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Page 6 of 10 Chu et al. Rare Dis Orphan Drugs J 2023;2:2 https://dx.doi.org/10.20517/rdodj.2022.25

to microstomia [Figure 1]. She was suspected of having dystrophic epidermolysis bullosa, and was therefore
referred to Clinical Genetics, and prescribed copious emollients for the management of her skin condition.
She developed persistent buccal ulcers with leukoplakia simultaneously, and the biopsy showed moderately
differentiated squamous cell carcinoma. Wide local excision with selective neck dissection and flap
reconstruction was performed, which confirmed localized right buccal mucosa squamous cell carcinoma
with no lymph node metastasis and clear excision margins. Residual trismus causing further feeding
problems was noted during recovery in addition to her esophageal stricture.

After assessment in the Clinical Genetics Clinic, she was referred to and sponsored by the Hong Kong
Genome Project (HKGP) with whole genome sequencing performed. Referral criteria and details of the
[11]
HKGP were documented and published by Chu et al. (2022) . Results showed homozygous FERMT1
(NM_017671.4):c.811C>T p.(Arg271Ter), which was one of the same variants identified in patient 1, and
was classified as pathogenic according to the ACMG guidelines . Parental testing confirmed that her
[10]
mother was a carrier of the variant, but testing was not available from the paternal side as her father had
already passed away.

DISCUSSION
This case report summarised the phenotype and genotype of two Hong Kong Chinese patients with Kindler
syndrome. The clinical presentations of the two patients were compatible with the phenotypes described in
previous literature. However, prior to genetic investigation, the actual subtype of EB was not differentiable
by the referring clinicians due to the mimicry clinical presentation of KS to other subtypes of EB, hindering
many cases of diagnosis . Genetic testing in the two families helped to reach a molecular diagnosis leading
[12]
to better clinical management. Patient 1 received his diagnosis just 2 weeks after birth, which prompted
early management by the multidisciplinary team. This informed the characteristics of progressive
poikiloderma and photosensitivity in childhood, which is not a feature of other subtypes of EB. The timely
diagnosis also enabled the strengthening of sun protection for patient 1 as he grew up, as well as the
surveillance for skin cancer and mucosal tumour starting in adolescence. On the other hand, patient 2 had a
longer diagnostic odyssey, with the molecular diagnosis confirmed at 49 years old. At the time of testing, the
spectrum of KS manifestation including mucosal involvement and SCC had been observed. The
identification of the underlying genetic disease-causing variant helped with extending cascade testing to the
two younger sisters with skin issues that were less characterised. Limitations in the clinical comparison
between these two patients included the significant difference in age, and their different pathogenic
mutation profiles, although the genotype-phenotype correlation for Kindler syndrome is currently not well
established. The ongoing Hong Kong Genome Project may help identify more patients with the same
condition in this locality with continued longitudinal follow-up, which may allow better characterization of
the influence of earlier genetic diagnosis on the clinical courses of this disease.

Both patients in the case report harbour the pathogenic variant of FERMT1(NM_017671.4):c.811C>T
p.(Arg271Ter) (heterozygous in patient 1 and homozygous in patient 2). This is a well-characterised variant
that has been reported in multiple literature and disease databases [13-17] . It was described as a common
variant found in a tribe residing in a small, isolated village in rural Panama, in which 26 patients were found
to harbour homozygous c.811C>T, and the high prevalence in the population is due to the high rate of
consanguinity [16,17] .

The early phenotypic profile of Patient 2, who was also homozygous for c.811C>T variant, is similar to that
described in the Panaman cohort and consistent with the classical KS phenotype. However, as most of the
Panaman patients described were either children or young adults at the time of reporting, the comparison of