Further delineation of renal-coloboma syndrome in patients with extreme variability of phenotype and identical PAX2 mutations

Renal-coloboma syndrome is a recently described autosomal dominant syndrome of abnormal optic nerve and renal development. Two families have been reported with renal-coloboma syndrome and mutations of the PAX2 gene. The PAX2 gene, which encodes a DNA-binding protein, is expressed in the developing ear, CNS, eye, and urogenital tract. Ocular and/or renal abnormalities have been consistently noted in the five reports of patients with renal-coloboma syndrome, to date, but PAX2 expression patterns suggest that auditory and CNS abnormalities may be additional features of renal-coloboma syndrome. To determine whether additional clinical features are associated with PAX2 mutations, we have used PCR-SSCP to identify PAX2 gene mutations in patients. We report here four patients with mutations in exon 2, one of whom has severe ocular and renal disease, microcephaly, and retardation, and another who has ocular and renal disease with high-frequency hearing loss. Unexpectedly, extreme variability in clinical presentation was observed between a mother, her son, and an unrelated patient, all of whom had the same PAX2 mutation as previously described in two siblings with renal-coloboma syndrome. These results suggest that a sequence of seven Gs in PAX2 exon 2 may be particularly prone to mutation.     

Unusual involvement of bone in primary systemic amyloidosis

Vesicoureteric reflux (VUR) is a common childhood condition characterised by regurgitation of urine from the bladder to the kidney. It is the commonest cause of end stage renal failure in children and an important cause in adults. Primary VUR is often familial, suggesting that genetic factors play an important role in its aetiology. Recently, VUR was observed as part of a syndrome, involving optic nerve colobomas and renal anomalies, caused by mutations of the PAX2 gene. PAX2 is a member of the paired box family of genes and is expressed in the ureteric bud and differentiating nephrogenic mesenchyme of the developing kidney. PAX2 has been shown to play a critical role in the development of both the kidney and the ureter. The occurrence of VUR in one family with the PAX2 mutation, and the expression pattern of PAX2 in developing ureteric bud, strongly suggested that PAX2 could be the cause of primary familial VUR. Single strand conformational polymorphism (SSCP) analysis of 23 affected subjects in eight families with primary familial VUR showed no alterations in exons 2-5 of the PAX2 gene. In addition, a polymorphic dinucleotide repeat marker located within the PAX2 gene segregated independently of the disease trait in one large family who primarily had VUR or reflux nephropathy. These results suggest that PAX2 is not a major cause of primary familial reflux.     

Ectopic pregnancy after a laparoscopically-assisted vaginal hysterectomy

PURPOSE/METHODS: Rubinstein-Taybi syndrome is a constellation of clinical findings characterized by mental and motor retardation, broad thumbs and broad first toes, marked growth retardation, microcrania, typical facies, high-arched palate, and cryptorchidism in males. Ocular and adnexal abnormalities are quite common and include antimongoloid slant of the palpebral fissures, epicanthal folds, congenital obstruction of the lacrimal excretory system, ptosis, strabismus, and severe ametropia. Macrocornea, microophthalmos, colobomas of the iris and of the optic nerve head, congenital cataract, and optic nerve atrophy have also been described. Congenital glaucoma is a rare complication. We examined a patient with Rubinstein-Taybi syndrome with bilateral congenital glaucoma. RESULTS/CONCLUSIONS: Examination of this patient revealed bilateral antimongoloid slants of the palpebral fissures, and bilateral congenital glaucoma. Gonioscopic examination revealed the iris to be inserted flatly into the trabecular meshwork. This case emphasizes the importance of detailed, complete ocular examinations in patients with Rubinstein-Taybi syndrome, and also highlights the occurrence of ocular abnormalities rarely associated with this disease.     

Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes

Waardenburg syndrome (WS) is a dominantly inherited and clinically variable syndrome of deafness, pigmentary changes, and distinctive facial features. Clinically, WS type I (WS1) is differentiated from WS type II (WS2) by the high frequency of dystopia canthorum in the family. In some families, WS is caused by mutations in the PAX3 gene on chromosome 2q. We have typed microsatellite markers within and flanking PAX3 in 41 WS1 kindreds and 26 WS2 kindreds in order to estimate the proportion of families with probable mutations in PAX3 and to study the relationship between phenotypic and genotypic heterogeneity. Evaluation of heterogeneity in location scores obtained by multilocus analysis indicated that WS is linked to PAX3 in 60% of all WS families and in 100% of WS1 families. None of the WS2 families were linked. In those families in which equivocal lod scores (between -2 and +1) were found, PAX3 mutations have been identified in 5 of the 15 WS1 families but in none of the 4 WS2 families. Although preliminary studies do not suggest any association between the phenotype and the molecular pathology in 20 families with known PAX3 mutations and in four patients with chromosomal abnormalities in the vicinity of PAX3, the presence of dystopia in multiple family members is a reliable indicator for identifying families likely to have a defect in PAX3.     

DNA modifications by the mutagen glyoxal: adduction to G and C, deamination of C and GC and GA cross-linking

OBJECTIVE: This study aimed to describe the clinical and histopathologic findings in four patients with complex limbal choristomas associated with linear nevus sebaceous syndrome (LNSS), a rare disorder including nevus sebaceous, seizures, and mental retardation, and often accompanied by ocular anomalies. DESIGN: Small observational case series. METHODS: A retrospective review of the clinical and histopathologic records of four patients. RESULTS: Each of four patients had complex limbal choristomas in the setting of clinical and histopathologic LNSS. The limbal choristomas were multiple in three patients and bilateral in two patients. Most choristomas involved the superotemporal limbus (6 of 10), although nasal (3 of 10) and inferior (1 of 10) limbal tumors also were present. Three patients had significant corneal astigmatism or involvement of the central cornea requiring surgical removal of their choristomas, one accompanied by a lamellar keratoplasty and another accompanied by two consecutive penetrating keratoplasties. Each graft eventually vascularized, reducing vision. One patient's vision was limited by amblyopia and another by occipital cortical dysgenesis with visual impairment. Histopathologic examination of the excised choristomas showed foci of lacrimal gland (3 of 4 patients), adipose tissue (3 of 4), neural tissue (1 of 4), cartilage (1 of 4), lymphoid follicles (1 of 4), skin adnexal tissue (1 of 4), and smooth muscle (1 of 4). Other associated ocular findings included an eyelid mass (1 of 4), colobomas of the eyelid (3 of 4), colobomas of the choroid and retina (2 of 4), nonparalytic strabismus (2 of 4), scleral ectasia (1 of 4), partial oculomotor palsy with ptosis and anisocoria (1 of 4), microphthalmia (1 of 4), hypertelorism (1 of 4), and cortical visual impairment (1 of 4). CONCLUSIONS: Complex limbal choristomas, although rare, can occur in the setting of LNSS and can be associated with multiple ocular and systemic abnormalities. Visual prognosis appears poor in most cases despite aggressive management.     

Effect of 5-hydroxytryptamine on bioelectric properties of airway epithelial cells in culture

Waardenburg syndrome type 1 is caused by mutations in PAX3. Over 50 human PAX3 mutations that lead to hearing, craniofacial, limb, and pigmentation anomalies have been identified. A PAX3 mutant allele, segregating in a family, can show reduced penetrance and variable expressivity that cannot be explained by the nature of the mutation alone. The Mus musculus Pax3 mutation Spd (Splotch-delayed, Pax3Spd), coisogenic on the C57BL/6J (B6) genetic background, produces in heterozygotes a white belly spot with 100% penetrance and very few other anomalies. By contrast, many Spd/+ BC1 progeny [F1 female Spd/+ (female Spd/+ B6 x male +/+ Mus spretus) x male +/+ B6] exhibit highly variable craniofacial and pigmentary anomalies. Of the BC1 Spd/+ progeny, 23.9% are estimated to be nonviable, and 32.1% are nonpenetrant for the white belly spot. The penetrance and expressivity of the Spd/+ genotype are controlled in part by the genetic background and the sex of the individual. A minimum of two genes interact with Spd to influence the craniofacial features of these mice. One of these genes may be either X-linked or sex-influenced, while the other is autosomal. The A-locus (Agouti) or a gene closely linked to A also plays a role in determining craniofacial features. At least one additional gene, possibly the A-locus or a gene linked to A, interacts with Spd and determines the presence and size of the white belly spot. The viability of BC1 mice is influenced by at least three factors: Spd, A-locus alleles or a gene closely linked to the A-locus, and the sex of the mouse. These BC1 mice provide an opportunity to identify genes that interact with and modify the expression of Pax3 and serve as a model to identify the genes that modify the expression of human PAX3 mutations.     

Clinical features of 201 cases with Duane''s retraction syndrome

OBJECTIVE: To summarize the clinical features of 201 cases with Duane's retraction syndrome (DRS) and discuss its differential diagnosis. METHODS: We retrospectively summarized the 201 cases from 1979 to 1996. The clinical features including chief complaints, sexual distribution, age at first visit, laterality, type of presentation, ocular deviation in the primary position, refractive errors, amblyopia, globe retraction, change of the palpebral fissure, upshoot and downshoot in adduction, binocular single vision, and its associated ocular and non-ocular anomalies were analysed. RESULTS: There were 99 males and 102 females with a female-to-male ratio 1:1. The 65.88% of DRS cases had left eye involvement with two-to-one predilection for the left eye. The most common form of the syndrome was type I (184 patients, 91.54%). Exotropia was the most common deviation in the primary gaze (72 patients, 35.8%). Among 118 patients, most had abduction deficits, globe retraction in adduction, and faceturn as to maintaining single binocular vision. Crocodial tears (26 patients, 11.93%) was the most frequently encounted ocular abnormalities. CONCLUSIONS: Diagnosis of DRS in a typical case is not difficult, however, children with bilateral abduction deficits which may mimic DRS must be differentiated from the following four motility disorders, namely, abducens nerve palsy, Moebius syndrome, congenital oculomotor apraxia, and congenital or infantile esotropia.     

Nevoid basal-cell syndrome: literature review and case report in a family

The Nevoid Basal-Cell Carcinoma Syndrome (NBCC), or as it is also referred to, basal-cell nevus syndrome or Gorlin-Goltz syndrome, is characterized by multiple early-appearing basal cell carcinomas, keratocytosis of the mandible, and anomalies of the ocular, skeletal reproductive system. We describe four patients in the same family, all of them possessing a large number of skin tumors associated with other typical clinical and X-Ray anomalies of NBCC. The definitive treatment of NBCC has yet to be established, however, early diagnosis is very important as well as the periodical follow-up examination of ten patients, mainly due to the transformations in the skin lesions that may occur.     

Stringent delineation of Pallister-Hall syndrome in two long surviving patients: importance of radiological anomalies of the hands

We report two unrelated, long surviving patients (2 and 17 years) with syndromal hypothalamic hamartoblastoma. Both showed mild facial dysmorphism (downward slanted palpebral fissures, ptosis, microretrognathia), cleft epiglottis, and developmental delay. The younger child had stenosis of the pulmonary arteries, complex urogenital malformations, and anal atresia. In the oldest patient, the hamartoma caused precocious puberty of the central type, combined with complete hGH deficiency. Both patients showed bony anomalies of the extremities: variable proximal synostosis between central (2nd to 4th) metacarpals or intercalary polydactyly with generalised brachydactyly, severe brachytelephalangism, syndactyly, and nail hypoplasia. Together with the absence of anomalies of cholesterol metabolism, a combination of oral frenula, laryngeal malformations, digestive abnormalities, intercalary polysyndactyly, generalised brachytelephalangism, and nail hypoplasia should allow the delineation of Pallister-Hall syndrome, even when a CNS tumour is absent. The radiological abnormalities are helpful in differentiating Pallister-Hall syndrome from the other syndromes in which hypothalamic hamartoblastoma is observed. This is of major importance for genetic counselling, since Pallister-Hall syndrome may be a dominantly inherited disorder, thus contrasting with most of the other disorders with the CAVE phenotype, which are recessively inherited.     

Fetal alcohol syndrome

The most notable features of fetal alcohol syndrome involve the face and eyes, and include microcephaly, short palpebral fissures, an underdeveloped philtrum and a thin upper lip. Evidence of intrauterine or postnatal growth retardation, mental retardation or other neurologic abnormalities, and at least two of the typical facial features are necessary to make the diagnosis. Newborns with the syndrome may be irritable, with hypotonia, severe tremors and withdrawal symptoms. Mild mental retardation, the most common and serious deficit, and a variety of other anomalies may accompany fetal alcohol syndrome. Sensory deficits include optic nerve hypoplasia, poor visual acuity, hearing loss, and receptive and expressive language delays. Atrial and ventricular septal defects, as well as renal hypoplasia, bladder diverticula and other genitourinary tract abnormalities, may occur. Complete abstinence during pregnancy is recommended, since alcohol consumption in each trimester has been associated with abnormalities, and the lowest innocuous dose of alcohol is not known.     

Distribution of serum pepsinogen I, II values and their ratios in residents of a rural area

Coloboma of the lens is characterized by notching of the equator of the lens. The cause of the condition is faulty development of the zonule. The lens deprived of its normal pull in the defective region is thicker and more spherical as if there were no loss of its substance. We report five cases of lens coloboma and localized zonular defect without any associated systemic anomalies. One case included retinal detachment; another included an iris coloboma; and a third included iris, choroid and optic disk colobomas and retinal detachment with lens coloboma. The remaining two cases were without associated ocular anomalies. The pathogenic mechanisms and relationship of this defect with the differentiation of the tertiary vitreous and development of the zonule is discussed. The defect most likely occurs in the third to fourth months of gestation during differentiation of the tertiary vitreous in response to toxic, inflammatory or genetic factors.     

How a community teaching hospital is changing to better serve its community

Many nonrheumatic diseases of childhood present with musculoskeletal abnormalities. A significant proportion of these disorders have a genetic basis, many involving defects in structural proteins of the connective tissue. Chief among these are collagen mutations resulting in spondyloepiphyseal dysplasias and Ehlers-Danlos syndrome, as well as fibrillin defects associated with Marfan's syndrome. A variety of other chromosomal anomalies are associated with musculoskeletal abnormalities, and may result from as yet unidentified connective tissue defects. In addition, metabolic diseases may result in findings of hyper- or hypomobility, or carpal tunnel syndrome. Helpful clinical clues to identify nonrheumatologic musculoskeletal disease, as well as recent advances in our understanding of the genetic basis of several of these disorders, are reviewed here.     

Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations

Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST, FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269-270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition-such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes-support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.     

Prader-Willi syndrome

BACKGROUND: First described in 1956, Prader-Willi syndrome is a neurogenetic condition characterized by infantile hypotonia, hypogonadism and obesity. Mental deficiency, behavioral abnormalities, and obvious dysmorphic features are frequently found as well. It is a relatively common condition, with an incidence estimated to be between 1 in 10,000 to 25,000 live births. Few studies have been published that investigated the ocular defects associated with this syndrome. METHODS: This case report discusses the systemic and oculo-visual abnormalities of a 34-year-old white male enrolled in the Easter Seal Society of Metropolitan Chicago/Illinois College of Optometry Eye Care and Treatment Program. Examination techniques commonly used for patients with cognitive/developmental dysfunctions were utilized. RESULTS: Our findings include ocular hypopigmentation with reduced visual acuity, a myopic refractive error, exotropia, corneal abnormalities, glaucoma, and other ocular and systemic health abnormalities. CONCLUSIONS: Reported ocular findings for patients with Prader-Willi syndrome include iris hypopigmentation with depressed visual acuity, moderate to high refractive error, and strabismus. Individual patients with this syndrome have also been reported with cataracts, congenital ocular fibrosis syndrome, diabetic retinopathy, and congenital ectropion uveal. The numerous ocular, systemic, and functional abnormalities of patients with Prader-Willi syndrome make it mandatory that all routinely receive primary optometric vision care.     

Epithelial-mesenchymal transdifferentiation and extracellular matrix gene expression in pleomorphic adenomas of the parotid salivary gland

OBJECTIVES: To determine the incidence of clinical resistance to intraocular cidofovir injection for treatment of acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis, and to identify virologic features associated with cidofovir treatment failure. PATIENTS and METHODS: Clinical resistance to intravitreal cidofovir was examined in 64 patients with CMV retinitis who received at least 1 injection of 20 pg of cidofovir. Histopathologic examination, culture, and polymerase chain reaction were used to detect CMV in ocular specimens. Antiviral resistance was assessed by plaque reduction assay and DNA sequencing. RESULTS: Clinical resistance to intravitreal cidofovir injections was identified in 3 patients (5%) and was associated with prior oral ganciclovir or intravenous cidofovir use. Ganciclovir- and cidofovir-resistant CMV isolates were cultured from 2 patients and harbored resistance-associated mutations in the UL97 and polymerase genes. Resistance mutations were also detected by direct analysis of vitreous. In 1 patient, different resistance mutations were identified in ocular vs extraocular CMV strains. CONCLUSIONS: Clinical failure of intravitreal cidofovir occurs infrequently, but may be associated with cidofovir-resistant CMV selected by prior ganciclovir or cidofovir treatment. Ocular CMV disease can result from a localized infection with a resistant CMV strain, and antiviral resistance may develop at a local site of infection independently from resistance that develops systemically.     

Molecular and cellular basis of radiation fibrosis

From a spina bifida clinic we have identified two patients with a syndrome of myelomeningocele and Waardenburg syndrome type 3 (WS3). The patients each possess a single, de novo, interstitial deletion of chromosome 2 (2q35-36.2), including the PAX3 gene. Deletion of PAX3 was confirmed by fluorescence in situ hybridization (FISH). Analysis with PAX3 and flanking microsatellites shows that the deleted interval of chromosome 2 is of paternal origin and is at least 2 and 6 cM in the two patients. Interstitial deletions in this region result in the Waardenburg syndrome (WS1), but have not been associated with neural tube defects (NTDs). Although other etiologies have not been formally excluded, these patients raise the possibility of a digenic etiology of their NTDs via a genetic interaction of the deleted PAX3 gene with a second unidentified locus.     

Alport syndrome. A review of the ocular manifestations

Alport syndrome has a prevalence of 1/5000, and 85% of patients have the X-linked form, where affected males develop renal failure and usually have a high-tone sensorineural deafness by the age of 20. The typical ocular associations are a dot-and-fleck retinopathy which occurs in about 85% of affected adult males, anterior lenticonus which occurs in about 25%, and the rare posterior polymorphous corneal dystrophy. The retinopathy and anterior lenticonus are not usually demonstrated in childhood but worsen with time so that the retinal lesion is often present at the onset of renal failure, and the anterior lenticonus, later. The demonstration of a dot-and-fleck retinopathy in any individual with a family history of Alport syndrome or with end-stage renal disease is diagnostic of Alport syndrome. The presence of anterior lenticonus or posterior polymorphous corneal dystrophy in any individual is highly suggestive of the diagnosis of Alport syndrome. Additional ocular features described in X-linked Alport syndrome include other corneal dystrophies, microcornea, arcus, iris atrophy, cataracts, spontaneous lens rupture, spherophakia, posterior lenticonus, a poor macular reflex, fluorescein angiogram hyperfluorescence, electrooculogram and electroretinogram abnormalities, and retinal pigmentation. All mutations demonstrated to date in X-linked Alport syndrome have affected the COL4A5 gene which encodes the alpha 5 chain of type IV collagen. This protein is probably common to the basement membranes of the glomerulus, cochlea, retina, lens capsule, and cornea. However, the alpha 3(IV) and 4(IV) as well as the alpha 5(IV) collagen chains are usually absent from the affected basement membranes, because the abnormal alpha 5(IV) molecule interferes with the stability of all three. The loss of these collagen molecules from the affected basement membranes results in an abnormal ultrastructural appearance. The ocular and other clinical features of autosomal recessive Alport syndrome are identical to those seen in X-linked disease, while retinopathy and cataracts are the only ocular abnormalities described in the rare autosomal dominant form of Alport syndrome. There are no ocular associations of thin basement membrane disease which is a common disease that probably represents the heterozygous expression of X-linked or autosomal recessive Alport syndrome.     

Dysraphic myelodysplasias associated with urogenital and anorectal anomalies: prevalence and types seen with MR imaging

OBJECTIVE: The purpose of this study was to determine by MR imaging the prevalence and types of dysraphic abnormalities of the spinal cord (i.e., myelodysplasias) associated with urogenital and anorectal malformations of childhood. MATERIALS AND METHODS: Since 1987, 92 patients with imperforate anus complex, cloacal malformation, and cloacal exstrophy have had MR imaging as a screening examination for occult dysraphic myelodysplasia. The prevalence and types of myelodysplasia were determined for each group. RESULTS: The prevalence of dysraphic myelodysplasia in each group of children was 17% (1/6) for low imperforate anus (ectopic anus), 34% (11/32) for high imperforate anus (with fistulization), 46% (19/41) for cloacal malformation, and 100% (13/13) for cloacal exstrophy. The most common abnormalities in each group were tethered cord with intradural or filar lipoma in imperforate anus; low-placed or dysplastic conus medullaris and tethered cord with lipoma or myelolipoma in cloacal malformation; and lipomyelocele, lipomyelomeningocele, or lipomyelocystocele in cloacal exstrophy. CONCLUSION: Our results show that the prevalence of myelodysplasia as seen on MR imaging is high in patients with urogenital and anorectal anomalies.