Family history and clefting as major criteria for CHARGE syndrome.

CHARGE syndrome is an autosomal dominant malformation syndrome associated with mutations in CHD7. The condition is typically sporadic with few familial cases reported. The diagnosis of CHARGE syndrome is based on a combination of major and minor criteria comprised of structural and functional abnormalities, most of which are part of the original CHARGE acronym, although additional anomalies have been added. To date, family history has not been considered in the diagnostic criteria. Here we report a family with a previously unreported missense mutation in exon 31 of CHD7, in which family history played a role in the diagnosis of CHARGE syndrome. Given the tremendous phenotypic variability and the dominant nature of CHARGE syndrome, we propose that family history be included as a major diagnostic criterion. A positive family history would include any individual with an apparently isolated unilateral major CHARGE anomaly or someone with a few of the minor features. Our cases support this proposal; had family history not been considered in this case, CHD7 testing might not have been pursued, leading to incomplete medical follow-up and erroneous genetic counseling. Additionally, with the increased incidence of orofacial clefting in this family, as well as in the literature, we suggest that cleft lip and/or palate be added to the major diagnostic criteria for CHARGE syndrome.

Aggressive juvenile polyposis in children with chromosome 10q23 deletion.

Juvenile polyps are relatively common findings in children, while juvenile polyposis syndrome (JPS) is a rare hereditary syndrome entailing an increased risk of colorectal cancer. Mutations in BMPR1A or SMAD4 are found in roughly half of patients diagnosed with JPS. Mutations in PTEN gene are also found in patients with juvenile polyps and in Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. Several previous reports have described microdeletions in chromosome 10q23 encompassing both PTEN and BMPR1A causing aggressive polyposis and malignancy in childhood. These reports have also described extra-intestinal findings in most cases including cardiac anomalies, developmental delay and macrocephaly. In this report we describe a boy with a 5.75 Mb deletion of chromosome 10q23 and a 1.03 Mb deletion within chromosome band 1p31.3 who displayed aggressive juvenile polyposis and multiple extra-intestinal anomalies including macrocephaly, developmental delay, short stature, hypothyroidism, atrial septal defect, ventricular septal defect and hypospadias. He required colectomy at six years of age, and early colectomy was a common outcome in other children with similar deletions. Due to the aggressive polyposis and reports of dysplasia and even malignancy at a young age, we propose aggressive gastrointestinal surveillance in children with 10q23 microdeletions encompassing the BMPR1A and PTEN genes to include both the upper and lower gastrointestinal tracts, and also include a flowchart for an effective genetic testing strategy in children with juvenile polyposis.

Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. CONCLUSIONS: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

Petty syndrome and Fontaine-Farriaux syndrome: Delineation of a single syndrome.

In 1990, Petty et al. described two patients representing a novel syndrome with "congenital progeriod" features and neither had classical progeria nor Wiedemann-Rautenstrauch syndrome, though many findings were overlapping. One of the cases had previously been described by Dr. Wiedemann in 1948. The key features of Petty syndrome include pre and postnatal growth restriction, decreased subcutaneous fat with loose skin, enlarged fontanelle with underdeveloped calvarium, coronal synostosis, unruly hair pattern with non-uniform distribution, prominent eyebrows, umbilical hernia, distal digital hypoplasia, and normal or near normal development. Significant overlap to other syndromes, particularly the Fontaine-Farriaux syndrome, is apparent. In 2004, Ardinger postulated that Petty syndrome, like classical progeria, might be secondary to a defect in the lamin A/C (LMNA) gene. The purpose of this paper is to describe two new unrelated cases of this unique syndrome that further delineate the phenotype, compare to phenotypically similar syndromes, and postulate that Petty syndrome could represent a new laminopathy. In addition, evidence suggesting that the Petty syndrome and Fontaine-Farriaux syndromes are variable expressions of the same condition is discussed.

Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics.

Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.

The Hunter-MacDonald syndrome with expanded phenotype including risk of meningioma: an update and review.

Hunter-MacDonald syndrome (HMS) is a rare, autosomal dominant skeletal dysplasia with multiple malformations. The skeletal manifestations of HMS include short stature, scoliosis, epiphyseal dysplasia with early osteoarthritis leading to joint replacement, prominent humeral insertions for the deltoids, camptodactyly, subluxation of the thumbs, and malformed feet. Craniofacial manifestations include normal head circumference, tall forehead, bitemporal narrowing, ptosis, short palpebral fissures, and short philtrum. Decreased hearing acuity, transient cranial nerve palsies, congenital heart defects, and meningioma are also reported. Herein, we present two cases, and, through review of the manifestations of HMS in affected and at-risk family members, we have observed that predisposition to brain tumor is a cardinal feature of this condition.

Expanding the phenotype of oculoectodermal syndrome: possible relationship to encephalocraniocutaneous lipomatosis.

Oculoectodermal syndrome (OES) is characterized by epibulbar dermoids, aplasia cutis congenita, and other abnormalities. Here, we report 2 new cases, review 13 previous cases, and propose that OES may be a mild variant of encephalocraniocutaneous lipomatosis (ECCL), differing primarily in its lack of intracranial pathology.

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.