Mutations of SMAD4 account for both LAPS and Myhre syndromes
- [Show abstract] [Hide abstract] ABSTRACT: We present three patients with overlapping interstitial deletions of 19p13.3 identified by high resolution SNP microarray analysis. All three had a similar phenotype characterized by intellectual disability or developmental delay, structural heart abnormalities, large head relative to height and weight or macrocephaly, and minor facial anomalies. Deletion sizes ranged from 792 Kb to 1.0 Mb and included a common region arr [hg19] 19p13.3 (3,814,392-4,136,989), containing eight genes: ZFR2, ATCAY, NMRK2, DAPK3, EEF2, PIAS4, ZBTB7A, MAP2K2, and two non-coding RNA's MIR637 and SNORDU37. The patient phenotypes were compared with three previous single patient reports with similar interstitial 19p13.3 deletions and six additional patients from the DECIPHER and ISCA databases to determine if a common haploinsufficient phenotype for the region can be established. © 2013 Wiley Periodicals, Inc.
- [Show abstract] [Hide abstract] ABSTRACT: Myhre syndrome is a rare disorder characterized by pre- and postnatal short stature, brachydactyly, facial dysmorphism (short palpebral fissures, maxillary hypoplasia, prognathism and short philtrum), thick skin, muscular-appearing body build, decreased joint mobility, mixed hearing loss, and cleft lip and palate. Other clinical features include skeletal dysplasia, developmental delay with intellectual disability and/or behavioral disturbance, cardiac defects, cryptorchidism, and bone anomalies. The disease is caused by recently identified SMAD4 mutations. Here we describe a 7-year-old boy with a molecularly proven Myhre syndrome who presented life-threatening recurrent pericarditis and systemic inflammatory symptoms that required treatment with steroid and recombinant interleukin-1 receptor antagonist.
- [Show description] [Hide description] DESCRIPTION: We report the case of a boy of Scandinavian descent diagnosed with Myhre syndrome (MS) at the age of ten years. The patient was initially diagnosed with CHARGE syndrome based on the association of unilateral choanal atresia, patent ductus arteriosus, soft cleft palate with swallowing difficulties necessitating PEG, growth retardation, cryptorchidism, bilateral hearing loss and immunoglobulin deficiency explaining his recurrent bacterial respiratory tract infections. The absence of iris- and/or retinal coloboma, normal semicircular canals and no typical dysmorphic features, however, made CHARGE a less likely diagnosis. Furthermore, the patient has progressive restrictive pulmonary disease, not explained by his immunodeficiency, as well as delayed wound healing and chronic pericarditis requiring permanent immune suppression. MS was suspected based on the presence of typical dysmorphic features, short stature, hearing impairment and limited joint mobility. A heterozygous mutation in SMAD4 affecting the codon for Ile500 (c.1498A>G, p.Ile500Val) confirmed the diagnosis. He also has signs of precocious puberty with so far no evidence of hormonal imbalance. This is in line with a previous report suggesting hypothalamic-hypophyseal malfunction in MS [Asakura et al., 2012]. The presence of respiratory problems and chronic pericarditis supports a previously reported observation that LAPS syndrome (Laryngotracheal stenosis, Arthropathy, Prognathism, and Short stature) and MS are in fact phenotypic variants of the same disorder [Noralane et al., 2012]. This case is particular by the finding of immunoglobulin deficiency, chronic immune pericarditis and delayed wound healing indicating a role for the SMAD4 and TGF Beta Signaling in immune and inflammatory response.
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