An autosomal dominant trait must exhibit certain characteristics. There must be vertical transmission (i.e., the trait appears in consecutive generations). A heterozygote exhibits the trait in some way. A parent of either gender with the trait passes it on to 50% of his or her children independent of the gender of the children. (The gender incidence of this trait would then be equal.) Children of unaffected parents are affected only by mutation.

Penetrance and expressivity are two parameters that have bearing on autosomal dominantly inherited disease. Penetrance is the ability of a genotype to be phenotypically detected. If a subject is known to have an autosomal dominant genotype and yet has no detectable phenotype, then that gene is impenetrant. Penetrance is binary; an autosomal dominant gene is either penetrant or impenetrant. Expressivity refers to the degree of variability that a penetrant autosomal dominant trait can have. For example, some affected individuals with neurofibromatosis may have few cutaneous neurofibromas, while others are severely disfigured.

Autosomal dominant diseases can also have seemingly unrelated manifestations in different organ systems and tissues, although only one gene is present. This is called pleiotropy.

MARFAN SYNDROME

A description of what we now call Marfan syndrome was probably first made by Williams, an ophthalmologist, in 1895, who did not include ectopia lentis as a manifestation. Ironically, it was a pediatrician who first published that association in 1914. Marfan's description of a 5½-year-old child with long, thin extremities, published in 1896, was more widely seen than Williams' the year before, and hence this syndrome now bears his name.

Marfan syndrome is an autosomal dominant condition with complete penetrance and a high degree of expressivity. It has an incidence of 1:66,000 with a gender ratio of unity.¹ Advanced paternal age is associated with the sporadic cases.²

The long arm of chromosome 15 has been identified as harboring the genetic defect for this disorder,³ which results from a point mutation in one of the fibrillin genes.⁴ Fibrillin is an important component of connective tissue microfibrils that form the framework for elastin deposition and are found in lens zonules, the aorta, and other connective tissue structures. The abnormal fibrillin leads to structural weakness resulting in ectopia lentis, aortic dissection, and other disorders and has been shown to cause syndactyly in mice.⁵ Recent work has suggested the possible role of matrix metalloproteinases (proteolytic enzymes) as well.⁶

Marfan syndrome's nonocular systemic manifestations are found in the skeletal and cardiovascular systems.

Cardiovascular abnormalities are the more significant systemic manifestations. In more than 95% of the cases in which a cause of death can be established, a cardiovascular problem is at fault.⁷ Dilatation of the aortic root (with or without aortic regurgitation), mitral valve prolapse, and mitral regurgitation are all seen. When aortic root dilatation is demonstrated, therapy with a β-blocker has been suggested to reduce cardiac contractility in an attempt to halt progression of the aortic root dilatation and prevent aortic dissection.⁸ More definitive work with β-blockers is still needed.

Abnormalities of the skeletal system include scoliosis, arachnodactyly, anterior chest deformities, increased arm span to total height ratio, joint laxity, and a high arched palate. Scoliosis is the most disabling skeletal abnormality. Attempts have been made in female adolescent patients to alleviate this problem with estrogen therapy. These hormones can suppress the adolescent growth spurt that greatly aggravates the scoliosis.

Ocular Manifestations

Of the many ocular abnormalities, by far the most common is ectopia lentis, occurring in 50% to 80% of affected individuals (Fig. 1). It is usually bilateral, symmetric, and nonprogressive. It may be subtle and detectable only by observing phacodonesis or iridodonesis, sometimes visible by gonioscopy. Lens dislocation is usually superotemporal. There can also be posterior displacement, leaving a gap between lens and iris pigment epithelium. When zonules can be seen, a reduced number is usually not observed.

Patients with Marfan syndrome may have poor vision. This often results from delayed and inadequate correction of the extremes of refractive error⁹ (especially moderate to high myopia). These and other factors, which compromise visual input, may be responsible for the increased incidence of strabismus seen in patients with Marfan syndrome.¹⁰

In Marfan syndrome, an increased axial length may also be seen. A slightly higher than normal axial length is common in patients with Marfan syndrome who have no ectopia lentis or retinal detachment. However, the axial length is higher in those patients with ectopia lentis and is even higher in those patients with retinal detachment.¹¹ Other retinal associations include lattice degeneration and atrophic holes.

Abnormalities may also be seen in the uveal tract. Choroidal thinning has been described in myopic eyes. The iris morphology is often striking. There can be a complete absence or marked reduction in the number of furrows or crypts, giving the anterior iris surface a smooth, velvety appearance (Fig. 2). Hypopigmentation of the iris pigment epithelium has been described^12,13 which probably corresponds to the transillumination of the iris base that is seen in 10% of cases.

The cornea can also be affected. Patients with Marfan syndrome can have flatter than average keratometric readings.^11,14 Megalocornea¹⁵ may also be present. In eyes with ectopia lentis (with or without retinal detachment), keratometric readings may show steepening in the meridian of the lens dislocation.

Other, nonspecific findings have been described in the few ocular histologic studies that have been performed in Marfan syndrome. Separation of individual zonular fibers into their composite filaments⁹ and angle anomalies (such as pectinate ligaments) have been reported.^12,13,16 Common to several pathologic studies is the large size of the globe corresponding to the larger axial lengths measured clinically.

THE PHACOMATOSES

The phacomatoses are a group of heredofamilial conditions that all have as a hallmark various hamartomas. The term comes from the Greek term for birthmark (“mother spot”). Hereditary hamartomatosis has been suggested as a better name for these diseases.¹⁷ We only consider the autosomal dominant disorders in this chapter (neurofibromatosis, tuberous sclerosis, and angiomatosis retinae). Despite the lack of hard evidence for autosomal dominant transmission, encephalotrigeminal angiomatosis (Sturge-Weber syndrome) is also discussed for completeness.

Neurofibromatosis

Manifestations of this condition had been observed for ages before being described by Robert William Smith in 1849.¹⁸ The more classic description was given by the German pathologist, Friedrich Daniel von Recklinghausen, who accurately described the diverse findings as a single entity in 1882¹⁹; it is often referred to as von Recklinghausen's disease. Probably because of the complex effects on these patients' personality as a result of the sometimes severe disfigurement, neurofibromatosis maintains a high profile in the lay press^20–24 and literature (e.g., The Elephant Man, a 1979 Broadway production written by Bernard Pomerance, and a 1980 British motion picture, although the correct diagnosis for the patient portrayed in those works was probably Proteus syndrome²⁵).

Neurofibromatosis is a proven autosomal dominant condition with variable penetrance and a high degree of expressivity. It is estimated to occur once per 3,300 live births.²⁶ Children of affected mothers are more severely affected than children of affected fathers; no clear mechanism is known for this maternal effect.

Recent work has allowed the division of this disorder into two major autosomal dominant conditions. Neurofibromatosis 1 (a defect on chromosome 17)²⁷ now refers to the much more common, classic syndrome with the wide-ranging systemic and ocular manifestations described below. Neurofibromatosis 2 results from an abnormality on chromosome 22.^28,29 This less common variant denotes the syndrome of bilateral acoustic neuromas that may also include neurofibromas and café-au-lait spots.

Although clinical findings are primarily neurocutaneous in nature, any organ system can be involved. The diagnosis requires six or more café-au-lait spots, each larger than 1.5 cm in diameter (Fig. 3). Axillary freckling is also highly suggestive of the diagnosis.^{30,31(pp508–509)} Areas of hypopigmentation or hyperpigmentation can also be seen.

The cutaneous tumors, which are common and can be extremely disfiguring, take one of three forms. A fibroma molluscum is usually referred to as the common neurofibroma. This hamartoma is the proliferation of peripheral nerve elements at the distal end of a cutaneous nerve. A plexiform neurofibroma (Fig. 4) has the appearance of a “bag of worms” and represents a diffuse proliferation of tissue within the nerve sheath. The most marked cutaneous change results from diffuse proliferation outside the sheath, elephantiasis neuromatosa. When a hamartoma develops in a restricted space, a compromise in that nerve's function can occur.

Neurofibromas may occur anywhere in the central nervous system. They can produce a neurologic deficit corresponding to the affected nerve. Although these neurofibromas are generally benign, malignant change has occurred.^32(p1) Meningiomas can also be seen with a higher incidence than the general population, especially involving the orbital portion of the optic nerve.³³ When they occur in this location, they are more aggressive than their benign counterparts found in other locations.

Pheochromocytoma has been noted more frequently in patients with neurofibromatosis than in the general population, although it may be difficult to distinguish the clinical features of neurofibromatosis from multiple endocrine neoplasia (MEN) type IIb, in which pheochromocytomas also occur along with neuromas, café-au-lait spots, and prominent corneal nerves.^34(p31–32) Other tumors, such as rhabdomyosarcoma and liposarcoma, have rarely been reported with this disorder which may represent an unrelated association.^32(p1)

Skeletal deformities, unrelated to the neural tumors, may also occur. Scapular elevation, asymmetries or absences of long bones, misshapen sphenoid or absence of its greater wing, scoliosis, spina bifida, rib fusion, and many others have all been described (Fig. 5).^{26,31(pp508–509),32(p1)}

Individuals affected with neurofibromatosis 2 often have bilateral acoustic neuromas, which are Schwann cell tumors arising from the vestibular nerves, producing hearing loss or unsteadiness of gait in the second or third decade of life.²⁸ Café-au-lait spots, cutaneous neurofibromas, and plexiform neurofibromas may also be seen in these patients and may even predate the acoustic nerve symptoms.

OCULAR MANIFESTATIONS.

Ocular involvement in neurofibromatosis involves the cornea, uvea, trabecular meshwork, optic nerve, and retina. Corneal nerves can be thickened; the nerves in the conjunctiva may be thickened as well. Along with an increased incidence of pheochromocytoma, corneal nerve hypertrophy is also seen in multiple endocrine neoplasia. The significance of this commonality is as yet unknown.

Hamartomas of the iris (melanocytic nevi) can be seen and are called Lisch nodules (Fig. 6). They are variable in size and have a smooth, domeshaped configuration.³⁵ One series³⁵ found these nodules in 92% of their affected population above the age of 6 years; this may mean that their absence prior to that age does not rule out their later occurrence. Hamartomas may also be seen in the trabecular meshwork.^34(p30) In a more recent series, the incidence of Lisch nodules was 100% of patients with neurofibromatosis beyond the second decade of life.³⁶

Congenital glaucoma may occur in neurofibromatosis. If the upper lid is affected by a neurofibroma, then the eye on that side has a 50% chance of having glaucoma.^34(p30)

The retina and optic nerve head may also be involved with hamartomas; in contradistinction to the uveal hamartomas, which are usually melanocytic nevi, the retinal and optic nerve head hamartomas are generally of glial elements.

Posterior to the papilla, the optic nerve may be involved by a glioma, which is different from the acquired gliomas of adulthood. The optic nerve glioma of neurofibromatosis is a true hamartoma, more accurately described^34(p30) as a juvenile pilocytic astrocytoma. They are generally benign, but malignant degeneration has been known to occur following radiotherapy.³⁷ Gliomata of the anterior visual pathway (nerve and chiasm) may occur in 15% of patients with neurofibromatosis using computed tomography (CT) scan criteria.³⁸ In all patients with optic nerve gliomata, the incidence of neurofibromatosis is 25%. The glioma may produce proptosis and visual loss.³⁹

The hamartomas may also be found in the nonocular neural elements of the orbit, most commonly as plexiform neurofibroma or neurilemmoma, possibly causing proptosis. Also, absence of the greater wing of the sphenoid may occur, resulting in pulsatile exophthalmos.

Ocular involvement in neurofibromatosis 2 is much less frequent and extensive than in type 1. Approximately half of affected patients have cortical or posterior subcapsular opacities.⁴⁰ Lisch nodules, which can be diagnostic of neurofibromatosis 1 when multiple, are rarely seen in neurofibromatosis 2.³⁶

TUBEROUS SCLEROSIS

This disorder is occasionally referred to as Bourneville's disease, after Desiré Maglorie Bourneville, the French physician who, in 1880, described the triad of seizures, mental retardation, and cutaneous changes.⁴¹ The multiple “potatolike” tumors found in the brain gave rise to the term tuberous sclerosis, as named by Bourneville.

The reported incidence varies from 1 to 5 to 7 per 100,000.^42,43 Similar to other autosomal dominant conditions, there is no gender predilection. Most cases appear to be new mutations; this occurrence is thought to be as high as 86% by some, although McKusick^2(p1834) casts doubt upon such a high figure. A high paternal age is not associated with these new mutations. Penetrance is low and expressivity is variable; tumors have been reported in many organs and locations^44–46 and can be caused by different mutations.⁴⁷

Systemic Manifestations

The major systemic manifestations occur in the central nervous system, although other organ systems are involved as well. Seizures (motor, focal, petit mal, and psychomotor) occur in 93% of affected individuals. Mental retardation occurs in 62% of all patients; virtually all patients with mental retardation also have seizures.

Multiple intracranial hamartomas usually occur only in patients with seizures. They form in the cerebrum, basal ganglia, and periventricular gray matter and can protrude into the ventricle. They are detectable by plain skull roentgenography.

The most widely recognized cutaneous manifestation is adenoma sebaceum, found in a butterfly distribution of the face. It occurs in 83% of affected individuals (Fig. 7). The term adenoma sebaceum is a misnomer because the lesion is an angiofibroma, not an adenoma, and has nothing to do with sebaceous glands. These small dermal tumors appear at approximately 2 years of age and resemble multiple papules or nodules.

The ash-leaf lesion is another characteristic cutaneous sign on the trunk and limbs. This lesion can be seen in 86% of patients and may be present at birth; some feel these to be pathognomonic of Bourneville's disease. Appreciating these small, ovoid patches is much easier under a Wood's lamp. Histologically, these lesions contain melanocytes without melanin; hence their depigmented appearance.

Shagreen patches are another highly characteristic cutaneous lesion. They are usually seen on the back as a slightly raised, corrugated area, resembling a pigskin or orange peel. A less frequently seen but characteristic skin lesion is the subungual or periungual fibroma. There are other nonspecific signs involving the skin and hair that include café-au-lait spots, poliosis, and subcutaneous nodules.

Ocular Manifestations

The eyes are involved in approximately half of affected individuals.⁴⁸ Giant drusen (glial or astrocytic hamartoma) of the optic nerve are common and have a multilobulated appearance resembling a mulberry, tapioca grains, or fish eggs (Fig. 8). When visual symptoms are produced, it is usually in the form of a field defect. The lesion may also bleed resulting in a vitreous hemorrhage. Giant drusen are also in the differential diagnosis of pseudopapilledema.

Glial hamartomas of the retinal nerve fiber layer may also occur (Fig. 9). Similar to their counterparts on the optic nerve and in the central nervous system, they can calcify and hence be identified by plain radiography.

VON HIPPEL-LINDAU DISEASE

Retinal angiomas as a distinct entity was defined by the German ophthalmologist Eugen von Hippel in 1904.⁴⁹ The association of angiomatous retinas and cerebellar capillary hemangiomas was made in 1926 by the Swedish neurologist, Arvid Lindau.⁵⁰ Hamartomas in these two areas remain the hallmarks of von Hippel-Lindau disease.

Because von Hippel-Lindau disease is a rare disorder, prevalence and occurrence data are unavailable. Approximately one-fifth of cases show an autosomal dominant pattern with incomplete penetrance.^43(p1) The balance of the cases are sporadic. The major systemic manifestation is cerebellar hemangioblastoma (capillary hemangioma), which usually becomes manifest in the fourth decade of life. It occurs in 20% of patients with retinal tumors.⁵⁰ Multiple hemangioblastomas are seen in 10% of cases. Cerebellar hemangioblastoma may cause increased intracranial pressure or neurologic symptoms specific for the cerebellum.

The hamartomas may be found in the spinal cord, usually involving the lower cervical and thoracic areas. They may cause a spastic paraparesis, which can progress to a full-fledged spinal cord compression syndrome. Tumors have also been reported in the medulla.

Tumors and cysts of other internal organs also occur. An increased incidence of pheochromocytoma in these patients is seen; the associated hypertension in the presence of a vascular brain tumor may lead to a subarachnoid hemorrhage. Hypertension may also be caused by the cerebellar tumors; in these cases, urinary catecholamines are normal.^2(p1889)

Kidney tumors or cysts may also occur in tuberous sclerosis. The renal tumors can produce a hematopoietic substance resulting in polycythemia. However, 10% to 20% of patients with cerebellar hemangioblastoma may have polycythemia without a renal tumor.^32(p3) The pathogenesis of the polycythemia without a renal tumor is unknown. Metastatic renal cancer has also been reported.^2(p1889)

Papillary cystadenoma of the epididymis can occur bilaterally in von Hippel-Lindau disease; the bilateral occurrence of this rare tumor is very suggestive of von Hippel-Lindau disease. This tumor can occur in the broad ligament of the uterus in affected women.

Cystic and other benign lesions have also been reported in the pancreas, liver, spleen, adrenals, bones, and omentum.

Ocular Manifestations

The only primary ocular manifestation of this condition is the retinal hemangioma, originally described by von Hippel. The hemangioma is composed of endothelial cells and pericytes. The tumors can be found anywhere in the retina but are usually located in the midperiphery. These vascular masses often leak, producing hemorrhages or exudates; it is from these secondary effects that patients complain of visual symptoms, usually by their mid-twenties or early thirties. The exudation can be quite severe, producing an exudative retinal detachment. Organization of the retinal detachment can lead to anterior chamber shallowing and secondary glaucoma.

STURGE-WEBER SYNDROME (ENCEPHALOTRIGEMINAL ANGIOMATOSIS)

As with many eponymic syndromes, those whose names are primarily associated with the disorder were not the first to describe it. Schirmer first described the association of buphthalmos and facial angioma in 1860.⁵¹ In 1879, Sturge added seizures to this association.⁵² A distinct clinical entity was further defined and established by Weber in 1929, when he added cerebral hemangiomas and contralateral hemiplegia to the syndrome.⁵³ Reliable prevalence and occurrence data are unavailable. There does not appear to be a clear sex or ethnic predilection.

Firm evidence for autosomal dominant transmission, as in repeated observation of affected kindreds, is lacking. One report of an affected father and son appeared in 1979.^2(p1719)

Systemic Manifestations

Similar to other phacomatoses, this disorder is primarily neurocutaneous in its systemic manifestations. The hallmark of Sturge-Weber syndrome is the nevus flammeus or port-wine stain (or birthmark) which is found in the first, first and second, or first, second and third divisions of the trigeminal nerve (Fig. 10). It is most often unilateral and respects the midline. It is present at birth and sometimes darkens with age. Histologically, the nevus flammeus is a cavernous hemangioma. Vascular lesions may also occur in the oral mucosa and lips.

Nonspecific central nervous system manifestations occur in a high proportion of affected individuals. Grand mal or focal motor seizures can occur in 80% and mental retardation in 60% of patients.^32(p5)

It is unclear whether these findings are directly related to the meningeal cavernous hemangiomas which affect many of these patients. The meningeal hemangiomas are usually ipsilateral to the facial nevus flammeus and may cause hemiparesis in 56% of affected individuals.^{31(pp495–497)}

Intracranial calcifications of an odd configuration (convoluted, gyriform, railroad track sign) can be seen on plain radiographs beginning in the second year of life. They are usually underlying the vascular hamartomas and may result from either cortical hypoxia produced by the tumors or calcium binding of transudated proteins.

Occurring less frequently than the neurocutaneous manifestations, the vascular hamartomas have been found in lung, pituitary, pancreas, ovaries, and gastrointestinal tract.

Ocular Manifestations

A choroidal cavernous hemangioma is found in the eye ipsilateral to the facial lesions in 40% of affected individuals. One-half of all choroidal cavernous hemangiomas are found in patients with Sturge-Weber syndrome. In contradistinction to choroidal cavernous hemangiomata in patients without Sturge-Weber syndrome, Sturge-Weber hemangiomata are diffuse and have poorly defined, infiltrative margins. There may also be a cystic degeneration of overlying retina and serous exudation into the subretinal space. Heterochromia irides may be seen in patients who have a choroidal hemangioma; the affected eye can have a darker iris.^43(p3)

Approximately 30% of patients with Sturge-Weber syndrome develop glaucoma. Most of the cases of glaucoma are manifest early in infancy, but cases do occur later in childhood and young adulthood. Glaucoma usually occurs when the upper or lower lid is affected by the cutaneous hemangioma, although bilateral and contralateral cases have been documented.^43(p3) The glaucoma is felt not to be related to the choroidal hemangioma that may be present.^34(p29) The mechanism of the glaucoma is unknown. Other cases have the anterior chamber drainage angle configuration typically found in primary infantile glaucoma.

WAARDENBERG'S SYNDROME

First described, in part, in 1926 by Mende, Waardenberg's syndrome was fully outlined by the Dutch physician in 1951.⁵⁴ It is an autosomal dominant disorder with variable expressivity the occurrence rate of which is approximately 1 in 4,000 live births. Advanced paternal age has been associated with spontaneous mutation.^{31(pp248–249)}

Systemic Manifestations

The cutaneous findings are prominent. A white forelock is commonly seen. This may be present at birth but can darken with age. A black forelock has also been described.^2(p1901) The hair may become prematurely gray. There may be poliosis. The eyebrows can develop a medial flare and become confluent.

The most disfiguring cutaneous manifestation is vitiligo, which can be widespread. Because of the hypopigmented hair and eye (described below), Waardenberg's syndrome is considered by some to be a form of partial albinism.^{31(pp248–249)}

The most serious manifestation of this disorder is deafness, usually bilateral. The defect seems to develop in the organ of Corti. Animal experimentation has suggested that this defect may be related to poor regulation of endolymphatic fluid.^2(p1903) Another neurologic manifestation, occurring infrequently, is aganglionic megacolon (Hirschsprung's disease).

Skeletal malformations including cleft lip/palate, cervical ribs, and Sprengel's deformity occur infrequently.

Ocular Manifestations

Telecanthus, an increased distance between the medial canthi, is a characteristic ophthalmologic finding. Hageman and Delleman have divided Waardenburg's syndrome into two types.⁵⁵ Type I Waardenburg's syndrome is characterized by telecanthus with deafness occurring in 25% of affected individuals. In type II, telecanthus does not occur, although up to 50% of patients are deaf.

Other findings include iris heterochromia, hypopigmentation and stromal hypoplasia and patchy fundus depigmentation, further adding to the characterizaton of Waardenburg's syndrome as a partial form of albinism.

MYOTONIC DYSTROPHY

The cardinal features of this disorder were first described by Steinert in Germany in 1909; myotonic dystrophy is sometimes referred to as Steinert's disease.^{56(pp160–161)} Approximately one-fourth of the cases are thought to be new mutations. As with neurofibromatosis, children of affected mothers are more severely affected than children of affected fathers.^2(p1223) This observation, along with the much more frequent mother-to-child transmission than father-to-child transmission, suggests some maternal factor in this disorder.

Systemic Manifestations

The hallmark of this disorder is myotonia, which is the inability to relax a contracted muscle. This is accompanied by muscle wasting and fatigue, affecting virtually all muscle groups. Symptoms begin usually in the third to fourth decade, although it can range from infancy to the sixties. Myotonia, especially of the forearm or jaw muscles, often precedes the onset of fatigue by several years. Typical facies include a dull, expressionless, myopathic look, with drooping of the lids and mouth and dysarthria. The chest muscles and diaphragm are also affected producing hypoventilation, adding to the generalized fatigue. The electromyogram can show the myotonia as well as myopathic discharges, even in clinically uninvolved muscles.

Also typical is male frontal baldness and testicular atrophy. Ovarian cysts, dysmenorrhea, generalized, mild pituitary hypofunction, and cardiac conduction abnormalities can also be seen. Mental deterioration can occur late. Patients usually succumb to cardiac failure or pneumonia.

Ocular Manifestations

Unique to myotonic dystrophy is the iridescent, polychromatic, Christmas tree–like opacities scattered throughout the anterior and posterior cortical layers of the lens. These may be seen in advance of any systemic symptoms or signs. A diffuse opacification of a thin layer near the posterior capsule can also occur. This can progress to a stellate opacity.

Other ocular manifestations include bilateral ptosis, which is associated with the generalized deficient muscular function, and external ophthalmoplegia. Blepharitis is commonly seen. Decreased corneal sensation and an epithelial dystrophy have also been described. A macular dystrophy which does not appear to cause any visual dysfunction may also occur in this condition.^34(p500),^57,58

CRANIOFACIAL DYSOSTOSES

Craniostenosis is premature closure or fusion of a cranial suture. When the facial bones (and their orbital extensions) are also involved, ocular manifestations become evident.

The infant skull must undergo rapid growth to accommodate the expanding brain, which has its most rapid growth during the first 6 months of life. Much of the remaining growth takes place during the next 18 months. It is felt that the cranial sutures, which may not completely fuse until late in life, allow for such expansion. Premature closure of the sutures does not allow the underlying brain to continue normal growth. (It is unclear whether mental retardation, which is frequently associated with these conditions, is entirely secondary to the inhibited growth). The skull and face is also deformed according to Virchow's law: skull growth will be hindered in the direction perpendicular to the direction of the fused suture and compensatory growth will take place in the direction parallel to the fused suture.⁵⁹

APERT'S SYNDROME (ACROCEPHALOSYNDACTYLY)

In 1894, Wheaton described two infants with cranial deformities and digital fusions.⁶⁰ Twelve years later, Apert reported nine more cases.⁶¹ Apert's syndrome is an autosomal dominant disease with variable expressivity. Its prevalence is approximately 1 in 160,000 live births. By far, most cases are new mutations associated with advanced paternal age.

Skeletal Manifestations

The coronal suture is prematurely fused, which produces a high, broad skull with a reduced anteroposterior dimension. There is often midfacial hypoplasia. The hard palate is narrow and high or even cleft. There is partial to complete syndactyly of the fingers and usually complete syndactyly of the toes. Various abnormalities of the elbow, shoulder, hip, and cervical spine have been noted.^{56(pp80–81)}

Systemic Manifestations

Isolated, nonspecific visceral anomalies have been described,^{2(p23),31(pp418–419)} including ventricular septal defect, pyloric stenosis, and pulmonary aplasia. Mental retardation is often seen and, as mentioned above, may not be a primary finding but secondary to the cranial anomaly. Acne vulgaris, especially of the forearms, has also been described.

Ocular Manifestations

There are few, if any, primary ocular abnormalities in this disorder. Five patients have been described with iris transillumination and fundus hypopigmentation; they had generalized hypopigmentation as well.⁶²

Anomalous insertion of the rectus muscles has been reported⁶³ and implicated in the strabismus that is also seen in this disorder. A high incidence of V-pattern strabismus has been noted.⁶⁴ Congenital absence of the superior rectus muscle⁶⁵ and keratoconus have also been rarely noted.⁶⁶

The more commonly seen ocular manifestations are secondary to the bony changes in the skull and orbits. The bony changes can produce a compressive optic atrophy. If the intracranial pressure is raised because of the skull deformity, papilledema can result. The shallow orbits caused by involvement of the sphenoid bone results in proptosis.

CROUZON'S SYNDROME

Crouzon⁶⁷ first described a craniofacial dysostosis in 1912 in a mother and child.⁶⁸ Since then, other pedigrees have been described, including another one reported by Crouzon in 1915, clearly establishing the autosomal dominant nature of this syndrome. Prevalence and occurrence rates are generally unavailable because this condition is so rare. Crouzon's syndrome is penetrant and has variable expressivity; clinically uninvolved siblings should be radiographically investigated to look for the characteristic findings (premature closure of the cranial sutures). Fresh mutations may be associated with an increased paternal age.^2(p480)

Skeletal Manifestations

As in Apert's syndrome, the coronal suture is often prematurely fused resulting in a broad, high, foreshortened skull, also with the same implications toward brain growth and mental retardation. The lambdoidal suture may also be fused. The midface is underdeveloped, similar to Apert's syndrome. Atresia of the auditory meatus, a high arched palate, and dental anomalies (adontia, malocclusion) have also been described.

Occurrence of some craniofacial skeletal abnormalities is much less frequent than in Apert's syndrome, and several have been described in isolated reports.

Ocular Manifestations

Crouzon's syndrome has no well-documented primary ocular manifestations although one unreferenced mention of ectopia lentis can be found.⁶⁹ Virtually all the manifestations are secondary to the craniofacial bony anomalies and are similar to those found in Apert's syndrome, including strabismus and absence of muscles (Fig. 11).⁶²

Exophthalmos is common and is caused by shallow orbits from sphenoid bone involvement. Strabismus, usually exotropia, may occur as well as congenital absences and anomalous insertions of muscles, as described above for Apert's syndrome.⁶⁵ Optic atrophy can occur secondary to bony compression.

TREACHER COLLINS SYNDROME

Credit for the first case description of this condition is given to Thompson,⁷⁰ who described a patient in 1846.⁷¹ Berry^{56(pp152–153)} added information to the literature in 1888, and Treacher Collins⁷² described two cases in 1900.⁷³ A more complete description with subdivisions was provided by Franceschetti in 1944, who later reported more cases with Klein in 1949.⁷⁴

Mandibulofacial dysostosis is a highly penetrant and variably expressive autosomal dominant disease. It is rare enough to make occurrence and prevalence data unavailable. Approximately one-half of all cases are thought to be new mutations.

Malar and zygomatic hypoplasia and micrognathia result in a fishlike facies (Fig. 12). Malformation of the external ear and auditory canal can be present as well as a conduction hearing deficit. Also found are facial and palatal clefts and dental malocclusion. Some patients have respiratory difficulty because of a narrow airway.

Ocular Manifestations

The most common ocular manifestation is an antimongolian slant to the palpebral fissures, found in 89% of affected individuals. Lid colobomas and madarosis, usually of the lower lids, are frequently found. Rarely is there microphthalmos or uveal colobomas.

SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA

Prevalence and occurrence data are unavailable for this rare autosomal dominant entity that was first described by Spranger and Widemann in 1966.⁷⁵ Unlike many other syndromes of dwarfism, patients with spondyloepiphyseal dysplasia (SED) congenita are not mentally retarded.

There are multiple anomalies of ribs and vertebrae giving a barrel chest. However, the skull and limbs are normal. The upper-to-lower body ratio is reduced and the arm span is greater than overall height, which usually ranges from 37 to 52 inches. The neck is short and the spine shows kyphoscoliosis and lumbar lordosis.

Ocular Manifestations

Entries in the ophthalmologic literature describe moderate to high myopia, vitreous degeneration and syneresis, and lattice degeneration.⁷⁶ Reports in the nonophthalmologic literature also describe retinal detachment in as high as one half of cases, although no details are given.^72,77

STICKLER'S SYNDROME

Stickler's syndrome, a hereditary arthroophthalmopathy, was first described in 1965 in a large kindred at the Mayo Clinic.⁷⁸ It has been described as the most common autosomal dominant connective tissue dysplasia in the Midwest.⁷⁹ Occurrence and prevalence data are not available for this autosomal dominant condition with variable expressivity.

Patients with Stickler's syndrome have a marfanoid habitus. There may be bony enlargement of the large joints and occasional scoliosis. There is often midface flattening due to a flat nasal bridge and malar hypoplasia (Fig. 13).

Ocular Manifestations

Patients are usually highly myopic. Many have peripheral perivascular pigmentary changes (but normal electroretinograms). Cataracts and open-angle glaucoma may develop. There is usually vitreous degeneration.^68,80,81

The gravity of this condition lies in the malignant retinal detachment that may occur. The prognosis for repair of these detachments is quite guarded.

EHLERS-DANLOS SYNDROME

Ehlers-Danlos syndrome is now recognized to be a heterogeneous group of hereditary disorders that have hyperextensible joints and skin as their common thread. The mode of inheritance can be autosomal dominant, autosomal recessive, or X-linked recessive, depending on the subtype. A more complete description of the various subtypes is found elsewhere.^{2(p578),56(p564)}

This disorder was first described in the Dutch literature in 1682 by Van Meekeren⁷⁷; descriptions by Ehlers⁸⁰and Danlos⁸¹ followed early in this century. (See elsewhere in these volumes for a complete description of all the subtypes; only the autosomal dominantly inherited ones are considered here.)

Systemic Manifestations

The classic features of Ehlers-Danlos syndrome include extreme hyperextensibility of the joints and skin. This can produce parchment-thin scars from minor skin trauma. The ears are usually drooping and can be pulled far from the head. Blood vessels rupture easily, leading to ecchymoses. Elasticity of the tissues can also affect the cardiac valves, leading to mitral or tricuspid valve prolapse and aortic root dilatation. Hernias (inguinal, diaphragmatic, and umbilical) are not uncommon. Skeletal deformities also occur, including kyphoscoliosis, overlapping toes, pes planus, and downsloping ribs.

Ocular Manifestations

Epicanthal folds, strabismus, myopia, microcornea/microphthalmos, and thin sclerae have all been described.^{31(pp482–485),56(p112),82} The classic ocular manifestation of this disorder is angioid streaks, which are found in some other conditions as well (such as pseudoxanthoma elasticum, Paget's disease, and sickle cell anemia). The streaks are reddish brown or gray in color and have a vascular-type branching pattern as they course through the fundus deep to the retinal vessels. They represent breaks in Bruch's membrane. Ectopia lentis has also been described,⁸³ presenting the same paradox as in Marfan syndrome since collagen has not been found in lens zonules.

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