127 research outputs found
An unusual presentation of Kabuki syndrome with orbital cysts, microphthalmia, and cholestasis with bile duct paucity
No full textKabuki syndrome (KS) is a rare developmental disorder characterized by multiple congenital malformations, postnatal growth retardation, intellectual disability, and recognizable facial features. It is mainly caused by mutations in either KMT2D or KDM6A. We describe a 14-year-old boy with KS presenting with an unusual combination of bilateral microphthalmia with orbital cystic venous lymphatic malformation and neonatal cholestasis with bile duct paucity, in addition to the typical clinical features of KS. We identified the novel KMT2D mutation c.10588delC, p.(Glu3530Serfs*128) by Mendeliome (Illumina TruSight One (R)) sequencing, a next generation sequencing panel targeting 4,813 genes linked to human genetic disease. We analyzed the Mendeliome data for additional mutations which might explain the exceptional clinical presentation of our patient but did not find any, leading us to suspect that the above named symptoms might be part of the KMT2D-associated spectrum of anomalies. We thus extend the range of KS-associated malformations and propose a hypothetical connection between KMT2D and Notch signaling. (C) 2016 Wiley Periodicals, Inc
Evaluation of growth, puberty, osteoporosis, and the response to long-term bisphosphonate therapy in four patients with osteoporosis-pseudoglioma syndrome.
No full textOsteoporosis-pseudoglioma syndrome (OPPG; MIM #259770) is a rare autosomal recessively inherited disease, characterized by early-onset osteoporosis and congenital blindness, caused by loss-of-function mutations in the LRP5 gene. Beneficial effects of bisphosphonate treatment in patients with OPPG are well known, while follow-up data on growth and pubertal parameters are limited. This article provides clinical follow-up data and long-term bisphosphonate treatment results in four OPPG patients from three unrelated families, ranging between 2.5 and 7 years of age at presentation. Clinical diagnosis was molecularly confirmed in all patients, with four different germline biallelic LRP5 mutations including a novel nonsense variant c.3517C>T (p.(Gln1173*)) in two siblings with marked phenotypic variability. Anthropometric and pubertal data and bone mineral density (BMD) measurements were evaluated retrospectively. Early puberty was observed in two patients. The bisphosphonate treatment duration of patients varied around 4-7 years and improvement in BMD z-scores with bisphosphonate treatment was demonstrated in all patients (z-score changes were +5.6, +4.0, +1.0, and +1.3). Although further research is needed to identify the possible association between early puberty and OPPG, all OPPG patients should be followed up with detailed endocrinological evaluation regarding pubertal status
Mutations in CDK5RAP2 cause Seckel syndrome
No full textSeckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152
heterozygotes
No full textHeterozygous loss-of-function mutations in ALX4 are responsible for enlarged parietal foramina, whereas patients with biallelic ALX4 mutations display a phenotypic spectrum of clinical findings, from mild to severe alopecia, cranium bifidum, hypertelorism, microphthalmia, with alar clefting being the pivotal sign in all affecteds. We report on four affected individuals in a three-generation family, displaying a phenotypic spectrum ranging from mild nasal clefting and broad columella to subtle changes in nasal configuration in addition to parietal foramina, caused by a novel ALX4 mutation(c.646C>G, p.Arg216Gly). This is the second report of a family showing vertical transmission of a dominant ALX4 mutation with facial involvement in addition to parietal foramina, mimicking mild recessive ALX4 phenotype. We discuss possible pathological mechanisms that may have lead to phenotypic variation in the family and challenges in genetic counseling. (C) 2014 Wiley Periodicals, Inc
Microcephaly, dysmorphic features, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds, and small cerebellum in four patients
No full textPontocerebellar hypoplasia (PCH) can occur as an isolated entity or part of a syndrome. PCH has been reported with facial dysmorphism, ocular anomalies, and genital anomalies, but the co-occurrence of all four has not been previously described. We report on four patients, born to two consanguineous families that are not related to one another, with distinctive facial features (short forehead, laterally extended, medially flared eyebrows), corneal dystrophy, underdevelopment of labioscrotal folds, and nonprogressive PCH. In addition, the patients show hair extruding from the lactiferous ducts, which to our knowledge has not been described before. The parental consanguinity, affected siblings of both genders, and absent manifestations in parents, indicate an autosomal recessive pattern of inheritance as most likely. (C) 2016 Wiley Periodicals, Inc
Schinzel-Giedion Syndrome with Congenital Megacalycosis in a Turkish Patient: Report of SETBP1 Mutation and Literature Review of the Clinical Features
No full textSchinzel-Giedion syndrome (SGS) is a rare autosomal dominant disorder that results in facial dysmorphism, multiple congenital anomalies, and an increased risk of malignancy. Recently, using exome sequencing, de novo heterozygous mutations in the SETBP1 gene have been identified in patients with SGS. Most affected individuals do not survive after childhood because of the severity of this disorder. Here, we report SETBP1 mutation confirmed by molecular analysis in a case of SGS with congenital megacalycosis
Fraser syndrome due to mutations in GRIP1--clinical phenotype in two families and expansion of the mutation spectrum.
No full textLoss-of-function mutations in Carboxypeptidase D cause a new syndrome with lymphedema and sensorineural hearing loss
No full text
Clinical and Molecular Analyses in 8 New Craniofrontonasal Syndrome Families: Revisiting the Mild End of the Phenotypic Spectrum in Females
No full textObjective: Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder caused by EFNB1 pathogenic variants. It is characterized by coronal synostosis, facial asymmetry, hypertelorism, bifid nasal tip, woolly hair, longitudinal nail ridging, and skeletal anomalies in heterozygous females. Hemizygous males paradoxically display a less severe phenotype. This study aims to further define the clinical and mutational spectrum of CFNS in 8 new families.
Materials and Methods: Nine female and 2 male patients were included. After detailed phenotypic characterization, Sanger sequencing of EFNB1 was performed, followed by deletion duplication analysis of mutation-negative patients.
Results: Universal findings in affected females included wide nasal bridge, hypertelorism, and nasal tip abnormalities. Clinical features were consistent with literature data in the majority, except for 2 females with a mild phenotype resembling hemizygous males. Rare or previously undescribed features included enlarged cisterna magna, nasolacrimal duct obstruction, mesoaxial polydactyly, small echogenic kidney, and hypoplastic labia minora in females, and metopic groove, columellar skin pit, and absent midline mustache hair in males. Genetic analyses identified 6 EFNB1 variants, including a novel variant, heterozygous in females and hemizygous in males. One female patient with a classical CFNS phenotype had no identifiable EFNB1 variant.
Conclusion: This study of the largest CFNS cohort from Türkiye expands the phenotypic spectrum in affected males and females and contributes to the genetic landscape of EFNB1 variants. Two females of the cohort with a phenotype at the mildest end of the CFNS spectrum emphasize the importance of recognizing atypical CFNS presentations for timely diagnosis and accurate genetic counseling
- …
