A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion.

BACKGROUND: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS: We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. RESULTS: We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development. CONCLUSIONS: Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).

Autoimmune endocrine disorders and coeliac disease in children and adolescents with juvenile idiopathic arthritis and rheumatic fever.

OBJECTIVES: There have been few studies on the association between childhood autoimmune and rheumatic diseases. Therefore, this study aims to assess the frequency of autoimmune thyroiditis (AT), coeliac disease (CD) and type 1 diabetes mellitus (T1DM) in children and adolescents with juvenile idiopathic arthritis (JIA) and rheumatic fever (RF). METHODS: This cross-sectional study includes 53 patients with JIA, 66 patients with RF and 40 healthy subjects controls. All subjects were evaluated for thyrotropin (TSH), triiodothyronine (T3), free thyroxine (FT4), antithyroglobulin (Tg) and antiperoxidase antibodies, fasting glucose, C-peptide, anti-glutamic acid decarboxylase (GAD), anti-islet cell (IA) and antitransglutaminase IgA (tTG) antibodies. Patients with thyroid dysfunction, positive anti-thyroid antibodies or tTG underwent thyroid ultrasonography and jejunal biopsy, respectively. RESULTS: In group 1 (n=53), 21 patients presented thyroid disorders (40%; 42% oligoarticular), either subclinical hypothyroidism (13%) or positive anti-thyroid antibodies (26%, 50% oligoarticular), significantly higher than in control group (p<0.009, OR=10.5, CI 1.29-85.2). In group 2 (n=66), thyroid disorders were identified in 11 patients, four (6%) with subclinical hypothyroidism and seven (11%) with positive anti-thyroid antibodies (p=0.06, compared with the control group). There were no cases of clinical overt hypothyroidism, positive anti-GAD or anti-IA, nor changes in serum C-peptide and glycemia. CD was confirmed in one patient from each group. CONCLUSIONS: Patients with JIA (especially the oligoarticular form) and RF should be investigated for thyroid dysfunction. Longitudinal studies could establish screening protocols for CD in patients with JIA and RF. The cost-effectiveness of T1DM screening is not justified in this population.

Co-occurrence of achondroplasia and Down syndrome: Genotype/phenotype association.

BACKGROUND: This report describes the sixth case of an unusual association: Down syndrome with achondroplasia. It also analyzes the effects of both of these disorders on patient phenotype. METHODS: A male infant was evaluated for Down syndrome. His appearance also suggested a diagnosis of achondroplasia. The child was evaluated by physical examination, radiography, cytogenetic study, and mutation analysis. RESULTS: Chromosome analysis showed a karyotype of 47,XY,+21 in all 30 cells analyzed. Radiographic examination showed typical findings of achondroplasia, such as disproportionately large skull, shortening of limb segments, and lumbar lordosis. FGFR3 screening showed a heterozygous G1138A mutation. CONCLUSIONS: The interaction of these two distinct genetic disorders in the same patient produces a phenotype typical of each syndrome with some overlapping signs. This case represents de novo origin of two disorders that both may be parental-age related.