Ectodermal dysplasia in Saudi Arabia: a rare case report and literature review

Introduction

Ectodermal dysplasia (ED) encompasses a genetically and clinically heterogeneous group of rare inherited disorders that impair the development and function of ectodermal structures, most notably hair, teeth, nails, and sweat glands (1,2). Multiple subtypes exist, including hypohidrotic ectodermal dysplasia (HED), Ellis-van Creveld syndrome, and focal dermal hypoplasia, each associated with distinct genetic mutations. The most commonly implicated genes in HED include EDA (X-linked), EDAR, EDARADD, and WNT10A (autosomal forms), which together account for over 90% of diagnosed cases (1). More recently, TSPEAR has emerged as a causative gene in autosomal recessive ED, particularly in populations with high rates of consanguinity (2).

Understanding these diverse genetic variants is essential for improving diagnostic precision, guiding personalized treatment, and informing genetic counseling (3). In Saudi Arabia, where consanguineous marriages exceed 50% in certain regions, ED is likely underdiagnosed and may present with region-specific genotypes (3). Several case reports have highlighted this phenotypic diversity, such as a Jazan case with a unique EVC2 deletion in Ellis-van Creveld syndrome. However, molecular documentation of ED cases in the region remains limited (4).

This case report presents a clinically documented case of HED in a 10-year-old Saudi male, emphasizing the classic phenotype and the diagnostic challenges encountered in a resource-limited setting. In contrast to previously published reports, this manuscript uniquely integrates regional genetic insights, highlights the emerging role of TSPEAR in ED, and contextualizes the case within Saudi Arabia’s specific genetic landscape. Our aim is to underscore the need for greater awareness, early recognition, and integration of comprehensive genetic testing in the diagnostic pathway of ED, especially in populations with high consanguinity. We present this article in accordance with the CARE reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-51/rc).

Case presentation

A 10-year-old male presented to the clinic with complaints of persistent dry skin and an absence of sweating since birth. His condition was first recognized at the age of one when he was evaluated for a skin rash. Since then, he has experienced persistent dryness of the skin without recurrent infections or itching. The patient reported ocular discomfort, including intermittent eye dryness, especially in air-conditioned environments. There was no history of conjunctivitis, photophobia, or blurred vision, although he occasionally rubbed his eyes. There was no current use of corrective lenses, and ophthalmologic examination revealed mild conjunctival dryness. A systematic review revealed no significant concerns regarding vision, nasal congestion, ear infections, respiratory distress, cardiovascular symptoms, gastrointestinal or genitourinary issues, musculoskeletal abnormalities, or neurological deficits. On examination, the patient’s skin was notably dry. His scalp hair was fair-colored and sparse with normal texture, and he exhibited loss of eyebrow hair. His nails appeared normal (Figure 1A). Oral examination revealed missing teeth, with the remaining teeth exhibiting a conical shape (Figure 1B). Growth assessment showed a weight of 22 kg, which is below the average for his age, while his height measured 135 cm, falling within the normal range. His body mass index (BMI) was 12.07 kg/m², indicating underweight status. His past medical history was unremarkable, with no history of surgeries, known allergies, or blood transfusions. Family history did not indicate similar conditions in relatives, though the parents were consanguineous, increasing the risk for autosomal recessive inheritance. Routine laboratory investigations yielded normal results. No specialized diagnostic tests were performed. The patient was diagnosed based on clinical findings. A skin biopsy was not deemed necessary due to the classic presentation. Sweat testing and salivary function assessment were not performed, as the required equipment was not available at our facility.

Figure 1 Clinical manifestations of hypohidrotic ectodermal dysplasia in a 10-year-old Saudi male patient. (A) The patient exhibits notably dry skin, sparse scalp hair (fair-colored with normal texture), and alopecia of the eyebrows. (B) Intraoral view showing oligodontia and conically shaped remaining teeth. These images are published with consent from the patient’s parents.

The differential diagnosis included hidrotic ED (Clouston syndrome), which shares similar features such as nail, hair, and dental anomalies; however, it is distinguished by the presence of normal sweating, unlike the hypo-hidrosis or anhidrosis seen in this patient. Another consideration was EEC (ectrodactyly-ectodermal dysplasia-cleft lip/palate) syndrome, characterized by ED in conjunction with limb malformations (ectrodactyly) and orofacial clefts. The absence of limb anomalies and facial clefts in this case helped exclude EEC syndrome.

Management was directed toward symptomatic relief and patient education. The patient was prescribed moisturizers for regular skin moisturization and lubricating eye drops (artificial tears) to address mild ocular surface dryness. Although vision was subjectively normal, a formal referral to ophthalmology was made to assess for chronic keratoconjunctivitis and prevent potential corneal complications. The patient initially presented with a persistent skin rash (xerosis), for which he was treated with topical corticosteroids and emollients, resulting in partial improvement. The patient was referred to a pediatric dental specialist for evaluation. Initial management focused on preventive care, including regular dental checkups, oral hygiene education. Due to hypodontia, a dental prosthesis was considered to support feeding and speech development, but final restorative interventions were deferred to a later age to accommodate jaw growth and tooth development.

The patient and family were educated about the genetic nature of anhidrotic ED, including its effects on the skin, teeth, hair, and sweat glands. The inheritance pattern, typically X-linked recessive, but also occurring in autosomal recessive and dominant forms was explained, and genetic counseling was recommended for further understanding and family planning.

A follow-up was scheduled to monitor symptom progression and growth, with a strong emphasis on multidisciplinary care. After initiating treatment with emollients and moisturizers, the patient’s dry skin showed noticeable improvement. Regular application helped restore skin hydration and reduce discomfort, although intermittent dryness still occurred, particularly in colder weather. Continued use of topical therapies remains part of the long-term management plan.

The multidisciplinary approach included dermatology for continued skin care, dentistry for the evaluation of missing and conical-shaped teeth, and genetic counseling to support diagnostic clarity and patient education. This case illustrates the characteristic features of anhidrotic ED and highlights the importance of symptomatic relief, genetic awareness, and coordinated, multidisciplinary management.

Ethical considerations: All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s parents for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This report describes a 10-year-old Saudi male presenting with classical features of HED, including dry skin, oligodontia, and sparse hair, born to consanguineous parents. The diagnosis was made clinically, as genetic testing could not be performed due to financial and systemic barriers. Unlike other Saudi cases reported in the literature, this patient did not undergo genetic confirmation, yet the clinical phenotype strongly suggests HED.

Genetic research has identified several key genes involved in ED, notably EDA, EDAR, EDARADD, and WNT10A. HED is most commonly inherited in an X-linked pattern due to mutations in the EDA gene (1,2). However, autosomal dominant and recessive forms have also been described, frequently associated with mutations in EDAR, EDARADD, and WNT10A. These genes are part of the EDA/NF-κB and WNT signaling pathways essential for ectodermal development (1-3). Together, mutations in these four genes account for approximately 90% of hypohidrotic or anhidrotic ED cases (5-7). Mutations in other genes, such as TRAF6 and IKBKG, have been associated with rare ED phenotypes. A combined approach incorporating phenotypic, genotypic, and pathway-based classification has improved diagnostic precision and understanding of ED pathophysiology (8,9).

In recent Saudi case reports, TSPEAR mutations have emerged as a notable contributor to ED, as summarized in Table 1 (10-14). For example, Alshegifi et al. in 2022 reported a 13-month-old female with HED carrying two TSPEAR variants: a pathogenic mutation (c.1726_1728delinsTT, Val576Leufs*38) and a likely pathogenic variant (c.1325A>C, Asn442Thr) (11). Similarly, Gholman et al. in 2019 described a 9-year-old female with a mild form of ED linked to TSPEAR mutations (12).

Among the four main causative genes, EDA mutations account for over half of all cases. Mutations in EDAR, EDARADD, and WNT10A represent smaller subsets. In approximately 10% of individuals with HED, the genetic cause remains unidentified. EDA, EDAR, and EDARADD encode proteins involved in embryonic development, particularly in mediating interactions between the ectoderm and mesoderm, two foundational tissue layers that contribute to the development of skin, hair, teeth, nails, and sweat glands. Disruptions in these genes lead to abnormal development of these structures, resulting in the characteristic features of HED (15,16).

The WNT10A gene, a key regulator in Wnt signaling, is especially critical for ectodermal structure development, most notably the teeth. Mutations in WNT10A impair this process, leading to a range of symptoms, from mild dental anomalies to the complete absence of permanent teeth. Phenotypic expression associated with WNT10A mutations tends to be more variable, even within the same family (17).

In addition to WNT10A, TSPEAR gene mutations (ED 14, OMIM #618180) have been identified as causative in autosomal recessive forms of ED. TSPEAR encodes a regulator of the Notch signaling pathway, which plays a key role in the morphogenesis of ectodermal tissues (2). Peled et al. in 2016 first described TSPEAR mutations in five patients from three consanguineous families of Arab Muslim and Ashkenazi Jewish descent. These patients exhibited variable degrees of hypotrichosis, hypodontia, and mild facial dysmorphism, with some also showing hypohidrosis and hair follicle abnormalities (18). More recently, Rabie et al. in 2022 studied 10 Egyptian patients from eight families and found that dental abnormalities were the most consistent clinical feature, followed by hair and nail anomalies. The study also highlighted ethnic variability in dysmorphic features, reinforcing the value of population-specific genotype–phenotype studies (19).

This report adds both a new clinical case and a focused review of TSPEAR-related ED in the region. It is relevant to consanguineous populations and integrates both local and international data. However, limitations include the lack of molecular testing due to access and cost issues. No formal psychosocial or family segregation analyses were conducted, and referrals to specialists were delayed.

Compared to other Saudi cases such as Alshegifi et al. [2022] (11) and Gholman et al. [2019] (12), our patient shows a typical HED phenotype but lacked access to confirmatory testing. In contrast, those cases confirmed TSPEAR-related ED. Internationally, cases from Peled et al. [2016] (18) and Rabie et al. [2022] (19) demonstrate phenotypic variability, particularly in dental and hair anomalies. This supports the idea that TSPEAR mutations may be underdiagnosed in Saudi Arabia.

The clinical features in this case, hypodontia, dry skin, and sparse hair are consistent with ED from either classical or emerging genes like TSPEAR. Without genetic testing, the etiology cannot be confirmed, but the case reflects real-world diagnostic limitations. The absence of family history may suggest a de novo mutation or unrecognized cases in earlier generations.

Given the high prevalence of consanguinity in Saudi Arabia and the increasing number of ED cases without mutations in EDA, EDAR, EDARADD, and WNT10A (1,2), it is strongly recommended to include TSPEAR in genetic panels for ED in Middle Eastern populations. WES and NGS have helped identify novel mutations in Saudi patients, including some involving WNT10A, in both syndromic and non-syndromic presentations (1,2). Compound heterozygous mutations have also been reported, complicating inheritance patterns and highlighting the need for further research into ED heterogeneity (20).

Despite advances in genetic research, testing remains limited in many regions of Saudi Arabia. While specialized centers such as KAMC and KFSHRC provide such services, many hospitals lack resources for molecular diagnostics. Challenges include high cost, limited awareness among physicians and patients, and a shortage of genetic counselors (21).

Expanding national screening programs and establishing regional genomic databases are essential to improve diagnosis and management. The Saudi Human Genome Program is a promising initiative that may enable earlier detection and targeted treatment of ED.

Finally, care must be taken during schooling and sports to prevent educational delays, bullying, heat exhaustion, injuries, and emotional distress. Early diagnosis and supportive care are crucial. Patients with ED often face difficulty in temperature regulation, leading to heat or cold intolerance. Providing supportive interventions can significantly improve their daily quality of life.

Conclusions

This case highlights the classical features of HED in a 10-year-old Saudi male and underscores the diagnostic and management challenges in low-resource settings. In the absence of genetic testing, clinical evaluation played a pivotal role. The increasing recognition of TSPEAR-related ED in regional literature emphasizes the need to expand diagnostic panels beyond traditional genes like EDA and EDAR. Given Saudi Arabia’s high consanguinity rates, there is an urgent need for accessible genetic testing, national screening programs, and improved provider awareness to facilitate early diagnosis, multidisciplinary care, and informed genetic counseling.

Acknowledgments

All the views expressed in this paper are the authors’ own views and not an official position of the institution.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-51/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-51/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-25-51/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s parents for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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