The face of Smith-Magenis syndrome: a subjective and objective study.

We report a study of 55 subjects with Smith-Magenis syndrome, aged 9 months to 35 years. Each person has been evaluated with an assessment of "gestalt" and detailed facial measurement, using previously published methodology, with compilation of Z score pattern profiles. The facial phenotype of SMS is quite distinctive, even in the young child. The overall face shape is broad and square. The brows are heavy, with excessive lateral extension of the eyebrows. The eyes slant upwards and appear close set and deep set. The nose has a depressed root and, in the young child, a scooped bridge. With time, the bridge becomes more ski jump shaped. The height of the nose is markedly reduced while the nasal base is broad and the tip of the nose is full. The shape of the mouth and upper lip are most distinctive. The mouth is wide with full upper and lower lips. The central portion of the upper lip is fleshy and everted with bulky philtral pillars, producing a tented appearance that, in profile, is striking. With age, mandibular growth is greater than average and exceeds that of the maxilla. This leads to increased jaw width and protrusion and marked midface hypoplasia. Craniofacial pattern analysis supports these subjective impressions. After mid-childhood, mandibular dimensions consistently exceed their maxillary counterparts. Craniofacial widths are greater than corresponding depths and heights. Nasal height is reduced while nasal width is increased. There is mild brachycephaly. The most marked age related changes are increased width of the nose and lower face (mandibular width) with reduction in nasal height and midfacial depth.

Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder.

BACKGROUND: The hyper-IgE syndrome with recurrent infections is a rare immunodeficiency characterized by recurrent skin and pulmonary abscesses and extremely elevated levels of IgE in serum. Associated facial and skeletal features have been recognized, but their frequency is unknown, and the genetic basis of the hyper-IgE syndrome is poorly understood. METHODS: We studied 30 patients with the hyper-IgE syndrome and 70 of their relatives. We took histories, reviewed records, performed physical and dental examinations, took anthropometric measurements, and conducted laboratory studies. RESULTS: Nonimmunologic features of the hyper-IgE syndrome were present in all patients older than eight years. Seventy-two percent had the previously unrecognized feature of failure or delay of shedding of the primary teeth owing to lack of root resorption. Common findings among patients were recurrent fractures (in 57 percent of patients), hyperextensible joints (in 68 percent), and scoliosis (in 76 percent of patients 16 years of age or older). The classic triad of abscesses, pneumonia, and an elevated IgE level was identified in 77 percent of all patients and in 85 percent of those older than eight. In 6 of 23 adults (26 percent), IgE levels declined over time and came closer to or fell within the normal range. Autosomal dominant transmission of the hyper-IgE syndrome was found, but with variable expressivity. Of the 27 relatives at risk for inheriting the hyper-IgE syndrome, 10 were fully affected, 11 were unaffected, and 6 had combinations of mild immunologic, dental, and skeletal features of the hyper-IgE syndrome. CONCLUSIONS: The hyper-IgE syndrome is a multisystem disorder that affects the dentition, the skeleton, connective tissue, and the immune system. It is inherited as a single-locus autosomal dominant trait with variable expressivity.

Sleep disturbance in Smith-Magenis syndrome (del 17 p11.2).

Smith-Magenis syndrome (SMS) is a clinically recognizable multiple congenital anomaly and mental retardation syndrome caused by an interstitial deletion of chromosome 17 p11.2. Although the physical and molecular genetic features of SMS are increasingly well understood, work is more limited on SMS's behavioral phenotype, which includes self-injury, tantrums, and sleep disturbance. This study examines the sleep behaviors of 39 individuals with SMS, ranging in age from 1.6 to 32 years (mean = 10.5). Prominent sleep problems, seen in 65 to 100% of the sample, included difficulties falling asleep, shortened sleep cycles, frequent and prolonged nocturnal awakenings, excessive daytime sleepiness, daytime napping, snoring, and bed-wetting. Medication to facilitate sleep was used by 59% of SMS subjects. Possible etiologic mechanisms of sleep disturbance in SMS are discussed, as are recommended interventions.

Behavioral phenotype of Smith-Magenis syndrome (del 17p11.2).

Smith-Magenis syndrome (SMS) is a distinct and clinically recognizable multiple congenital anomaly (MCA) and mental retardation syndrome caused by an interstitial deletion of chromosome 17 p11.2. The phenotype of SMS has been well described and includes: a characteristic pattern of physical features; a hoarse, deep voice; speech delay with or without associated hearing loss; signs of peripheral neuropathy; variable levels of mental retardation; and neurobehavioral problems. Although self-injury and sleep disturbance are major problems in SMS, studies are limited on the behavioral phenotype of SMS. This report reviews the current state of knowledge about SMS and presents new data based on syndrome-specific observations by the authors' longitudinal experience working with SMS, specifically related to the behavioral aspects of SMS. This information should have relevance for parents, clinicians, geneticists, and educators involved in the care of individuals with SMS.

Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin.

Williams syndrome (WS) is a neurodevelopmental disorder with a variable phenotype. Molecular genetic studies have indicated that hemizygosity at the elastin locus (ELN) may account for the cardiac abnormalities seen in WS, but that mental retardation and hypercalcemia are likely caused by other genes flanking ELN. In this study, we defined the minimal critical deletion region in 63 patients using 10 microsatellite markers and 5 fluorescence in situ hybridization (FISH) probes on chromosome 7q, flanking ELN. The haplotype analyses showed the deleted cases to have deletions of consistent size, as did the FISH analyses using genomic probes for the known ends of the commonly deleted region defined by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D7S1870. The genetic distance between these two markers is about 2 cM. Of the 51 informative patients with deletions, 29 were maternal and 22 were paternal in origin. There was no evidence for effects on stature by examining gender, ethnicity, cardiac status, or parental origin of the deletion. Heteroduplex analysis for LIMK1, a candidate gene previously implicated in the WS phenotype, did not show any mutations in our WS patients not deleted for ELN. LIMK1 deletions were found in all elastin-deletion cases who had WS. One case, who has isolated, supravalvular aortic stenosis and an elastin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS phenotype or is simply deleted due to its close proximity to the elastin locus.

Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome.

Deletions of the distal short arm of chromosome 1 (1p36) represent a common, newly delineated deletion syndrome, characterized by moderate to severe psychomotor retardation, seizures, growth delay, and dysmorphic features. Previous cytogenetic underascertainment of this chromosomal deletion has made it difficult to characterize the clinical and molecular aspects of the syndrome. Recent advances in cytogenetic technology, particularly FISH, have greatly improved the ability to identify 1p36 deletions and have allowed a clearer definition of the clinical phenotype and molecular characteristics of this syndrome. We have identified 14 patients with chromosome 1p36 deletions and have assessed the frequency of each phenotypic feature and clinical manifestation in the 13 patients with pure 1p36 deletions. The physical extent and parental origin of each deletion were determined by use of FISH probes on cytogenetic preparations and by analysis of polymorphic DNA markers in the patients and their available parents. Clinical examinations revealed that the most common features and medical problems in patients with this deletion syndrome include large anterior fontanelle (100%), motor delay/hypotonia (92%), moderate to severe mental retardation (92%), growth delay (85%), pointed chin (80%), eye/vision problems (75%), seizures (72%), flat nasal bridge (65%), clinodactyly and/or short fifth finger(s) (64%), low-set ear(s) (59%), ear asymmetry (57%), hearing deficits (56%), abusive behavior (56%), thickened ear helices (53%), and deep-set eyes (50%). FISH and DNA polymorphism analysis showed that there is no uniform region of deletion but, rather, a spectrum of different deletion sizes with a common minimal region of deletion overlap.

The Pointer syndrome: a new syndrome with skeletal abnormalities, camptodactyly, facial anomalies, and feeding difficulties.

We describe a brother and sister with a unique combination of skeletal findings including camptodactyly (phalangeal dislocations), facial anomalies, neonatal respiratory problems, and feeding problems due to poor suck. Metaphyseal splaying, osteopenia, endosteal bone apposition, campomelia, and multiple fractures characterize the other skeletal abnormalities. The parents are first cousins once removed and are unaffected. These cases appear to represent a previously undescribed autosomal recessive disorder.

Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients.

We have used bivariate flow karyotyping to quantify the deletions involving chromosome 17 in sixteen patients with Smith-Magenis syndrome (SMS). The fluorescence intensities of mitotic chromosomes stained with Hoechst 33258 and chromomycin were quantified in a dual-beam flow cytometer. For each patient, the position of the peak representing the deleted chromosome 17 was compared to those of the normal homologs of an unaffected parent. The patients could be classified into four groups based on the size of their deletions. The deletions ranged from approximately 9-10 Mb (approximately 10-11% of the chromosome) to below the detection limit of the technique (2 Mb). Different deletion sizes were detected among patients whose high-resolution banding results were similar. Some deletions detected by banding were not detected by flow analyses. Deletion estimates are largely consistent with the results of molecular analyses. Patients with larger deletions that extend into band 17p 12 have abnormal electrophysiologic studies of peripheral nerves. Deletion size does not appear to correlate with the degree of mental retardation, presence of behavioral abnormalities, craniofacial anomalies or common skeletal findings in SMS. By identifying patients with varying deletion sizes, these data will aid the construction of a long-range deletion-based map of 17p11.2 and identification of the genes involved in this syndrome.

Ophthalmic manifestations of Smith-Magenis syndrome.

PURPOSE: The Smith-Magenis syndrome (SMS) is a multiple-anomaly, mental retardation syndrome associated with deletions of a contiguous region of chromosome 17p11.2. Prior reports have described ophthalmic anomalies with SMS, including telecanthus, ptosis, strabismus, myopia, iris anomalies, cataracts, optic nerve hypoplasia, and retinal detachment. This report defines the ophthalmic spectrum in 28 individuals with SMS subjected to a multidisciplinary clinical and molecular survey. METHODS: Individuals with deletion of chromosome 17p11.2 detected by high-resolution cytogenetic analysis underwent complete ophthalmologic evaluation comprised of ophthalmic history, visual acuity, cycloplegic refraction, motility, and biomicroscopic and ophthalmoscopic examination. RESULTS: Among the 28 subjects, ranging in age from 0.8 to 29.3 years, the most frequent ocular findings were iris anomalies (68%), microcornea (50%), myopia (42%), and strabismus (32%). Bilateral microphthalmos with uveal and retinal coloboma was observed in one individual. No subject had cataract or retinal detachment. CONCLUSIONS: This is the largest single-center series of subjects with SMS that includes ophthalmic evaluation. As in prior reports, iris anomalies and strabismus were observed, but microcornea had not been noted previously. The absolute refractive error was hypermetropic in half of these subjects. Cataract, ptosis, and retinal pathology, including detachment, were not observed in any subject. All individuals with SMS should be evaluated by an ophthalmologist, with special attention to strabismus, microcornea, iris anomalies, and refractive errors.

Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS.

Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1 neuropathy.

Autosomal dominant Charcot-Marie-Tooth type-1A neuropathy (CMT1A) is a demyelinating peripheral nerve disorder that is commonly associated with a submicroscopic tandem DNA duplication of a 1.5-Mb region of 17p11.2p12 that contains the peripheral myelin gene PMP22. Clinical features of CMT1A include progressive distal muscle atrophy and weakness, foot and hand deformities, gait abnormalities, absent reflexes, and the completely penetrant electrophysiologic phenotype of symmetric reductions in motor nerve conduction velocities (NCVs). Molecular and fluorescense in situ hybridization (FISH) analyses were performed to determine the duplication status of the PMP22 gene in four patients with rare cytogenetic duplications of 17p. Neuropathologic features of CMT1A were seen in two of these four patients, in addition to the complex phenotype asociated with 17p partial trisomy. Our findings show that the CMT1A phenotype of reduced NCV is specifically associated with PMP22 gene duplications, thus providing further support for the PMP22 gene dosage mechanism for CMT1A.

Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic, neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65%, brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter.

A clinical and molecular study of mosaicism for trisomy 17.

Trisomy 17 has never been reported in a live birth. We present a case of mosaic trisomy 17 in a male presenting with mental retardation, seizures, attention deficit hyperactivity and autistic disorders, hearing loss, growth retardation, microcephaly, and minor anomalies. Although peripheral blood lymphocyte chromosomes were normal, trisomy 17 was present in the skin fibroblasts. The percentage of abnormal cells appears to have increased from 18% in an initial skin biopsy at age 3 years 8 months to 80% at age 8 years 8 months. Molecular analysis using 13 highly polymorphic markers spanning the length of chromosome 17 demonstrated the extra chromosome 17 in the skin to be of paternal origin. Three alleles were never seen in the trisomic cell line, suggesting that the extra chromosome arose through a mitotic duplication error after conception. Uniparental disomy was excluded in the euploid blood sample. Although Smith-Magenis syndrome involves a deletion of proximal 17p, some of the clinical features of this mosaic trisomy 17 patient, such as decreased REM sleep and increased tolerance to pain, are suggestive of phenotypic features observed in Smith-Magenis syndrome. We speculate that there are dosage-sensitive genes located in 17p11.2 that produce these phenotypes for either deficiencies or over-expression of their gene products.

Hispanic origin and neural tube defects in Houston/Harris County, Texas. I. Descriptive epidemiology.

High prevalences of anencephaly and neural tube defects (NTDs) have recently been recorded for several Texas counties bordering Mexico. In addition, a few investigators have reported Hispanics to be at elevated risk for NTDs (anencephaly and spina bifida). Factors contributing to this risk have not been established. The authors conducted a study of NTDs in Harris County, Texas, to determine the prevalence of each defect. Prevalence was established by identifying cases among resident live births and fetal deaths (stillbirths at > or = 20 weeks) occurring from April 1, 1989, through December 31, 1991. Using multiple case ascertainment methods, 59 cases of anencephaly and 32 cases of spina bifida were detected, resulting in prevalences of 3.8 (95% confidence interval 2.9-4.9) and 2.0 (95% confidence interval 1.4-2.8) per 10,000 live births, respectively. The ratio of anencephaly prevalence to spina bifida prevalence was 2:1 in 1989, 1:1 in 1990, and 3:1 in 1991, with a significant difference in 1991. The female:male prevalence ratio was 1.0 for spina bifida and 2.2 for anencephaly, and was higher still for anencephaly among non-Hispanics (prevalence ratio = 5.6). For each defect, Hispanics experienced a prevalence approximately three times that of non-Hispanics. This ethnic difference was greater for males with anencephaly and for females with spina bifida. For anencephaly, the Hispanic:white/Anglo prevalence ratio (4.2) and the African-American:white/Anglo prevalence ratio (1.9) were greatly elevated and the Hispanic:African-American prevalence ratio (2.2) was similar, relative to comparable studies from the past two decades. The prevalence of anencephaly recorded for public hospitals (7.0 per 10,000) was three times greater than that for private hospitals (2.4 per 10,000). Spina bifida figures were similar for public (prevalence = 2.2 per 10,000) and private (prevalence = 2.0 per 10,000) hospitals. A significantly higher prevalence of both defects was documented among Hispanics in Harris County. The higher anencephaly rates among Hispanics, African-Americans, and those using public hospitals in an era of NTD screening, prenatal diagnosis, and elective pregnancy termination suggest that socioeconomic and perhaps cultural/religious factors might influence the recorded birth prevalence of this defect in particular groups.

Hispanic origin and neural tube defects in Houston/Harris County, Texas. II. Risk factors.

Several investigators have reported Hispanics to be at elevated risk for neural tube defects (anencephaly and spina bifida). Factors contributing to this risk have not been established. The authors conducted a case-control study of neural tube defects (NTDs) among births occurring in Harris County, Texas, from April 1, 1989, through December 31, 1991. Through the use of multiple ascertainment methods, 59 cases of anencephaly and 32 cases of spina bifida were detected. Controls (n = 451) were sampled for the same time period from Harris County vital records. Regardless of how Hispanic ethnicity was classified, having a Hispanic parent was a risk factor for both anencepahly and spina bifida. The primary etiologic question was whether increased NTD risk in Hispanics is explained by maternal diabetes or by other factors (e.g., maternal birthplace, prenatal care, reproductive history, age, socioeconomic status). Mexico-born Hispanics were no more likely than Texas-born Hispanics to deliver a fetus or infant with an NTD. Having a Hispanic mother was a risk factor for anencephaly among infants born to women with early prenatal care (odds ratio (OR) = 4.54, 95% confidence interval (CI) 2.21-9.40) but not for those born to latecomers. Earlier prenatal care seemed "protective" for non-Hispanics (OR = 0.18, 95% CI 0.06-0.65) but not for Hispanics. After simultaneous adjustment for eight variables in multivariate analysis, having a Hispanic (versus non-Hispanic) mother remained a strong risk factor for both anencephaly (OR = 2.58, 95% CI 1.19-5.61) and spina bifida (OR = 3.71, 95% CI 1.48-9.31). Any previous pregnancy termination/fetal loss was also associated with anencephaly in a final logistic regression model (OR = 2.48, 95% CI 1.20-5.10), and having a teenage mother (aged < 20 years) approached significance (OR = 2.21, 95% CI 0.92-5.31). "Hispanic mother" was the only study variable significantly associated with spina bifida in multivariate analysis. Results for diabetes suggested no association with anencephaly (OR = 1.24, 95% CI 0.25-6.17). An increased risk of NTDs among Hispanics remained after controlling for other factors. For anencephaly, this risk might be partially explained by economic and cultural differences between Hispanics and non-Hispanics, and the effect of these factors on rates of prenatal diagnosis and elective pregnancy termination.

Haploinsufficiency of cytosolic serine hydroxymethyltransferase in the Smith-Magenis syndrome.

Folate-dependent one-carbon metabolism is critical for the synthesis of numerous cellular constituents required for cell growth, and serine hydroxymethyltransferase (SHMT) is central to this process. Our studies reveal that the gene for cytosolic SHMT (cSHMT) maps to the critical interval for Smith-Magenis syndrome (SMS) on chromosome 17p11.2. The basic organization of the cSHMT locus on chromosome 17 was determined and was found to be deleted in all 26 SMS patients examined by PCR, FISH, and/or Southern analysis. Furthermore, with respect to haploinsufficiency, cSHMT enzyme activity in patient lymphoblasts was determined to be approximately 50% that of unaffected parent lymphoblasts. Serine, glycine, and folate levels were also assessed in three SMS patients and were found to be within normal ranges. The possible effects of cSHMT hemizygosity on the SMS phenotype are discussed.

Smith-Magenis syndrome deletion: a case with equivocal cytogenetic findings resolved by fluorescence in situ hybridization.

The availability of markers for the 17p11.2 region has enabled the diagnosis of Smith-Magenis syndrome (SMS) by fluorescence in situ hybridization (FISH). SMS is typically associated with a discernible deletion of band 17p11.2 upon cytogenetic analysis at a resolution of 400-550 bands. We present a case that illustrates the importance of using FISH to confirm a cytogenetic diagnosis of del(17)(p11.2). Four independent cytogenetic analyses were performed with different conclusions. Results of low resolution analyses of amniocytes and peripheral blood lymphocytes were apparently normal, while high resolution analyses of peripheral blood samples in two laboratories indicated mosaicism for del(17)(p11.2). FISH clearly demonstrated a 17p deletion on one chromosome of all peripheral blood cells analyzed and ruled out mosaicism unambiguously. The deletion was undetectable by flow cytometric quantitation of chromosomal DNA content, suggesting that it is less than 2 Mb. We conclude that FISH should be used to detect the SMS deletion when routine chromosome analysis fails to detect it and to verify mosaicism.

A gene for a severe lethal form of X-linked arthrogryposis (X-linked infantile spinal muscular atrophy) maps to human chromosome Xp11.3-q11.2.

X-linked arthrogryposis Type I (X-linked infantile spinal muscular atrophy) is a rare disorder showing hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have studied an X-linked arthrogryposis family using highly polymorphic microsatellite markers throughout the X chromosome. Meiotic breakpoint analysis (concordance analysis) based on shared regions of the founder X chromosome was successful in localizing the X-linked arthrogryposis gene to Xp11.3-q11.2. In this region, the highest two-point lod score was found with DXS991 (Zmax = 2.63, theta = 0.00). In multipoint linkage analysis covering the entire X chromosome, only the region defined by MAOB and DXS991 showed positive lod scores and all other regions showed negative lod scores. These data establish the first gene mapping assignment of an X-linked lethal form of human lower motor neuron disease.