Punctiform and Polychromatic Pre-Descemet's Corneal Dystrophy

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Punctiform and Polychromatic Pre-Descemet's Corneal Dystrophy (PPPCD) is a very rare, asymptomatic corneal dystrophy with little supporting research. PPPCD is characterized by small punctate, polychromatic opacities in the pre-Descemet's membrane and is an inherited corneal disease often observed in family clusters. Diagnosis of PPPCD is achieved primarily via biomicroscopy, however, biomechanical testing, confocal microscopy, and anterior segment OCT may also be useful in diagnosis. Due to the asymptomatic nature of PPPCD, treatment is not recommended and visual prognosis is good.

Disease Entity

Punctiform and Polychromatic Pre-Descemet's Corneal Dystrophy ICD-10 H18.50

Disease

Punctiform and Polychromatic Pre-Descemet’s Corneal Dystrophy (PPPCD) is a very rare, inherited and asymptomatic corneal dystrophy with very little supporting research[1] that is characterized by pre-Descemet membrane small punctiform, polychromatic opacities[1–6]. It was first reported in 1979 and is now classified as a pre-Descemet corneal dystrophy, category 4, meaning that this dystrophy is yet to be more thoroughly defined as a distinct entity[7].

Etiology

PPPCD follows an autosomal dominant inheritance pattern with high penetrance and minimal variable expressivity[1,5,6]. This means that offspring who inherit gene variants associated with this condition are likely to exhibit its characteristics.

Risk Factors

To date, the novel missense PRDX3 c.568G>C (p.Asp190His), OR2M5 c.773T>C, and rare intronic PDZD8 c.872+10A>T variants have all been associated with being affected by PPPCD[3,5,8]. However, more associations have been made with the missense PRDX3[5] and intronic PDZD8[8] variants.

PRDX3 is a peroxiredoxin enzyme encoded by the PRDX3 gene found on human chromosome 10q26.11 and is a member of a peroxidase family which helps to maintain intracellular reactive oxygen species (ROS) homeostasis[9–11]. PRDX3 performs its redox functions mainly within mitochondria[9,10] and is predicted by in silico prediction tools to damage protein function[3]. Further research is needed to develop a complete understanding of how a missense mutation of this gene causes or contributes to this condition.

PDZD8 is a protein located in the endoplasmic reticulum membrane and mitochondria-associated endoplasmic reticulum membrane and is encoded by the PDZD8 gene on chromosome 10q25.3-q26.11[12]. It has been found to enable lipid and metal ion binding activity, affecting several cellular processes in the mitochondria and endoplasmic reticulum[12]. Although further research is needed to understand the pathogenesis of PPPCD more completely, the rare intronic variant of PDZD8 c.872+10A>T has been observed to create an intronic cryptic donor splice site subsequently producing transcription isoforms which may play a role in its development[8].

General Pathology

PPPCD presents on slit-lamp microscopy with numerous punctiform, hyperreflective, and polychromatic opacities of varying sizes around 10-15 micrometers[4] distributed evenly with the highest density located throughout the entire posterior corneal stroma[6]. The polychromaticity of the punctiform opacities has been described as shades of yellow, green, and red[6]. One study also documented anterior subcapsular lenticular opacities in a patient with a PRDX3 gene variant, indicating that the opacities may not be exclusively located in the pre-Descemet membrane. In contrast to other corneal dystrophies, keratocytes in PPPCD are generally normal[6].

Pathophysiology

The pathophysiology is not yet well-elucidated, but it has been shown via in silico prediction tools and in vivo splice assays that the novel missense PRDX3 and rare intronic PDZD8 gene variants, respectively, play a role in causing protein damage or altered transcription isoforms[3,8]. These findings suggest that these gene variants may alter downstream processes which result in the development of the opacities located in the pre-Descemet's corneal area. However, further research is required to confirm and elucidate these pathogenic mechanisms.

Primary prevention

There is no known primary form of prevention against PPPCD.

Diagnosis

Diagnosis of PPPCD is primarily a clinical diagnosis obtained via visual inspection during slit-lamp examination. However, biomechanical testing, confocal microscopy, and anterior segment OCT may also be useful in diagnosis[1,3,6,13].

History

Patients with PPPCD do not experience symptoms, so it is discovered incidentally upon slit-lamp examination[1,6]. Furthermore, there has been no documented predilection for age or sex[6,8].

Physical examination

The physical examination is performed via biomicroscopy[1,13].

Signs

One study[3] found that patients with this condition had refractive, topographic, or corneal biomechanical abnormalities associated with significantly increased corneal stiffness, so evaluating these corneal qualities on physical examination may also be helpful in diagnosing PPPCD.

Symptoms

No cases of patients diagnosed with PPPCD have revealed symptoms of visual impairment, eye disease, or systemic disease.

Clinical diagnosis

The clinical diagnosis is reached visually and is relatively easy given its apparent minimally variable expressivity and distinct appearance[1,3,8].

Diagnostic procedures

Imaging techniques such as specular and confocal microscopy and anterior segment OCT are the main diagnostic procedures. Confocal microscopy may be useful in detecting similarly described opacities in both the anterior and middle corneal stroma as well but in lower densities than those found in the posterior stroma[1,4]. However, corneal biomechanical evaluation may provide support for differentiating between PPPCD and other similar corneal dystrophies[3].

Laboratory test

PPPCD is mainly diagnosed clinically. However, genetic analysis performed via Sanger sequencing and Whole-Exon Sequencing in combination with genetic analysis software may also be used to screen for gene variants associated with this condition[3,8].

Differential diagnosis

- Cornea farinata

- Deep filiform dystrophy

- Deep punctiform dystrophy

- Deep blue dot corneal degeneration

- Fleck corneal dystrophy

- Pre-Descemet corneal dystrophy

- Cogan’s microcystic corneal dystrophy

Management

PPPCD is largely an asymptomatic condition and therefore does not require management. However, any corneal dystrophy that results in excessive stromal deposition may be associated with decreased visual acuity, so regular follow up may be recommended[1,2,6,14,15].

General treatment

There is no treatment for this condition other than corneal transplant if stromal involvement were to cause significant visual impairment.

Medical therapy

No medical therapy is indicated.

Medical follow up

Medical follow up may be initiated if the eye care provider is concerned about the extent of stromal involvement. However, PPPCD is not thought to be symptomatic so follow up may be unnecessary[1,2,6].

Surgery

Surgery is not indicated unless there is extensive stromal involvement necessitating a corneal transplant.

Surgical follow up

Surgical follow up is only indicated in the case of a corneal transplant per usual guidelines.

Complications

No complications have been associated with PPPCD.

Prognosis

PPPCD with no other co-existing corneal disease has a good prognosis.

Additional Resources

  1. Moshirfar M, Bennett P, Ronquillo Y. Corneal Dystrophy. StatPearls. Published online August 11, 2021. Accessed May 18, 2022. https://www.ncbi.nlm.nih.gov/books/NBK557865/

References

  1. Benito-Pascual B, Arriola-Villalobos P, Díaz-Valle D, Benítez del Castillo-Sánchez JM. Biomicroscopia confocal en 4 pacientes con distrofia corneal policromática. Archivos de la Sociedad Española de Oftalmología. 2018;93(10):470-475. doi:10.1016/J.OFTAL.2018.06.004
  2. Lagrou L, Midgley J, Romanchuk KG. Punctiform and Polychromatophilic Dominant Pre-Descemet Corneal Dystrophy. Cornea. 2016;35(4):572-575. doi:10.1097/ICO.0000000000000772
  3. Alió Del Barrio JL, Chung DD, Al-Shymali O, et al. Punctiform and Polychromatic Pre-Descemet Corneal Dystrophy: Clinical Evaluation and Identification of the Genetic Basis HHS Public Access. Am J Ophthalmol. 2020;212:88-97. doi:10.1016/j.ajo.2019.11.024
  4. Angélica M, Recine H, Sonia K, et al. Heredity and in vivo confocal microscopy of punctiform and polychromatic pre-Descemet dystrophy. doi:10.1007/s00417-018-3993-x
  5. Choo CH, Boto de los Bueis A, Chung DD, Aldave AJ. Confirmation of PRDX3 c.568G>C as the Genetic Basis of Punctiform and Polychromatic Pre-Descemet Corneal Dystrophy. Cornea. 2022;41(6). doi:10.1097/ICO.0000000000002828
  6. Fernandez-Sasso D, Acosta JEP, Malbran E. Punctiform and polychromatic pre-Descemet’s dominant corneal dystrophy. British Journal of Ophthalmology. 1979;63:336-338.
  7. Weiss JS, Møller HU, Lisch W, et al. The IC3D Classification of the Corneal Dystrophies. Published online 2008. doi:10.1097/ICO.0b013e31817780fb
  8. Alice Rose Barrington, Doug Chung, Jorge Alio del Barrio, Kavya Jatavallabhula, Vinay Swamy, Anthony J Aldave. Punctiform and Polychromatic Pre-Descemet Corneal Dystrophy: report of two families and the identification of a segregating intronic variant in PDZD8 using whole-exome sequencing | IOVS | ARVO Journals. Investigative Ophthalmology & Visual Science. Published 2019. Accessed May 16, 2022. https://iovs.arvojournals.org/article.aspx?articleid=2744726
  9. Lee YJ. Knockout Mouse Models for Peroxiredoxins. doi:10.3390/antiox9020182
  10. Mukhopadhyay SS, Leung KS, Hicks MJ, Hastings PJ, Youssoufian H, Plon SE. Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia. Journal of Cell Biology. 2006;175(2):225-235. doi:10.1083/jcb.200607061
  11. PRDX3 peroxiredoxin 3 [Homo sapiens (human)] - Gene - NCBI. Accessed May 16, 2022. https://www.ncbi.nlm.nih.gov/gene/10935
  12. PDZD8 PDZ domain containing 8 [Homo sapiens (human)] - Gene - NCBI. Accessed May 16, 2022. https://www.ncbi.nlm.nih.gov/gene/118987
  13. Ye YF, Yao YF, Zhou P, Pan F. In vivo confocal microscopy of pre-Descemet’s membrane corneal dystrophy. Clinical and Experimental Ophthalmology. 2006;34(6):614-616. doi:10.1111/J.1442-9071.2006.01288.X
  14. Moshirfar M, Bennett P, Ronquillo Y. Corneal Dystrophy. StatPearls. Published online August 11, 2021. Accessed May 18, 2022. https://www.ncbi.nlm.nih.gov/books/NBK557865/
  15. Sridhar MS. Anatomy of cornea and ocular surface. Indian Journal of Ophthalmology. 2018;66(2):190. doi:10.4103/IJO.IJO_646_17
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