Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

Abstract

Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Introduction

Kindler's syndrome (KS) is a very rare, autosomal recessive disorder caused by mutations in the FERMT1 gene. It is originally described by Kindler in 1954, ¹ and ∼250 cases have been reported in the literature since then. The largest series of patients is a cluster of 26 patients identified within a tribe in the Bocas-del-Toro province on the North-Western Caribbean coast of Panama. ²

Until recently, it was recognized as one of the orphan diseases. However, in 2008, KS was included in the spectrum of epidermolysis bullosa (EB) based on the report of the Third International Consensus Meeting on Diagnosis and Classification of EB which proposed a new classification of EB. According to this new classification, EB is divided into four major types—intraepidermal (EB simplex), junctional, dermolytic EB, and mixed (KS) types—based on distinguishing ultrastructural sites of blister formation. ³

KS describes a specific entity that is characterized by the presence of clinical phenotypic features unique among EB (most notably photosensitivity) and blistering that arises in multiple levels within and/or beneath the basement membrane zone, rather than within a discrete plane, as occurs in all other EB types. ⁴

Case Description

We present two cases of KS in two sisters born to consanguineous parents (the parents are first-degree cousins). They were being followed up in pediatric hematology for recurrent episodes of neutropenia, although did not strictly fulfill the criteria of cyclic neutropenia.

Case 1

The patient is a 21-year-old female, born by spontaneous vaginal delivery, fourth in birth order. She presented at the age of 3 months with a history of chronic watery diarrhea which started at the age of 2 weeks. Colonoscopy showed severe distal colitis, biopsy showing abscess formation with increased inflammatory cells in lamina propria, and evidence of cleft distortion with decreased mucous. Small bowel biopsy revealed partial villous atrophy. So, a diagnosis of milk-induced colitis was made and breastfeeding was stopped.

Her diarrhea improved over time, but she developed neutropenia (absolute neutrophil count (ANC) around 600/μL (normal range: 1,500–7,500/μL)] which started at 6 months of age. This neutropenia was cyclic, although did not fulfill the criteria for cyclic neutropenia. She has a history of developing recurrent episodes of skin infections during these phases of neutropenia. Initially, she was managed conservatively with intermittent antibiotic courses. With time, the episodes became more frequent and more severe, and she was therefore started on granulocyte colony-stimulating factor at the age of 5 years and continued till the age of 11 years. She continued to have mild episodic neutropenia till the age of 17 years but presently is maintaining a normal neutrophil count without any medication.

She was first seen in the dermatology clinic at the age of 4 years, and at that time, she had poikilodermatous skin on the dorsum of hands, feet, and face. There was a history of blistering lesions of the dorsum of hands which started from infancy and improved over time. Two skin biopsies were taken for histology and direct immunofluorescence (DIF). Histology showed poikilodermatous changes with negative DIF except for mild immunoglobulin M deposits in superficial dermis (of unknown significance). A diagnosis of Rothmund–Thomson's syndrome was considered and the patient was referred to medical genetics for confirmation, but no mutations of the RECQL4 gene were detected. She also had a history of atopic dermatitis which was managed by topical steroids and emollients.

Later on, whole exome sequencing analysis was done using next-generation sequencing which showed a homozygous loss-of-function (LOF) variant of FERMT1 (FERMT1:NM_017671:exon9:c.1090-IG > A). According to the American College of Medical Genetics and Genomics (ACMG) guidelines, it should be classified as a pathogenic variant. These homozygous LOF variants of FERMT1 are a common mechanism of KS.

During her follow-up in our clinic, she was also found to have moderate to severe dental caries without much of gingivitis and is being followed up by our dental colleagues. Lately, the patient has started to develop pseudoainhum in three fingers ( Fig. 1 ).

Fig. 1.

Pseudoainhum in three digits (Case 1).

Case 2

A 16-year-old girl, sixth in birth order, sibling of case 1 started with chronic constipation since infancy with recurrent upper respiratory tract infections in the form of recurrent tonsillitis and acute otitis media. She was also found to have episodic neutropenia (initial ANC in the range of 800) which improved over time without any treatment. In addition, she was found to be negative for RECQL4 gene mutations. She was seen in the dermatology clinic at the age of 3 years, and at that time, she had early atrophic changes in the skin of both hands and feet with no prominent poikiloderma, and after some time, she developed poikiloderma over the face, dorsum, and hands and feet which was evident from the age of 6 years. Evaluation for chronic constipation showed esophageal stricture at the upper esophageal sphincter for which multiple sessions of esophageal dilatations were performed. Furthermore, whole exome sequencing analysis was done which showed the same homozygous LOF variant of FERMT1 (FERMT1:NM_017671:exon9:c.1090-IG > A). She also developed recently dental caries.

Discussion

Various conditions that can cause blistering, atrophy of the skin, and/or poikilodermatous changes must be differentiated from KS. ^{5 6} It might be difficult to differentiate KS from other variants of EB in newborns. Progressive improvement of blistering, photosensitivity, poikilodermatous changes, and cutaneous atrophy with age help differentiate KS from EB. ⁷ Our first patient also presented with blistering over the acral areas in infancy which improved over time but resulted in the development of poikiloderma, although none of our patients reported photosensitivity ( Table 1 ) ( Figs. 1 and 2 ).

Table 1. Comparison of different features in our two cases.

	Case 1	Case 2
Age at diagnosis	21 y	16 y
Sex	Female	Female
Whole exome sequencing analysis positive findings
Variant	FERMT1:NM_017671:exon9:c.1090-1G   >   A—(homozygous)	FERMT1:NM_017671:exon9:c.1090-1G   >   A—(homozygous)
Clinical features
Recurrent neutropenia	Yes	Yes
Photosensitivity	No	No
Acral blister	Yes	Yes
Atrophy and poikilodermatous changes	Yes	Yes
Teeth	Caries	Caries (started recently)
Hair	Normal	Normal
Oral cavity	Normal	Normal
Esophageal strictures	No	Yes
Pseudoainhum	Yes	No

Fig. 2.

Poikiloderma of both hands (Cases 1 and 2).

Fischer et al in 2005 proposed five major and two minor clinical diagnostic criteria, as well as associated findings, for the diagnosis of KS. The major proposed criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, gingival fragility, and/or swelling. The minor proposed criteria are syndactyly and mucosal involvement (anal, esophageal, urethral, and laryngeal stenosis). The associated findings are nail dystrophy, ectropion of the lower lid, palmoplantar keratoderma, pseudoainhum, leukokeratosis of the lips, squamous cell carcinoma, anhidrosis/hypohidrosis, skeletal abnormalities, and dental caries/periodontitis. They considered the diagnosis as “certain” if four major criteria are present. In the presence of three major and two minor criteria, the diagnosis is “probable” and the diagnosis is considered to be “likely” if two major criteria and two minor criteria or associated findings are present. ⁸ The above-proposed criteria provide clinical grounds for the diagnosis and help clinicians to narrow down the differential and confirm the diagnosis by genetic testing.

The diagnosis of KS can be established by immunofluorescence mapping and/or detecting mutations in the FERMT1 gene. ^{5 9} The FERMT1 gene encodes the kindlin-1, a protein associated with integrins and focal adhesions. It is located next to basal keratinocytes and helps in the linking of actin filaments to membrane proteins. LOF of this protein thereby affects the structure and adhesion of the keratinocytes and therefore explains the associated fragility of the skin. ^{10 11}

About 84 unique pathogenic variants have been identified in the FERMT1 gene so far, ² most of which create premature stop codons resulting in the LOF of kindlin-1. In addition, amino acid substitutions, splice site variants, and intronic variants have also been identified. As most of the variants are null, resulting in the absence of kindlin-1, their nature does not appear to have a significant influence on the clinical presentation. Thus, the genotype–phenotype correlations are not well established for KS. The obvious clinical variability present in KS patients suggests a role of environmental and/or epigenetic factors. ^{2 10}

Guerrero-Aspizua et al in a recent large case series of 91 patients with KS also did not find any specific mutation having a predictive value in the development of squamous cell carcinoma (SCC). However, they noticed a different profile of mutations in patients bearing tumors and tumor-free patients. While mutations in the overall series were distributed along the whole length of the gene, the mutations in the patients bearing SCC were mostly present in the N-terminal part of the gene. Thus, the phenomenon of genotype–phenotype correlation cannot be entirely ruled out. ¹²

Our patients fulfilled three of the major criteria and only one minor criterion in addition to the associated finding of pseudoainhum which did not make the diagnosis even as probable as per the above-proposed classification ( Table 1 ). However, the detection of a LOF mutation in the FERMT1 gene, which according to ACMG guidelines, should be classified as a pathogenic variant, confirmed the diagnosis. ¹³

The cutaneous findings of KS may also be simulated by various other photosensitivity disorders related to impaired DNA repair. These include Rothmund–Thomson's syndrome, xeroderma pigmentosum, Bloom's syndrome, Cockayne's syndrome, etc., besides other conditions with photosensitivity and poikiloderma.

Patients with Rothmund–Thomson's syndrome develop poikiloderma and photosensitivity like KS. However, the presence of additional features such as hypogonadism, sparse hair, and cataracts in the former distinguishes it from KS. None of our patients had these additional features. Besides, the RECQL4 gene mutation analysis was negative.

Xeroderma pigmentosum is an autosomal recessive disorder with decreased ability to repair DNA damage such as that caused by ultraviolet light. It is characterized by extreme photosensitivity, pigmentary, and poikilodermatous changes on photoexposed skin, but lacking the skin fragility as seen in KS. These patients also have early-onset skin cancers and might have multiple neurological abnormalities. Both our patients were lacking photosensitivity which made this diagnosis unlikely. Patients with Bloom's syndrome have photosensitivity and develop telangiectasias and erythema of the sun-exposed areas without showing true poikiloderma. Short stature, recurrent infections, and increased frequency of hematological malignancies are also features of this disease. Cockayne's syndrome is characterized by erythema in photo-distributed areas, atrophy, and hyperpigmentation. It can be differentiated from KS by the presence of dwarfism, cachexia, progressive pigmentary retinopathy, deafness, and bird-like facies.

Reticulated hyperpigmentation, nail dystrophy, and leukoplakia are characteristic features of dyskeratosis congenita. The pigmentary changes are not truly poikilodermatous and bullae are not usually seen. None of our patients was having any of the distinguishing features of the above conditions.

Clericuzio-type poikiloderma with neutropenia (PN) is a rare autosomal recessive disorder characterized by poikiloderma, permanent noncyclic neutropenia, recurrent sinopulmonary infections, pachyonychia, and palmoplantar hyperkeratosis. Mutations in the C16ORF57 gene, which is located on chromosome 16q13, have been identified as the cause of PN. ^{14 15}

Our patients also had PN. However, the neutropenia was cyclic and not permanent. Besides, the other features of PN were not present and no mutation in the C16ORF57 gene was detected on whole exome sequencing analysis.

Our patients have no photosensitivity which is usually seen in patients with KS. However, they have an additional feature of cyclic neutropenia which has not been described in KS. Although clinical presentation narrowed down the differential diagnosis, the final confirmation was made only upon the detection of a homozygous mutation which required whole exome sequencing analysis to reach a diagnosis. Our case further highlights the importance of whole exome sequencing analysis in the diagnosis of genodermatosis especially in cases where the clinical presentation is not classic or there is overlapping of features.