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Oculocutaneous Albinism Associated with Apert's Syndrome
OCULOCUTANEOUS ALBINISM ASSOCIATED WITH APERT'S SYNDROME S H E I L A M A R G O L I S , M.D., I R W I N M. S I E G E L , P H . D . , A N D R E W C H O Y , M.D., AND G O O D W I N M. B R E I N I N , M.D.
New York, New York 1
In 1906, Apert described the classic syndrome of oxycephaly (tower skull) with syndactyly, the latter defined as fu sion of digits two to four resulting in a mid-digital hand mass with a common nail. Premature craniostenosis results in a skull resembling a fireman's helmet. Also typical of patients with Apert's disease is a flattened occiput, a dish-face appear ance caused by maxillary hypoplasia, a parrot beak nose, prognathic lower jaw, cleft or Byzantine arch palate, bifid uvula, and dental anomalies. 2 Ocular abnormali ties in Apert's syndrome are: proptosis, divergent strabismus, orbital hypertelorism, antimongolid fissures, optic atro phy, 3 and, rarely, megalocornea. 4 Albinism is a congenital disorder mani fested by a deficiency of melanin in the tissues thought to be caused by a deficit of one of the enzymes mediating pigment formation, such as tyrosinase. Genera lized oculocutaneous albinism, an autosomal recessive disease, is characterized by a lack of pigment throughout the body. Patients with X-chromosomelinked ocular albinism, on the other hand, have normal skin and hair pigmentation, but lack adequate pigmentation in the uvea and the retinal pigment epithelium. The ocular manifestations of albinism From the New York University Medical Center, Department of Ophthalmology, New York, New York. This study was supported in part by grants EY00213 and EY00309 from the National Eye Insti tute, DE03568-03 from the National Institute of Dental Research, and a departmental grant from Research to Prevent Blindness, Inc. This study was presented at the Association for Research in Vision and Ophthalmology meeting in Sarasota, Florida, April 29, 1977. Reprint requests to Sheila Margolis, M.D., De partment of Ophthalmology, New York University Medical Center, 550 First Ave., New York, NY 10016.
are: poor visual acuity, photophobia, pendular nystagmus, hypopigmentation of the fundus, and iris transillumination. Typically the macula is hypoplastic or aplastic; the foveal reflexes are dimin ished or absent. Most patients with albi nism show iris transillumination even though some (the tyrosinase-positive vari ety) have pigmented irides ranging from blue to dark brown, 5 ' 6 which appear nor mal before instrument examination. Such an observation results from sufficient stromal pigment for iris color, but insuffi cient melanin in the posterior pigment epithelial layer with consequent iris translucency. The patients presented here demon strated a form of albinism characterized by good visual acuity, photophobia, dilu tion of skin and hair color, and iris transillumination without pendular nys tagmus, together with oxycephaly and syndactyly characteristics of Apert's dis ease. SUBJECTS AND M E T H O D S
At the New York University Medical Center for Craniofacial Anomalies, nine patients underwent complete ocular ex amination, fundus and anterior segment photography, and in several cases, electrophysiologic evaluation of retinal func tion. The ocular examination included slitlamp biomicroscopy and both direct and indirect ophthalmoscopic examination. We performed anterior segment transil lumination photography with a fundus camera and a fiber optic bundle probe placed against the lower eyelid to trans mit a high intensity light into the globe. The procedure for the electroretinogram (ERG) and electro-oculogram (EOG) are
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Fig. 2 (Margolis and associates). Case 1. Syndac tyly of feet.
Fig. 1 (Margolis and associates). Case 1. Patient with typical Apert's syndrome with oxycephaly, mid facial hypoplasia, hypertelorism, antimongoloid fissures, exophthalmos, and strabismus.
normally. All contact with the family was lost after 1968. The patient had typical Apert's syndrome (Fig. 1): (1) oxycephaly (tower skull), (2) midface hypoplasia, (3) orbital hypertelorism, (4) antimongoloid palpe brai fissures, (5) exophthalmos, and (6) strabismus. The skeletal malformations, syndactyly of all limbs (Figs. 2 and 3) were also consistent with this entity.
described elsewhere.7 Four of the nine patients had determinations of serum tyrosine and phenylalinine levels. Karyotyping and banding techniques 8 were performed on chromsome material ob tained from peripheral lymphocytes on two of the patients. CASE REPORTS Case 1—This 23-year-old white man had a frater nal twin sister, an anencephalic girl who lived only 44 minutes after birth. The mother's pregnancy had been complicated by shortness of breath caused by excessive weight gain, and her period of labor was 3V2 hours. The birth weight of the patient was 1,899.4 g. Initial examination of the infant showed hydrocephalus, cleft palate with webbed fingers and toes. Although the patient was not expected to live, he survived and was placed in a state institution after 8V2 months. At the time of the patient's birth the father was age 30 years and the mother age 28 years; both were in good health. Another set of twins was stillborn following a five-month pregnancy, and the last child, a boy sibling, was said to be developing
Fig. 3 (Margolis and associates). Case 1. Syndac tyly of hands.
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A cleft palate with associated structural speech impairment and midthoracic dextroscoliosis were also present. Additionally, mental retardation, possi bly caused by complete absence of educational exposure, was noted. Ocular examination—Corrected visual acuity in each eye was 6/9 (20/30) demonstrated on the Snellen illiterate E game. Refractive error was R.E.: +0.25 = -1.00 x 15 degrees, and L.E.: +1.75 = -0.75 x 170 degrees. Normal intraocular pressures were recorded by applanation tonometry. The pa tient had prominent supraorbital ridges with hypoplastic infraorbital rims (Fig. 1). Palpebrai fissures were markedly antimongoloid and the globes mea sured by exophthalmometry were R.E.: 15 mm, and L. E.: 14 mm, on a base of 110. The interpupillary distance was 72 mm, and intercanthal distance was 37 mm. There was no nystagmus. The anterior segment was normal. The irides transilluminated in a diffuse spokewheel pattern, especially prominent in the right eye at the 5 o'clock position (Fig. 4). The lens and vitreous were normal in both eyes. The fundus (Fig. 5) had distinct optic nerve margins with slight temporal pallor in the left eye. Tortuosity of the retinal vessels was increased in both fundi. The macular region showed mild granularity (Fig. 6) with a diffuse foveal reflex in both eyes. The fundus demonstrated diffuse hypopigmentation with easily visualized choroidal ves sels in the midperiphery (Fig. 7). In the primary position at distance and near, there was an exotropia of 10 prism diopters with a right hypertropia of 15 prism diopters. There was a marked V esotropia pattern; on upgaze, the devia tion was identical to the primary position. However, on downgaze, an esotropia of 25 prism diopters with a small right hypertropia became manifest. Rota-
Fig. 4 (Margolis and associates). Case 1. Diffuse iris transillumination especially prominent at the 5 o'clock position.
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Fig. 5 (Margolis and associates). Case 1. Left eye. Fundus photograph shows temporal pallor of optic nerve with increased tortuosity of the retinal vessels.
tions showed overaction of both inferior oblique muscles with concomitant underaction of the su perior oblique muscles. The near point of conver gence was remote. Case 2—This 19-year-old white woman had been born with multiple congenital anomalies typical of Apert's syndrome. The patient's prenatal and birth history were noncontributory. A paternal cousin had
Fig. 6 (Margolis and associates). Case 1. Left eye. Macular region showing mild granularity and illdefined foveal reflex.
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Fig. 7 (Margolis and associates). Case 1. Left eye. There is generalized hypopigmentation in the midperiphery with visualization of the choroidal vascu lature. a cleft palate. The father and mother were both 28 years old at the time of the patient's birth, and there was no history of consanguinity. One sister was normal. The patient had undergone surgical proce dures to relieve craniostenosis, syndactyly of the hands and feet, and the mouth and palate anomalies. Case 3—This 27-year-old white -Woman had been born with facial and hand deformities typical of Apert's syndrome (Figs. 8 and 9). However, there was no prenatal complication except a fall during the third month of the mother's pregnancy. The patient's younger sister was normal. At the birth of the child both parents were 32 years of age. Corrective surgery for syndactyly and strabismus, as well as eight procedures for maxillofacial recon struction had been performed. Ocular examination—The patient's best corrected visual acuity was R.E.: 6/15 (20/50), and L.E.: 6/12 (20/40). Refraction was R.E.: -1.25 = -4.00 x 95 degrees, and L.E.: -1.25 = -0.50 x 125 degrees. Single binocular vision was present with a head turn to the right. Intraocular pressure was R.E.: 16 mm Hg, and L.E.: 15 mm Hg. The globes were promi nent with antimongoloid fissures; the exophthalmometer reading was 19.0 mm and 20.0 mm on a base of 110 mm. The interpupillary distance was 65 mm and intercanthal distance was 35 mm. There was an occlusion nystagmus in both eyes. With the exception of iris transillumination, re sults of the anterior segment examination were with in normal limits. Orientation of the Y sutures in the lens was horizontal instead of the normal vertical position. Ophthalmoscopic examination of the right eye revealed a pink tilted disk, normal retinal vascula ture, and a diffuse foveal reflex. The macula was
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Fig. 8 (Margolis and associates). Case 3. Patient with Apert's syndrome demonstrating craniofacial abnormalities. displaced inferiorly (Fig. 10); pigmentation was reduced in the inferior and nasal quadrants (Fig. 11). The left disk and retinal vasculature appeared normal, but the generalized pigment deficiency made the choroidal vessels visible throughout much of the posterior pole (Fig. 12). The foveal area was similar in each eye. There was a V-esotropia pattern; upgaze distance and near measurements showed a 5-prism diopter exotropia, with a right hypertropia of 20 prism diopters. Downgaze showed an esotropia of 25
Fig. 9 (Margolis and associates). Case 3. Syndac tyly of hands typical of Apert's syndrome.
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Fig. 10 (Margolis and associates), Case 3. Right eye. Disk is tilted and macula is inferiorly displaced. Note hypopigmentation of the inferonasal retina.
Fig. 12 (Margolis and associates). Case 3. Right eye. Normal appearing disk with pigment deficiency in the inferior portion of the retina.
prism diopters, with a right hypertropia of 20 prism diopters. We noted moderate overaction of both inferior oblique muscle, as well as moderate underaction of both superior oblique muscles. There was also marked underaction of the left superior rectus. The near point of convergence was 30 cm and the Titmus fly test revealed no stereopsis.
Case 4—This 13-year-old white girl had syndactyly of the hands and feet, oxycephaly resulting from complete closure of the coronal sutures, shallow orbits, and bilateral exophthalmos. Prenatal history was noncontributory although the mother reported a history of previous spontaneous abortion. The pa tient had three normal sisters and a first cousin with syndactyly of the fourth and fifth fingers. Another cousin reportedly had one short limb. The father was 42 years and the mother 40 years of age at the patient's birth. A craniotomy was performed at an early age to open the coronal sutures and a follow-up examina tion showed a normal motor progression, preserva tion of vision, and normal speech and intelligence. Over the years, various surgical procedures have been performed to correct the patient's physical deformities: cleft palate, bifid uvula, and fusion of fingers, all typical of Apert's syndrome. Case 5—This 17-year-old girl had been born with oxycephaly, syndactyly, and a supernumerary nip ple on the right side. The mother's pregnancy and delivery were uncomplicated. Three other siblings were reportedly normal. Family history was noncontributory for any deformities or consanguinity. At the patient's birth, both parents were 22 years old. Numerous surgical procedures were performed on the patient to correct the syndactyly and strabismus. Case 6—We examined an 8-year-old black boy with Apert's disease and no history of prenatal or birth complications. At birth, he demonstrated the typical findings of oxycephaly and syndactyly. The father's and mother's ages were 52 years and 29 years, respectively. There were no other siblings and no family history of consanguinity or birth defects. He underwent a cranial stripping procedure at 6
Fig. 11 (Margolis and associates). Case 3. Right Eye. Hypopigmentation of the entire nasal half of the retina. The choroidal vessels are easily visible.
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months of age to correct premature closure of the coronal sutures. Case 7—This 2V2-year-old Italian girl had multi ple congenital anomalies including midfacial hypoplasia of the maxillary bones and syndactyly of both hands and feet. Her hair and irides were dark brown. Family history was noncontributory for con sanguinity and any congential deformities. At the patient's birth her father was age 29 years, the mother's age was 25 years. In April 1973, at 4 months of age, the patient had an exploration of the right zygomaticofrontal suture line and a biopsy at that site. One month later, she underwent cranial stripping for bilateral synostosis of the coronal su ture. At age 1 year, strabismus surgery was per formed. Case 8—This 10-year-old black girl had Apert's syndrome and a history of photophobia and tearing. At ten weeks of the child's gestation, the mother had had pelvic infection and rash treated with tetracycline (Achromycin) and, until the seventh month of pregnancy, she had had intermittent vaginal bleed ing. The birth was uncomplicated, but the child's birth weight was low at 1,871 g. Four other siblings were reported to be normal. The mother's sister, who died one day after birth, reportedly had an "overlap ping skull." At the time of our patient's birth, the father was 36 years old, the mother was 31 years old. Both parents were normal. Case 9—This 2-year-old white boy also demon strated the typical anomalies of Apert's syndrome. The hair and irides were dark brown. Family history was noncontributory for consanguinity and congen ital deformities. One other sibling was reported to be normal; a geneticist reported both parents were normal as well. At the child's birth, the father was 31 years old, the mother was 26 years old. DISCUSSION
Apert's syndrome is characterized by oxycephaly and syndactyly of the hands and feet.1 Antimongoloid obliquity of the palpebrai fissures, hypertelorism, proptosis, strabismus, and optic atrophy are fre quently associated ocular findings. Of 304 cases reviewed by Ferriman,9 15 had papilledema and 57 had postpapilledema optic atrophy. Although numerous papers have been written on this syndrome, none has yet reported a frequent and signifi cant association of Apert's syndrome with a diffuse hypopigmentation of hair, skin, and eyes. In 1920, Park and Powers10 found 29 reported cases coinciding with Apert's criteria and added an additional case. In their ophthalmoscopic findings, is an iso
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lated description of an albinoid fundus: Not only was the pigment epithelial layer of the retina wanting [in melanin], as in albinos, but the intercapillary islands of stromal pigment were missing as well. Thus, the vessels were clearly visible and the underlying capillaries of the choroid were easily traced . . .
No further mention of this finding, nor explanation for its existence has since been made. In our study, ocular findings in five of nine cases (Table) with typical Apert's syndrome were: an albinoid fundus, loca lized areas of iris transillumination, dif fuse or absent foveal reflex, and photo phobia. Decreased fundus pigmentation varied from a deficit restricted to the midperiphery where the choroidal vasculature is more easily visible, to a hypopig mentation involving almost the entire posterior pole. Patients with hypopig mentation of the fundus also showed ab sent or diffuse foveal reflexes. Although several of the cases demonstrated some classical signs of albinism, none of these manifestations were severe. The reduc tion in visual acuity was slight, the iris and fundus depigmentation was incom plete, photophobia was mild, and, with the exception of Case 5, there was no true nystagmus. One patient (Case 3), howev er, did have occlusion nystagmus. Each of the patients described had skin and hair color lighter than other family mem bers, but not more hypopigmented than some members of the general population. The degree of ocular hypopigmentation is related to the amount of body pigmen tation in any particular patient. For exam ple, the lighter haired, lighter complexioned patients (Cases 1-5, Table) show greater iris transillumination and fun dus depigmentation than black patients (Cases 6 and 8) or the Italian patient (Case 7).Goodman, Ripps, and Siegel11 reported similar findings in patients with Xchromosome-linked ocular albinism; the degree of ocular pigmentation was less
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6/7 6/7 (20/25) (20/25) Not Done
6/9 (20/30) 6/6 (20/20) 6/12 (20/40) 6/7 (20/25) 6/9 (20/30) 6/7 (20/25) + (Latent)
Visual Acuity L.E. Nystagmus
6/9 (20/30) 6/7 (20/25) 6/15 (20/50) 6/7 (20/25) 6/7 (20/25) 6/7 (20/25) Not Done
R.E.
Photophobia
Diffuse Diffuse Normal
Blue Hazel Blue Dark brown Dark brown Dark brown Brown
+ + +
— — -
Diffuse
Normal
Normal
R.E., none L.E., diffuse Diffuse
Blue
Light brown Light brown Light Brown Dark brown Dark brown Dark brown Brown
Diffuse
Hazel
+
Fovea! Reflex
+
Albinoid Fundus
Light brown Blond
Transillumination
Fair Skin
Iris Color
SYNDROME
Hair Color
* C h r o m o s o m e s t u d i e s normal. t T y r o s i n e and p h e n y l a l a n i n e l e v e l s normal; E R G a n d E O G normal. ^Abnormal horizontal m u s c l e insertions. § A b s e n c e of all p u n c t a , trichiasis of b o t h l o w e r e y e l i d s .
Age (yrs)
Case No.
O C U L A R A N D CUTANEOUS FINDINGS IN PATIENTS W I T H APERT'S
TABLE
Orthotropia
V-pattern esotropia V-pattern exotropia V-pattern esotropia V-pattern esotropia V-pattern exotropia V-pattern exotropia Left esotropia Orthotropia
Strabismus
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ALBINISM WITH APERT'S SYNDROME
when the general body pigmentation was light, and greater when the individual was dark complexioned. Although hypopigmentation has not been previously observed with Apert's syndrome, albinism has been associated with several other diseases. 6 Klein 12 pre sented a 10-year-old girl with pigmentary anomalies and multiple congenital mal formations at the Swiss Genetic Society in 1947. This child had a small bird-like head, absence of pigmentation of the eye brows, lashes, and the skin of the upper torso, hypertelorism, antimongoloid fis sures, divergent strabismus, arched pal ate, dental anomalies, and syndactyly. Additionally, there was thoracolumbar webbing and deafness. The irides were slate blue but not diaphanous; the fundi were normal except for hypopigmentation in the periphery where the choroidal ves sels were easily seen. Klein labeled the discrete amelanosis as a partial albinism. Similar findings were noted in BustiRosner's 1 3 report of a pedigree having members with obvious albinism and as sociated craniofacial anomalies. Several of the affected patients had blond hair and eyelashes, blue translucent irides, strabismus, nystagmus, and hypopigmented fundi with macular hypoplasia, all typical signs of albinism. In addition to the ocular findings, peculiar-shaped skulls, prognathism, microstomia, dental anomalies, and an arched palate were noted. Apert's syndrome is generally acknowl edged to be transmitted as autosomal dominant. 1 4 This view is confirmed by several studies of affected mothers and daughters, 1 5 - 1 7 as well as affected fathers and sons. 18 In a recent report, the disease was followed through three successive generations. 19 By contrast, none of our patients (ex cept the patient in Case 4, who had one cousin with isolated syndactyly and an other with one short limb), had either simi
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larly affected siblings or parents with the disorder. In the largest reported series of patients with Apert's syndrome, Blank 2 noted only two of his 39 cases indicated instances of a parent and child similarly affected. In most of Blank's patients, as in ours, the disease did not result from a dominantly inherited trait, but possibly from an autosomal recessive variety. However, none of the parents of Blank's affected cases were consanguineously re lated, nor were ours. A rare disorder such as Apert's syndrome is ordinarily associ ated with a moderate degree of consan guineous marriages. From these data we concluded there is no one mode of transmission for Apert's syndrome. For our patients, the most like ly mode of transmission was autosomal recessive. However, one cannot exclude some less likely possibilities; for exam ple, all our patients may represent sponta neous mutations. Although it is not likely that several patients would have reported with the same mutated gene over such a small time span, our referral center is one of the few in the United States for cranio facial disorders and we may have inad vertently pooled patients with rarely oc curring mutation events. Most previously performed chromo some studies 2 0 and those on two of nine patients tested in our group were normal. Dodson and co-workers 21 described a deletion-translocation of the short arm of chromosome 2 to the long arm of a Group C chromosome, 11 or 12, in a patient with Apert's syndrome. However, in reviewing cytogenetic studies on patients with Apert's disease, these authors concluded that no specific chromosomal abnormality could be assigned to this syndrome, and indeed most patients showed no detecta ble chromosomal aberration. Finally, extrachromosomal and nonheritable factors, such as exposure to drugs, x-rays, viral or other inflammatory agents, trauma or other cause of mechanical in-
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trauterine insult may be causes of Apert's syndrome. However, none of the mothers questioned indicated any of these circum stances during pregnancy. Advanced age of the parents, particularly of the father, has also been suggested as a prime factor in the transmission of the syndrome.2,22 Blank2 found the modal age for the fa thers was 37 years, with a range of 35 to 39 years; and the mothers' modal age was 32 years, with a range of 30 to 34 years. The fathers' and mothers' ages are 10 and five years older, respectively, than parents in the general population. After consider able statistical analysis Blank found the father's age to be the main factor. Our cases support this observation since two fathers were over 40 years and six were between the ages of 28 and 32 years at the child's conception, but only three of the nine mothers were over the age of 30 years. If the ocular hypopigmentation in Apert's syndrome is a consistent feature of this disorder, what embryological evi dence ties together the seemingly dispa rate elements of melaninization and skel etal developments? Two factors are im portant to consider. Degenhardt23 defined the critical teratogenic period for the dif ferentiation of the skull and hands as between the 29th and 35th day of embry onic life. He derived his evidence from studies on thalidomide-induced phocomelia in which the sensitive period for the drug action was shown to occur be tween the 28th and 42nd days after con ception.24 Degenhardt also noted a possi ble relationship between the degree of hand malformation and the stage of de velopment at which it might occur. Dis turbances occurring in earlier stages pro duced more severe hand deformities, while less severe forms are associated with later stages of embryonic develop ment. The other line of evidence derives from the normal embryological development of
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the eyes and limbs. The second phase of retinal differentiation as well as the seg mentation and individualization of the digits, occurs during the same time peri od, between the 42nd and 49th day of embryogenesis (12 to 17 mm, stage).10·25 A disturbed synchronization of these devel oping systems may result in those phenotypic expressions of eye and limb incor porated in the syndrome described by Apert. The anomalous distribution and amounts of pigmented tissue in affected individuals may be explained by assum ing that an insult occurring early in em bryogenesis disturbs the migrating melanoblasts developed in the sensory crest26 and thus interferes with pigment migra tion to peripheral sites such as skin, hair bulbs, sensory and ocular tissue. Thus the associated features of generalized hypopigmentation of skin and hair in this disease can be related to disturbance of melanoblast migration occurring at the same time as limb differentiation. While decreased amounts of iris stromal pigment may be related to such events, the diaphanous appearance of the iris is a result of melanin loss in the posterior epithelial layer, and not in the stroma. Brown irides of tyrosinasepositive albinos, for example, transillumi nate easily.8 The posterior epithelial leaf of the iris derives from optic cup neuroectoderm and the lack of melanin in this layer (which produces transillumination in most patients with Apert's syndrome) cannot be attributed to a disturbance in melanocyte migration from the neural crest early in embryonic life. Clearly, many circumstances can be involved in the etiology of a multisystem anomaly, including primary heritable fac tors, extrachromosomal influences, and environmental causes. To assess these contributory factors intelligently an ap propriate animal model incorporating the features of Apert's syndrome must be discovered.
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Five of nine patients with Apert's syn drome (acrocephalosyndactyly) showed an associated hypopigmentation of hair, skin, and eyes. The hair color of these five patients ranged from light brown to blond, the skin was pale, and the irides hazel or blue. Iris transillumination and hypopigmentation of the fundus were present and associated with absent or diffuse foveal reflexes. Unlike most forms of classic ociilocutaneous albinism, how ever, there was good visual acuity and no pendular nystagmus. The evidence indi cated that the lack of pigmentation associ ated with the characteristic skeletal anomalies of Apert's syndrome resulted from a disturbance of independent, ge netically related, processes occurring at a common point in gestation. REFERENCES 1. Apert, E.: De L'acrocephalosyndactylie. Bull Mem. Soc. Med. Hop. (Paris) 23:131, 1906. 2. Blank, C. E.: Apert's syndrome (a type of acrocephalosyndactyly). Observation on a British series of 39 cases. Ann. Hum. Genet. 24:151, 1960. 3. Falls, H. F.: Craniofacial skeletal syndrome. In Crow, J. F., and Neel, J. V. (eds.): Third Internation al Congress Human Genetics, Sect. 8. Baltimore, Johns Hopkins Press, 1967, pp. 402-412. 4. Calamandrei, D.: Megalcornea in due pazienti con sindrome craniosinotoscia. Q. Ital. Oftalmol. 3:278, 1950. 5. Siegel, I. M.: The albino as a low vision patient. In Faye, E. (ed.): Clinical Low Vision. Boston, Little Brown, 1976, pp. 255-261. 6. Witkop, C. J.: Albinism. In Harris, H., and Hirschhorn, K. (eds.): Advances in Human Genetics. New York, Plenum Press, 1971, pp. 61-142. 7. Carr, R. E., and Siegel, I. M.: Electroretinographic aspects of several retinal diseases. Am. J. Ophthalmol. 58:95, 1964. 8. Mittwoch, U.: Cytogenetics. In Fraser, G., and Mayo, O. (eds.): Textbook of Human Genetics. Ox ford, Blackwell, 1975, pp. 198-268. 9. Ferriman, D.: Acrocephaly Acrocephalosyn dactyly. London, Oxford University Press, 1941, pp. 1-109.
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10. Park, E. A., and Powers, G. F.: A study of acrocephalosyndactylism. Am. J. Dis. Child. 20:235,
1920, 11. Goodman, C , Ripps, H., and Siegel, I. M.: X-linked ocular disorders. Trait expressivity in male and carrier female. Arch. Ophthalmol. 73:387,1965. 12. Klein, D.: Albinism partial leucism avec surdi-motiliti, blepharophimosis et dysplasia myoosteo-articulaire. Helv. Paediatr. Acta. 1:38, 1950. 13. Busti-Rosner, L.: Deux cas c'albinisme uni versal imcomplet d'un biotype particulare dan souche valaisanne. J. Genet. Hum. 5:197, 1956. 14. McKuskick, V. A.: Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Recessive, and X-linked Phenotypes, 3rd ed. Baltimore, Johns Hopkins Press, 1971, pp. 6-8. 15. Weech, A. A.: Combined acrocephaly and syndactylism occurring in mother and daughter. Bull. Hosp., Johns Hopkins, 40:73, 1927. 16. Saethre, M.: Ein Beitrag zum Turmschadelproblem (Pathogenese, Erblichkeit und Symptom atologie) Deutsch. 2. Nervenheilk. 119:533, 1931. 17. Roberts, K. B., and Hall, J. G.: Apert's acrocephalysyndactyly in mother and daughter, cleft palate in mother. In Bergsma, D. (ed.): The Clinical Delineation of Birth Defects, part 6. Orofacial Struc tures. Baltimore, Williams and Wilkins, 1971, pp. 262-263. 18. Chotzen, F.: F. Eine eigenartige familiare Entwicklungsstörung (Akrocephelosyndaktylie, dysostosis craniofacialis und hypertelorismus) Monatsschr. Kinderheilkd. 55:97, 1932. 19. Bartsocas, C. S., Weber, A. L., and Crawford, J. D.: Acrocephalosyndactyly type 3 Chotzen's syn drome. J. Pediatr. 88:267, 1970. 20. Buchanon, M. B.: Acrocephalosyndactyly or Apert's syndrome. Br. J. Plast. Surg. 21:406, 1968. 21. Dodson, W. E., Muselés, M., Kennedy, J. L. Jr., and Al-Asish, M.: Acrocephalosyndactyly associ ated with chromosomal translocation 46, XX, t(2P-; Cq+) Am. J. Dis. Child. 120:360, 1970. 22. Grebe, H. Die Akrocephalosyndaktylie. Ztsschr. Menschl. Vererb. Konstitutionslehre. 28: 209, 1944. 23. Degenhardt, K. H.: Zum Entwicklungsmech anischen Problem der Akrocephalosyndaktylie, Ztsschr. Menschl. Vererb. Konstirutionslehre. 29: 791, 1950. 24. Lenz, W., and Knapp, K.: Die Thalidomidembryopathie. Dtsch. Med. Wochenschr. 87:1232, 1962. 25. Mann, I.: The Development of the Human Eye. New York, Grüne and Stratton, 1964, pp. 282-288. 26. Weston, J. A.: The migration and differ entiation of neural crest cells. Adv. Morphog. 8:41, 1970.
New York, New York 1
In 1906, Apert described the classic syndrome of oxycephaly (tower skull) with syndactyly, the latter defined as fu sion of digits two to four resulting in a mid-digital hand mass with a common nail. Premature craniostenosis results in a skull resembling a fireman's helmet. Also typical of patients with Apert's disease is a flattened occiput, a dish-face appear ance caused by maxillary hypoplasia, a parrot beak nose, prognathic lower jaw, cleft or Byzantine arch palate, bifid uvula, and dental anomalies. 2 Ocular abnormali ties in Apert's syndrome are: proptosis, divergent strabismus, orbital hypertelorism, antimongolid fissures, optic atro phy, 3 and, rarely, megalocornea. 4 Albinism is a congenital disorder mani fested by a deficiency of melanin in the tissues thought to be caused by a deficit of one of the enzymes mediating pigment formation, such as tyrosinase. Genera lized oculocutaneous albinism, an autosomal recessive disease, is characterized by a lack of pigment throughout the body. Patients with X-chromosomelinked ocular albinism, on the other hand, have normal skin and hair pigmentation, but lack adequate pigmentation in the uvea and the retinal pigment epithelium. The ocular manifestations of albinism From the New York University Medical Center, Department of Ophthalmology, New York, New York. This study was supported in part by grants EY00213 and EY00309 from the National Eye Insti tute, DE03568-03 from the National Institute of Dental Research, and a departmental grant from Research to Prevent Blindness, Inc. This study was presented at the Association for Research in Vision and Ophthalmology meeting in Sarasota, Florida, April 29, 1977. Reprint requests to Sheila Margolis, M.D., De partment of Ophthalmology, New York University Medical Center, 550 First Ave., New York, NY 10016.
are: poor visual acuity, photophobia, pendular nystagmus, hypopigmentation of the fundus, and iris transillumination. Typically the macula is hypoplastic or aplastic; the foveal reflexes are dimin ished or absent. Most patients with albi nism show iris transillumination even though some (the tyrosinase-positive vari ety) have pigmented irides ranging from blue to dark brown, 5 ' 6 which appear nor mal before instrument examination. Such an observation results from sufficient stromal pigment for iris color, but insuffi cient melanin in the posterior pigment epithelial layer with consequent iris translucency. The patients presented here demon strated a form of albinism characterized by good visual acuity, photophobia, dilu tion of skin and hair color, and iris transillumination without pendular nys tagmus, together with oxycephaly and syndactyly characteristics of Apert's dis ease. SUBJECTS AND M E T H O D S
At the New York University Medical Center for Craniofacial Anomalies, nine patients underwent complete ocular ex amination, fundus and anterior segment photography, and in several cases, electrophysiologic evaluation of retinal func tion. The ocular examination included slitlamp biomicroscopy and both direct and indirect ophthalmoscopic examination. We performed anterior segment transil lumination photography with a fundus camera and a fiber optic bundle probe placed against the lower eyelid to trans mit a high intensity light into the globe. The procedure for the electroretinogram (ERG) and electro-oculogram (EOG) are
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Fig. 2 (Margolis and associates). Case 1. Syndac tyly of feet.
Fig. 1 (Margolis and associates). Case 1. Patient with typical Apert's syndrome with oxycephaly, mid facial hypoplasia, hypertelorism, antimongoloid fissures, exophthalmos, and strabismus.
normally. All contact with the family was lost after 1968. The patient had typical Apert's syndrome (Fig. 1): (1) oxycephaly (tower skull), (2) midface hypoplasia, (3) orbital hypertelorism, (4) antimongoloid palpe brai fissures, (5) exophthalmos, and (6) strabismus. The skeletal malformations, syndactyly of all limbs (Figs. 2 and 3) were also consistent with this entity.
described elsewhere.7 Four of the nine patients had determinations of serum tyrosine and phenylalinine levels. Karyotyping and banding techniques 8 were performed on chromsome material ob tained from peripheral lymphocytes on two of the patients. CASE REPORTS Case 1—This 23-year-old white man had a frater nal twin sister, an anencephalic girl who lived only 44 minutes after birth. The mother's pregnancy had been complicated by shortness of breath caused by excessive weight gain, and her period of labor was 3V2 hours. The birth weight of the patient was 1,899.4 g. Initial examination of the infant showed hydrocephalus, cleft palate with webbed fingers and toes. Although the patient was not expected to live, he survived and was placed in a state institution after 8V2 months. At the time of the patient's birth the father was age 30 years and the mother age 28 years; both were in good health. Another set of twins was stillborn following a five-month pregnancy, and the last child, a boy sibling, was said to be developing
Fig. 3 (Margolis and associates). Case 1. Syndac tyly of hands.
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A cleft palate with associated structural speech impairment and midthoracic dextroscoliosis were also present. Additionally, mental retardation, possi bly caused by complete absence of educational exposure, was noted. Ocular examination—Corrected visual acuity in each eye was 6/9 (20/30) demonstrated on the Snellen illiterate E game. Refractive error was R.E.: +0.25 = -1.00 x 15 degrees, and L.E.: +1.75 = -0.75 x 170 degrees. Normal intraocular pressures were recorded by applanation tonometry. The pa tient had prominent supraorbital ridges with hypoplastic infraorbital rims (Fig. 1). Palpebrai fissures were markedly antimongoloid and the globes mea sured by exophthalmometry were R.E.: 15 mm, and L. E.: 14 mm, on a base of 110. The interpupillary distance was 72 mm, and intercanthal distance was 37 mm. There was no nystagmus. The anterior segment was normal. The irides transilluminated in a diffuse spokewheel pattern, especially prominent in the right eye at the 5 o'clock position (Fig. 4). The lens and vitreous were normal in both eyes. The fundus (Fig. 5) had distinct optic nerve margins with slight temporal pallor in the left eye. Tortuosity of the retinal vessels was increased in both fundi. The macular region showed mild granularity (Fig. 6) with a diffuse foveal reflex in both eyes. The fundus demonstrated diffuse hypopigmentation with easily visualized choroidal ves sels in the midperiphery (Fig. 7). In the primary position at distance and near, there was an exotropia of 10 prism diopters with a right hypertropia of 15 prism diopters. There was a marked V esotropia pattern; on upgaze, the devia tion was identical to the primary position. However, on downgaze, an esotropia of 25 prism diopters with a small right hypertropia became manifest. Rota-
Fig. 4 (Margolis and associates). Case 1. Diffuse iris transillumination especially prominent at the 5 o'clock position.
DECEMBER, 1977
Fig. 5 (Margolis and associates). Case 1. Left eye. Fundus photograph shows temporal pallor of optic nerve with increased tortuosity of the retinal vessels.
tions showed overaction of both inferior oblique muscles with concomitant underaction of the su perior oblique muscles. The near point of conver gence was remote. Case 2—This 19-year-old white woman had been born with multiple congenital anomalies typical of Apert's syndrome. The patient's prenatal and birth history were noncontributory. A paternal cousin had
Fig. 6 (Margolis and associates). Case 1. Left eye. Macular region showing mild granularity and illdefined foveal reflex.
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Fig. 7 (Margolis and associates). Case 1. Left eye. There is generalized hypopigmentation in the midperiphery with visualization of the choroidal vascu lature. a cleft palate. The father and mother were both 28 years old at the time of the patient's birth, and there was no history of consanguinity. One sister was normal. The patient had undergone surgical proce dures to relieve craniostenosis, syndactyly of the hands and feet, and the mouth and palate anomalies. Case 3—This 27-year-old white -Woman had been born with facial and hand deformities typical of Apert's syndrome (Figs. 8 and 9). However, there was no prenatal complication except a fall during the third month of the mother's pregnancy. The patient's younger sister was normal. At the birth of the child both parents were 32 years of age. Corrective surgery for syndactyly and strabismus, as well as eight procedures for maxillofacial recon struction had been performed. Ocular examination—The patient's best corrected visual acuity was R.E.: 6/15 (20/50), and L.E.: 6/12 (20/40). Refraction was R.E.: -1.25 = -4.00 x 95 degrees, and L.E.: -1.25 = -0.50 x 125 degrees. Single binocular vision was present with a head turn to the right. Intraocular pressure was R.E.: 16 mm Hg, and L.E.: 15 mm Hg. The globes were promi nent with antimongoloid fissures; the exophthalmometer reading was 19.0 mm and 20.0 mm on a base of 110 mm. The interpupillary distance was 65 mm and intercanthal distance was 35 mm. There was an occlusion nystagmus in both eyes. With the exception of iris transillumination, re sults of the anterior segment examination were with in normal limits. Orientation of the Y sutures in the lens was horizontal instead of the normal vertical position. Ophthalmoscopic examination of the right eye revealed a pink tilted disk, normal retinal vascula ture, and a diffuse foveal reflex. The macula was
833
Fig. 8 (Margolis and associates). Case 3. Patient with Apert's syndrome demonstrating craniofacial abnormalities. displaced inferiorly (Fig. 10); pigmentation was reduced in the inferior and nasal quadrants (Fig. 11). The left disk and retinal vasculature appeared normal, but the generalized pigment deficiency made the choroidal vessels visible throughout much of the posterior pole (Fig. 12). The foveal area was similar in each eye. There was a V-esotropia pattern; upgaze distance and near measurements showed a 5-prism diopter exotropia, with a right hypertropia of 20 prism diopters. Downgaze showed an esotropia of 25
Fig. 9 (Margolis and associates). Case 3. Syndac tyly of hands typical of Apert's syndrome.
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Fig. 10 (Margolis and associates), Case 3. Right eye. Disk is tilted and macula is inferiorly displaced. Note hypopigmentation of the inferonasal retina.
Fig. 12 (Margolis and associates). Case 3. Right eye. Normal appearing disk with pigment deficiency in the inferior portion of the retina.
prism diopters, with a right hypertropia of 20 prism diopters. We noted moderate overaction of both inferior oblique muscle, as well as moderate underaction of both superior oblique muscles. There was also marked underaction of the left superior rectus. The near point of convergence was 30 cm and the Titmus fly test revealed no stereopsis.
Case 4—This 13-year-old white girl had syndactyly of the hands and feet, oxycephaly resulting from complete closure of the coronal sutures, shallow orbits, and bilateral exophthalmos. Prenatal history was noncontributory although the mother reported a history of previous spontaneous abortion. The pa tient had three normal sisters and a first cousin with syndactyly of the fourth and fifth fingers. Another cousin reportedly had one short limb. The father was 42 years and the mother 40 years of age at the patient's birth. A craniotomy was performed at an early age to open the coronal sutures and a follow-up examina tion showed a normal motor progression, preserva tion of vision, and normal speech and intelligence. Over the years, various surgical procedures have been performed to correct the patient's physical deformities: cleft palate, bifid uvula, and fusion of fingers, all typical of Apert's syndrome. Case 5—This 17-year-old girl had been born with oxycephaly, syndactyly, and a supernumerary nip ple on the right side. The mother's pregnancy and delivery were uncomplicated. Three other siblings were reportedly normal. Family history was noncontributory for any deformities or consanguinity. At the patient's birth, both parents were 22 years old. Numerous surgical procedures were performed on the patient to correct the syndactyly and strabismus. Case 6—We examined an 8-year-old black boy with Apert's disease and no history of prenatal or birth complications. At birth, he demonstrated the typical findings of oxycephaly and syndactyly. The father's and mother's ages were 52 years and 29 years, respectively. There were no other siblings and no family history of consanguinity or birth defects. He underwent a cranial stripping procedure at 6
Fig. 11 (Margolis and associates). Case 3. Right Eye. Hypopigmentation of the entire nasal half of the retina. The choroidal vessels are easily visible.
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months of age to correct premature closure of the coronal sutures. Case 7—This 2V2-year-old Italian girl had multi ple congenital anomalies including midfacial hypoplasia of the maxillary bones and syndactyly of both hands and feet. Her hair and irides were dark brown. Family history was noncontributory for con sanguinity and any congential deformities. At the patient's birth her father was age 29 years, the mother's age was 25 years. In April 1973, at 4 months of age, the patient had an exploration of the right zygomaticofrontal suture line and a biopsy at that site. One month later, she underwent cranial stripping for bilateral synostosis of the coronal su ture. At age 1 year, strabismus surgery was per formed. Case 8—This 10-year-old black girl had Apert's syndrome and a history of photophobia and tearing. At ten weeks of the child's gestation, the mother had had pelvic infection and rash treated with tetracycline (Achromycin) and, until the seventh month of pregnancy, she had had intermittent vaginal bleed ing. The birth was uncomplicated, but the child's birth weight was low at 1,871 g. Four other siblings were reported to be normal. The mother's sister, who died one day after birth, reportedly had an "overlap ping skull." At the time of our patient's birth, the father was 36 years old, the mother was 31 years old. Both parents were normal. Case 9—This 2-year-old white boy also demon strated the typical anomalies of Apert's syndrome. The hair and irides were dark brown. Family history was noncontributory for consanguinity and congen ital deformities. One other sibling was reported to be normal; a geneticist reported both parents were normal as well. At the child's birth, the father was 31 years old, the mother was 26 years old. DISCUSSION
Apert's syndrome is characterized by oxycephaly and syndactyly of the hands and feet.1 Antimongoloid obliquity of the palpebrai fissures, hypertelorism, proptosis, strabismus, and optic atrophy are fre quently associated ocular findings. Of 304 cases reviewed by Ferriman,9 15 had papilledema and 57 had postpapilledema optic atrophy. Although numerous papers have been written on this syndrome, none has yet reported a frequent and signifi cant association of Apert's syndrome with a diffuse hypopigmentation of hair, skin, and eyes. In 1920, Park and Powers10 found 29 reported cases coinciding with Apert's criteria and added an additional case. In their ophthalmoscopic findings, is an iso
835
lated description of an albinoid fundus: Not only was the pigment epithelial layer of the retina wanting [in melanin], as in albinos, but the intercapillary islands of stromal pigment were missing as well. Thus, the vessels were clearly visible and the underlying capillaries of the choroid were easily traced . . .
No further mention of this finding, nor explanation for its existence has since been made. In our study, ocular findings in five of nine cases (Table) with typical Apert's syndrome were: an albinoid fundus, loca lized areas of iris transillumination, dif fuse or absent foveal reflex, and photo phobia. Decreased fundus pigmentation varied from a deficit restricted to the midperiphery where the choroidal vasculature is more easily visible, to a hypopig mentation involving almost the entire posterior pole. Patients with hypopig mentation of the fundus also showed ab sent or diffuse foveal reflexes. Although several of the cases demonstrated some classical signs of albinism, none of these manifestations were severe. The reduc tion in visual acuity was slight, the iris and fundus depigmentation was incom plete, photophobia was mild, and, with the exception of Case 5, there was no true nystagmus. One patient (Case 3), howev er, did have occlusion nystagmus. Each of the patients described had skin and hair color lighter than other family mem bers, but not more hypopigmented than some members of the general population. The degree of ocular hypopigmentation is related to the amount of body pigmen tation in any particular patient. For exam ple, the lighter haired, lighter complexioned patients (Cases 1-5, Table) show greater iris transillumination and fun dus depigmentation than black patients (Cases 6 and 8) or the Italian patient (Case 7).Goodman, Ripps, and Siegel11 reported similar findings in patients with Xchromosome-linked ocular albinism; the degree of ocular pigmentation was less
23
19
27
13
17
8
2'/s
10
l*f
2t
3t
4*t
5
6
7t
8§
6/7 6/7 (20/25) (20/25) Not Done
6/9 (20/30) 6/6 (20/20) 6/12 (20/40) 6/7 (20/25) 6/9 (20/30) 6/7 (20/25) + (Latent)
Visual Acuity L.E. Nystagmus
6/9 (20/30) 6/7 (20/25) 6/15 (20/50) 6/7 (20/25) 6/7 (20/25) 6/7 (20/25) Not Done
R.E.
Photophobia
Diffuse Diffuse Normal
Blue Hazel Blue Dark brown Dark brown Dark brown Brown
+ + +
— — -
Diffuse
Normal
Normal
R.E., none L.E., diffuse Diffuse
Blue
Light brown Light brown Light Brown Dark brown Dark brown Dark brown Brown
Diffuse
Hazel
+
Fovea! Reflex
+
Albinoid Fundus
Light brown Blond
Transillumination
Fair Skin
Iris Color
SYNDROME
Hair Color
* C h r o m o s o m e s t u d i e s normal. t T y r o s i n e and p h e n y l a l a n i n e l e v e l s normal; E R G a n d E O G normal. ^Abnormal horizontal m u s c l e insertions. § A b s e n c e of all p u n c t a , trichiasis of b o t h l o w e r e y e l i d s .
Age (yrs)
Case No.
O C U L A R A N D CUTANEOUS FINDINGS IN PATIENTS W I T H APERT'S
TABLE
Orthotropia
V-pattern esotropia V-pattern exotropia V-pattern esotropia V-pattern esotropia V-pattern exotropia V-pattern exotropia Left esotropia Orthotropia
Strabismus
a
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σ n w S w
o r o o
t-
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O o T) K
>
C3 50
o
>
n
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M SB
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00
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ALBINISM WITH APERT'S SYNDROME
when the general body pigmentation was light, and greater when the individual was dark complexioned. Although hypopigmentation has not been previously observed with Apert's syndrome, albinism has been associated with several other diseases. 6 Klein 12 pre sented a 10-year-old girl with pigmentary anomalies and multiple congenital mal formations at the Swiss Genetic Society in 1947. This child had a small bird-like head, absence of pigmentation of the eye brows, lashes, and the skin of the upper torso, hypertelorism, antimongoloid fis sures, divergent strabismus, arched pal ate, dental anomalies, and syndactyly. Additionally, there was thoracolumbar webbing and deafness. The irides were slate blue but not diaphanous; the fundi were normal except for hypopigmentation in the periphery where the choroidal ves sels were easily seen. Klein labeled the discrete amelanosis as a partial albinism. Similar findings were noted in BustiRosner's 1 3 report of a pedigree having members with obvious albinism and as sociated craniofacial anomalies. Several of the affected patients had blond hair and eyelashes, blue translucent irides, strabismus, nystagmus, and hypopigmented fundi with macular hypoplasia, all typical signs of albinism. In addition to the ocular findings, peculiar-shaped skulls, prognathism, microstomia, dental anomalies, and an arched palate were noted. Apert's syndrome is generally acknowl edged to be transmitted as autosomal dominant. 1 4 This view is confirmed by several studies of affected mothers and daughters, 1 5 - 1 7 as well as affected fathers and sons. 18 In a recent report, the disease was followed through three successive generations. 19 By contrast, none of our patients (ex cept the patient in Case 4, who had one cousin with isolated syndactyly and an other with one short limb), had either simi
837
larly affected siblings or parents with the disorder. In the largest reported series of patients with Apert's syndrome, Blank 2 noted only two of his 39 cases indicated instances of a parent and child similarly affected. In most of Blank's patients, as in ours, the disease did not result from a dominantly inherited trait, but possibly from an autosomal recessive variety. However, none of the parents of Blank's affected cases were consanguineously re lated, nor were ours. A rare disorder such as Apert's syndrome is ordinarily associ ated with a moderate degree of consan guineous marriages. From these data we concluded there is no one mode of transmission for Apert's syndrome. For our patients, the most like ly mode of transmission was autosomal recessive. However, one cannot exclude some less likely possibilities; for exam ple, all our patients may represent sponta neous mutations. Although it is not likely that several patients would have reported with the same mutated gene over such a small time span, our referral center is one of the few in the United States for cranio facial disorders and we may have inad vertently pooled patients with rarely oc curring mutation events. Most previously performed chromo some studies 2 0 and those on two of nine patients tested in our group were normal. Dodson and co-workers 21 described a deletion-translocation of the short arm of chromosome 2 to the long arm of a Group C chromosome, 11 or 12, in a patient with Apert's syndrome. However, in reviewing cytogenetic studies on patients with Apert's disease, these authors concluded that no specific chromosomal abnormality could be assigned to this syndrome, and indeed most patients showed no detecta ble chromosomal aberration. Finally, extrachromosomal and nonheritable factors, such as exposure to drugs, x-rays, viral or other inflammatory agents, trauma or other cause of mechanical in-
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AMERICAN JOURNAL OF OPHTHALMOLOGY
trauterine insult may be causes of Apert's syndrome. However, none of the mothers questioned indicated any of these circum stances during pregnancy. Advanced age of the parents, particularly of the father, has also been suggested as a prime factor in the transmission of the syndrome.2,22 Blank2 found the modal age for the fa thers was 37 years, with a range of 35 to 39 years; and the mothers' modal age was 32 years, with a range of 30 to 34 years. The fathers' and mothers' ages are 10 and five years older, respectively, than parents in the general population. After consider able statistical analysis Blank found the father's age to be the main factor. Our cases support this observation since two fathers were over 40 years and six were between the ages of 28 and 32 years at the child's conception, but only three of the nine mothers were over the age of 30 years. If the ocular hypopigmentation in Apert's syndrome is a consistent feature of this disorder, what embryological evi dence ties together the seemingly dispa rate elements of melaninization and skel etal developments? Two factors are im portant to consider. Degenhardt23 defined the critical teratogenic period for the dif ferentiation of the skull and hands as between the 29th and 35th day of embry onic life. He derived his evidence from studies on thalidomide-induced phocomelia in which the sensitive period for the drug action was shown to occur be tween the 28th and 42nd days after con ception.24 Degenhardt also noted a possi ble relationship between the degree of hand malformation and the stage of de velopment at which it might occur. Dis turbances occurring in earlier stages pro duced more severe hand deformities, while less severe forms are associated with later stages of embryonic develop ment. The other line of evidence derives from the normal embryological development of
DECEMBER, 1977
the eyes and limbs. The second phase of retinal differentiation as well as the seg mentation and individualization of the digits, occurs during the same time peri od, between the 42nd and 49th day of embryogenesis (12 to 17 mm, stage).10·25 A disturbed synchronization of these devel oping systems may result in those phenotypic expressions of eye and limb incor porated in the syndrome described by Apert. The anomalous distribution and amounts of pigmented tissue in affected individuals may be explained by assum ing that an insult occurring early in em bryogenesis disturbs the migrating melanoblasts developed in the sensory crest26 and thus interferes with pigment migra tion to peripheral sites such as skin, hair bulbs, sensory and ocular tissue. Thus the associated features of generalized hypopigmentation of skin and hair in this disease can be related to disturbance of melanoblast migration occurring at the same time as limb differentiation. While decreased amounts of iris stromal pigment may be related to such events, the diaphanous appearance of the iris is a result of melanin loss in the posterior epithelial layer, and not in the stroma. Brown irides of tyrosinasepositive albinos, for example, transillumi nate easily.8 The posterior epithelial leaf of the iris derives from optic cup neuroectoderm and the lack of melanin in this layer (which produces transillumination in most patients with Apert's syndrome) cannot be attributed to a disturbance in melanocyte migration from the neural crest early in embryonic life. Clearly, many circumstances can be involved in the etiology of a multisystem anomaly, including primary heritable fac tors, extrachromosomal influences, and environmental causes. To assess these contributory factors intelligently an ap propriate animal model incorporating the features of Apert's syndrome must be discovered.
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Five of nine patients with Apert's syn drome (acrocephalosyndactyly) showed an associated hypopigmentation of hair, skin, and eyes. The hair color of these five patients ranged from light brown to blond, the skin was pale, and the irides hazel or blue. Iris transillumination and hypopigmentation of the fundus were present and associated with absent or diffuse foveal reflexes. Unlike most forms of classic ociilocutaneous albinism, how ever, there was good visual acuity and no pendular nystagmus. The evidence indi cated that the lack of pigmentation associ ated with the characteristic skeletal anomalies of Apert's syndrome resulted from a disturbance of independent, ge netically related, processes occurring at a common point in gestation. REFERENCES 1. Apert, E.: De L'acrocephalosyndactylie. Bull Mem. Soc. Med. Hop. (Paris) 23:131, 1906. 2. Blank, C. E.: Apert's syndrome (a type of acrocephalosyndactyly). Observation on a British series of 39 cases. Ann. Hum. Genet. 24:151, 1960. 3. Falls, H. F.: Craniofacial skeletal syndrome. In Crow, J. F., and Neel, J. V. (eds.): Third Internation al Congress Human Genetics, Sect. 8. Baltimore, Johns Hopkins Press, 1967, pp. 402-412. 4. Calamandrei, D.: Megalcornea in due pazienti con sindrome craniosinotoscia. Q. Ital. Oftalmol. 3:278, 1950. 5. Siegel, I. M.: The albino as a low vision patient. In Faye, E. (ed.): Clinical Low Vision. Boston, Little Brown, 1976, pp. 255-261. 6. Witkop, C. J.: Albinism. In Harris, H., and Hirschhorn, K. (eds.): Advances in Human Genetics. New York, Plenum Press, 1971, pp. 61-142. 7. Carr, R. E., and Siegel, I. M.: Electroretinographic aspects of several retinal diseases. Am. J. Ophthalmol. 58:95, 1964. 8. Mittwoch, U.: Cytogenetics. In Fraser, G., and Mayo, O. (eds.): Textbook of Human Genetics. Ox ford, Blackwell, 1975, pp. 198-268. 9. Ferriman, D.: Acrocephaly Acrocephalosyn dactyly. London, Oxford University Press, 1941, pp. 1-109.
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10. Park, E. A., and Powers, G. F.: A study of acrocephalosyndactylism. Am. J. Dis. Child. 20:235,
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