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3M syndrome is a rare autosomal recessive genetic disorder characterized by severe growth retardation, dysmorphic facial features, skeletal dysplasia, and normal intelligence. Variants in CUL7, OBSL1, and CCDC8 genes have been reported to be responsible for this syndrome. in this study, the clinical and molecular findings of four 3M syndrome cases from three families are presented. All cases had growth retardation, relative macrocephaly, and typical dysmorphic facial features. Their neurological developments were normal. Sequencing of CUL7, OBSL1, and CCDC8 genes revealed two different novel homozygous variants in CUL7 in Families 1 and 3 and a previously reported homozygous pathogenic variant in OBSL1 in Family 2. in conclusion, a comprehensive dysmorphological evaluation should be obtained in individuals presenting with short stature and in such individuals with typical facial and skeletal findings, 3M syndrome should be considered. Our report expands the genotype of 3M syndrome and emphasizes the importance of thorough physical and dysmorphological examination.

Fragile X syndrome (FXS) is the most common hereditary disorder of intellectual disability. Cognitive deficits involve executive function, attention, learning and memory. Advanced neuroimaging techniques are available, and (1)H magnetic resonance spectroscopy (MRS) can be used as a complementary method to MR imaging to understand disease processes in brain, by in vivo demonstration of brain metabolites. MRS was performed in 13 male patients with FXS full mutation, and 13 age- and sex-matched healthy controls. FXS diagnosis was based on clinical evaluation, followed by detection of FMR1 full mutation. Axial T2 TSE, sagittal T1 SE and coronal 3D MPRAGE images were obtained for both morphological imaging and voxel localization. Following evaluation of conventional images, multivoxel MRS (CSI) through supraventricular white matter and single voxel MRS (svs) with an intermediate echo time (TE:135 ms) from the cerebellar vermis were performed. Choline/Creatine (Cho/Cr), N-acetyl aspartate/Creatine (NAA/Cr), and Choline/N-acetyl aspartate (Cho/NAA) ratios were examined at right frontal (RF), left frontal (LF), right parietal (RP), left parietal (LP), and cerebellar vermian (C) white matter. Statistical analyses were done using t-test and Mann-Whitney U tests. A statistically significant difference was observed in RP Cho/NAA ratio (cell membrane marker/neuroaxonal marker), FXS patients having lower levels than controls (P = 0.016). The results should be evaluated cautiously in parallel to consequences in brain metabolism leading to alterations in neurotransmitter levels, osmoregulation, energy metabolism and oxidative stress response described in animal models. MRS may serve to define a metabolic signature and biomarkers associated with FXS.

Cerebrofaciothoracic dysplasia (CFT) (OMIM #213980) is a multiple congenital anomaly and intellectual disability syndrome involving the cranium, face, and thorax. The characteristic features are cranial involvement with macrocrania at birth, brachycephaly, various CT/MRI findings including hypoplasia of corpus callosum, enlargement of septum pellicidum, and diffuse hypodensity of the grey matter, flat face, hypertelorism, cleft lip and cleft palate, low-set, posteriorly rotated ears, short neck, and multiple costal and vertebral anomalies. The underlying genetic defect remains unknown. Using combination of homozygosity mapping and whole-exome sequencing, we identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in the human transmembrane and coiled-coil domains protein 1 (TMCO1) in four out of five families of Turkish origin. The entire critical region on chromosome 1q24 containing TMCO1 was excluded in the fifth family with characteristic findings of CFT providing evidence for genetic heterogeneity of CFT spectrum. Another founder TMCO1 mutation has recently been reported to cause a unique genetic condition, TMCO1-defect syndrome (OMIM #614132). TMCO1-defect syndrome shares many features with CFT. This study supports the fact that TMCO1-defect syndrome, initially thought to represent a distinct disorder, indeed belongs to the genetically heterogeneous CFT dysplasia spectrum. (c) 2013 Wiley Periodicals, Inc.

Catel-Manzke syndrome is characterized by hyperphalangism with bilateral deviation of the index fingers and micrognathia with or without cleft palate. Some atypical patients present with additional malformations. No molecular basis is yet available. Most patients have an unremarkable family history but autosomal recessive inheritance has been recently suggested in a consanguineous family with recurrence in sibs. Catel-Manzke syndrome has overlapping features with Desbuquois dysplasia type 1 due to CANT1 (calcium-activated nucleotidase 1) mutations and also with "chondrodysplasia with joint dislocations, gPAPP type" due to IMPAD1 (Inositol Monophosphatase Domain containing 1) mutations recently reported in four patients, all characterized by short stature, joint dislocations, brachydactyly and cleft palate. The aim of our study was to screen CANT1 and IMPAD1 in Catel-Manzke patients. Three patients were diagnosed as classical Catel-Manzke syndrome and two as Catel-Manzke like patients, based on the presence of additional features. We identified two homozygous loss-of-function IMPAD1 mutations in the two Catel-Manzke like patients (p.Arg187X and p.Ser108ArgfsX48). The phenotype was characterized by severe growth retardation with short and abnormal extremities, cleft palate with micrognathia and knee hyperlaxity. Radiographs of hands and feet revealed numerous accessory bones with abnormally shaped phalanges and carpal synostosis. Based on this report, we concluded that IMPAD1 should be screened for patients with Catel-Manzke and additional features.

We describe a 3-month-old male infant with cleft palate, glossoptosis, micrognathia, and bilateral clinodactyly, an association which is characteristic of Catel-Manzke syndrome. In addition, the patient had ligamentous laxity in the knee which is a rare finding of this syndrome. The mode of inheritance of Catel-Manzke syndrome is unknown. Most cases are thought to be sporadic but the present patient with consanguinity between the parents and a possibly affected sib provide support for autosomal recessive inheritance.