Homozygous indel mutation in CDH11 as the probable cause of Elsahy-Waters syndrome.

Two sisters from a consanguineous couple were seen in genetics department for facial dysmorphic features and glaucoma. They both had broad foreheads, hypertelorism, megalocorneas, thick eyebrows with synophrys, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, younger one also had cataracts and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of 2nd and 3rd fingers, history of impacted teeth with dentigerous cyst in the elder one, and intellectual disability (mild and borderline). The sisters were considered to have Elsahy-Waters syndrome. In order to elucidate the underlying molecular cause, sisters and their healthy parents were genotyped by SNP arrays, followed by homozygosity mapping. Homozygous regions were further analyzed by exome sequencing in one affected individual. A homozygous indel variant segregating with the condition was detected in CDH11 (c.1116_1117delinsGATCATCAG, p.(Ile372MetfsTer9)), which was then validated by using Sanger sequencing. CDH11 encodes cadherin 11 (osteo-cadherin) that regulates cell-cell adhesion, cell polarization and migration, as well as osteogenic differentiation. Further experiments revealed that CDH11 expression was decreased in patient-derived fibroblasts as compared to the heterozygous parent and another healthy donor. Immunostaining showed absence of the protein expression in patient fibroblasts. In addition, cell proliferation rate was slow and osteogenic differentiation potential was delayed. We consider that this study reveals loss-of-function mutations in CDH11 as a probable cause of this phenotype. Next generation sequencing in further patients would both prove this gene as causative, and finely delineate this clinical spectrum further contributing in identification of other possibly involved gene(s).

A spectrum of TP63-related disorders with eight affected individuals in five unrelated families.

TP63-related disdorders broadly involve varying combinations of ectodermal dysplasia (sparse hair, hypohydrosis, tooth abnormalities, nail dysplasia), cleft lip/palate, acromelic malformation, split-hand/foot malformation/syndactyly, ankyloblepharon filiforme adnatum, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. TP63-related disorders are associated with heterozygous pathogenic variants in TP63 and include seven overlapping phenotypes; Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), Ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC3), Limb-mammary syndrome (LMS), Acro-dermo-ungual-lacrimal-tooth syndrome (ADULT), Rapp-Hodgkin syndrome (RHS), Split-hand/foot malformation 4 (SHFM4), and Orofacial cleft 8. We report on five unrelated families with 8 affected individuals in which the probands presented with varying combinations of ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, lacrimal duct obstruction, and ankyloblepharon filiforme adnatum. The clinical diagnosis involved AEC syndrome (2 patients), EEC3 syndrome (2 patients), and a yet hitherto unclassified TP63-related disorder. Sanger sequence analysis of the TP63 gene was performed revealing five different variants among which four were novel and three were de novo. The identificated TP63 variants co-segregated with the other affected individuals in the families. The abnormalities of ectoderm derived structures including hair, nails, sweat glands, and teeth should alert the physician to the possibility of TP63-related disorders particularly in the presence of orofacial clefting.

Hyaline fibromatosis syndrome: a rare, yet recognizable syndrome.

BACKGROUND: Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous hyaline material in connective tissues. The hallmarks of the disease are joint contractures, generalized skin stiffness, hyperpigmented papules over extensor surfaces of joints, fleshy perianal masses, severe diarrhea, and gingival hypertrophy. The severity of the disease varies and prognosis is poor. No specific treatment is yet available. Most patients with the severe form of the condition pass away before the second year of age. In this study, we describe the clinical and molecular findings of a cohort of seven hyaline fibromatosis syndrome patients who were diagnosed and followed up at a single tertiary reference center in Turkey. METHODS: Genomic DNA was extracted by standard salting out method from peripheric blood samples of three patients. In one patient DNA extraction was performed on pathology slides since peripheric blood DNA was not available. All coding exons of the ANTXR2 were amplified and sequenced on ABI Prism 3500 Genetic Analyser. RESULTS: Sanger sequencing was performed in 3 patients and homozygous c.945T>G p.(Cys315Trp), c.1073dup p.(Ala359CysfsTer13), and c.1074del p.(Ala359HisfsTer50) variants were identified in ANTXR2. All patients passed away before the age of five years. CONCLUSIONS: HFS is a rare, progressive disorder with a broad phenotypic spectrum. HFS can be recognized easily with distinctive clinical features. Nevertheless, it has poor prognosis with increased mortality due to severe clinical decompensation.

Further Expanding the Mutational Spectrum of Gorlin Syndrome in Three Unrelated Families.

Introduction: Gorlin syndrome is a rare, autosomal dominant multi-systemic disorder with a predisposition to the development of cancers such as medulloblastoma and nevoid basal cell carcinoma. Heterozygous pathogenic variants in PTCH1 are responsible for 90% of Gorlin syndrome cases. Pathogenic variants in PTCH1 cause overstimulation of the sonic hedgehog signaling pathway, which plays a role in the development of embryonic structures and tumorigenesis. Clinical major and minor diagnostic criteria for Gorlin syndrome have been determined. Odontogenic keratocyst (OKC) is the most common reason for medical admission in Gorlin syndrome. In this article, it is aimed to draw attention to the fact that patients with Gorlin syndrome are not very rare in our country and the variability in phenotypic and dysmorphic findings may be a clue for the diagnosis. Methods: Exome sequencing was performed on the Illumina NextSeq550 System platform by using the Ion Ampliseq exome RDY kit for Illumina. Sanger sequencing was performed accordingly for the other affected individuals in both families. Results: In this study, the clinical and molecular findings of 9 Gorlin syndrome patients from three unrelated families are presented. Macrocephaly, calcification of falx cerebri, palmar-plantar pits, rib anomalies, and OKC were detected in decreasing order in more than half of the patients. A novel heterozygous frameshift PTCH1 variant in family 1, a nonsense previously reported PTCH1 variant in family 2, and a novel heterozygous splice-site PTCH1 variant in family 3 were detected. Conclusion: Gorlin syndrome should be kept in mind in patients presenting with macrocephaly, palmoplantar pits, and OKC history. Careful examination of all family members is essential in the timely diagnosis of other affected individuals with minor phenotypic findings.

Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand abnormal calcification type: Further expanding the mutational spectrum and dental findings of three new patients.

Genetic skeletal disorders are clinically and genetically heterogeneous group of disorders that affect the normal development, growth, and maintenance of the human skeleton. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type (SMED-SL/AC; MIM# 271665) is a rare autosomal recessive genetic skeletal disorder characterized by distinctive facial features, disproportionate short stature, vertebral, metaphyseal, and epiphyseal abnormalities. This unique phenotype is caused by biallelic loss-of-function variants in Discoidin domain receptor 2 gene (DDR2, MIM# 191311). To date, only 10 pathogenic variants (six missense, two nonsense, one deletion, and one splice site) in DDR2 have been reported in patients with SMED-SL/AC. Dental anomalies related to skeletal dysplasia can include various abnormalities in the number, shape, and position of teeth in the jaw, as well as enamel hypoplasia and dentinogenesis imperfecta. Although abnormal dentition has previously been reported, orodental findings were described in only six patients with SMED-SL/AC. This study aimed to define the clinical, dental, radiological, and molecular findings of three new SMED-SL/AC patients from three unrelated families. Three DDR2 variants, two of which were novel, were detected with the aid of Sanger sequencing. Interestingly, one of the patients was diagnosed with Wilson's disease (WD) during the follow-up, a co-occurrence that has never been reported in patients with SMED-SL/AC so far.

Kohlschütter-Tönz Syndrome With a Novel ROGD1 Variant in 3 Individuals: A Rare Clinical Entity.

Kohlschütter-Tönz syndrome (OMIM 226750) is a rare disorder with autosomal recessive inheritance among epileptic encephalopathy syndromes. To date, only 31 Kohlschütter-Tönz syndrome families have been reported in the literature. Early-onset epilepsy, progressive global developmental delay, and amelogenesis imperfecta are the main components of the syndrome. Mutations in ROGDI (MIM 226750) and SLC13A5 (MIM 615905) are responsible for Kohlschütter-Tönz syndrome. Here, we report on the clinical and molecular characteristics of 3 individuals from 2 families, all harboring the same homozygous novel deleterious variant in ROGD1, along with a long-term follow-up and review of the literature. Although the phenotypic features are almost consistent in Kohlschütter-Tönz syndrome, overlooking dental findings and diverse degrees of variability in clinical findings makes diagnosis challenging occasionally. Because there is a limited number of reported patients, identification of new patients and delineation of clinical and molecular findings will increase the awareness of clinicians and enable establishing genotype-phenotype correlations.

Natural history of TRPV4-Related disorders: From skeletal dysplasia to neuromuscular phenotype.

TRPV4-related disorders constitute a broad spectrum of clinical phenotypes including several genetic skeletal and neuromuscular disorders, in which clinical variability and somewhat overlapping features are present. These disorders have previously been considered to be clinically distinct phenotypes before their molecular basis was discovered. However, with the identification of TRPV4 variants in the etiology, they are referred as TRPV4-related disorders (TRPV4-pathies), and are now mainly grouped into skeletal dysplasias and neuromuscular disorders. The skeletal dysplasia group includes metatropic dysplasia, parastremmatic dysplasia, spondyloepiphyseal dysplasia Maroteaux type, spondylometaphyseal dysplasia Kozlowski type, autosomal dominant brachyolmia, and familial digital arthropathy-brachydactyly, whereas the neuromuscular group includes congenital distal spinal muscular atrophy (SMA), scapuloperoneal SMA and Charcot-Marie-Tooth neuropathy type 2C with common manifestations of peripheral neuropathy, joint contractures, and respiratory system involvement. Apart from familial digital arthropathy-brachydactyly, skeletal dysplasia associated with TRPV4 pathogenic variants share some clinical features such as short stature with short trunk, spinal and pelvic changes with varying degrees of long bone involvement. Of note, there is considerable phenotypic overlap within and between both groups. Herein, we report on the clinical and molecular spectrum of 11 patients from six different families diagnosed with TRPV4-related disorders. This study yet represents the largest cohort of patients with TRPV4 variants from a single center in Turkey.

Cryptic trisomy 5q35.2qter and deletion 1p36.3 characterised using FISH and array-based CGH.

A 10(6/12)-year-old boy was referred to the genetics department because of mental retardation and dysmorphic findings including microcephaly, flat face, down-slanting palpebral fissures, strabismus, prominent ears, bulbous nasal tip, down-turned corners of the mouth, narrow palate, clinodactyly of the fifth fingers and generalised eczema. Cytogenetic analysis revealed a karyotype of 47,XY,+mar of paternal origin. Multicolour FISH showed the marker chromosome to be derived from chromosome 15. For further elucidation of the phenotype, array-based comparative genomic hybridisation (aCGH) was performed, which revealed dup(5)(q35.2qter) and del(1)(p36.3). Parental FISH analysis revealed that the translocation occurred de novo. Despite the presence of a clinical phenotype along with a microscopically visible chromosomal aberration, a complex cryptic cytogenetic abnormality was causative for the phenotype of the patient. Elucidation of this complex aberration required combination of the whole cytogenetic toolbox.

Cerebro-facio-thoracic dysplasia: expanding the phenotype.

We report a further two patients with cerebro-facio-thoracic dysplasia, a rare autosomal recessive condition with thoracic costovertebral dysplasia, developmental delay and characteristic facial features. One of our patients has the additional features of large, bilateral colobomas of the optic nerve, ptosis, small conical teeth and severe left-sided talipes. He also has hypermobile joints, especially in his hands and anterior subluxation of the shoulders. The second patient has hypodensity of the grey matter on magnetic resonance imaging, which is the second report of this finding in cerebro-facio-thoracic dysplasia. In addition, he has hypoplasia of the corpus callosum. These cases illustrate the expanding phenotype of this condition, and support the hypothesis that this is an autosomal recessive condition.