Midfacial Toddler Excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism

Nivedita Sarveswaran; Yunisa Pamela; Akhila A N Reddy; Akash P Mustari; Anchala Parthasarathi; Anthony J Mancini; Anuradha Bishnoi; Arun C Inamadar; Bayanne Olabi; Fiona Browne; Gargi N Deshmukh; Kenneth McWilliam; Keshavamurthy Vinay; Sahana Srinivas; Samantha Ibbs; Sivakumar Natarajan; Vadlamudi R Rao; Vijay Zawar; Vykuntaraju K Gowda; Samiha S Shaikh; Celia Moss; Christopher G Woods; Ichrak Drissi

doi:10.1093/bjd/ljae151

Midfacial Toddler Excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism

Br J Dermatol. 2024 Apr 9:ljae151. doi: 10.1093/bjd/ljae151. Online ahead of print.

Authors

Nivedita Sarveswaran¹, Yunisa Pamela^{1

2}, Akhila A N Reddy³, Akash P Mustari⁴, Anchala Parthasarathi³, Anthony J Mancini⁵, Anuradha Bishnoi⁴, Arun C Inamadar⁶, Bayanne Olabi⁷, Fiona Browne⁸, Gargi N Deshmukh⁹, Kenneth McWilliam¹⁰, Keshavamurthy Vinay⁴, Sahana Srinivas¹¹, Samantha Ibbs¹², Sivakumar Natarajan¹³, Vadlamudi R Rao⁹, Vijay Zawar¹⁴, Vykuntaraju K Gowda¹⁵, Samiha S Shaikh¹, Celia Moss^{12

16}, Christopher G Woods¹, Ichrak Drissi¹

Affiliations

¹ Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, UK.
² Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
³ Dr. Anchala Skin Institute and Research Center, Hyderabad, India.
⁴ Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
⁵ Division of Dermatology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁶ Department of Dermatology, Shri BM Patil Medical College & Hospital, BLDE University, Bijapur, India.
⁷ Department of Dermatology, Edinburgh Royal Infirmary, UK.
⁸ Department of Paediatric Dermatology, Children's Health Ireland (CHI) at Crumlin Crumlin, Ireland.
⁹ Genome Foundation, Hyderabad, India.
¹⁰ Paediatric Neurology, Neurosciences Department, Royal hospital for Children and Young people, 50 Little France Cres, Edinburgh, UK.
¹¹ Department of Pediatric Dermatology, Indira Gandhi Institute of Child Health, Bangalore, India.
¹² Department of Paediatric Dermatology, Birmingham Children's Women's and Children's NHS Foundation Trust, Birmingham, UK.
¹³ The Newcastle Upon Tyne Hospitals NHS Foundation Trust, UK.
¹⁴ Department of Dermatology, Dr. Vasantrao Pawar Medical College and Research Center, Nashik, India.
¹⁵ Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India.
¹⁶ College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.

PMID: 38591490
DOI: 10.1093/bjd/ljae151

Abstract

Background: PRDM12 polyalanine tract expansions cause two different disorders; Midfacial Toddler Excoriation Syndrome (MiTES) - itch with normal pain sensation associated with homozygous 18 alanines (18A), and congenital insensitivity to pain (CIP) with normal itch with homozygous 19A. Knowledge of the phenotype, genotype, and disease mechanism of MiTES is incomplete. Why PRDM12 18A versus 19A can cause almost opposite phenotypes is unknown; no other poly-alanine or poly-glutamine tract expansion disease causes two such disparate phenotypes.

Methods: We assessed the genotype and phenotype of 9 new, 9 atypical, and 6 previously reported patients diagnosed with MiTES. Using cell lines with homozygous PRDM12 of 12A (normal), 18A (MiTES) and 19A (CIP) we examined PRDM12 aggregation and subcellular localisation by image separation confocal microscopy and sub-cellular fractionation western blotting.

Results: MiTES presents in the first year of life, and in all cases the condition regresses over the first decade leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12-CIP are rarely found. The genotype-phenotype study of PRDM12 polyalanine tract shows that 7A -15A are normal; 16A -18A are associated with MiTES; 19A leads to CIP; and no clinically atypical MiTES cases had an expansion. PRDM12 aggregation and sub-cellular localisation differ significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein aggregation disease.

Conclusion: We provide diagnostic criteria for MiTES, and improved longitudinal data. MiTES and CIP are distinct phenotypes despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells.. We hypothesise that the developmental environment of the trigeminal ganglion is unique and critically sensitive to prenatal and postnatal levels of PRDM12.