Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006

CHAPTER 8: SELECTED GENETIC SYNDROMES WITH OPHTHALMIC FEATURES 463

FIGURE 8-9. Five-year-old boy with Proteus syndrome. On the left, note large corneal diameter secondary to congenital glaucoma and large tumor of the neck. (Courtesy of Dr. R. Sid Wilroy, University of Tennessee, Memphis, TN.)

would be lethal if the mutation were carried in nonmosaic fashion.70

Clinical Features and Systemic Associations

A workshop on PS held in 1998 at the National Institute of Health developed guidelines for evaluation of patients with PS.10 The general characteristics mandatory for diagnosis are a mosaic distribution of lesions, progressive course, and sporadic occurrence, regardless of specific manifestations in a given patient with PS.10 A great variability of clinical findings is common in PS. Asymmetrical growth is perhaps the only constant feature of the syndrome.

The disorder, named after the Greek god Proteus (the polymorphous), is composed of hemihypertrophy, skull exostoses, digital overgrowth, and various soft tissue tumors. These tumors may include subcutaneous and internal fatty, fibrous tumors, as well as lymphatic and vascular malformations. The growth

potential and behavior of these tumors and malformations are unpredictable. Other neoplasms may also occur. The spectrum of cutaneous lesions includes café au lait spots, pigmented skin nevi, and epidermal nevi. A unique feature of patients with PS is cerebriform convolutions of the volar skin of the soles and palms. These lesions are facultative but not obligatory. Histologically, they are connective tissue nevi and, when present, are almost pathognomonic for PS.33,202

Many of the ocular malformations seen in Proteus syndrome may be traced to “maldevelopment” and subsequent malfunction of the neuroretina.42 The other ocular findings in Proteus syndrome that can be explained on the basis of neuroretinal abnormalities include strabismus, nystagmus, high myopia, retinal pigment abnormalities with vitreoretinal traction, cataracts secondary to ocular digital reflex or retinal detachment, and posterior segment hamartomas.42 Pathological examination has revealed diffuse disorganization of the retina, with focal and diffuse retinal gliosis and retinal pits, focal absence and/or proliferation of the retinal pigment epithelium, and congenital absence of choroidal vessels.60 An ERG on one patient has shown severe rod cone dysfunction.42 Glaucoma, optic disc drusen, and optic atrophy have also been reported.33,42,60,120

Proteus syndrome should be differentiated from Klippel– Trenaunay–Weber syndrome (KTW), neurofibromatosis type 1 (NF1), Bannayan–Riley–Ruvalcaba syndrome, encephalocraniocutaneous lipomatosis (ECCL), and Maffucci syndrome.96,154

Inheritance

All cases have been sporadic events in otherwise normal families.

Prognosis

Characteristic features of PS become obvious over the first year of life and are generally progressive throughout childhood. The generalized hypertrophy usually ceases after puberty. Moderate mental retardation is present in 20% of cases.96 Morbidity is significant. In some cases, overgrowth of legs, fingers, and toes may require amputation. Spinal stenosis and neurological sequelae may develop because of vertebral anomalies or tumor infiltra-

CHAPTER 8: SELECTED GENETIC SYNDROMES WITH OPHTHALMIC FEATURES 465

tion. Cystic emphysematous lung disease may be associated with severe morbidity and, in some cases, death.96

RUBINSTEIN–TAYBI SYNDROME

Originally described in 1963, Rubinstein–Taybi syndrome (RTS) is a multiple congenital anomaly mental retardation syndrome that combines distinctive craniofacial changes including a “beaked” nose with broad thumbs and broad big toes (Fig. 8-10).161

Etiology

The majority of cases of RTS are sporadic. The genetic locus of RTS appears to be at 16p13.3, a region that encodes the human cAMP-regulated enhancer-binding protein (CBP). About onefourth of cases are caused by submicroscopic deletions detectable by fluorescent in situ hybridization (FISH). Various other alterations in the candidate gene of RTS have been reported in the medical literature.15,161 However, RTS remains a clinical diagnosis.

Clinical Features and Assessment

Ophthalmic manifestations are common in patients with RTS. A review of 207 patients described in the literature found that 117 of these patients had ocular abnormalities.195 External features contributing to the characteristic faces of RTS include downward slanting palprebral fissures, hypotelorism, epicanthal folds, long eyelashes, high arched eyebrows, ptosis, and strabismus (Fig. 8-10).159 Additionally, lacrimal duct anomalies, corneal abnormalities, congenital glaucoma, congenital cataract, and colobomas (iris, lens, retinal, and/or optic nerve) were the most frequently described serious ocular abnormalities.

In a series of 571 affected individuals reported by Rubinstein in 1990,160 refractive errors were found in 56%, strabismus in 71%, ptosis in 29%, and lacrimal duct anomalies in 37% of cases.

In a series reported in 2000,195 high myopia was found to be present in 25% of individuals, and photophobia was found in 11 patients, with no demonstrable cause in 7 of these patients. Seventy-five percent of study patients had macular anomalies,

CHAPTER 8: SELECTED GENETIC SYNDROMES WITH OPHTHALMIC FEATURES 467

including mild or absent foveal reflexes, increased reddening of the foveal area, or unusual distribution of pigmentation in the posterior pole. Of 18 ERGs recorded in these patients, 14 (78%) showed abnormalities, including decreased cone responses and combined decrease in cone and rod responses. Visual handicap was noted to occur in 20% of patients (visual acuity less than or equal to 0.3). Glaucoma has been reported associated with Rubinstein–Taybi syndrome and can be congenital or juvenile in onset.113

Systemic Associations

The most characteristic facial abnormality found in all patients is the abnormal shape of the nose: prominent, and/or beaked, with or without low nasal septum. In addition, the following anomalies are frequently described in regard to RTS patients: facial hirsutism, abundant scalp hair, small mouth, and a grimacing smile. The facial manifestations are less characteristic in early infancy than at a later age.12,160

Microcephaly is present in about one-third of the patients with RTS.95 Palatal and dental abnormalities are frequent with cleft of soft and/or hard palate and overcrowding of teeth. Progressive distortion of the midface adds to the dysharmony of the upper and lower jaw, resulting in a grotesque facial appearance.

The broad thumbs are usually described as spatulate, short, stubby, clubbed, and large (Fig. 8-10B). Radial angulation of the distal phalanx of the thumb is common. Other fingers tend to be somewhat broad and short. Persistent fetal pad of the fingertip is a peculiar feature of RTS. The broadening of the hallux is often overlooked because of the great range of normal variation. Nail anomalies of the hallucies often reflect duplication of the underlying bony structures. While polydactyly of the hallux is common, duplication of the thumb is rare.

Most structural cardiac defects seen in RTS are flow lesions. The significant incidence and potential severity of cardiac anomalies warrant strong consideration of cardiac evaluation in patients with RTS.174 Structural and functional urinary tract abnormalities in both genders and cryptorchidism in males have been reported.95

Hypotonia and various skeletal anomalies including atlantoaxial instability, vertebral anomalies, scoliosis and kyphosis, spina bifida occulta, and sternal and rib anomalies are present in nearly half of the patients with RTS.160

Stridor, hoarseness, husky voice, and laryngospasm have been repeatedly observed in patients with RTS. Keloid formation is increased in RTS. Certain tumors, including medulloblastoma, neuroblastoma, oligodendroglioma, pheochromocytoma, rhabdomyosarcoma, leiomyosarcoma, pinealoma, and angioblastic meningioma have all been reported in RTS.124,175

Prenatal growth appears to be normal, while postnatally the weight, height, and head circumference fall below the 5th percentile in the first few months of life. Height velocity is relatively normal, except for the lack of a pubertal growth spurt, which probably contributes to the short stature.175

Patients with RTS have an increased risk when undergoing general anesthesia because of their high arched palate, crowded teeth, laryngospasm, propensity for cardiac arrhythmias, and atlantoaxial instability. Sleep disturbances in RTS may result from these above abnormalities as well.72,175

The medical history of patients with RTS is often characterized by feeding difficulties, recurrent respiratory and ear infections, and severe chronic constipation.175 The ages of puberty and menarche do not differ from those of the general population.

Inheritance

See Etiology.

Prognosis

In general, individuals with RTS have global developmental delay. They frequently experience speech difficulties. Mental retardation may vary from mild to severe. The average IQ score for RTS patients is 51. Patients with RTS usually display pleasant personality traits—happy, loving, and friendly. At the same time, they may engage in self-stimulatory behaviors.175

WALKER–WARBURG SYNDROME (WWS)

Walker–Warburg syndrome (WWS) is an autosomal recessive genetic disorder characterized by malformation of the brain and the eyes with muscular dystrophy. Walker published the first description of a lethal case with lissencephaly, hydrocephalus, microphthalmia, and retinal dysplasia.197 Warburg reviewed

CHAPTER 8: SELECTED GENETIC SYNDROMES WITH OPHTHALMIC FEATURES 469

similar cases and noted that most patients with this condition did not live past infancy.200 WWS is also known as HARD / E, an abbreviation for hydrocephalus, agyria, and retinal dysplasia, with or without encephalocele, as well as COMS (cerebro- ocular-muscular dystrophy syndrome), and MEB (muscle–eye– brain disease).46,143,186

Etiology

The etiology of WWS is unknown.

Clinical Features and Assessment

Of the three minimal criteria required for the diagnosis of WWS, retinal dysplasia is the ophthalmic manifestation required to meet diagnostic criteria.144 Retinal dystrophy often manifests as bilateral leukocoria and results from dysplastic retinae that are pale or elevated and unattached. This nonattachment of the retina can be used for prenatal ultrasound diagnosis.27 Persistent hyperplastic primary vitreous and Peter’s anomaly can also create the leukocoria noted in this syndrome. Microphthalmia and coloboma of the choroid and disc have been described. Postmortem examination of the eyes may be necessary to detect the full range of ocular involvement seen in these patients.144 Total agenesis of the optic nerves and pathways has been reported.206 Posterior lenticonus and ectopia lentis have all been described in postmortem examination.112 A distinct “leopard spot” retinopathy has also been described in two sibling cases with the characteristic brain and muscle pathology found in WWS.7

Systemic Associations

Type II lissencephaly with widespread agyria and scattered areas of macrogyria and/or polymicrogyria are invariably present in patients with WWS. In addition to the typical neuronal migrational abnormalities, the cerebral cortex is abnormally thick and severely disorganized with absent white matter interdigitations. Various midline developmental abnormalities of the CNS may also be present.46 Cerebellar malformations are present in all patients with WWS. Hypoplasia of the cerebellar vermis is often associated with enlargement of the fourth ventricle to form a retrocerebellar cyst, usually referred to as Dandy–Walker malformation.203 Posterior encephaloceles are an important but

inconstant (25%–50%) manifestation of WWS. Enlargement of the ventricular system with or without progressive hydrocephalus is very frequent (53%–95%).46

The other hallmark of WWS is a congenital muscular dystrophy; this presents with hypotonia at birth, variable congenital contractures, an elevated serum creatine kinase, “myopathic” changes on electromyography (EMG), and pathological changes in muscle tissue.46 The disruption in the basal lamina may play a primary role in the degeneration of muscle fibers in WWS.192 Occasionally patients with WWS may have cleft lip/palate, renal dysplasia, and genital anomalies in males.97

The spectrum of WWS was delineated by Dobyns et al.46 and includes several disorders considered previously to be distinct: the cerebro-ocular-muscular syndrome (COMS) and muscle– eye–brain syndrome (MEB).46 Patients with Fukuyama congenital muscular dystrophy (FCMD) may have features that overlap with WWS. However, haplotype analysis using polymorphic microsatellites flanking the FCMD locus on 9q31–q33 failed to demonstrate links between WWS and FCMD.166 Clinical characteristics in WWS tend to be more severe than in FCMD. Molecular studies, however, have demonstrated a broader clinical spectrum of FCMD than it was previously presumed.207 Therefore, it is possible that some of the severe cases of FCMD in the past may have been misclassified as WWS. The classification of these disorders will remain difficult until the molecular base of each of these conditions becomes available.

Inheritance

WWS is an autosomal recessive genetic defect, with 25% recurrence risk in families with an affected child. Prenatal diagnosis of eye and CNS malformations by fetal ultrasonography for atrisk families should be the standard of care. In cases with negative family history where brain dysgenesis is detected prenatally, the possibility of WWS should be raised.27

Prognosis

The majority of affected children with WWS usually die within the first 60 days of life.46 However, 5% to 10% of affected infants with less severe retardation may survive more than 5 years. In these cases, severe psychomotor retardation, muscle hypotonia,

CHAPTER 8: SELECTED GENETIC SYNDROMES WITH OPHTHALMIC FEATURES 471

visual impairment, and progressive seizure disorder are common.104

References

1.Aicardi J, Lefebvre J, Lerique-Koechlin A. A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol 1965;19:609–610.

2.Allanson J. Rubinstein–Taybi syndrome: the changing face. Am J Med Genet Suppl 1990;6:38–41.

3.Alport A. Hereditary familial congenital haemorrhagic nephritis. Br Med J 1927;1:504–506.

4.Alström C, Hallgren B, Nilsson L, et al. Retinal degeneration combined with obesity, diabetes mellitus, and neurogenous deafness. A specific syndrome (not hitherto described) distinct from the Laurence–Moon–Bardet–Biedel syndrome. A clinical, endocrinological, and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand Suppl 1959;129:1–35.

5.Apkarian P, Spekreijse H, Swaay E, et al. Visual evoked potentials in Prader–Willi syndrome. Doc Ophthalmol 1989;71:355–367.

6.Barker D, Hostikka S, Zhou J, et al. Identification in the COL4A5 collagen gene in Alport syndrome. Science 1990;248:1224–1227.

7.Barth R, Pagon R, Bunt-Milam A. ‘Leopard spot’ retinopathy in Warburg syndrome. Ophthalmic Paediatr Genet 1986;7(2):91–96.

8.Bass H. Nephritis-deafness (sensorineural) hereditary type. In: Buyse ML (ed) Birth defect encyclopedia. Cambridge: Blackwell, 1990:1222.

9.Bertoni J, von Loh S, Allen R. The Aicardi syndrome: report of 4 cases and review of the literature. Ann Neurol 1979;5:475–482.

10.Biesecker L, Happle R, Mulliken J, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 1999;84:389–395.

11.Bowling B, Chandna A. Superior lacrimal canalicular atresia and nasolacrimal duct obstruction in the CHARGE association. J Pediatr Ophthalmol Strabismus 1994;31:336–337.

12.Braddock S, Lachman R, Charman C, et al. Radiological features in Brachmann–de Lange syndrome. Am J Med Genet 1993;47:1006– 1013.

13.Bray G, Wilson W. Prader–Labhart–Willi syndrome: an overview. Growth Genet Horm 1986;2(3):1–5.

14.Brilliant M, King R, Francke U, et al. The mouse pink-eyed dilution gene: association with hypopigmentation in Prader–Willi and Angelman syndromes and with human OCA2. Pigment Cell Res 1994; 7(6):398–340.

15.Breuning M, Dauwerse H, Fugazza G, et al. Rubinstein–Taybi syndrome caused by submicroscopic deletion within 16p13.3. Am J Med Genet 1993;52:249–254.

16.Brooks J, Leonard C, Coccaro P. Opitz (BBB/G) syndrome: oral manifestations. Am J Med Genet 1992;43:595–601.

17.Brosh R, Balajee A, Selzer R, et al. The ATPase domain but not the acidic region of Cockayne syndrome group B gene product is essential for DNA repair. Mol Biol Cell 1999;10(11):3583–3594.

18.Burke J, Clearkin L, Talbot J. Recurrent corneal epithelial erosions in Alport’s syndrome. Acta Ophthalmol (Copenh) 1991;69:555–557.

19.Burke L, Jones M. Kabuki syndrome: underdiagnosed recognizable pattern in cleft palate patients. Cleft Palate Craniofac J 1995;32:77–84.

20.Butler M. Hypopigmentation: a common feature of Prader–Willi syndrome. Am J Hum Genet 1989;45:140–146.

21.Butler M, Meaney F. Standards for selected anthropometric measurements in Prader–Willi syndrome. Pediatrics 1991;88:853–860.

22.Carcione A, Piro E, Albano S, et al. Kabuki make-up (Niikawa– Kuroki) syndrome: clinical and radiological observations in two Sicilian children. Pediatr Radiol 1991;21:428–431.

23.Carney S, Brodsky M, Good W, et al. Aicardi syndrome: more than meets the eye. Surv Ophthalmol 1993;37:419–424.

24.Cassidy S, McKillop J, Morgan W. Sleep disorders in Prader–Willi syndrome. Dysmorph Clin Genet 1990;4:13–17.

25.Cassidy S. Prader–Willi syndrome. Curr Probl Pediatr 1984;14:1–55.

26.Chevrie J, Aicardi J. The Aicardi syndrome. In: Pedley TA, Meldrum BS (eds) Recent advances in epilepsy. New York: Churchill Livingstone, 1986:189–210.

27.Chitayat D, Toi A, Babul R, et al. Prenatal diagnosis of retinal nonattachment in the Walker–Warburg syndrome. Am J Med Genet 1995;56:351–358.

28.Chu D, Finley S, Young D, et al. CNS malformation in a child with Kabuki (Niikawa–Kuroki) syndrome: report and review. Am J Med Genet 1997;72:205–209.

29.Clementi M, Tenconi R, Turolla L, et al. Apparent CHARGE association and chromosome anomaly: chance or contiguous gene syndrome. Am J Med Genet 1991;42:246–250.

30.Cochat P, Guibaud P, Garcia-Torres R, et al. Diffuse leiomyomatosis in Alport syndrome. J Pediatr 1988;113:339–343.

31.Cockayne E. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936;11:1–8.

32.Cohen M. Understanding Proteus syndrome, unmasking the elephant man, and stemming elephant fever. Neurofibromatosis 1988; 1:260.

33.Cohen M Jr. Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet 1993;47:645–652.

34.Cohen M Jr, Hayden P. A newly recognized hamartomatous syndrome. In: Bergsma D (ed) Penetrance and variability in malformation syndromes. New York: Liss, 1979:291–296.

35.Collin G, Marshall J, Cardon L, et al. Homozygosity mapping at Alstrom syndrome to chromosome 2p. Hum Mol Genet 1997;6:213– 219.