Expanding the phenotypic and genotypic characteristics of trichohepatoenteric syndrome: a report of eight patients from five unrelated families.

BACKGROUND: Trichohepatoenteric syndrome (THES) is characterized by neonatal-onset intractable diarrhea. It often requires long-term total parenteral nutrition (TPN). In addition, other characteristic findings of the syndrome include growth retardation, facial dysmorphism, hair abnormalities, various immunological problems and other rare system findings. Two genes and their associated pathogenic variants have been associated with this syndrome: SKIC3 and SKIC2. METHODS AND RESULTS: In this case series, the clinical findings and molecular analysis results of a total of 8 patients from 5 different families who presented with persistent diarrhea and were diagnosed with THES were shared. Pathogenic variants were detected in the SKIC3 gene in 6 of our patients and in the SKIC2 gene in 2 patients. It was planned to compare the clinical findings of our patients with other patients, together with literature data, and to present yet-undefined phenotypic features that may be related to THES. In our case series, in addition to our patients with a novel variant, patient number 2 had a dual phenotype (THES and Spondyloepimetaphyseal dysplasia, sponastrime type) that has not been reported yet. Delay in gross motor skills, mild cognitive impairment, radioulnar synostosis, osteoporosis, nephropathy and cystic lesions (renal and liver) were observed as unreported phenotypic findings. CONCLUSIONS: We are expanding the clinical and molecular repertoire of the syndrome regarding patients diagnosed with THES. We recommend that the NGS (next-generation sequencing) multigene panel should be used as a diagnostic tool in cases with persistent diarrhea.

Developmental characteristics of Williams-Beuren syndrome and evaluation of adaptive behavioral skills.

Background/aim: Williams-Beuren syndrome (WBS) is a rare genetic disorder with delays in language and cognitive development, but, with increased awareness of clinical features and a reliable diagnostic test, WBS is becoming more widely recognized in childhood. Adaptive behavior skills and/or maladaptive behavior are important for the prognosis of individuals with WBS. The aim of this study was to investigate the clinical and developmental characteristics of patients with WBS and further increase awareness about it by evaluating the adaptive skills and maladaptive behaviors of the patients. Materials and methods: The data of WBS patients followed-up at the Developmental Behavioral Pediatrics Unit were reviewed. Patient data on perinatal and postnatal history, developmental stages, physical and neurological examination findings were collected. The International Guide for Monitoring Child Development (GMCD) was administered to each child. In addition, semistructured interviews were conducted with the parents using the Vineland Adaptive Behavior Scales, Second edition (Vineland-II). Results: A total of 12 patients diagnosed with WBS via detection of the 7q11.23 deletion, of whom 6 were girls, were retrospectively reviewed. The mean age at the time of review was 54.6 ± 32.5 months. The mean age at first presentation to the Developmental Behavioral Pediatrics Outpatient Clinic was 15 ± 11.5 months. In the first developmental evaluation using the GMCD, there was a delay in fine and gross motor domains in 6 patients, in the language domains in 4 patients, and in all of the domains in 2 patients. Findings with Vineland-II showed socialization and communication domains as strengths, but the daily living skills and motor skills domains were weaknesses. In terms of maladaptive behavior, the patients tended to frequently have behavioral problems, neurodevelopmental disease, anxiety disorders, eating problems, and sleeping problems. Conclusion: This retrospective review of 12 patients indicated a general delay in overall development, and confirmed impairment in both adaptive and maladaptive functioning in WBS.

Autosomal recessive cutis laxa: a novel mutation in the FBLN5 gene in a family.

FBLN5-related cutis laxa (CL) is a rare syndrome that can be inherited in an autosomal dominant or recessive manner. Autosomal recessive cutis laxa (ARCL), type IA, has been reported to be more severe. The disease is characterized by microcephaly, sagging cheeks, loose, wrinkled and redundant skin, emphysema, aorta or pulmonary artery abnormalities, inguinal hernia, and anomalies of internal organs. Homozygous mutations in the FBLN5 gene are responsible for the clinical manifestations. We report a family study of a child with ARCL. FBLN5 genes of the patient and parents were sequenced using next-generation sequencing technologies. Analyses showed that the patient was homozygous for the novel c.518A>G, p.R173H mutation in exon 6 of the FBLN5 gene, whereas the parents were heterozygous. The mutation was found to be 'possibly pathogenic' in bioinformatic analysis. We identified a novel FBLN5 mutation in a CL patient; pedigree and parental genetic analyses suggested ARCL. Our results also suggest that the mutation analysis provides useful evidence to support the clinical diagnosis and define the inheritance mode of CL in an apparently sporadic case.

A mitochondrial neurogastrointestinal encephalomyopathy with intestinal pseudo-obstruction resulted from a novel splice site mutation.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disorder characterized by gastrointestinal dysmotility, cachexia, ptosis, peripheral neuropathy and leukoencephalopathy. The diagnosis is often not made until 5-10 years after the onset of symptoms. MNGIE is caused by mutations in thymidine phosphorylase gene TYMP. Here, we present a 19-year-old boy with MNGIE who had a chronic intestinal pseudo-obstruction, and we describe his family history. Genetic analysis revealed a novel homozygous c.765+1G>C intronic mutation which is expected to disrupt splicing of TYMP in the patient. Family screening revealed that the brother was also affected and the mother was a carrier. MNGIE should be considered and genetic testing instigated if individuals with cachexia have neuromuscular complaints or symptoms of chronic intestinal pseudo-obstruction.

A Rare Mosaic Karyotype of 45,X/46,X,psu idic(Y)(p11.32)/46,XY with SHOX Haploinsufficiency, External Male Genitalia, and Short Stature.

In this case study, we describe a 3-year-old boy who was referred to the Inonu University Hospital with short stature complaint. His height was 86 cm (-2.96 SDS), weight was 12 kg (-2.43 SDS), and head circumference was 46.5 cm (-2.34 SDS). Chromosomal analyses were performed on cultured peripheral blood lymphocytes of the patient and his parents and showed the patient's karyotype mos 45,X[20]/46,X,idic(Y)(p11.32)[29]/46,XY[1]. The karyotypes of the parents were normal. Subsequently, specific FISH probes were hybridized to the related regions of the sex-determining region Y (SRY), centromere X/Y (CEP X/Y), and short stature homeobox (SHOX) genes. Simultaneous SNP array-CGH was conducted. As to our knowledge, we present the first patient with mosaic isodicentric Y chromosome with 3 different cell lines and normal male external genitalia. Our results suggest that it would be beneficial to study cytogenetic and molecular cytogenetic methods together for better diagnostic accuracy and treatment.