WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

Primary Hypertrophic Osteoarthropathy Mimicking Juvenile Idiopathic Arthritis: A Novel SLCO2A1 Mutation and Imaging Findings.

Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare, multisystemic, autosomal recessive condition typically presenting with digital clubbing, osteoarthropathy, and various skin manifestations. Radiographs show distinctive periosteal reaction and thickening along the long bones. PHO is caused by homozygous mutations in the HPGD gene in chromosome 4q34.1 or the SLCO2A1 gene in 3q22.1q22.2. Here, we report on a 20-year-old male with enlarged and swollen joints with arthralgia, palmoplantar hyperhidrosis, and large hands and feet with marked digital clubbing. We also present radiographic, MRI, and ultrasonographic features of the case. These clinical and imaging findings were compatible with the diagnosis of PHO, and a novel homozygous mutation, c.576C>G, p.Ile192Met, was found in SLCO2A1.

A Novel PORCN Frameshift Mutation Leading to Focal Dermal Hypoplasia: A Case Report.

Focal dermal hypoplasia (FDH), also known as Goltz-Gorlin syndrome, is a rare, multisystemic, X-linked dominant genodermatosis characterized by defective development of mesodermal and ectodermal tissues. Major clinical features of the disorder are skin manifestations, skeletal defects, and developmental eye abnormalities. FDH is caused by heterozygous mutations in the PORCN gene located at Xp11.23, and 90% of individuals with FDH are females. Here, we report a female patient with cutaneous changes, multiple eye anomalies, short stature, and ectrodactyly of the right foot. These clinical findings were compatible with the diagnosis of FDH, and a novel mutation, NM_022825.3:c.488delG was found in the PORCN gene causing a premature stop codon.

Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature.

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.

A Novel PTCH1 Frameshift Mutation Leading to Nevoid Basal Cell Carcinoma Syndrome.

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare multisystemic autosomal dominant disorder typically presenting with cutaneous basal cell carcinomas, multiple keratocysts, and skeletal anomalies. NBCCS is caused by heterozygous mutations in the PTCH1 gene in chromosome 9q22, in the PTCH2 gene in 1p34, or the SUFU gene in 10q24.32. Here, we report on an 18-month-old boy presenting with medulloblastoma, frontal bossing, and multiple skeletal anomalies and his father who has basal cell carcinomas, palmar pits, macrocephaly, bifid ribs, calcification of falx cerebri, and a history of surgery for odontogenic keratocyst. These clinical findings were compatible with the diagnosis of NBCCS, and a novel mutation, c.1249delC; p.Gln417Lysfs*15, was found in PTCH1 causing a premature stop codon.

Skin-Dominant Phenotype in a Patient with H Syndrome: Identification of a Novel Mutation in the SLC29A3 Gene.

H syndrome (OMIM 602782) is a very rare autosomal recessive genodermatosis with multisystem involvement. Hallmarks of this disorder are juvenile onset and progressive, hyperpigmented, hypertrichotic lesions with histiocytic infiltration. Associated systemic manifestations form a long list, and there is high variability between patients. In some patients, dysmorphic and other systemic features may be so subtle that the disorder may readily be mistaken as an acquired skin disease and treated as such. Herein, we report a novel homozygous c.1339G>A (p.Glu447Lys) mutation in the SLC29A3 gene in a patient with skin-dominant presentation of H syndrome. Additionally, due to the present case, double superior vena cava can be added to the list of possible cardiovascular manifestations of H syndrome.

Unusual Chromosomal Rearrangement Resulted in Interstitial Monosomy 9p: Case Report.

We report on a 4.5-year-old boy with interstitial monosomy 9p in a unique and complex de novo rearrangement. The patient had been referred for craniofacial dysmorphism, delayed psychomotor development, and various congenital malformations. We combined cytogenetic studies and FISH analyses to delineate the deletion. The result of our cytogenetic studies was 46,XY,der(9)(p22pter). In order to confirm the deletion, we also performed FISH analysis, which showed that the 9p subtelomeric region was inserted into chromosome 13. Molecular karyotyping was performed to describe the exact genomic breakpoints of the rearrangement. In conclusion, this case is a complex insertion/deletion abnormality which has not been reported before.

Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey.

BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.

Promising effect of intravenous immunoglobulin therapy for epidermolysis bullosa pruriginosa.

BACKGROUND: Epidermolysis bullosa pruriginosa (EBP) is rare a clinical variant of dystrophic epidermolysis bullosa characterized by trauma-induced bullae formation, milia and nail dystrophy accompanied by severe pruritus. Treatment pruritus of EBP focuses on immunosuppressive treatment with limited efficacy. Treatment strategies are not well-established. AIM: To provide the genetic characterization of a multi-generational EBP family and discuss the efficacy of intravenous immunoglobulin treatment in EBP. MATERIALS & METHODS: The clinical characteristics of patients diagnosed with EBP in three consecutive generations were determined. The mutation is analyzed in the index patient's genomic DNA by Sanger sequencing, and this mutation was confirmed in other affected members of the family. Index case with severe phenotype was treated with intravenous immunoglobulin (IVIG). RESULTS: A heterozygous single nucleotide transition, c.6127G>A, in exon 73 of COL7A1 was identified in all affected members. Physical examination of patients revealed lichenoid papules on extensor surfaces of extremities, excoriations, milia formation and nail dystrophy. Majority of patients had elevated serum IgE levels (%86 (6/7)) without a medical history for atopy. Female patients had generalized involvement and severe phenotype. The skin lesions of the index case were refractory to high dose systemic steroids and cyclosporine treatment. Lesions improved significantly with intravenous immunoglobulin therapy. CONCLUSION: In severe cases, unresponsive to other therapies, IVIG may be a preferable therapeutic approach to modulate the inflammatory response in patients with EBP.