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Page 2 of 10 Chu et al. Rare Dis Orphan Drugs J 2023;2:2 https://dx.doi.org/10.20517/rdodj.2022.25

existing mutation spectrum KS in East Asians.

Keywords: Kindler syndrome, FERMT1, Chinese, Hong Kong Genome Project

INTRODUCTION
Kindler syndrome (KS, MIM#173650) is a rare subtype of epidermolysis bullosa (EB) with autosomal
recessive inheritance. About 400 cases have been reported worldwide to date since this syndrome was first
described in 1954 by Theresa Kindler . KS is characterized by skin fragility and blistering at birth, followed
[1,2]
by the development of photosensitivity and progressive poikilodermatous skin changes. Other clinical
characteristics include scarring in infancy, hyperkeratosis of palms and soles with fissuring,
pseudosyndactyly associated with repeated blistering, and various mucosal manifestations such as
ectropion, urethral stenosis, and labial leukokeratosis. Generalized poikiloderma eventually develops and
persists throughout adult life in most affected individuals. KS’ phenotype is progressive and evolving during
[2]
lifetime; skin blistering and photosensitivity occur less frequently with age . Mucosal manifestations,
including chronic gingivitis, dental caries, periodontitis, advanced periodontal bone loss and leukokeratosis
[2,3]
of buccal mucosa, are frequent and prominent features in adulthood . KS patients also have an increased
lifetime risk of developing squamous cell carcinoma (SCC), with the cumulative risk of SCC increased to
[4]
67% by the age of 60, among which 54% will develop metastatic disease with high mortality .
The KS determinant gene, FERMT1, encodes a 677 amino acid protein, kindlin-1, a component of focal
[5,6]
contacts in keratinocytes expressed in the epidermis, particularly in the basal keratinocytes . It was
reported that loss of kindlin-1 in keratinocytes leads to loss of cell polarity, decreased adhesion, reduced cell
proliferation and increased apoptosis, resulting in abnormal skin fragility with defects in actin-extracellular
[5,7]
matrix linkage . It differs from classic keratin-extracellular matrix linkage underlying the pathology of
other subtypes of epidermolysis bullosa . It has also been shown that reduced production of kindlin-1
[5]
protein in keratinocytes is associated with altered mitochondrial structure, localization and function,
making them prone to damage by oxidative stress, which could be a mechanism for susceptibility to the
[8]
development of cancers .

KS is caused by the presence of biallelic pathogenic loss-of-function variants in FERMT1. Most reported
FERMT1 variants associated with KS are null variants, while in-frame deletions and missense variants are
proposed to be associated with milder clinical findings and later onset of complications . Consanguineous
[8]
marriage has been reported to be one of the major reasons for KS . Individuals with a family history of KS
[9]
or carriers of FERMT1 pathogenic variants are recommended to receive prenatal genetic testing, allowing
early diagnosis in at-risk infants, which is pivotal for follow-up genetic counselling and early initiation of
[2]
treatment, leading to improved long-term outcomes .

This case report summarises two Chinese individuals from Hong Kong who have the same pathogenic
variant that has never been reported in East Asians. With the advancement in genomic sequencing
technologies, while one patient received his molecular genetic diagnosis in infancy (patient 1), the other
(patient 2) had suffered diagnostic odyssey for over 40 years. The present paper aims to outline the
difficulties in differentiating KS from other dermatological conditions, and the significance and clinical
utility of identifying the disease-causing genetic variants in children and adults with KS.