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Introduction

Ectodermal dysplasia (ED) syndromes are a heterogeneous group of disorders that are characterized by congenital defects in two or more ectodermal structures. Among these structures, at least one must involve the hair, teeth, nails, or sweat glands (1,2). ED may also impact the skin, eye (lens or retina), inner ear, development of fingers and toes, nerves and other body parts (2). At least 150 different types of ED have been observed (2). EDs are classified in subgroups according to the presence or absence of the four primary defects observed in ED: Trichodysplasia (hair dysplasia), dental dysplasia, onychodysplasia (nail dysplasia), dyshidrosis (sweat gland dysplasia) (2).

A rare type of ED, ED-12 is described by congenital absent teeth, dystrophic toenails, hypohidrosis, and hair abnormalities and is linked to mutations in the keratinocyte differentiation factor 1 (KDF1) gene (3). Additionally, KDF1 is the most recently identified rare candidate gene for tooth agenesis (4). This gene is essential for skin epidermal differentiation and it is known that KDF1 deficiency results in significant abnormalities in skin development (5). However, the exact role and importance of KDF1 is still not entirely known (5).

In the present study, a case of a three-generation family was described where the novel mutation c.812A>C (p.Lys271Thr or K271T) in KDF1 was identified in four family members. The family was referred to the Clinical Laboratory Genetics, Access to Genome P.C. (Athens, Greece), after the birth of their first child that presented with natal teeth. Following the detection of the novel KDF1 mutation, further testing was performed in other family members and it was revealed that the father and paternal grandfather of the child were also carriers of the same mutation. Moreover, the second child of the family that was born 2 years later, was also born with natal teeth and was a carrier of the same mutation. This is an extremely rare case of the presence of natal teeth in carriers of a KDF1 mutation, since only 2 cases have been described thus far (3,6).

Case report

The family was referred to Clinical Laboratory Genetics, Access to Genome P.C., after a newborn presented with 12 natal teeth at birth (III-1) (Fig. 1). Whole exome sequencing (WES) was performed using next generation sequencing [accession no. ERR14252058; European Nucleotide Archive (ENA)]. DNA was isolated from the newborn's whole blood cells. Exome amplification was performed using Ion AmpliSeq™ Exome RDY (cat. no. A38264; Thermo Fisher Scientific, Inc.). Nucleotide Sequencing was performed using Ion Chef Instrument and Ion GeneStudio™ S5 System (Thermo Fisher Scientific, Inc.). The analysis involved 4,431 genes that are associated with known genetic diseases and syndromes. Alamut® Visual (version 1.7.1; SOPHiA GENETICS SAS) and Varsome Clinical (V.9.2.2; Saphetor SA) bioinformatic analysis systems were used for the data analysis. All findings from the analysis above were evaluated according to the American College of Medical Genetics and Genomics guidelines as well as the international scientific literature (7). The reference genome that was used is UCSC hg19. Bioinformatic analysis revealed a novel mutation in KDF1, namely c.812A>C (p.Lys271Thr or K271T).

Figure 1 Pedigree and clinical manifestations of the family including carriers of the KDF1 mutation. (A) The pedigree of a family revealing the carriers of the KDF1 mutation that includes the clinical manifestations of each member. (B) NT of III-1. (C) AD of III-1. (D) DT of I-1. (E) DT of II-1. KDF1, keratinocyte differentiation factor 1; NT, natal teeth; AD, atopic dermatitis; DT, dystrophic toenails; HD, hypodontia; I-1, paternal grandfather; II-1, father; III-1, child.

In order to confirm the presence of the mutation, Sanger sequencing was performed in the patient. Following DNA amplification by PCR, part of the KDF1 gene was sequenced and was compared with the control sequence. The sequences of the primers used were forward, 5'-CCACAGTGACTAAAGACCCCATTCC-3' and reverse, 5'-TCGTGGCTCCGAGGAGTACTAT-3'. The results confirmed the presence of the novel c.812A>C mutation in KDF1.

Sanger sequencing of KDF1 was performed on parental DNA, isolated from whole blood cells, in order to determine if the mutation was inherited or if it occurred de novo. Sequencing analysis revealed that the father of the patient (II-1) was also a carrier of the same mutation, indicating that the c.812A>C mutation was inherited. The paternal grandfather (I-1) and the second child (III-2) of the family, born 2 years later, were also tested and the results confirmed that they are carriers of the c.812A>C mutation in KDF1 (Fig. 2).

Figure 2 Sanger sequencing results showing part of the KDF1 gene, indicating that two children (III-1 and III-2), their father (II-1) and their paternal grandfather (I-1) are carriers of the same c.812A>C mutation, while their mother (II-2) is not. KDF1, keratinocyte differentiation factor 1.

Clinical characteristics of the carrier members

All four family members that carried the KDF1 mutation had characteristics of ED. According to the clinical history of the family, I-1 was born with natal teeth and now, at age 74, I-1 has hypodontia. Moreover, I-1 has dystrophic toenails and atopic dermatitis. Next, II-2 was born with five natal teeth and now, at age 40, has hypodontia. Moreover, II-2 has dystrophic toenails. Patients III-1 and III-2 were both born with natal teeth (III-1 had 12 and III-2 had seven natal teeth), and patient III-1 also has atopic dermatitis (Fig. 1; Table I).

Table I Summary of the clinical characteristics of the affected family members.

Table I

Summary of the clinical characteristics of the affected family members.

Member	Natal teeth	Hypodontia	Atopic dermatitis	Dystrophic toenails
I-1	+ (unknown number)	+	+	+
II-1	5	+	-	+
III-1	12	-	+	-
III-2	7	-	-	-

[i] -, Absence of condition; I-1, paternal grandfather; II-1, father; III-1, child; III-2, child.

Prenatal ultrasound examination of III-1 and III-2 during pregnancy did not reveal any anomalies. Regarding patient III-1, the scan at 12 weeks of gestation revealed a nuchal translucency measurement of 1.22 mm and the risk for common triploidies was low. The anomaly scan at 21+2 weeks and the third trimester growth scan at 32+2 weeks of gestation revealed normal fetal structure and growth. For patient III-2, the first trimester scan at 12+2 weeks of gestation revealed a nuchal translucency measurement of 1.98 mm and the risk for Trisomy 21 was 1 in 381. Both the anomaly scan at 21+2 weeks and the growth scan at 32+2 weeks of gestation showed normal fetal structure and growth.

Discussion

Mutations in KDF1 are associated with the manifestation of clinical characteristics of ED-12 (hypohidrotic/hair/tooth/nail type, Phenotype MIM no. 617337; OMIM®, John Hopkins University, Baltimore, USA) following autosomal dominant mode of inheritance. In the present study, a case of a family with a familial, previously undescribed mutation in KDF1, present in four family members and three generations is described. All carrier members exhibited clinical manifestations of ED. The novel mutation is a missense mutation that has not been reported in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and Decipher (https://www.deciphergenomics.org/) databases and is not described in the international literature. Bioinformatic analysis suggested that the mutation likely affects the structure and function of the KDF1 protein and according to the ACMG/AMP guidelines, it is categorized as a variant of unknown significance based on the PM2, PP2, PP3 criteria (7).

In 2013, KDF1 was first described by Lee et al (8). They described a Kdf1 mouse mutant that had a short snout and short limbs. This gene was expressed in epidermal cells during epidermal development. The Kdf1 mouse mutant showed a thickened epidermis and defective epidermal barrier formation due to keratinocyte defects. Zeng et al (9) showed that KDF1 is also expressed in tooth germs during tooth development, indicating that KDF1 plays an important role during tooth germ development (9).

To date, only a few cases of KDF1 mutations have been reported and the phenotype associated with the mutations varies (Table II). A heterozygous KDF1 mutation was first reported to cause ED-12 (autosomal dominant hypohidrotic ED) by Shamseldin et al (3). In their study, they described the case of a multi-generational family with ED, where the affected members exhibited tooth agenesis, hypohidrosis, lusterless hair, dystrophic toenails, lateral thinning of eyebrows and keratosis pilaris (3). Only one of the patients had natal teeth. Another case of a newborn with natal teeth was described by Aljohar et al (6). This was the first case of multiple teeth present at birth due to a KDF1 mutation (6). ED due to a KDF1 mutation has also been described by Manaspon et al (10). They identified a novel de novo mutation in KDF1 in a 5-year-old patient with ED. Moreover, Kamat et al (11) described a patient with hypohidrotic ED that had peg-shaped teeth due to the presence of a novel mutation in KDF1.

Table II Data regarding the four family members of this case report and patients from other studies that carry a KDF1 mutation.

Table II

Data regarding the four family members of this case report and patients from other studies that carry a KDF1 mutation.

Case	Phenotype	Teeth	Age at diagnosis	Mutation	Inheritance	(Refs.)
I-1	ED manifestations	Natal teeth at birth, presently hypodontia	71 years	c.812A>C	N/A	Present study
II-1	ED manifestations	5 Natal teeth at birth, presently hypodontia	37 years	c.812A>C	Paternal	Present study
III-1	ED manifestations	12 Natal teeth	2 weeks	c.812A>C	Paternal	Present study
III-2	ED manifestations	7 Natal teeth	2 weeks	c.812A>C	Paternal	Present study
Patient from Zeng et al	NSTA	Several absent teeth	7 years	c.908G>C	Maternal	(9)
Patient from Manaspon et al	ED	Loss of all teeth	5 years	c.823A>C	De novo	(10)
Patient from Aljohar et al	ED	Multiple natal teeth	1 week	c.753 > A	Maternal	(6)
Patient II:8 from Shamseldin et al	ED	Loss of all teeth	16 years	c.753C>A	Paternal	(3)
Patient II:2 from Shamseldin et al	ED	Loss of all teeth	30 years	c.753C>A	Paternal	(3)
Patient II:6 from Shamseldin et al	ED	Loss of all teeth	21 years	c.753C>A	Paternal	(3)
Patient III:2 from Shamseldin et al	ED	Natal	1 year	c.753C>A	Maternal	(3)
Patient II:7 from Shamseldin et al	ED	Loss of all teeth	17 years	c.753C>A	Paternal	(3)
Patient I:1 from Shamseldin et al	ED	Loss of all teeth	52 years	c.753C>A	N/A	(3)
Patient II-1 from Yu et al	NSTA	Several absent teeth	21 years	c.920G>C	Paternal	(4)
Patient from Kamat et al	Hypohidrotic ED	Peg shaped	3 years	c.449G>A	N/A	(11)

[i] KDF1, keratinocyte differentiation factor 1; ED, ectodermal dysplasia; NSTA, non-syndromic tooth agenesis, N/A, not available.

As aforementioned, KDF1 is the most recently identified rare candidate gene for tooth agenesis. Zeng et al (9) described the case of a 7-year-old patient with non-syndromic tooth agenesis (NSTA) that had invaginated lingual fossa and high susceptibility to dental caries. The patient was found to be a carrier of a novel KDF1 mutation. Yu et al (4) have also described a case of NSTA in a patient carrying a novel KDF1 mutation. In the present case report, the novel KDF1 mutation led to the presence of natal teeth in all carriers. Thus far, only 2 cases of KDF1 mutations leading to natal teeth at birth have been reported (3,6). To the best of our knowledge, this was the third instance of the presence of natal teeth at birth due to a KDF1 mutation. The presence of natal teeth in newborns with ED is highly uncommon (6).

As Zeng et al (9) suggested, the phenotype differences between patients with KDF1 mutations may be due to the different mutations or the difference in genetic background of the patients. In the present case report, all affected family members that were reported were born with natal teeth. Moreover, both adult members that are carriers of the mutation now have hypodontia. However, dystrophic toenails and atopic dermatitis are present in two out of the four affected members.

In the present study, the case of four family members across three generations who are carriers of the previously unreported c.812A>C mutation in KDF1 were described. The present case report included the clinical manifestations of all carrier members. Notably, all four affected family members had natal teeth at birth and to the best of our knowledge, this was the third report of natal teeth at birth due to a KDF1 mutation. The findings of the present case report are significant for establishing genotype-phenotype associations related to KDF1 mutations. Furthermore, they are crucial for genetic counseling, particularly in cases where this KDF1 mutation is detected prenatally.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study may be found in the European Nucleotide Archive (ENA), under accession no. ERR14252058 or at the following URL: https://www.ebi.ac.uk/ena/browser/view/ERR14252058.

Authors' contributions

CK substantially contributed to the design of the present study and prepared the manuscript. EM and IP were in charge of patient management and project supervision, as well as critically revised the manuscript. IP, EM, ES, CE, and ElP performed WES and Sanger sequencing and analyzed patient data. EfP, SS, AC, PA, ME and GN were responsible for assessment of the patients and advised on patient treatment. EM and IP confirmed the authenticity of all raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All procedures were conducted according to The Declaration of Helsinki 1975, as revised in 2008.

Patient consent for publication

Written informed consent was obtained from all adult family members for the inclusion of their data and images, as well as the data and images of their children. Any information revealing the identities of family members was not included.

Competing interests

The authors declare that they have no competing interests.

References