The peroxisomal disorder spectrum and Heimler syndrome: Deep phenotyping and review of the literature

Abstract

The spectrum of peroxisomal disorders is wide and comprises individuals that die in the first year of life, as well as people with sensorineural hearing loss, retinal dystrophy and amelogenesis imperfecta. In this article, we describe three patients; two diagnosed with Heimler syndrome and a third one with a mild-intermediate phenotype. We arrived at these diagnoses by conducting complete ophthalmic (National Eye Institute), auditory (National Institute of Deafness and Other Communication Disorders), and dental (National Institute of Dental and Craniofacial Research) evaluations, as well as laboratory and genetic testing. Retinal degeneration with macular cystic changes, amelogenesis imperfecta, and sensorineural hearing loss were features shared by the three patients. Patients A and C had pathogenic variants in PEX1 and Patient B, in PEX6. Besides analyzing these cases, we review the literature regarding mild peroxisomal disorders, their pathophysiology, genetics, differential diagnosis, diagnostic methods, and management. We suggest that peroxisomal disorders are considered in every child with sensorineural hearing loss and retinal degeneration. These patients should have a dental evaluation to rule out amelogenesis imperfecta as well as audiologic examination and laboratory testing including peroxisomal biomarkers and genetic testing. Appropriate diagnosis can lead to better genetic counseling and management of the associated comorbidities.

Management of oral manifestations of a child with Heimler Syndrome-2

“…In addition to a thorough evaluation, genetic testing and a peroxisomal panel should be performed. Early and appropriate diagnosis and timely genetic counselling can lead to better management of peroxisomal disorders 10…”

PEX6 Mutations in Peroxisomal Biogenesis Disorders

“…Additionally, the presence of neurologic changes and the absence of enamel changes and nail disease make a diagnosis of Heimler syndrome less likely. 14 Given our patient's overall milder phenotypic manifestations, his age and his ability to participate in additional clinical testing provided an opportunity to study his peroxisomal function. Although the PEX6 c.802_815del mutation Figure 5.…”

Identification of a Homozygous PEX26 Mutation in a Heimler Syndrome Patient

“…Pathogenic mutations in at least 13 different PEX genes encoding peroxins are responsible for a group of PBDs and Zellweger spectrum disorders (ZSDs) [ 21 ]. ZSDs have an estimated prevalence of 1:50,000 births and consist of a spectrum of disorders from a severe to mild form: Zellweger syndrome (ZS, OMIM #214100), neonatal adrenoleukodystrophy (NALD, OMIM #601539), infantile Refsum disease (OMIM #601539), and HS [ 22 ].…”