In this issue

Abstract

Swarr et al (p. 565) offer several new findings about Potocki-Shaffer syndrome (PSS), a contiguous gene syndrome associated with deletions in 11p11.2. PSS is marked by openings in the two bones that form the top and sides of the skull, multiple benign bone tumors called exostoses, intellectual disability, delayed development, a distinctive facial appearance, and problems with vision. In this study, researchers identified and evaluated six patients with PSS according to a protocol that included assessments by practitioners of several medical specialties and various diagnostic studies. The researchers also used array comparative genomic hybridization to further characterize the deletion in five patients. The researchers newly identified an association of PSS syndrome with sensorineural hearing loss and autistic behaviors. The study data also highlight the characteristic facial features, biparietal foramina, moderate-to-severe developmental delay and intellectual disability, myopia and strabismus, and multiple exostoses already seen with this disorder. Based on these findings and a review of the 31 previously reported cases of PSS, the researchers made recommendations for the care of children with the syndrome. These include referral to early childhood intervention and a developmental-behavioral specialist at the time of diagnosis, a full skeletal survey at diagnosis or by age three, and screening for strabismus and nystagmus by primary care providers at every well-child examination, with referral to a pediatric ophthalmologist at diagnosis or by age six months. The researchers also suggest that infants with PSS be evaluated for sensorineural hearing loss by three months of age and get a behavioral audiogram at age one year and annually thereafter. Parents of children with PSS should get fluorescence in situ hybridization (FISH) studies to find chromosomal rearrangements that would increase risk of PSS in future offspring, researchers write. Castori et al (p. 556) describe the natural history and various manifestations of hypermobility type Ehlers-Danlos syndrome (HT-EDS). A relatively frequent but commonly misdiagnosed variant of Ehlers-Danlos syndrome, HT-EDS is characterized mainly by marked joint instability and mild cutaneous involvement, while additional manifestations include chronic pain, asthenia, and gastrointestinal and pelvic dysfunction. The researchers report on 21 patients selected from a group of 40 subjects with suspected mild hereditary connective tissue disorder. They outline six distinct clinical presentations in a tabulation the authors describe as mnemonic for clinical geneticists attempting to accurately diagnose this condition. HT-EDS's natural history includes three phases—hypermobility, pain, and stiffness—which the researchers delineate based on distinguishing manifestations.1 Main manifestations of Ehlers-Danlos syndrome hypermobility type. Joint hypermobility (e-i): hyperextension of the thumb in passive apposition to the flexor aspect of the forearm (e), hyperextension of the elbow (f) and knee (g) beyond 10°, forward flexion of the trunk with the knees extended and the palms resting flat on the floor (h), and hyperextension of the mecarpophalangeal joint of the V finger in passive dorsiflexion beyond 90° (i). They also identify a group of additional, apparently uncommon abnormalities associated with HT-EDS. These include dolichocolon, dysphonia, and Arnold-Chiari type I malformation. Further investigation of these abnormalities may contribute to an understanding of the pathogenesis of the protean manifestations of HT-EDS and lead to more effective evaluation and management of affected individuals, according to researchers. FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral microphthalmia, write Reis et al (p. 582).1 Patient photographs. B: Patient 1 with prosthetics removed demonstrating bilateral severe microphthalmia. Because autosomal dominant and recessive mutations in FOXE3 among humans have been associated with variable phenotypes, including anterior segment anomalies, cataracts, and microphthalmia, the researchers sequenced FOXE3 in 116 probands. The spectrum of ocular defects in these probands ranged from anterior segment dysgenesis and cataract to anophthalmia/microphthalmia. The researchers found recessive FOXE3 mutations in four of 26 probands affected with bilateral microphthalmia, representing 15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype. FOXE3-positive microphthalmia was accompanied by aphakia and/or corneal defects. The researchers identified missense variants at varying frequencies in patient and control groups. Because some of these variants appear to be race-specific, the researchers emphasized the importance of using race/ethnicity-matched control populations in evaluating the relevance of genetic screening results.