Gastrointestinal disorders in Curry–Jones syndrome: Clinical and molecular insights from an affected newborn

Curry–Jones syndrome (CJS) is a pattern of malformation that includes craniosynostosis, pre‐axial polysyndactyly, agenesis of the corpus callosum, cutaneous and gastrointestinal abnormalities. A recurrent, mosaic mutation of SMO (c.1234 C>T; p.Leu412Phe) causes CJS. This report describes the gastrointestinal and surgical findings in a baby with CJS who presented with abdominal obstruction and reviews the spectrum of gastrointestinal malformations in this rare disorder. A 41‐week, 4,165 g, female presented with craniosynostosis, pre‐axial polysyndactyly, and cutaneous findings consistent with a clinical diagnosis of CJS. The infant developed abdominal distension beginning on the second day of life. Surgical exploration revealed an intestinal malrotation for which she underwent a Ladd procedure. Multiple small nodules were found on the surface of the small and large bowel in addition to an apparent intestinal duplication that seemed to originate posterior to the pancreas. Histopathology of serosal nodules revealed bundles of smooth muscle with associated ganglion cells. Molecular analysis demonstrated the SMO c.1234 C>T mutation in varying amounts in affected skin (up to 35%) and intestinal hamartoma (26%). Gastrointestinal features including structural malformations, motility disorders, and upper GI bleeding are major causes of morbidity in CJS. Smooth muscle hamartomas are a recognized feature of children with CJS typically presenting with abdominal obstruction requiring surgical intervention. A somatic mutation in SMO likely accounts for the structural malformations and predisposition to form bowel hamartomas and myofibromas. The mutation burden in the involved tissues likely accounts for the variable manifestations.


| INTRODUCTION
Curry-Jones syndrome (CJS; OMIM #601707) is a pattern of malformation that includes craniosynostosis, pre-axial polysyndactyly, agenesis of the corpus callosum, cutaneous and gastrointestinal abnormalities (Temple et al., 1995). The first two cases were presented as unknown syndromes at the David W. Smith workshop on malformations in 1987 (Curry, 1987). Cohen (1988) recognized the cases as a pattern of malformation and termed the CJS after the physicians who had described the first two cases. Eleven unrelated cases have been reported in the literature presenting with craniofacial abnormalities, patchy cutaneous findings, and polysyndactyly (Grange et al., 2008;Mingarelli, Mokini, Castriota-Scanderbeg, & Dallapiccola, 19999;Temple et al., 1995;Thomas et al., 2006;Twigg et al., 2016).
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Until recently, the genetic etiology of CJS was not known. All cases of CJS occurred sporadically and karyotype analyses of blood and fibroblasts from affected skin were normal. Based on clinical observations including asymmetric features and patchy cutaneous manifestation, it was hypothesized that CJS was due to a somatic mutation arising in early post-zygotic embryonic development.
However, symmetric polydactyly and syndactyly was not consistent with this hypothesis. Grange et al. (2008) reported two new children with CJS including one child with a desmoplastic medulloblastoma and another child with a trichoblastoma of the skin and thus hypothesized that CJS may be due to a defect in the sonic hedgehog (Shh) pathway. However, sequencing of PTCH and GLI, genes coding for key proteins in the Shh signaling pathway, was negative.
Recently, Twigg et al. (2016)  Gastrointestinal abnormalities are a cardinal feature of CJS.
Previously described findings include pseudo-obstruction, malrotation, and gastrointestinal myofibromas or smooth muscle hamartomas (Grange et al., 2008;Temple et al., 1995). Here, we present a child with CJS who presented with abdominal distension in the newborn period. This case, listed in table 1 of Twigg et al. (2016) as case #10, was found to have the recurrent, mosaic mutation of SMO (c.1234 C>T; p.Leu412Phe) that causes CJS. This report presents a detailed clinical description and is accompanied with a more complete molecular analysis. In addition we compare the gastrointestinal features with prior cases in the literature and discuss the developmental pathophysiologic correlates to further delineate the syndrome.

| CASE DESCRIPTION
The proband is a female infant born at 41 weeks EGA to an 18-year-old G1P0 Hispanic-Samoan mother and non-consanguineous 18-year-old Hispanic father. The mother had routine prenatal care and there were no significant exposures. Pregnancy was complicated by pyelectasis and absent cavum septum pellucidum detected on ultrasound during the second trimester fetal anatomy survey. Upon transfer of care at 35 weeks (after the family relocated), she was started on weekly nonstress tests due to the presence of suspected fetal anomalies. A repeat ultrasound obtained at 39 3/7 weeks GA showed accelerated fetal growth (gestational age equivalents: biparietal diameter: 40 0/7 weeks, head circumference 40 6/7 weeks, abdominal circumference 39 6/7 weeks, femur length 37 1/7 weeks), and apparent fusion of the anterior lateral ventricles, concerning for alobar holoprosencephaly.
The infant was delivered by cesarean section after a failed induction of labor with Apgars of 9 and 9 at 1 and 5 min, respectively. The infant was large for gestational age with a birth weight of 4,165 g (96th percentile, z-score 1.88), length of 53.3 cm (98th percentile, z-score 2.23), and occipitofrontal head circumference of 38.5 cm (∼100th percentile, z-score 3.90) (WHO 0-2 years female growth chart). Following NICU discharge, the infant had intermittent emesis, poor weight gain on 24 kcal fortified formula, and chronic constipation.
She was admitted at 5 months of age for failure to thrive. The infant was noted to have a focal area of esophageal narrowing just below the level of the thoracic inlet on a modified barium swallow study. An Intraoperative findings included a markedly dilated transverse colon.
The infant was discharged home on continuous gastrostomy tube feedings after 45 hospital days.
The infant was readmitted when she was 8 months old for feeding intolerance and weight loss. Upon admission, this formerly macrosomic infant had a weight for age less than the first percentile (hyperpigmented or affected compared with unaffected) but also with the layers of the skin. The factors that drive a higher mutant allele frequency within the epidermis are unknown. In addition, detection of the mutant allele within apparently unaffected skin at a low level suggests that the mutation arose early in skin development. Indeed, the presence of mosaicism as well as detection of the mutant allele in multiple different tissue types suggests that the mutation occurred as a post-zygotic error early in embryonic development.
SMO is a key component of the HH-GLI pathway and its protein product, smoothened, is essential for normal HH signal transduction.

Congenital gastrointestinal malformations including malrotation
have been reported in studies of Shh −/− mice (Ramalho-Santos et al., 2000). Similar studies have not been replicated in Smo −/− mice as the knockout results in an embryonic lethal phenotype (Zhang, Ramalho-Santos, & McMahon, 2001).
The identical recurrent mutation in SMO that accounts for the multiple malformations in CJS is also observed in several cancers including ameloblastoma (Sweeney et al., 2014), basal cell carcinoma (Atwood et al., 2015;Sharpe et al., 2015;Xie et al., 1998), medulloblastoma (Jones et al., 2012;Pugh et al., 2012), and meningioma (Brastianos et al., 2013). The mutant protein results in constitutive activation of smoothened in the absence of HH signaling in mouse Smo −/− embryonic fibroblasts and is associated with increased cell division (Sweeney et al., 2014). This finding may help account for the propensity to develop benign neoplasms such as smooth muscle hamartomas in affected tissues in the bowel. Gastrointestinal manifestations included structural malformations such as malrotation (n = 5), congenital short gut (n = 1), and intestinal duplication (n = 1). One child underwent screening imaging at 9 months of age due to reports of gastrointestinal abnormalities in CJS and was found to have an asymptomatic malrotation (Grange et al., 2008). These  Table 2 for recommended evaluation). This condition probably reflects a high level of mosaicism in multiple affected tissues. Individuals with lower level mosaicism may have less obvious features, particularly cutaneous features (Khamaysi et al., 2016). The diagnosis of CJS should be considered in infants with craniosynostosis, polysyndactyly, or patchy skin manifestations, who have unexplained recurrent gastrointestinal symptoms.