Catel-Manzke syndrome is characterized by the combination of Pierre Robin sequence and radial deviation, shortening as well as clinodactyly of the index fingers, due to an accessory ossification center. Mutations in TGDS have been identified as one cause of Catel-Manzke syndrome, but cannot be found as causative in every patient with the clinical diagnosis. We performed a chromosome microarray and/or exome sequencing in three patients with hand hyperphalangism, heart defect, short stature, and mild to severe developmental delay, all of whom were initially given a clinical diagnosis of Catel-Manzke syndrome. In one patient, we detected a large deletion of exons 1-8 and the missense variant c.1282C > T (p.Arg428Trp) in KYNU (NM_003937.2), whereas homozygous missense variants in KYNU were found in the other two patients (c.989G > A (p.Arg33OGln) and c.326G > C (p.Tip109Ser)). Plasma and urine metabolomic analysis of two patients indicated a block along the tryptophan catabolic pathway and urine organic acid analysis showed excretion of xanthurenic acid. Biallelic loss-of-function mutations in KYNU were recently described as a cause of NAD deficiency with vertebral, cardiac, renal and limb defects; however, no hand hyperphalangism was described in those patients, and Catel-Manzke syndrome was not discussed as a differential diagnosis. In conclusion, we present unrelated patients identified with biallelic variants in KYNU leading to kynureninase deficiency and xanthurenic aciduria as a very likely cause of their hyperphalangism, heart defect, short stature, and developmental delay. We suggest performance of urine organic acid analysis in patients with suspected Catel-Manzke syndrome, particularly in those with cardiac or vertebral defects or without mutations in TGDS.

Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease characterized by dense and fragile bone, caused by a defect in osteoclasts responsible for the bone destruction. In this study, we aimed to investigate the mutations in TCIRG1 and SNX10 that are responsible for 50% and 4% of the cases, respectively. All amplicons were sequenced by Sanger sequencing following PCR amplification. As a result, six different mutations of the TCIRG1 gene were found in five of the twelve unrelated cases. These include two novel mutations, namely c.630 + 1G > T mutation and c.1778_1779delTG mutation of the gene which are identified as homozygous. A compound heterozygosity of known mutations c.649_674del26 and c.1372G > A and homozygous presence of the known c.2235 + 1G > A mutation were also observed in different patients, In addition, as a result of the prenatal testing in a family with osteopetrosis infant, the c.1674-1G > A mutation was detected as homozygous for the fetus. In TCIRG1, c.166C > T change, which is indicated as likely benign according to ClinVar database, was heterozygous. Several known polymorphisms; c.117 + 83T > C, c.417 + 11A > G and c.714-19C > A in TCIRG1 gene; c.24 + 36T > A and c.112-84G > A in SNX10 gene were also detected. In conclusion, our study revealed that five of the twelve cases carry at least one mutation of TCIRG1 gene. Further studies with more patients and other genes would help better understanding of genetic etiology of the disease.

The bones of the skull are held together by fibrous joints called sutures. Premature fusion of these sutures leads to a pathologic condition called as craniosynostosis. Although at least 50 nuclear genes including FGFR2, TWIST1, TCF12, and SMAD6 were identified as causative of craniosynostosis; only 25% of the patients can be genetically diagnosed. Here, we report a 3-year-old Turkish Caucasian boy with sagittal craniosynostosis with a de novo loss-of-function mutation in exon 4 of the AXIN2 gene for the first time. The patient has frontal bossing, high anterior hair line, depressed nasal bridge, bilateral epicanthus and low set ears which are correlated with his scaphocephaly. As a negative regulator of the Wnt signaling pathway which is one of the key modulators of craniosynostosis syndrome, it has been shown in model organisms that Axin2 orchestrates the regulation of beta-catenin especially in the intramembranous ossification process. This clinical report adds value to the literature that AXIN2 gene mutations could be a potential cause in human calvarial malformations, especially for the sagittal synostosis.

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

Although the carriers with apparently balanced structural rearrangements have usually normal phenotype, phenotypical abnormalities can be seen in approximately 6% de novo cases. A number of different mechanisms are involved in the appearance of these phenotypic abnormalities, one of which is submicroscopic chromosomal imbalances at chromosomal breakpoints. Our goal was to unravel the possible submicroscopic chromosomal imbalances at chromosomal breakpoints by using array-CGH analysis in patients with apparently balanced structural rearrangements and to link these to the clinical findings. A total of nine patients with reciprocal translocation carriers (2 familial, 7 de novo) and six patients with inversion carriers (2 familial, 4 de novo) were included in this study. In order to evaluate the possible microdeletions and microduplications at the chromosomal breakpoints, DNA samples were isolated from the peripheral blood of the patients (and their parents) and investigated using array-CGH analysis. Array-CGH analysis revealed submicroscopic chromosomal imbalances at breakpoints in 3 of the 7 (43%) de novo reciprocal translocation carriers. Additionally, 1 out of 4 (25%) de novo inversion carriers were found to have a submicroscopic chromosomal imbalance in unrelated chromosome seen in cytogenetic analysis. Furthermore, no submicroscopic chromosomal imbalances were detected in either of the two familially transmitted reciprocal translocation carriers. Based on the results of both array-CGH analysis and conventional cytogenetic analysis, the karyotypes of the patients were designated as follows: 46, XY, t(13; 16)(q14; q12.1)dn.arr[hg19]13q14.2-q21.1(50,131,521-57,306,322)x1dn; 46, XY, t(6; 9)(q13; p12)dn.arr[hg19]6q14.1(78,016,882-83,293,127),9p23p22.3(12,249,507-15,939,627) x1dn; 46, XX, t(X; 16)(p11.21; p11.2)dn.arr[hg19]Xp11.22(50,367,783-50,441,087)x3dn; 46, XX, inv.(18)(p11.23q11.2)dn.arr[hg19]22q11.21(18,706,001-21,505,417)x1mat. Our results demonstrate the necessity of using array-CGH to evaluate patients with apparently balanced structural rearrangements in order to determine the submicroscopic chromosomal imbalances at chromosomal breakpoints that are related to the observed clinical abnormalities. (C) 2017 Elsevier Inc. All rights reserved.

Mucopolysaccharidosis type III (MPS III) is a neurodegenerative disorder. In MPS III patients, heparan sulfate accumulates in many tissues especially the central nervous system. There are limited data regarding bone involvement in MPS III compared to other MPS types. The aim of this study was to evaluate bone mineral density (BMD) and the prevalence of low bone mass, and to explore the association between BMD, vitamin D levels, bone fracture, and patient characteristics in MPS III. A clinical assessment and interview was held to obtain data about family history, height, weight, body mass index (BMI), nutrition, walking capacity, bone fracture, epilepsy, and medical therapy of 15 patients with MPS III. Height, weight, and BMI z scores were calculated. Laboratory tests including 25-hydroxyvitamin D (25-OH-D) were measured. BMD measurements for the lumbar spine were obtained using dual-energy X-ray absorptiometry (DXA). BMD z scores were adjusted for height-for-age z score (HAZ) to provide correction for height deficits. Lumbar spine BMD z score was low (<−1) in five patients for chronological age and normalized in two of five patients after adjustment for HAZ. Three patients continued to have low BMD; these were older than the other patients and one had a history of long bone fracture. Two of these patients were observed to have lost walking capacity at 10 and 14 years, and the other was walking with support. Six patients had deficient, and three patients had insufficient levels of 25-OH-D. Two osteoporotic patients had significantly lower levels of 25-OH-D. We found that older patients with immobility are at high risk of osteoporosis and bone fracture, and vitamin D deficiencies/insufficiencies are widely seen. We recommend monitoring BMD by DXA and checking vitamin D metabolism to assess low bone mass and fracture risk in older MPS III patients with immobility.

Mucolipidosis II or I-cell disease is a rare lysosomal enzyme hydrolase trafficking due to deficient activity of the multimeric enzyme UDP-Nacetylglucosamine-l-phosphotransferase. It is a severe inborn error of lysosomal storage that causes progressive multisystem deterioration and death within the first year of life. The diagnosis of ML II is often difficult in an infant due to clinical variety, phenotypic overlap and the enzyme analysis required. Mucolipidosis II and rickets may have similar physical, biochemical and radiographic findings in newborns. The diagnosis of Mucolipidosis II is often missed, as it may present with rickets-like picture. In this article, we describe two neonatal mucolipidosis II patients mimicking rickets, and we evaluated them by clinical, metabolic and imaging findings via literature and also emphasized the difficulties in diagnosis of this rare disease.

Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism caused by a number of loss-of-function mutations in the ALPL gene. It is characterized by defective bone and tooth mineralisation associated with low serum and bone alkaline phosphatase activity. The clinical presentation of this disease is extremely variable. For this reason, the diagnosis can be difficult and is often missed out or delayed. Hypophosphatasia is classified into subtypes based on the age of onset and clinical features. The clinical severity is associated with the age at diagnosis and the lack of tissue-nonspecific alkaline phosphatase activity; the severe forms of hypophosphatasia are primarily perinatal and infantile forms. Severe forms may present with many neurological problems such as seizures, hypotonia, irritability. Herein, we report the case of an infantile hypophosphatasia patient who presented with pyridoxine-responsive seizures and a novel homozygous mutation in the ALPL gene was detected. There is a limited number of hypophosphatasia patients with pyridoxine-responsive seizures in the literature, so early diagnosis of infantile hypophosphatasia in the clinically compatible patients allows more effective postnatal care/management and genetic counseling for further pregnancies.

Apert syndrome is a rare autosomal dominant genetic disorder characterised by irregular craniosynostosis, midfacial hypoplasia and syndactyly. The birth prevalence is 1 in 65,000 livebirths. Most of the cases are sporadic and associated with allelic mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Two mutations, P253R and S252W, have been defined as responsible in the majority of Apert syndrome cases. In this report, two Apert syndrome cases which diagnosed prenatally with two different FGFR2 gene mutations are presented. Case 1: A 24-year-old pregnant woman diagnosed as Apert syndrome was referred for fetal anomalies at 29 weeks of gestation. Fetal ultrasound showed cloverleaf skull, proptosis, frontal bossing, bilateral syndactyly in hands and feet. Postnatal examination confirmed the prenatal findings and mutation analysis revealed heterozygous P253R mutation in FGFR2 gene both for the mother and the infant. Case 2: Fetal ultrasound revealed abnormal skull, brain appearance and clenched hands at 16 weeks gestation in a 39 -year-old G3P2 woman without a remarkable history. Two weeks later, irregular skull shape, brachycephaly and bilateral syndactyly in hands and feet were detected. Amniocentesis revealed heterozygous S252W mutation in FGFR2 gene. Postmortem examination was consistent with the prenatal findings. Abnormal skull shape, unusual brain and extremity appearance and can suggest craniosynostosis syndromes. FGFR2 gene mutation analysis should be offered in such cases additional to karyotype analysis.

Isochromosome 18p is a rare chromosomal disorder that occurs with a frequency of approximately one in every 180,000 live births, and affects both genders equally. MOst cases result from a de novo formation. In the literature, there are currently only a small number of reports that describe the phenotypic and clinical features of Isochromosome 18p. In this article, we report six cases that displayed the phenotypic and clinical features of Isochromosome 18p, and which were subsequently confirmed by conventional karyotyping and fluorescence in situ hybridization. We also discuss the clinical features of these patients in the context of the cases previously reported in the literature.