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.

Keywords: amelogenesis imperfect; heimler syndrome; peroxisomal disorders; retinal degeneration; sensorineural hearing loss.

FIGURE 1

Ophthalmologic characteristics of patients with mild peroxisomal biogenesis disorders. (a, c, and e) Macular optical coherence tomography images of Patients A, B, and C, respectively, showing cystic spaces and discontinuity of the outer retinal layers. (b and d) Color and autofluorescence ultrawide-field retinal images of patients with Heimler syndrome (Patients A and B). Their retinal dystrophy is characterized by few pigment redistribution, mild vessel attenuation, and a mostly mid-peripheral involvement with a hyper-hypoautofluorescence pattern. (f) Color and autofluorescence ultrawide-field retinal images of Patient C. In this case, we notice pigment clumping throughout the retina, moderate–severe vessel thinning, and a more extensive hyper-hypoautofluorescence (“salt and pepper”) pattern

FIGURE 2

(a) Front view of teeth in Patient A as seen in 2D photo and 3D intraoral scan in the top row. Bottom row shows the occlusal view of the upper (maxillary) teeth in the 2D and 3D views, respectively. The Grade 2 enamel loss was restricted to the molars in upper and lower arch of Patient A. (b) 2D photos and 3D scans of Patient B showing enamel loss affecting all teeth except the incisors. The upper first molars were severely broken (asterisk) and enamel was lost on all surfaces of affected teeth. (c) Patient C had most primary teeth that were unaffected except the second molars (black arrowhead). The erupting first molars (red arrowhead) and incisors had severe enamel loss indicating a Grade 4 enamel defect. (d) Magnified view of the molars marked by red box from Patients A, B, and C showing the severity of enamel loss. (e) Facial surface of canine tooth in Patient B showing partial enamel loss marked by red line. E, enamel, D, dentin

FIGURE 3

(a–c) Panoramic X-ray reformatted from CBCT. (d–f) Sagittal slice through an anterior (left panel) and one posterior tooth (right panel) from the cone-beam computed tomography scans. (a) Panoramic X-ray of Patient A showing multiple restorations. Enamel is seen as the thin white line outlining the teeth. Several posterior teeth needed restoration due to loss of enamel. (b) Patient B had three restorations visible on the panoramic X-ray and both maxillary first molars have broken crowns (white asterisk) and pulp exposure due to severe enamel loss. (c) Panoramic X-ray of Patient C showing retained primary teeth (white asterisk) and multiple unerupted permanent teeth. The erupting central incisors (red asterisk) seem to have broken incisal edges indicating hypoplastic enamel. (d) Left panel shows 2D slice through anterior tooth in Patient A with normal enamel (red arrowhead). Right panel shows a 2D slice through the molar with thin enamel (red arrowhead). (e) Anterior tooth enamel is irregular and thin on the left panel in Patient B whereas the molar on right panel has no enamel on the occlusal surface and thin enamel on the proximal surface (red arrow heads). (f) Patient C has broken incisal edge with exposed pulp cavity (red arrowhead) of the anterior tooth in left panel. Right panel shows an erupting molar with irregular and patchy enamel seen as white to light gray dots red arrowhead). (g) Bar graph comparing the volumes of enamel and dentin in the three patients. Patients A, B, and C had 65.08, 52.17, and 44.78 cu.mm of enamel, respectively. (h) Bar graph comparing the thickness of enamel in all three patients. The enamel thickness was 1.82, 0.95, and 1.07 mm in Patients A, B, and C, respectively. R: Right, L: Left

FIGURE 4

Audiograms representing air conduction thresholds for the right (red) and left (blue) ears of Patient A (dashed lines) and Patient B (solid lines). Bone conduction thresholds (not shown) were equal to air conduction thresholds. Shaded gray denotes range of normal hearing sensitivity

FIGURE 5

Variants associated with Heimler syndrome to date. (a) PEX1 protein, (b) PEX6, and (c) PEX26. Missense and nonsense variants are shown above the diagram; splicing, insertions, deletions, and copy-number variations are underneath