Intensive genetic and genomic research in recent decades has contributed tremendously to the elucidation of the genetic background of rare (prevalence 1:2000) monogenic diseases. In parallel with this, one of the consequences of today’s digital development is that online available databases provide the widest range of insights in a given topic. These incredible developments are clearly demonstrated by the fact that in the Online Mendelian Inheritance in Man (OMIM, https://www.omim.org/) database 144 rare monogenic isolated or syndromic dental diseases are presented. Among the rare monogenic dental diseases with extradental manifestations, there are 55 ones that are also associated with cutaneous manifestations.

In the case of suspected rare monogenic dental-cutaneous disease, detailed documentation of anamnestic data is essential to determine the exact clinical diagnosis (phenotype). Information must be obtained on dental abnormalities, cutaneous alterations and additional symptoms that may be associated. The inheritance of the disease within the family should be observed, drawing the family tree can provide significant help in clarifying the inheritance of the diseases.

Of the 55 rare monogenic dental-cutaneous diseases, 23 have autosomal dominant inheritance (AD; Table 1) and 27 entities are inherited with autosomal recessive manner (AR; Table 2).

Regarding the ratio of dominant and recessive syndromes, they occur in almost the same proportion among these diseases.

Among these rare monogenic diseases characterized by teeth and skin manifestations as well, there are only 5 with X-linked inheritance pattern (Table 3).

Molecular genetic testing is usually carried out after the identification of the clinical phenotype, with the written consent of the person concerned or his legal representative after genetic counseling. The task of clinical genetic counseling work is to provide information on the nature, etiology and risk of recurrence of the disease. In case of rare monogenic dental-cutaneous diseases, the specific, causal therapeutic modalities are not yet widely available, therefore the prevention and treatment of dental, cutaneous and additional non-dental and non-cutaneous manifestations is the primary goal of medical work.

Regarding the frequency of the different cutaneous manifestations of rare monogenic dental diseases, 37 diseases (67%) of the 55 are featured by the presence of skin manifestations. The observed skin symptoms in this group of diseses are the following ones: hypohidrosis, hyperkeratosis, dry skin, skin fragility, hyperhidrosis, and aplasia cutis congenital, sagging, redundant skin, photosensitive skin, dermatitis, wrinkled skin, keratosis pilaris (Fig. 1). Hypohidrosis and different forms of hyperkeratosis are the characteristics of 12 diseases (21%), dry skin is a common feature of 9 (16%) and skin fragility is a frequent symptom in 7 entities (12%).

Regarding the frequency of the different cutaneous manifestations of rare monogenic dental diseases, 34 diseases of the 55 (61%) are featured by the presence of nail manifestations. The associated nail abnormalities are the following: dysplastic nails, nail ridging, nail pits, koilonychia, onycholysis and onychogryphosis (Fig. 2). Dysplastic nails are the characteristics of 25 diseases (45%) and hypoplastic nails are linked with 7 ones (12%).

Regarding the frequency of the different cutaneous manifestations of rare monogenic dental diseases, 40 diseases of 55 (72%) are featured by the presence of hair abnormalities. The associated hair symptoms are the following: sparse hair, alopecia, hypertrichosis, thin hair and wooly hair (Fig. 3). Sparse hair is a characteristic of 27 diseases (49%) and alopecia linked to 10 (18%).

Besides the most common cutaneous manifestations in rare monogenic dental diseases, there are some clinical features, that are only associated with one specific disease among the reviewed rare monogenic dental diseases with cutaneous manifestations (Table 4).

It is important to know about the most frequent teeth abnormalities in the group of rare monogenic diseases with cutaneous and dental abnormalities, since it is easy to notice them during the dermatological examination. Missing teeth and abnormal-shaped teeth are the two most common features associated with monogenic dental-cutaneous diseases. Missing teeth are present in 35 (64%) of the investigated 55, while shape abnormalities of the teeth are a frequent symptom in 34 (62%) of this group. Enamel abnormalities are associated with 12 entities (22%), while delaped or unerupted teeth are linked with 11 diseases (20%). Other relatively rarely detected teeth abnormalities are hypernumerary teeth, chronic periodontitis and dentin abnormalities.

Among the other non-dental and non-cutaneous manifestations ophthalmological, skeletal, otorhinolaryngological, neurological, urogenital, pulmonary, cardiovascular and gastrointestinal abnormalities occur frequently, however, the most common ones are the ophthalmological and skeletal anomalies.

In the case of the presented pathologies, the exact description of the dental-cutaneous and additional possible clinical symptoms, as well as the clarification of the inheritance process, can greatly facilitate the establishment of the diagnosis. Molecular genetic testing can confirm the established clinical diagnosis by clarifying the genetic background. At the same time, during the everyday clinical genetics routine, we also encounter quite complex cases. In the following, by presenting some of our own cases, we highlight that different variants of the same gene can result in different clinical entities, moreover, even the same variants of the same gene can cause the development of different clinical symptoms in the affected patients. With our cases, we would like to draw the attention to the fact that the phenotypic variability can be quite large in the case of rare, genetically determined dental symptoms (also) associated with cutaneous symptoms, and how important it is to involve a clinical geneticist in clarifying each such case or family.

Regarding the genetic background, the rare pathogenic or likely pathogenic mutations of 42 disease-causing genes have been associated with the group of rare monogenic dental diseases with cutaneous manifestations. The explanation for this phenomenon is that different variants of the same disease-causing gene can lead to the development of different entities. As an example diseases caused by variants in the wingless-type MMTV integration site family member 10A (WNT10A) gene can be inherited as AD or AR and can lead to the development of 3 different rare diseases such as tooth agenesis 4 (STHAG4; OMIM 150400), odontoonichodermal dysplasia (OODD; OMIM 257980) and Schöpf-Schulz-Passarge syndrome (SSPS; OMIM 224750) [1–4]. These three entities have overlapping dental features such as the genesis of a variable number of permanent teeth (most commonly missing upper and lower premolars), small, pin-shaped teeth, and conical teeth. In OODD and SSPS, there may be palmar plantar hyperkeratosis and hypotrichosis including sparse eyebrows, sparse, dry, thin, brittle hair and nail abnormalities [1,2]. In the differential diagnosis of OODD and SSPS, the presence of eyelid cysts is decisive, in the case of which the SSPS clinical diagnosis arises [1,2].

In connection with the detection of a case in a British family, we confirmed that two different clinical variants associated with mutations in the WNT10A gene, such as OODD and SSPS, can even occur within the same family (Table 5). Eyelid cysts previously attributed to SSPS were present in a family member carrying the homozygous nonsense mutation (p.Cys107X) of the gene, while in homozygous missense (p.Phe228Ile) or compound heterozygous patients (1 heterozygous missense and 1 heterozygous nonsense mutation carriers) the OODD clinical variant was formed [1,2]. In the British family, dental symptoms were the most common among all clinical symptoms in the family [1,2].

Another interesting feature of our research is that the missense mutation we detected (p.Phe228Ile) was first identified in an US family affected by STHAG4, where hypodontia affecting the lateral incisors and premolar teeth developed in the patients [3]. Furthermore, Van den Boogaard et al. [4] detected the missense (p.Phe228Ile) and nonsense (p.Cys107X) mutations in 11 patients with tooth agenesis, who did not show the characteristics of OODD or SSPS in either homozygous, heterozygous or compound heterozygous form [4]. All of this clearly illustrates how varied the clinical symptoms can be even in patients carry variants of the same gene or even exactly the same rare variant.

Entities caused by CTSC gene variants show an AR inheritance pattern and can result in the development of 3 different entities, whose common clinical feature is the development of aggressive periodontitis. In aggressive periodontitis type 1 (PPP; OMIM 170650) there are no associated extradental symptoms, while in Papillon-Lefevre syndrome (PLS; OMIM 245000) and Haim-Munk syndrome (HMS; OMIM 245010) the clinical picture is characterized by hyperkeratosis of the palms and soles. Other clinical characteristics of HMS are the development of pes planus, acro-osteolysis, arachnodactyly and nail abnormalities. In the case of a Hungarian female sibling pair from Szeged, dental and dermatological symptoms appeared in early childhood and the dermatological symptoms developed first. Due to the rapidly progressive, generalized periodontitis characteristic of the disease, early loss of milk teeth and later involvement and loss of permanent teeth appeared in both patients. Genetic screening identified a homozygous missense mutation (p.Gly301Ser) in the CTSC gene in both members of the examined sibling pair suffering from Papillon–Lefevre syndrome. The significance of our studies is that they draw attention to a rare disease, the Papillon-Lefevre syndrome, in which the first symptoms that develop can also be dental symptoms [5,6]. Moreover, investigating two independent Hungarian patients from Kaposvár, the genetic screening of the CTSC gene revealed the presence of the same homozygous nonsense mutation (p.Arg250X), however one patient exhibited the PLS phenotype and the other developed HMS (Fig. 6) phenotype [7]. Although these patients were not aware that they were related, haplotype analysis (especially genotypes of the rs217116 and rs217115 polymorphisms) clearly indicated that the patients carry the same haplotype, whereas unrelated healthy controls carried several different haplotypes.

Whole exome sequencing revealed two putative phenotype-modifying variants in these two patients: a missense mutation (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in intracellular signalling of cystatin F, a known inhibitor of the cathepsin protein, and a missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene, influencing the function of the cathepsin protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein [8].

Diseases caused by mutations in the EDA1 gene show XLD (X-linked dominant) or XLR (X-linked recessive) inheritance and can lead to the development of two different clinical entities: one with only dental symptoms, this is tooth agenesis 1 (STHAGX1; OMIM 303500), the other entity is ectodermal dysplasia 1, also known as Christ-Siemens-Touraine syndrome (ECTD1; OMIM 305100), the characteristic triad of which is reduced sweating, reduced or missing fur and dental symptoms [9]. We performed the genetic examination of a Hungarian patient who had the complete triad of ECTD1 [9]. The identified variant affects the tumor necrosis factor (TNFα) binding domain of the EDA1 protein; presumably through the dysfunction of this domain it can contribute to the induction of pathological cell biological processes, which cause the disease [9]. The interesting feature about the missense mutation identified on the EDA1 gene (p.Val324Glu) is that heterozygous carrier women are almost completely symptom-free: their coat and hair are normal and sweating is in the normal range (Table 6). Only the presence of cone-shaped teeth can draw attention to the heterozygous carrier status [9].

As a result of the explosive technological development in the field of genetics and genomics over the past decades, enormous progress has been made in understanding the genetic background of rare monogenic dental diseases with cutaneous manifestations. Reviewing the clinical and genetic characteristics of these diseases may raise the attention of the clinicans and helps the initiation of genetic screening. A study investigating the monogenic skin diseases (genodermatoses) with teeth abnormalities have already been published [10]. However, our study is unique in the aspects that we have focused primarily on monogenic dental diseases and we have performed a comprehensive review of the OMIM data and incorporated cases from our own clinical practice.

The reviewed examples of the WNT10A, CTSC and EDA1 phenotypic spectra clearly illustrate that the variants of the same disease-associated gene can lead to the development of variable clinical entities. If the possibility of a rare, genetically determined dental-cutaneous disease arises on the basis of the above summarized dental and cutaneous manifestations, then it is definitely worth referring the patient to genetic counseling and possibly genetic testing.