FOXI3 pathogenic variants cause one form of craniofacial microsomia.

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.

A clinical study of Sotos syndrome patients with review of the literature.

Sotos syndrome is characterized by tall stature, advanced bone age, typical facial abnormalities, and developmental delay. The associated gene is NSD1. The study involved 22 patients who fulfilled the clinical criteria. Phenotypic characteristics, central nervous system findings, and cardiovascular and urinary tract abnormalities were evaluated. Meta-analysis on the incidence of cardinal clinical manifestations from the literature was also performed. Macrocephaly was present in all patients. Advanced bone age was noted in 14 of 22 patients (63%), and its incidence presented significant statistical difference in the meta-analysis of previous studies. Some patients had serious clinical manifestations, such as congenital heart defects, dysplastic kidneys, psychosis, and leukemia. Clinical and laboratory examinations should be performed to prevent and manage any unusual medical aspect of the syndrome. Facial gestalt and macrocephaly, rather than advanced bone age, are the strongest indications for clinical diagnosis.

Three novel mutations in greek sotos patients with rare clinical manifestations.

BACKGROUND: Sotos syndrome is an autosomal dominant disease characterized by tall stature, advanced bone age, typical morphological abnormalities of the face and developmental delay. It is caused by mutations in the NSD1 gene located on chromosome 5. NSD1 mutations are detected in the majority of the Sotos patients, and include intragenic NSD1 mutations and microdeletions in the 5q35 region. Cardiovascular and urogenital symptoms are more frequent in the microdeletion group. METHODS: Mutation analysis was performed in 4 patients with Sotos syndrome with typical phenotypic characteristics. RESULTS: In each of the 4 patients a NSD1 mutation was found (2 frame shifts, 1 nonsense and 1 missense mutation). Two of our patients presented dysplastic kidneys with cysts and psychosis, respectively. CONCLUSIONS: We describe 4 Greek patients with Sotos syndrome. Apart from the typical phenotypic characteristics, 2 of our patients presented rare clinical manifestations such as dysplastic kidneys and psychosis. The 3 detected mutations are novel.

Tumor development in three patients with Noonan syndrome.

The diagnosis of Noonan syndrome is essentially clinical, based upon the distinct phenotype and the involvement of the cardiovascular system. Tumor development is a rare manifestation of Noonan syndrome but can be explained by the molecular pathophysiology involved in the disorder. We present three Noonan patients who developed solid tumors. The first patient, a 4-year-old girl, developed granular cell tumors as did her mother in childhood. The second patient, a 1-year-old boy, had a low grade pilocytic astrocytoma, the clinical expression of which was persistent headache. MRI showed a pituitary mass in the posterior lobe. It was surgically removed. The third patient, a 7-year-old boy was found to have Sertoli tumors in his right cryptorchid testis. All three patients fulfilled the clinical criteria for Noonan syndrome. However, genetic testing was negative in patients 1 and 3. The diagnosis of Noonan syndrome was made based on distinct phenotypic findings in three patients who had different types of tumors.

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.