The evolving craniofacial phenotype of a patient with Sensenbrenner syndrome caused by IFT140 compound heterozygous mutations

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List of key featuresCiliopathyEarly-onset, retinal dystrophyEnd stage renal diseaseIFT140Retinal dystrophySensenbrenner syndromeIntroductionCiliopathies are a vast group of genetic disorders caused by altered cilia assembly, maintenance or function (Hildebrandt et al., 2011). Mutations in genes that encode components of the intraflagellar transport complex A (IFT-A), which drives retrograde ciliary transport, are a major cause of skeletal ciliopathies (Perrault et al., 2012). Alterations of all IFT-A components have previously been reported to cause Sensenbrenner, Jeune asphyxiating thoracic dystrophy (JATD), Mainzer–Saldino (MSS) and/or short-rib polydactyly syndromes [IFT43 (MIM 614068), IFT122 (MIM 606045), IFT139 (MIM 612014), IFT140 (MIM 614620), IFT144 (MIM 608151) and WDR35 (MIM 613602)]. Sensenbrenner syndrome, also known as cranioectodermal dysplasia, is a rare multiple anomaly syndrome with a distinctive craniofacial appearance, skeletal, ectodermal, connective tissue, renal and liver anomalies (Lin et al., 2013). Advances with next-generation sequencing expanded our knowledge of its phenotypic variability and molecular heterogeneity (Walczak-Sztulpa et al., 2010; Arts et al., 2011; Lin et al., 2013). The diagnosis is established in those with typical clinical findings and can be confirmed in 40% of affected individuals by identification of biallelic mutations in one of four genes known to be causing Sensenbrenner syndrome (IFT122, WDR35, WDR19 or IFT43) (Walczak-Sztulpa et al., 2010; Arts et al., 2011; Lin et al., 2013). Mutations in IFT140 can result in a clinical phenotypic continuum ranging from isolated retinal dystrophy (Bifari et al., 2015) to MSS and, less commonly, JATD (Perrault et al., 2012; Schmidts et al., 2013), but it has not been described in patients with a clinical presentation of Sensenbrenner syndrome so far.We report the evolving facial phenotype in a child with compound heterozygosity for IFT140 mutations and Sensenbrenner syndrome. We therefore propose that mutations in the IFT140 gene may also cause Sensenbrenner syndrome and we present a bifid uvula as an additional feature of this syndrome.Clinical reportA 1-month-old boy was referred to the genetic clinic because of facial dysmorphisms and striking brachydactyly (Figs 1 and 2). He was the second child of healthy, nonconsanguineous, white British parents; an older brother was fit and well. There was no significant antenatal history. He was born at 41+3 weeks of gestation; his birth weight was 4 kg (+1 SD), height was 49 cm (−1 SD) and head circumference was 36 cm (+1 SD). He was hypotonic and had oedema of the hands, feet and neck. By the end of the first week of life, the oedema had resolved and the muscle tone had normalized. He was readmitted at 5 days because of weight loss despite feeding well on the bottle. Three months later, he was admitted with an adenovirus infection and stayed in hospital for 4 weeks on inspired oxygen. He was readmitted 2 weeks later, still positive for adenovirus, but had picked up a rhinovirus infection as well and stayed in for another 9 weeks. Following these infections, he developed a chronic lung disease and had a persistent oxygen requirement. Standard bronchoscopy evidenced a bifid uvula, but was otherwise normal. A 24-h oesophageal pH test was also normal. By the age of 9 months, significant developmental delay was evident: he had poor head control, was not fixing or following, showed head lag when pulled to sit and made no attempt to raise his head when prone. By 15 months, he developed nystagmus and had full-field electroretinograms that showed markedly reduced rod and cone responses.

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