New Fetal Case of Blomstrand Chondrodysplasia and Review of the Literature

Blomstrand chondrodysplasia (BOCD) is a very rare autosomal recessive lethal skeletal dysplasia characterized by advanced skeletal ossification, markedly short limbs, hydrops fetalis and typical facial dysmorphism comprising proptosis, maxillary hypoplasia, micrognathia and a large-protruding tongue. Accompanying non-skeletal features include preductal aortic coarctation, gut malrotation, and hemosiderosis of the liver. Radiological evaluation is crucial for clinical diagnosis. Increased bone density, very short tubular bones with wide ends, short and thickened ribs and clavicles are typical findings. Only 14 cases have been reported previously. Inactivating mutations of the parathyroid hormon receptor-1 gene (PTHR1) are associated with BOCD. BOCD is allelic with Eiken syndrome, and Jansen type metaphyseal chondrodysplasia, presumably caused by truncating mutations in the C-terminal cytoplasmic tail, and activating mutations, respectively.Here, we present a new case with Blomstrand chondrodysplasia with a novel mutation in PTHR1.The fetus was the third-born to consanguineous parents. At the 21stgestational week, ultrasound examination showed proptosis, short nose, severe micrognathia, tetramicromelia, and narrow thorax. Fetal karyotype and chromosomal array revealed normal results. Parents chose to terminate the pregnancy due to expected lethal course related with the phenotype. Postmortem clinical examinationshowed broad forehead, proptosis, midface hypoplasia, microstomia, submucosal cleft palate, severe micrognathia, generalized oedema, and narrow thorax, and very short limbs with severe brachydactyly. The radiological findingswere short-dense-bowed tubular bones with flared wide metaphyseal ends, constricted diaphyses, split-ends of humeri and femora, short-thick ribs and clavicles, leading to the diagnosis of BOCD. Sanger sequencing ofthe PTH1R gene revealed a homozygous change, c.1309T>C, leading to p.Trp437Arg. This novel mutation was predicted to be damaging by in silico analyses.New BOCD case will be discussed in view of molecular findings,and a review of the literature will be presented

Altı Olguda Stuve-Wiedmann Sendromunun Klinik ve Moleküler Karekterizasyonu

Stuve-Wiedemann sendromu (SWS), beslenme güçlüğü ve uzun kemiklerin konjenital eğrilmesi ile karakterize, nadir görülen, otozomal resesif bir iskelet hastalığıdır. Solunum yetmezliği, hipertermi ve otonomik disfonksiyon nedeniyle ölüm oranı yüksektir. LIFR'deki bialelik mutasyonlardan kaynaklanır. Burada sunulan 6 olgu ile SWS'nin klinik ve moleküler tanısına katkı sağlanması beklenmektedir.Bu çalışmada fetal ve postnatal toplam 6 olgu bildiriyoruz. Bir olgu hariç tüm olguların prenatal ve postnatal iskelet bulguları SWS ile geniş ölçüde uyumluydu. Otonomik disfonksiyon tüm olgularda vardı. 2 olgu solunum yetmezliği nedeniyle kaybedildi.Tüm olgularda prenatal ve postnatal klinik bulgular SWS ile geniş ölçüde uyumluydu. Akrabalık olan beş olguda anterior ultrasonografide femurda belirgin eğrilik tespit edildi. İki olgu solunum yetmezliği nedeniyle kaybedildi. 6 olguda dört farklı mutasyon tespit edildi, bunlardan biri literatürde daha önce bildirilmemişti.Bir hasta başlangıçta perioral ağrı hissinde azalma ve kendine zarar verme davranışı nedeniyle Herediter duyusal ve otonomik nöropatiler grubunda değerlendirildi. Olgunun belirgin iskelet bulguları yoktu ve klinik exome analizi ile SWS tanısı aldı.Antenatal ultrasonografide özellikle (ebeveynlerin akraba olduğu durumlarda) femur eğriliği olan tüm olgularda ayırıcı tanıda SWS mutlaka düşünülmelidir. Bazı hastalarda, genç yaşta bile iskelet bulguları hafif olabilir ve sendrom daha çok duysal semptomlarla prezente olabilir. Daha önce Türk populasyonuna spesifik olarak bildirilen p.Arg692 *, olgularımızın üçünde, kurucu mutasyon olarak tespit edildi

Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes