Nicolaides-Baraitser syndrome (NCBRS) is a rare autosomal dominant disease characterized by developmental delay, distinctive craniofacial features, sparse hair, and is caused by de novo mutations in the SMARCA2 gene. We report the case of an 11-year-old male with NCBRS presenting with bilateral congenital glaucoma. The diagnosis was based on clinical presentation, such as attention deficit hyperactivity disorder, cognitive delay, and characteristic craniofacial features, and confirmed by the presence of a de novo mutation in the SMARCA2 gene through whole-exome sequencing. This case of a child with bilateral congenital glaucoma contributes further evidence of abnormal ocular features associated with the phenotypic spectrum of NCBRS, marking only the third such case reported in the literature. This rare association of NCBRS with bilateral congenital glaucoma highlights the importance of ophthalmologic screening in patients with NCBRS.

Neurodevelopmental and multiple malformation disorders spanning large phenotypic series can often lead to obscure diagnoses in the clinic. Blended phenotypes from multiple etiologies can compound this issue. We present a rare familial case of two siblings with Nicolaides-Baraitser syndrome (NCBRS) complicated by an initial diagnosis of syndromic craniosynostosis in one of the patients. Whole exome sequencing (WES) was performed for the affected siblings using the Agilent SureSelect kit and Illumina HiSeq 2500 system, followed by GATK variant calling and in-house annotation. Sanger sequencing was used to validate candidate variants in all immediate family members. A pathogenic de novo variant in TCF12 (p.Gln646Ter), consistent with craniosynostosis type 3 (CRS3), was identified in the proband, along with a novel likely pathogenic variant in SMARCA2 (p.Ile833Phe) involved in NCBRS. The latter was also detected in the sister and is thus suspected to have arisen through germline mosaicism. Various overlapping phenotypic manifestations complicated clinical diagnosis. This case expands the molecular and clinical spectrum of NCBRS and CRS3 and underscores the utility of trio-based WES in detecting blended phenotypes of disorders with growing phenotypic spectrums. Paternal germline mosaicism may underlie high recurrence and inform reproductive counseling.

Nicolaides‑Baraitser syndrome (NBS) is an ultrarare SMARCA2‑related neurodevelopmental disorder, whose cutaneous hallmarks traditionally include early hypotrichosis and coarse, sparse scalp hair. We describe a four‑year‑old girl with genetically confirmed NBS who presented with years‑long, worsening eczematous dermatitis and diffuse, non‑scarring alopecia that far exceeded the baseline hypotrichosis described in the syndrome. Clinical examination revealed erythematous, lichenified patches distributed across the trunk, extremities, and flexural creases, accompanied by generalized scalp thinning without follicular dropout or scarring. Standard emollient care and low‑ to mid‑potency topical corticosteroids had provided only transient relief; a step‑up regimen was initiated consisting of twice‑daily mometasone cream for flares, tacrolimus 0.03 % ointment for maintenance, wet‑wrap therapy, oral antihistamines, and barrier‑repair moisturizers. Hair‑loss management included nightly topical mometasone solution and ketoconazole shampoo, together with multivitamin supplementation. The constellation of severe atopic dermatitis and progressive alopecia in this patient suggests that SMARCA2 dysfunction may compromise epidermal barrier integrity and hair‑follicle cycling, rendering affected children particularly susceptible to eczematous inflammation and telogen shift. Early dermatologic recognition and aggressive barrier‑focused therapy are therefore pivotal for mitigating pruritus, preventing secondary infection, and improving quality of life in NBS. This case broadens the dermatologic phenotype of NBS and underscores the need for prospective studies to clarify genotype-phenotype correlations and guide targeted interventions for skin and hair involvement in this syndrome. SMARCA2-related Nicolaides-Baraitser syndrome (SMARCA2-NCBRS) is characterized by commonly shared dysmorphic features including sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly (typically acquired), seizures, and developmental delay / intellectual disability. Developmental delay / intellectual disability is severe in nearly half of affected individuals, moderate in one third, and mild in the remainder. Nearly one third never develop speech or language skills. Seizures are of various types and can be difficult to manage, requiring multiple anti-seizure medications to achieve reasonable control. Regression or lack of developmental progress has been noted with the onset of seizures in some affected individuals. Behavioral issues can include autistic-like features (perseveration, hyperacusis), with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder. Cryptorchidism is common in males. About half of affected individuals have growth deficiency and short stature. Delayed tooth eruption with hypo- or oligodontia has also been reported. Radiographic findings may include cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays) of the hands; platyspondyly; flat intervertebral disc space; and pelvic/femoral anomalies. Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects. The diagnosis of SMARCA2-NCBRS is established in a proband with suggestive findings and a heterozygous SMARCA2 pathogenic variant identified by molecular genetic testing. Treatment of manifestations: Standard therapy for developmental delay / intellectual disability, behavioral issues, epilepsy, poor growth, myopia, astigmatism, hearing loss, dental issues, cryptorchidism, and congenital heart defects. Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor those with seizures; assess for new manifestations; monitor developmental progress and educational needs; assess for behavioral issues such as short attention span, sensitivity to loud noises, and oral sensitivity; and evaluate mobility and self-help skills. Dental evaluation at least every six months after the eruption of first dentition. Annual audiology evaluation in childhood. Ophthalmology evaluation per treating ophthalmologist. SMARCA2-NCBRS is expressed in an autosomal dominant manner and typically caused by a de novo SMARCA2 pathogenic variant; the risk to other family members is presumed to be low. Once a SMARCA2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

The International Rare Diseases Research Consortium (IRDiRC) Telehealth (TH) Task Force explored the use of TH for improving diagnosis, care, research, and education for rare diseases (RDs). The Task Force reviewed related literature published from January 2017 to August 2023, and identified various models and implementation strategies of TH for RD. The Task Force highlighted the reported value and benefits of using TH for RDs, along with the limitations and opportunities. The number of publications sharply increased since 2021, coinciding with the onset of the COVID-19 pandemic, which forced the rapid adoption of TH in many healthcare settings. One of the major benefits of TH for RDs lies in its capacity to surmount geographical barriers, which helps in overcoming the constraints posed by limited numbers and geographical dispersion of specialists. This was evident during the pandemic when TH was used to maintain a level of continued medical care and research when face-to-face visits were severely restricted. TH, through which clinical research can be decentralized, can also facilitate and enhance RD research by decreasing burden, expanding access, and enhancing efficiency. This will be especially beneficial when coupled with the adoption of digital health technologies, such as mobile health (mHealth) and wearable devices for remote monitoring (i.e., surveillance of outpatient data transmitted through devices), along with big data solutions. TH has also been shown to be an effective means for RD education and peer mentoring, enabling local health care providers (HCPs) to care for RD patients, which indirectly ensures that RD patients get the expertise and multidisciplinary care they need. However, limitations and weaknesses associated with using TH for RD care and research were also identified, including the inability to perform physical examinations and build relationships with HCPs. Therefore, TH has been recommended as a complement to, rather than substitute for, face-to-face consultations. There is also a concern that TH may lead to an amplification of health disparities and inequities related to social determinants of health for those with RDs due to lack of access to TH technologies, inadequate digital literacy, and geographical, socio-cultural, and linguistic barriers. Finally, the Task Force also discussed evidence and knowledge gaps that will benefit from future research efforts to help advance and expand the use of TH for RD care, research, and education.