal, cardiac, and facial features with subtle differences. FMD2 features include joint contractures, coarse facial features, and tracheal stenosis. Meanwhile, patients with CSCFS may display growth restriction, bone fusion, and cardiac defects. Because this patient is too young to clinically display features of either, close surveillance is essential to monitor for associated complications. 

Case Description: A now 1-year-old male was born at 37 weeks via cesarean section to 35-year-old G3P1102. He was admitted to the NICU for intermittent tachypnea, and no cardiac abnormalities were noted. At 5 weeks he was re-admitted after difficulty feeding and breathing. An echocardiogram revealed cardiomyopathy. Objectively, he had disproportionate limbs with mesomelia, wide-spaced eyes, downslanting palpebral fissures, a long face, micrognathia, low-set ears, and hypospadias, raising concern for an underlying genetic etiology. 

Working Diagnosis: Rapid genome sequencing obtained through an NHGRI-supported study (SouthSeq) revealed MAP3K7 c.143G>A,p.Gly48Glu – a de novo heterozygous likely pathogenic missense variant. 

Management: Both FMD2 and CSCFS are rare, and the continual study of such are necessary to gain further classifications of the syndromes and early diagnosis. While valvular defects are described in both FMD2 and CSCFS, cardiomyopathy has not been reported in either. At this time, it is important to monitor for complications for both of these syndromes such as hearing loss, vertebral bone fusion, and tracheal stenosis, as it is difficult to determine which condition the patient has. Early intervention may prove to be essential in the management of this patient’s development. 

Download Abstract
Back to Abstracts