Patients with this syndrome,89,90 who usually appear normal at birth, have a deficiency of cystathionine synthetase, which is inherited as an autosomal-recessive trait. The disorder may be somewhat more common in those of Irish descent. A 50 per cent reduction of cystathionine synthetase activity has been found in liver biopsies of parents of affected individuals (who do not excrete homocystine), thus identifying the heterozygous state.
Ectopia lentis (which tends to be inferior in direction, in contrast to lens dislocation in Marian's syndrome), often associated with glaucoma, is a common finding in patients over 10 years of age. Congenital cataracts are less often found. Flushing of the face in the malar region after physical exercise or exertion in hot weather is characteristic. Livedo reticularis and sparse, fine, light-colored hair are observed in most patients (Figure 48). Some have "tissue-paper" atrophic, cutaneous scars similar to those seen in Ehlers-Danlos syndrome or porphyria. About 50 per cent of patients are mentally retarded. Seizures, extreme nervousness, and electroencephalographic abnormalities have been observed in about half of the cases.
Marfanoid body build, pectus excavatum or carinatum, kyphoscoliosis, genu valgum, pes cavus, and osteoporosis develop in childhood in most patients and become more pronounced with age. Affected individuals have frequently been diagnosed as having Marian's syndrome.
Vascular changes leading to luminal obstruction, thrombosis, and embolism occur in both arterial and venous circulation, with eventual cerebral, myocardial, or renal infarction in about 40 per cent of the cases. These thromboembolic episodes seem to occur frequently following surgical procedures and/or general anesthesia. Degeneration of the media of the aorta is usually noted at autopsy.
A positive cyanide-nitroprusside test on the urine is suggestive of homocystinuria. Diagnosis can be established by demonstration of homocystine in the urine by highvoltage paper electrophoresis or chromatography.
Figure 48. Homocystinuna.
HURLER AND HUNTER SYNDROMES
Division of what was initially thought to be a single disorder of mucopolysaccharide metabolism resulted in (1) Hurler's syndrome, an autosomal-recessive form with production, storage, and urinary excretion of chondroitin sulfate B (dermatan sulfate) and heparitin (heparan) sulfate; (2) Hunter's syndrome, an X-linked recessive disorder with excretion of the same mucopolysaccharides; (3) Sanfilippo's syndrome, an autosomal-recessive form associated with excretion of only heparitin (heparan) sulfate; (4) Scheie's syndrome, an allelic form of Hurler's syndrome; and (5) Maroteaux-Lamy syndrome, an autosomal-recessive form with excretion of only dermatan sulfate. Discussion here will be limited to the first two entities.91,92
Patients with Hurler's syndrome (Figure 49) and, to a lesser extent, with Hunter's syndrome (Figure 50) present the following manifestations: (1) characteristic grotesque skeletal deformities, (2) mental retardation, (3) hepatosplenomegaly, (4) corneal clouding, (5) deafness, and (6) cardiac abnormalities.
The Hurler-Hunter syndromes are not clinically apparent at birth but may be diagnosed by means of histochemical analysis of kidney biopsies and through paper chromatography of the urine. The facies becomes characteristic around one year of age. Because of premature closure of the sagittal suture, the skull is scaphocephalic. Hypertelorism, flat nasal bridge, heavy lids, snub nose with large nostrils, open mouth with protruding prominent tongue, and short neck are the characteristic facial features.
Figure 49. Hurler's syndrome. (From Gorlin. R. J., and Goldman. H. M. Thoma's Oral Pathology. St. Louis: The C. V. Mosby Company, 1970.)
The lips are thick, and the upper lip is especially prominent. Hypoplasia of the condyloid process of the mandible is an almost constant feature. Cystic alterations around the molar teeth are also frequently noted.
Hirsutism, especially of brows and lashes, as well as hypertrichosis of the arms and hands, has been noted in most patients.
Bilateral diffuse corneal opacity is present in at least 80 to 90 per cent of patients with Hurler's syndrome but is less frequent in those with Hunter's syndrome. The opacity is due to deposition of mucopolysaccharide in the medial and deep layers of the cornea.
Deafness is often pronounced in Hunter's syndrome but is less severe in Hurler's syndrome. Chronic rhinitis and upper respiratory infections are frequently present in both disorders.
Flexion contractures of the fingers produce a "claw hand." Contractures also occur in the hips and knees. In sitting, a low thoracic gibbus of the spine can often be detected. Other anomalies can be summarized as follows: prominent supraorbital ridges, shoe-shaped sella, and short, wide metacarpals with pointed bases.
Figure 50. Hunter's syndrome.
Generally, these patients do not survive more than 10 years; death results from "heart failure" due to accumulation of mucopolysaccharide in the heart valves. In Hunter's syndrome, survival is higher.
HYAUNOSIS CUTIS ET MUCOSAE
This syndrome,93·94 consisting of (1) yellowish nodular infiltration of skin and mucous membranes and (2) hoarseness, was first described in 1908 by Siebenmann.
The syndrome is transmitted as an autosomal-recessive trait.
Discrete or confluent yellowishivory or waxy nodules, from pinhead to matchhead size, usually occur on the face, neck, axillae, and hands early in life. On the margin of the eyelids, beadlike excrescences appear, followed by loss of cilia.
The mouth is the most extensively affected area. Nearly all oral tissues become infiltrated with yellowishwhite, elevated, pea-size plaques, which appear most frequently before puberty and gradually increase in severity. The lower lip, usually more severely affected, assumes a cobblestone appearance. Radiating fissures may appear at the angles of the mouth (Figure 51). With infiltration of the buccal mucosa, the papilla of the parotid duct may become stenosed, with ensuing retrograde parotitis. Extension of the infiltration to the pharynx may result in dysphagia. The tongue becomes firm or woody, thick, large, and bound to the oral floor, with marked infiltration of the frenum and sublingual and fimbriated plicae. The dorsum loses its papillae.
The dentition may be severely affected. Teeth may fail to develop or may be hypoplastic, especially the upper lateral incisors, cuspids, and upper or lower second bicuspid teeth; or the enamel may be severely hypoplastic.
Intracranial calcification has been found in a considerable number of patients. It is located above the pituitary fossa in the hippocampus, falx cerebri, or temporal lobes.
The voice may be hoarse from birth or may become so at puberty. The inability to cry at birth in most patients testifies to early laryngeal impairment. Laryngoscopic examination reveals yeÜowish-white plaques in the epiglottis, aryepiglottic folds, and interarytenoid region. The cords are thickened and nodular, and closure is insufficient. Dyspnea may be severe, and laryngectomy may be necessary.
Figure 51. Hyalinosis cutis et mucosae. (From Jensen. A. Acta Derm. 42 . 164.)
Brownish-yellow wartlike hyperkeratotic lesions appear on the knees, elbows, and proximal interarticular surfaces of the fingers.
HYPODONTIA and MESODERMAL DYSGENESIS OF THE IRIS AND CORNEA
This syndrome95*96 is composed of (1) hypodontia (partial anodontia) and (2) hypoplasia of the indiai stroma. The disorder is inherited as an autosomal-dominant trait with 95 per cent penetrance and variable expression, especially for the dental abnormalities.
The most frequent ocular findings are (1) hypoplasia and flattening of the anterior surface of the iris and (2) anterior synechiae running from the iris to the cornea across the anterior chamber, producing abnormalities of the iridocorneal angle. Dyscoria or slitlike pupils result from traction of these synechiae. Other ocular findings include aniridia, optic atrophy, microcornea, and corneal opacity.
Pupillary anomalies are present in over 70 per cent of patients, the most frequent finding being ectopic pupil. Secondary juvenile glaucoma is a frequent complication that can cause loss of function and lead to total blindness. Hypertelorism is present in 25 per cent of cases. The nose is generally broad.
Oral manifestations include a relatively underdeveloped premaxilla and marked hypodontia. The maxillary hypoplasia is responsible for an apparent mandibular prognathism and receding upper lip, which give a sunken-mouth appearance. A severe reduction in the number of teeth has been noted in several reported cases. In less seriously affected patients, the teeth most commonly missing are the maxillary incisors. Enamel hypoplasia, conical crown form, microdontia, and malposition have also been associated with this syndrome.
Abnormalities of the extremities, including fingers and toes, have been observed in several cases and include genu valgum, congenital luxation of the hip, chnodactyly, and brachydactyly. In the feet there may be broad intermetatarsal spaces and hypoplasia of metatarsals.
HYPOHIDROTIC ECTODERMAL DYSPLASIA
The major components of this syndrome97'98 are (1) hypodontia, (2) hypotrichosis, and (3) hypohidrosis. Structures of ectodermal origin are principally affected.
The syndrome is usually transmitted as an X-linked recessive trait. However, at least 30 females have manifested the complete syndrome. The increased parental consanguinity in these cases suggests autosomalrecessive inheritance and illustrates the genetic heterogeneity of this syndrome. Dominant hidrotic forms of ectodermal dysplasia are different from the disorder considered here.
The facies is quite characteristic, and patients often look enough alike to be considered sibs. The skull resembles an inverted triangle. Marked frontal bossing, depressed nasal bridge (simulating the saddle nose of congenital syphilis), protuberant lips, and obliquely inserted ears are the most prominent facial features (Figure 52). Linear wrinkles are seen about the eyes and mouth.
At birth, the body is devoid of lanugo hair; after puberty, the beard is generally normal, but axillary and pubic hair is scant. The scalp hair is generally blond, fine, stiff, and short. The eyelashes and especially the eyebrows are often entirely missing.
The most striking oral finding is hypodontia or, in some cases, anodontia. The few teeth that may be present are often retarded in eruption and have a conical crown form.
The syndrome may not be manifested until the second year of life and, because the physical features are not so apparent, the child may present a "fever of unknown origin." The inability to sweat, due to marked aplasia of the eccrine sweat glands, results in intolerance to heat, with severe hyperpyrexia. The skin is soft and thin and, owing to the absence of sebaceous glands, presents severe dryness. Eczema is not uncommon. Small hyperkeratotic plaques are frequently noted on the palms and soles. The finger- and toenails are usually normal or slightly spoonshaped.
Mental retardation is occasionally associated with the syndrome.
Figure 52. Hypohidrotic ectodermal dysplasia. (From Gorlin, R. J., Old, T., and Anderson. V. E. Z. Kinderheilk. 108 , 1.)
INFANTILE CORTICAL HYPEROSTOSIS
This syndrome99,100 consists of (1) bilateral swelling over the mandible or other bones, (2) new bone formation in these areas, (3) hyperirritability, and (4) mild fever. The disorder is manifest before six months of age and is inherited as an autosomaldominant trait. A congenital anomaly of the arteries supplying the affected areas, with consequent hypoxia, has been suggested as a possible causative factor.
The onset is generally observed between the second and the sixth months of life. Some cases have been reported to occur in utero.
The swelling usually takes place over the ramus, angle, and body of the mandible bilaterally, giving the face a striking appearance with pallor over the affected area (Figure 53).
The covering soft tissues are tender and edematous and often undergo mixed stages of remission and exacerbation. Pain can be so severe as to cause pseudoparalysis of the face.
Figure 53. Infantile cortical hyperostosis.
The periosteal new bone formation slowly undergoes resorption, with complete resolution at about one year of age. Radiologic evidence of the disorder may persist for many years.
Irritability, pain, and mûd fever may precede the bone enlargment in at least 70 per cent of affected infants. Fifty per cent of the patients have anemia and leukocytosis; the sedimentation rate is increased in those cases with marked bone formation.
Only 25 per cent of affected infants fail to exhibit involvement of the mandible.
The fifth and sixth ribs bilaterally are the next most frequently affected bones. Other bones - such as clavicle, tibia, ulna, femur, humerus, and fibula - may be affected as well, often only in the shaft.
LENZ MICROPHTHALMIA SYNDROME
Lenz described a syndrome101,102 consisting of (1) microphthalmia, (2) skeletal anomalies of the hands and clavicles, (3) renal anomalies, (4) genital anomalies, and (5) defects of the dentition. X-linked recessive transmission seems likely. No affected male has reproduced, however, and therefore autosomal-dominant inheritance with predominant male sex limitation cannot be excluded. Minor malformations have been noted in female heterozygous carriers in some instances. Female carriers have also been noted to have an increased abortion rate.
Figure 54. Lenz microphthalmia syndrome. (From Herrmann, J. . and Opitz, J. Birth Def. Orig. Art. Ser. 5: 2 , 138.)
Unilateral or bilateral eye defects, ranging from microphthalmia to clinical anophthalmia, are observed. Mongoloid slanting of the palpebral fissures may be present. Microcornea, strabismus, nystagmus, epicanthal folds, and other eye defects have been noted. The ears have been observed to be asymmetric, dysplastic, hypoplastic, and protuberant in some cases. Micrognathia has also been noted (Figure 54).
Camptodactyly of the fifth fingers, clinodactyly of the second fingers, duplication of the thumbs, cutaneous syndactyly of the third and fourth toes, wide gap between the first and second toes, pseudoclubbing of the toes, flat feet, calcaneovalgus deformity, and varus deformity have been observed.
Short stature, microcephaly, cylindrical thorax with sloping shoulders and clavicular defects, low scapulas, notching of vertebral bodies, mild cubitus valgus, limited extension in both hip joints, and mild genua valga with internally rotated knees and prominent fibulas have been reported.
Unilateral renal agenesis, bilateral renal agenesis, renal dysgenesis, hydroureter, cryptorchidism, and hypospadias have been described.
Congenital heart defects, atresia of the ileum, umbilical hernia, unusual dermatoglyphics, and defective speech have also been noted.
Highly arched palate, crooked anterior teeth, and agenesis of the permanent maxillary lateral incisors have been reported. Mental retardation has been described in several cases.
(Multiple Lentigines Syndrome)
The name employed by Gorlin et al. for this syndrome 103·104 serves as a mnemonic aid to its components: (1) multiple /entigines, (2) electrocardiographic conduction abnormalities, (3) ocular hypertelorism, (4) pulmonic stenosis, (5) atrial septal defect, (6) retardation of growth, and (7) sensorineural deafness.
The syndrome is inherited as an autosomal-dominant trait with high penetrance and variable expression. Male-to-male transmission has been observed, ruling out X-linked inheritance.
The face is usually triangular, with biparietal bossing, hypertelorism, ptosis of eyelids, epicanthal folds, and low-set ears. Patients frequently exhibit mild pterygium colli and mandibular prognathism (Figure 55).
The most striking feature is the presence of numerous lentigines (up to 5 mm. in diameter), which are dark brown and generally concentrated over the neck and upper trunk. The facial skin, scalp, palms, soles, and genitalia can also be the site of a few lentigines. They either are congenital or appear shortly after birth and increase with age. Occasionally, a few quite dark "café noir" spots can be found. In some cases, lentigines may be absent.
Lentigines differ from common ephelides in appearing earlier and having no relationship to sun exposure.
Cardiac abnormalities are a common feature, consisting of both anatomic malformations and electrocardiographic conduction defects. The former usually consist of obstructive cardiomyopathy and mild or atypical valvular pulmonary stenosis. Subaortic stenosis and other abnormalities may also occur. Cardiac conduction defects are especially common. There can be widening of the QRS complex and bundle-branch block, abnormal P waves and prolongation of the P-R interval, and ST and T wave changes. The S1, S2, S3 abnormality is frequently seen.
Skeletal alterations - retarded growth (below the 25th percentile), pectus carinatum or excavatum, dorsal kyphosis, and winging of the scapulae - are mild.
Profound childhood deafness of the sensorineural type has been present in 15 per cent of reported cases.
Gonadal hypoplasia, hypospadias, undescended testicles, hypoplastic ovaries, and late puberty have been associated with this syndrome.
Figure 55. Leopard syndrome· (Courtesy of D. C. Macmillan and H. R. Vickers.)
This disorder105,106 was first described in 1948 by Donahue, who called it dysendocrinism. Later, owing to the conceptual similarity of affected patients to dwarf cobblers from Irish folklore, Donahue and Uchilda coined the name leprechaunism.
The syndrome is probably inherited as an autosomal-recessive trait. Several instances of consanguinity among parents of affected patients have been recorded.
Leprechaunism is characterized by an elfin facies with flat nasal bridge, wide nostrils, hypertelorism with prominent eyes, micrognathia, pointed chin, hirsutism (especially on the forehead), thick lips, and large, low-set ears (Figure 56).
Patients have a mild microcephaly with apparent motor and mental retardation. The anterior fontanel remains open.
Affected individuals are disproportionally dwarfed with growth deficiency, retarded osseous maturation, and marked lack of subcutaneous fat. Large hands and feet, with bilateral webbing of third and fourth fingers and camptodactyly, are frequent findings.
Figure 56. Leprechaunism.
Failure to thrive, leading to extreme marasmus and early death, is also characteristic.
Other constant findings are enlarged clitoris or penis, precocious breast development in female infants, Leydig cell hyperplasia in the male, follicular development with cystic degeneration of the ovaries, increased pituitary gonadotropin, and hyperplasia of the islets of Langerhans with altered carbohydrate metabolism. Other abnormalities also have been noted in the liver, thymus, kidneys, and heart.
Associated anomalies have included hypoplastic nails, small oral cavity, pectus excavatum, talipes equinovarus, pyloric stenosis, and bilateral inguinal hernias.
LIPOATROPHIC DIABETES WITH ACANTHOSIS NIGRICANS
This syndrome, 107,108 first described by Lawrence in 1946 and extended in scope by Berardinelli in 1954 and Seip in 1959, consists of generalized absence of adipose tissue, elevated metabolic rate without hyperthyroidism, hyperlipemia followed by hepatomegaly with fatty metamorphosis, and sometimes cirrhosis. Around puberty, insulinresistant diabetes mellitus without ketosis is frequently noted.
The disorder is inherited as an autosomal-recessive trait. At least 50 cases have been reported. The disorder has been described with greater frequency in Portuguese, Norwegians, and Negroes.
A distinctive facies results from the lack of facial fat. The features are coarsened and, together with the large hands and feet, produce a somewhat acromegaloid appearance (Figure 57). Affected females appear rather masculine. Mental deficiency and, in rare instances, epilepsy may be features of the disorder. There appears to be an enlargement of the ventricles of the brain, particularly the third ventricle.
Figure 57. Lipoatrophic diabetes with acanthosis nigricans. (Courtesy of W. B. Reed, Burbank. Calif.)
The cutaneous features consist of hirsutism and acanthosis nigricans; both are often present at birth and increase in severity until adolescence. The acanthosis nigricans especially affects the flexural areas, the neck, and the hands and feet.
There is an increased growth rate, and patients reach 90 per cent of adult height during their first 10 years; but the epiphyses close early, resulting in normal or reduced height. Often the penis or clitoris is enlarged at birth but assumes normal size by puberty.
Most striking is the complete absence of subcutaneous fat, impressing the observer with the patient's muscularity and phlebomegaly.
The syndrome originally reported in 1963 by Beckwith109110 consists of (1) macroglossia, (2) omphalocele or umbilical hernia, (3) postnatal gigantism, (4) visceromegaly, and (5) linear indentations of the ear lobe.
Macroglossia is the most constant feature of the disorder, being present in over 90 per cent of reported cases. Linear grooving of the ear lobe is present in about one-third of reported cases, although many reports may have overlooked this anomaly. Glabellar nevus flammeus is frequently associated with the syndrome (Figure 58). Such lesions tend to become less prominent during the first year of life. Microcephaly has also been reported.
Figure 58. Macroglossia-omphalocele syndrome. (From Wiedemann, H. R. Z. Kinderheilk. 106 , 171.)
Hypoplasia of the middle third of the face - together with class 3 malocclusion, anterior open bite, and retroclined mandibular incisors - is a frequent oral feature.
Either omphalocele or umbilical hernia has been reported in about 90 per cent of cases. Some patients have diastasis recti. Gigantism at birth is present in less than half of the cases. Growth may even be subnormal for a few months, but in most cases somatic gigantism eventually results, with height and weight often above the 90th percentile. Advanced bone age is invariably present; occasionally, there may be widening of the metaphyses and cortical thickening of long bones. Hemihypertrophy has also been noted. Visceromegaly has been described in about half of the patients, with hepatomegaly and nephromegaly being the most frequent and cardiomegaly and pancreatomegaly occurring less often.
Polycythemia seems to be a constant feature of the syndrome. Posterior eventration of the diaphragm is often present.
Symptomatic hypoglycemia may be a feature in one- third to one- half of patients. Hyperlipemia, hypercholesteremia, hypocalcemia, adrenal cortical carcinoma, nephroblastoma, and gonadoblastoma have also been noted.
Intelligence has been normal in most cases, although mild to moderate retardation was a regular feature in Beckwith's series.
(Treacher Collins Syndrome, Franceschetti-Zwahlen-Klein Syndrome)
Treacher Collins (a name often erroneously hyphenated) described the essential components of the syndrome. In During the 1940s, Franceschetti and co-workers published extensive reviews of this syndrome and gave it the name mandibulofacial dysostosis.
It is inherited as autosomaldominant with incomplete penetrance and variable expression. About 300 cases have been described.
The facial appearance is quite characteristic (Figure 59). The sloping palpebral fissures, sunken cheek bones, deformed pinnae, receding chin, and large fishlike mouth present a clinical picture that, once seen, is unforgettable.
The supraorbital ridges are poorly developed, and there are increased digital markings. The body of the malar bones may be totally absent; more often they are grossly and symmetrically underdeveloped, with nonfusion of the zygomatic arches.
The palpebral fissures slope laterally downward (antimongoloid obliquity), and often (in about 75 per cent) there is a coloboma in the outer third of the lower lid. About one-half have a deficiency of cilia medial to the coloboma.
The pinna is often deformed, crumpled forward, or misplaced. Over one-third have absence of the external auditory canal or ossicle defect, accompanied by deafness. Extra ear tags and blind fistulas may occur anywhere between the tragus and the angle of the mouth.
The nasal-frontal angle is usually obliterated and the bridge of the nose raised. Because of the lack of malar development, the nose appears large. The nares are often narrow and the alar cartilages hypoplastic.
The mandible is almost always hypoplastic. The palate is noted to be high or cleft in over 40 per cent of the cases.
Roentgenographic studies have shown sclerosis of the middle and inner ear, with poor delineation of their structure. The mastoids are not pneumatized and are frequently sclerotic. The paranasal sinuses are often small and may be completely absent. The lower margin of the orbit is defective. The angle of the mandible is more obtuse than normal, and the ramus may be deficient. The undersurface of the body of the mandible is often pronouncedly concave. The coronoid and condyloid processes are flat or even aplastic.
Figure 59. Mandibulofacial dysostosis. (From Rogers. B. O. Plast. Reconstr. Surg. 17 , 109.)
The syndrome described in 1896 by Marfan112 consists of (1) arachnodactyly, disproportionate skeletal growth, and other skeletal anomalies; (2) ectopia lentis; and (3) fusiform and dissecting aneurysms of the aorta and aortic insufficiency.
The syndrome is inherited as an autosomal-dominant trait. The frequency appears to be at least 3 per 200,000 population.
The head is usually dolichocephalic, with prominent supraorbital ridges and a long, thin face (Figure 60). Bilateral ectopia lentis due to weakened or broken suspensory ligaments is present in at least 50 per cent of the patients, the lenses often dislocating upward. In addition, the lens may be abnormally small and spherical; occasionally it may be completely dislocated into the anterior or, rarely, posterior chamber. Myopia is commonly observed. The sclerae may be blue.
The extremities are disproportionately long, and the lower segment (pubis to sole) is greater than the upper segment (vertex to pubis). Normally the upper-to-lowersegment ratio is 0.93 in the white adult. The US-LS ratio in Marian's syndrome is about 0.85 for the white adult. The hand-height and footheight ratios are usually in excess of 11 per cent and 15 per cent, respectively. The metacarpal index (average ratio of length to width of metacarpals 2 to 5) ranges from 8.5 to 10.5, in contrast to the normal values of 5.5 to 8.0. The length of the middle finger is usually more than one and a half times the length of its metacarpal.
Pectus excavatum and carinatum, late-developing kyphoscoliosis, weakness of joint capsules manifested by flat foot, and hyperextensibility of joints with habitual dislocations are commonly observed.
Diffuse dilatation of the ascending aorta, dissecting aneurysm, or both may occur and are preceded by aortic regurgitation in at least 65 per cent of patients. The pulmonary artery may be similarly affected.
There is deficiency of subcutaneous fat, and hernia is frequent. Striae distensae of the pectoral and anterior deltoid areas are common.
Figure 60. Marian's syndrome.
Maxillonasal dysplasia113,114 is characterized by a very distinctive facies that Binder has called arhinencephaloid (Figure 61). The nose is flattened, with a depressed subnasal or alar base area and a short, compact nasal bridge with elimination of the nasofrontal angle. The upper lip has a convex contour, and the nostrils are half-moon shaped. There is hypoplasia of the premaxillary area of the upper jaw, with flattening of the maxillary base, sagittal shortening of the dental arch, and normal jaw width. All patients have had a relative mandibular prognathism, with reverse overbite. The nasal mucosa has been described as atrophic, but sense of smell is normal.
Roentgenographic examination demonstrates aplasia or hypoplasia of the anterior nasal spine and, frequently, unilateral or bilateral hypoplasia of the frontal sinuses. There are no other associated anomalies, and intelligence is not affected.
Binder suggested that this disorder represents the most minimal expression of the arhinencephalic or holoprosencephalic states, the most extreme example of which is cyclopia. This theory, however, needs support.
Figure 61. Maxillonasal dysplasia. (From Binder, K. H. Deutsch, zahnârtl. Z.17, 438.)
In 1966, Melnick and Needles described a syndrome115,116 characterized by generalized bone dysplasia and abnormal facies.
The syndrome is clearly inherited as an autosomal-dominant trait. While diagnosis is based on roentgenographic findings, within a single family the unusual facies would suggest the bony alterations.
The facies is characterized by micrognathia, full cheeks, prominent eyes, and large ears (Figure 62). The neck is long, the shoulders are narrow, and the upper portion of the arms is short.
Roentgenography demonstrates delayed closure of the anterior fontanel and sclerosis of the skull base and mastoid processes. The paranasal sinuses tend to remain underdeveloped. Vertebral bodies - especially those of the axis, atlas, and occipital condyles - are unusually tall. The thoracic vertebrae exhibit an anterior concavity with double beaking. The clavicles have cortical irregularity with flaring. Sternal ossification is delayed.
Figure 62. Melnick-Needles syndrome. (Courtesy of F. H. Stelling and P. Meunier.)
Changes in the long bones are striking. There is bowing of the radius and tibia, producing an S-shaped appearance. The metaphyses at the proximal and distal ends of the humerus, fibula, and tibia are flared. Coxa valga is marked. The iliac bones are flared at the crest and flattened in the acetabular area, while the ischial bones are tapered. The ribs are ribbonlike, and there is cortical irregularity.
This syndrome117,118 was described in the early 1880s. The complex consists of (1) congenital, usually bilateral, facial paralysis; (2) unilateral or bilateral loss of the abductors of the eye; (3) anomalies of the extremities; (4) aplasia of brachial and thoracic muscles; and (5) involvement of other cranial nerves, especially hypoglossal.
The cause is unknown. Moebius indicated that it was nuclear agenesis, but other investigators suggested that nuclear atrophy was secondary to failure of muscle formation. Autopsy has revealed hypoplasia of the affected cranial nerves (6 and 7) and the muscles they supply, as well as diminution in number of nuclear cells.
Nearly all cases are sporadic. The sexes appear to be equally affected.
Figure 63. Moebius' syndrome.
From birth there is a masklike facies that becomes most apparent during crying or laughing. Facial paralysis is usually bilateral and frequently asymmetric (Figure 63). Not uncommonly, it spares the lower face. Failure to close the eyes during sleep and open mouth produce a characteristic appearance.
There is inability to abduct the eyes beyond the midline, but convergence is present to a variable degree. Nystagmus is rarely seen. Ptosis of lids occurs in possibly 10 per cent of cases. Vision and pupillary reflexes are unaffected. Epicanthus is frequent.
The lips are often paralyzed, though less frequently than the upper part of the face. The angles of the mouth droop and allow saliva to escape. Atrophy, fasciculations, and paralysis of the tongue due to hypoglossal nuclear involvement have been noted in at least one-third of the patients. Defective speech is often present because of paralysis of both lips and tongue and, occasionally, the larynx.
Ear anomalies, such as defective pinna and/or deafness, have been noted.
The most common skeletal anomaly is clubfoot, either unilateral or bilateral, which occurs in at least 30 per cent of patients. Syndactyly, agenesis of digits, Polydactyly, brachydactyly, valgus deformities of the phalanges, congenital dislocation of the hip, and bony and fibrous ankylosis of the interphalangeal joints have been associated with the syndrome. The muscle groups most often missing are the pectoralis, trapezius, quadriceps, serratus magnus, and semimembranosus. The accessory nerve is rarely affected.
Mental retardation occurs in about 10 per cent but is not severe.
Morquio's syndrome119120 is a hereditary biochemical disorder characterized by (1) the presence of a mucopolysaccharide, keratan sulfate, in patients' urine; (2) epiphyseal dysplasia; (3) universal platyspondyly, with resultant dwarfism; and (4) corneal clouding and dental abnormalities.
The syndrome was independently reported in 1929 by Morquio of Uruguay and Brailsford of England. It is transmitted as an autosomalrecessive trait.
Affected children generally appear normal at birth, but the syndrome becomes apparent by the time they are two or three years old.
Although there is no specific facies, many patients show a mild ocular hypertelorism and a slightly depressed nasal bridge (Figure 64). Intelligence is normal. Owing to shortening of the neck, the head seems to rest directly on the shoulders. The trunk is also short, producing a reduced height. Mild scaphocephaly, due to premature closure of the sutures, also can be present.
Figure 64. Morquio-Brailsford syndrome. (Courtesy of S. M. Garn.)
Deciduous and permanent teeth have gray crowns with pitted enamel. The enamel is very thin, with a tendency to flake off, and the dental cusps are poorly formed.
The cervical spine presents marked curvature, producing restricted movement of the neck. Kyphosis or kyphoscoliosis, universal platyspondyly, genua valga, pes planus, and pectus carinatum are characteristic. Often there is a gibbuslike deformity of the lumbar spine.
MUCOCUTANEOUS MELANOTIC PIGMENTATION AND GASTROINTESTINAL POLYPOSIS
(Peutz -Jeghers Syndrome)
Sir John Hutchinson, in 18%, was probably the first to describe the syndrome of mucocutaneous melanotic deposits and gastrointestinal polyposis,121,122 although he was unaware of the presence of polyposis. Peutz noted the relationship of the two entities in 1921, and Jeghers and his colleagues drew widespread attention to the syndrome in 1949.
Figure 65. Mucocutaneous melanotic pigmentation and gastrointestinal polyposis. (Courtesy of D. Dahlin, Rochester, Minn.)
The disorder is inherited as an autosomal-dominant trait with a high degree of penetrance.
Fifty per cent of patients exhibit discrete brown to bluish-black macules of the skin, chiefly around the oral, nasal, and orbital orifices. The number of pigmented spots varies (Figure 65).
Pigmented macules invade the lips, especially the lower, and the oral mucosa in about 98 per cent of the patients; the gingiva and palate and, rarely, the tongue and oral floor are less frequently affected. The melanotic spots are larger than those on the skin. The cutaneous pigmented macules tend to fade after puberty, but the intraoral pigmentation is more persistent. Pigmented spots have also been reported in the conjunctiva and nasal mucosa.
The most important component of the syndrome is the polyposis of the gastrointestinal tract. The hamartomatous polyps involve the following sites, in descending order of frequency: jejunum, ileum, large bowel, rectum, stomach, duodenum, and appendix.
Polyps may produce intussusception and occasionally lead to severe intestinal obstruction and death. The age of onset cannot be precisely determined, but generally there is a history of gastrointestinal problems before the third decade of life. There is sparse evidence that the polyps are premalignant. Some patients have had polyps of the bladder, nose, cervix, and bronchi, but this is unusual.
MULTIPLE MUCOSAL NEUROMAS, PHEOCHROMOCYTOMA, MEDULLARY THYROID CARCINOMA, AND MUSCLE WASTING
This syndrome,123,124 inherited as an autosomal-dominant trait, was initially described as an association of (1) multiple mucosal neuromas, (2) pheochromocytoma, (3) medullary carcinoma of the thyroid, and (4) muscle wasting of the extremities. Some aspects of the syndrome can be explained by hyperplasia and/or neoplasia of neural crest derivatives.
A distinct facies has been noted and is characterized by large nodular lips and thickening and often eversion of upper eyelids (Figure 66). Oral and labial involvement is the first component of the syndrome to appear, almost invariably before the eighth year of life.
The mucosal neuromas principally affect the lips. Both lips are extensively and nodularly enlarged and have been described as blubbery in appearance. The eyelid margins are thickened and often everted, contributing to the unusual facies. Pedunculated nodules, up to 6 mm. in diameter, are present on the palpebral conjunctiva in nearly all patients.
Other manifestations include lingual neuromas that are limited largely to the anterior dorsal surface of the tongue and appear as pink pedunculated nodules. Buccal, gingival, palatal, pharyngeal, nasal, and other mucosas can be the site- of these lesions. In several cases the neuromas either were congenital or were noticed in early infancy.
Seen microscopically, the mucosal nodules are plexiform neuromas - i.e., unencapsulated masses of convoluted myelinated and unmyelinated nerves.
Numerous white medullated nerve fibers traverse the cornea to anastomose in the pupillary area. They can be seen with ease under slit-lamp examination.
The pheochromocytoma may produce weakness, choking and flushing, pounding headache, hypertension, palpitation, profuse sweating, and intractable diarrhea. The attacks may last from minutes to hours and may terminate in shock or death. The tumors are often (in about 60 per cent) bilateral. They may be evident as early as puberty, but in most cases they appear anytime before the fourth decade.
Medullary carcinoma of the thyroid, a tumor derived from the neural crest via the ultimobranchial body, produces both amyloid and calcitonin. It may appear as early as the 18th year, but in most cases it appears sometime before the 35th year. In several patients it has metastasized, causing death. Several patients have had megacolon, and others have had neurofihromatous lesions of Auerbach's and Meissners plexuses.
Most patients have exhibited an asthenic or somewhat marfanoid build, with severe muscular wasting, especially of the extremities, simulating a myopathic state.
Figure 66. Multiple mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma, and muscle wasting.
(von Recklinghausen's Neurofibromatosis)
This syndrome,125,126 inherited as an autosomal-dominant trait, is composed of multiple skin tumors and cutaneous pigmentation.
The skin tumors consist of neurinomas, soft fibromas, or, most often, neurofibromas. They may be present at birth, or they may appear early in life and increase in number and size at puberty. The size varies' from that of a pea to a huge pendulous growth. They are spread all over the cutaneous surface; neurinomas occur most often on the extremities, fibromas on the trunk. The facial appearance is quite striking when the tumors develop on the skin of the face, especially on the eyelids.
Figure 67. Multiple neurofibromatosis
Phakomas, congenital glaucoma, buphthalmos, corneal opacity, detached retina, and neurofibromatosis of the lids are the most frequent ophthalmologic findings.
Café-au-lait pigmentation of the skin usually appears within the first decade and is present in 90 per cent of patients (Figure 67). Its color varies from yellowish to chocolate-brown, and it generally precedes the tumors. It occurs most often about the axilla ("the freckled axilla sign") and waist, presenting a smooth contour.
Malignant degeneration of one of the neurofibromas occurs in a few patients. Mental retardation is usually absent, although it has been associated with the syndrome. Epilepsy is a frequent finding. Glial proliferations and even large glial brain tumors and neuromas of nearly all cranial nerves, as well as neurinomas of the spinal nerves and fibroblastomas of the meninges, may occur.
Kyphoscoliosis is present in at least 40 per cent of affected persons. Other congenital bony anomalies include spina bifida, syndactyly, absence of patella, dislocation of radius and ulna, and overgrowth of an extremity or even a digit.
Oral involvement is uncommon. Only 4 to 7 per cent of patients have single or multiple tumors; these may affect any area of the oral cavity but are usually limited to the tongue. The intraoral tumors are similar to those found in the skin.
MULTIPLE NEVOID BASAL CELL CARCINOMAS, ODONTOGENIC KERATOCYSTS, AND SKELETAL ANOMAUES SYNDROME
The major components of this syndrome127,128 are (1) multiple nevoid basal cell carcinomas; (2) cysts of the jaws; (3) vertebral and rib anomalies, chiefly bifid rib; and (4) calcified falx cerebri. The syndrome is inherited as an autosomal-dominant trait.
A characteristic facies appears to be part of the syndrome, though it is not present in every case (Figure 68). Frontal and temporoparietal bossing is often marked, giving the skull a pagetoid appearance. Exotropia may be present. Broad nasal root is extremely common and may be associated with true ocular hypertelorism (increased inter-innercanthal, interpupillary, and interouter-canthal distances) or dystopia canthorum (increased distance between inner canthi only). Mild mandibular prognathism has been present in most patients.
The nevoid basal cell carcinomas, generally appearing in childhood or at puberty, may affect the nose, eyelid, and cheeks. They are fleshcolored to pale brown. Milia are often mixed with the skin carcinomas. Various associated eye anomalies - such as congenital cataract, glaucoma, and coloboma of the choroid and optic nerve - can be present.
Nevoid basal cell carcinomas are also present on the trunk, arms, and neck. As seen microscopically, they cover the wide spectrum of basal cell and adnexal carcinomas: superficial, multicentric, pigmented, adenoid, and solid.
The jaws show numerous cysts, varying in size from microscopic to several centimeters, which are lined by a uniformly thick keratinized or parakeratinized stratified squamous epithelium. They have a marked tendency to recur after surgical removal.
Bifurcation may affect more than one rib and be bilateral. Shortened fourth metacarpal, bridging of sella, calcification of the falx cerebri, spina bifida occulta in the cervicothoracic area, and kyphoscoliosis are also frequent findings.
Medulloblastoma has been reported in several instances; in some families, a sibling of an affected individual had died in early childhood of medulloblastoma.
Figure 68. Multiple nevoid basal cell carcinoma syndrome.
MULTIPLE PTERYGIUM SYNDROME
Buried in the literature, most often under the erroneous diagnosis of arthrogryposis or Bonnevie-Ullrich syndrome, is a disorder129,130 consisting of (1) growth retardation; (2) multiple pterygia of the neck and fingers and the antecubital, popliteal, and intercrural areas; and (3) cleft palate.
Affected sibs and parental consanguinity have been described. The syndrome appears to be inherited as an autosomal-recessive trait.
The palpebral fissures often have mild anrimongoloid obliquity, and frequently there is mild ptosis of the eyelids (Figure 69).
Cleft palate has been found in most patients.
Growth is usually retarded, below the third percentile; the patient's adult height rarely exceeds 135 cm.
Figure 69. Multiple pterygium syndrome.
The popliteal pterygia may markedly inhibit walking and, even if only mild, produce a bizarre stance and gait. Pterygia in the cervical area may resemble those in Turner's syndrome. In rare cases, they may completely surround the neck. There is often mild soft- tissue syndactyly between the fingers and flexion deformity of the digits, the thumbs being flexed and apposed.
Intercrural webs may be present in both males and females. In the former, the penis and scrotum are retropositioned. This may be associated with cryptorchidism and inguinal hernia. The labia majora may be absent.
Talipes equinovarus, either unilateral or bilateral, has been noted, as has rocker-bottom feet due to vertical talus. Scoliosis and other rib and vertebral anomalies may be present.
Figure 70. Noonan's syndrome.
(XX and XY Turner Phenofype Syndrome)
Noonan's syndrome131,132 consists of short stature, congenital cardiac defects, and frequently mild mental retardation. Our knowledge of the phenotypic spectrum is grossly biased by the many case reports that emphasize similarities to Turner's syndrome. Over 50 major and minor anomalies have been observed in Noonan's syndrome. The use of the term "male Turner's syndrome" for this disorder is inaccurate, misleading, and objectionable.
The hereditary aspect of Noonan's syndrome has not been resolved. Buccal smears and karyotypes are normal. In some instances affected sibs with normal parents have been noted. The disorder has also been observed in several generations. X-linked dominant, autosomaldominant, and multifactorial modes of transmission have all been proposed.
Hypertelorism, mild antimongoloid obliquity, ptosis of the eyelids (in about 60 per cent), epicanthal folds, prominence or folding of the upper transverse portion of the helix, and low-set ears have been observed. Occasionally, pterygium colli may be present. Strabismus and saddle nose have also been noted (Figure 70).
Mild mental retardation is commonly observed.
Short stature is a common feature; adult males and females are usually 65 and 60 inches, respectively. Pectus carinatum, pectus excavatum, cubitus valgus, and short, clinodactylous fifth finger are noted in over 50 per cent. Scoliosis, kyphosis, lordosis, spina bifida occulta, KlippelFeil anomaly, and a variety of other skeletal defects have also been observed.
Cardiovascular anomalies are present in 40 to 60 per cent. The right side of the heart is most frequently involved. Valvular pulmonic stenosis, pulmonary artery branch stenosis, supravalvular pulmonary stenosis, atrial septal defect, patent ductus arteriosus, and aortic valve stenosis have been observed. Coarctation of the aorta and Ebstein's anomaly of the tricuspid valve have rarely been noted.
Gonadal differentiation and function may vary from complete absence to normal gonadal function and fertility. Puberty may be somewhat delayed. Cryptorchidism, but usually normal or even large phallus, has been observed.
Dermatoglyphic findings frequently include low total finger ridge count. Distally placed axial triradii and simian creases have been observed in some cases.
Noonan's syndrome should be distinguished from Turner's syndrome. Short stature is present in Turner's syndrome, but stature varies in Noonan's syndrome. Gonadal dysgenesis is usually present in Turner's syndrome, but varies from agonadism to normal gonadal function in Noonan's syndrome. In Turner's syndrome the left side of the heart may be affected (coarctation of the aorta), but in Noonan's syndrome the right side of the heart may be involved (usually valvular pulmonic stenosis). Mental retardation is a common feature of Noonan's syndrome but not of Turner's syndrome. The total finger ridge count tends to be low in Noonan's syndrome and high in Turner's syndrome. Renal anomalies, which are not generally encountered in Noonan's syndrome, are frequent in Turner's syndrome.
OCULOAURICULOVE RTEBRAL DYSPLASIA
"Hemifacial microsomia" is a term used by Gorlin and Pindborg to refer to patients with unilateral (1) microtia, (2) macrostomia, and (3) failure of formation of the mandibular ramus and condyle. They suggested that oculoauriculovertebral dysplasia probably represents a variant of this symptom complex with its associated anomalies, most often hemivertebrae, and epibulbar dermoids of the eye. 133,134 Since many patients with transitional forms have been seen, we do not believe that separation into two distinct syndromes is merited.
The incidence of the syndrome is at least 1 per 5,600 births. About 60 per cent are male. The vast majority of cases have been sporadic. We suspect that the disorder has multifactorial inheritance.
The facies is asymmetric, owing to hypoplasia and/or displacement of the pinna with a variable degree of impairment (Figure 71). The maxillary, temporal, and malar bones on the affected side are reduced in size. The ipsilateral eye may be at a lower level than that on the opposite side. Further flattening may result from aplasia or hypoplasia of the mandibular ramus and condyle. Frequently, there is frontal bossing. About 10 per cent of patients have bilateral involvement, but it is nearly always more severe on one side, with no side predilection.
Malformation of the external ear may vary from complete aplasia to a distorted pinna, which is displaced anteriorly and inferiorly. Conduction deafness due to middle-ear abnormalities and/or absence or deficiency of the external auditory meatus, has been noted in about 30 per cent. Supernumerary ear tags may occur anywhere from the tragus to the angle of the mouth. In the presence of epibulbar dermoids, the ear tags tend to be bilateral.
Often the palpebral fissure is somewhat lowered on the affected side. Epibulbar dermoid and/or lipodermoid is a variable feature. The dermoid is usually located at the limbus or corneal margin in the lower outer quadrant. The lipodermoid is usually found in the upper outer quadrant. Some patients have both a dermoid and a lipodermoid in the same eye. In two-thirds of the cases they are bilateral, the lesions in the remaining third being unilateral.
In the presence of epibulbar dermoids, the incidence of macrostomia may be somewhat higher. It is generally unilateral and on the side of the more severely affected ear. Commonly these patients have agenesis of the ipsilateral parotid gland.
About 60 per cent of patients with epibulbar dermoids also have unilateral coloboma of the superior lid. Choroidal or iridai coloboma and congenital cystic eye may occasionally be associated with the syndrome.
Figure 71. Oculoauricutovertebral dysplasia (From Gorlin, R. J., et al. J. Pediat 63 , 991.)
Hypoplasia or aplasia of muscles - such as the masseter, temporalis, pterygoideus, and those of facial expression on the affected side - has been observed, as has pulmonary agenesis or lung hypoplasia.
Skeletal anomalies include cuneiform vertebrae, cervical complete or partial synostosis or block of two or more vertebrae, hemivertebrae, spina bifida, anomalous ribs, minimal hypoplasia of the mandibular condyle, and unilateral aplasia of the mandibular ramus and/or condyle with absence of the glenoid fossa. Microtia is present in over 70 per cent of patients with agenesis of the ramus. The gonial angle is commonly flattened, and the maxilla is narrow on the affected side. Intraorally, palatal width, from the midline palatal raphe to the lingual surface of the teeth on the affected side, is decreased. The palatal and tongue muscles may be unilaterally hypoplastic and/or paralyzed. About 7 per cent have an associated cleft lip and/or palate.
This syndrome135'136 consists of (1). facies that typically includes a thin nose with hypoplastic alae and narrow nostrils, (2) microcornea with iris anomalies, (3) syndactyly and camptodactyly of the fourth and fifth fingers, and (4) enamel hypoplasia similar to amelogenesis imperfecta.
The syndrome exhibits autosomaldominant inheritance.
The characteristic facies also includes small sunken eyes and true ocular hypertelorism (Figure 72). The nasal alae are hypoplastic, and the nostrils are rather slitlike. Epicanthal folds are frequent. Microcornea is the most constant eye finding. The corneal diameter is generally less than 10 mm. Other eye findings are microphthalmos, secondary glaucoma, congenital cataract, persistence of pupillary membrane, disk coloboma, synechia, strabismus, and optic atrophy. The eyelid aperture is reduced to about 24 to 25 mm. in width. In most cases vision has been essentially normal.
Several patients have proved to be microcephalic. The ears generally have malformed pinnae. Conduction deafness has been noted in some patients.
Figure 72. Oculodentoosseous dysplasia. (From Gorlin. R. J., and Pindborg, J. J. Syndromes of the Head and Neck. New York: McGraw-Hill Book Co., Blakiston Division, 1964.)
The most frequent skeletal anomaly is syndactyly of the fourth and fifth fingers (the third finger may also be involved), with camptodactyly and ulnar clinodactyly. Roentgenograms show the middle phalanx of these fingers to be cube- shaped. There is aplasia or hypoplasia of the middle phalanx of one or more toes, which clinically appear normal. Syndactyly of the third and fourth toes is an occasional finding.
The femurs present a mild broadening of the metaphyseal area similar to that seen in Gaucheas disease and craniometaphyseal dysplasia. The hand and feet bones are generally osteoporotic. Marked thickening of the mandible has been noted in several cases.
The teeth are usually yellow on eruption. Both upper and lower dentition may be affected by a generalized enamel hypoplasia, similar to that seen in amelogenesis imperfecta.
Dry, thin, and sparse hair that fails to grow to normal length has been noted in several patients.
This syndrome137,138 consists of (1) dyscephaly, (2) parrot nose, (3) mandibular hypoplasia, (4) proportionate nanism, (5) hypotrichosis, and (6) bilateral congenital cataracts.
There appears to be no hereditary basis for the syndrome.
The face is small with a characteristic parrot nose, receding chin, and brachycephaly (rarely scaphocephaly or microcephaly). Open fontanels and gaping of the longitudinal and lambdoid sutures are frequent findings.
The nose is thin, pointed, and curved and, combined with the mandibular hypoplasia, gives the patient a parrotlike appearance. Hypotrichosis - especially of the scalp, brows, and cilia - is a constant feature (Figure 73).
Ocular anomalies include microphthalmia, bilateral congenital cataracts that often rupture spontaneously and resorb, and blue sclerae. Most patients manifest nystagmus and/or strabismus.
The most common oral finding is hypoplasia of the mandible, generally accompanied by a "double" cutaneous chin with a central cleft or dimple. Roentgenography of the temporomandibular joint area shows the joint to be displaced approximately 2 cm. forward. The palate is high and narrow, and the mouth is usually small. Dental anomalies - such as malocclusion, malformation of teeth, and natal teeth - commonly occur.
Axillary and pubic hair is scant.
Other associated findings include osteoporosis, syndactyly, cutaneous atrophy, lordosis and/or scoliosis, and spina bifida.
ORAL-FACIAL-DIGITAL (OFD-I) SYNDROME
The syndrome of (1) multiple hyperplastic f renula, (2) cleft tongue, (3) dystopia canthorum, (4) hypoplasia of nasal alar cartilages, (5) median cleft of the upper lip, (6) asymmetric cleft palate, (7) various digital malformations, and (8) mild mental retardation was first defined in 1954 by Papillon-Leage and Psaume.139*140 Similar cases had been reported earlier under various names.
The OFD-I syndrome is inherited as an X-linked dominant trait limited to females and lethal in males.
The facies characteristically shows lateral displacement of the inner canthi, hypoplasia of the alar cartilages, and broad nasal root. The upper lip is short, usually with a pseudocleft in the midline (Figure 74).
Evanescent milia of the face and ears are common, but they disappear before three years of age. Dryness and/or alopecia of the scalp is present in about 65 per cent of patients.
Oral manifestations include a thick hyperplastic upper frenum, which, in part, eradicates the mucobuccal fold in the area. The frenum also extends through the upper lip beyond the vermilion border, producing a small midline "cleft." Lateral clefts of the palate are produced by bilateral grooves arising from the maxillary buccal frenula. The palate is then divided into an anterior segment (behind the canines) and two posterior processes. The soft palate often has a complete asymmetric cleft.
FigurE 73. Oculomandìbulodyscephary with hypotrichosis.
Figure 74. Oral-facial-digital syndrome I.
The lower mucobuccal fold is traversed by thick fibrous bands, especially in the region of the lower lateral incisor, which produce clefting of the alveolar process and, by extension, bi-, tri-, or tetrafurcation of the tongue.
About 50 per cent of the patients present a small whitish hamartomatous mass at the midline of the ventral surface of the tongue. This mass is formed by fibrous connective tissue, salivary gland tissue, a few striated muscle fibers, and, in rare cases, cartilage. One-third of the patients may present ankyloglossia.
Several digital malformations - such as clinodactyly, syndactyly, brachydactyly, and polydactyly, in decreasing order of frequency - are associated with the syndrome. Toe malformations are less common and include unilateral hallucal polysyndactyly, syndactyly, and brachydactyly. Roentgenograms of hands and feet show the short tubular bones to be shorter and thicker than normal, with some degree of osteoporosis.
One-third to one-half of the patients are mildly mentally retarded, with I.Q.s of 70 to 90.
A similar syndrome (OFD-II, Mohr-Rimoin syndrome) is inherited as an autosomal-recessive trait. Patients have bilateral polysyndactyly of the halluces and manual hexadactyly.
OSTEOGENESIS IMPERFECTA, DENTINOGENESIS IMPERFECTA, CLEAR (BLUE) SCLERAE, OTOSCLEROSIS, AND LOOSE LIGAMENTS
This syndrome141,142 consists of (1) fragile bones, (2) clear or blue sclerae, (3) deafness, (4) loose ligaments, and (5) a dentinogenesis imperfecta-like alteration.
The syndrome is inherited as an autosomal-dominant trait. Only about one-third of affected persons, however, have a familial history of the disorder. The remaining twothirds comprise largely sporadic cases and rarely patients with familial pedigrees that possibly suggest autosomal-recessive inheritance. Those with a family history of the syndrome are inclined to have it in a milder form and to manifest it later in life.
Only about one in three patients presents the complete syndrome.
The degree of expression is variable. Of patients having blue sclerae, about 60 per cent have the bone disease and possibly only about 30 per cent have otosclerosis.
In the congenital type of osteogenesis imperfecta, intrauterine fractures may be so numerous that the child may be bom dead or may survive for only a short time. Micromelia is often quite striking.
Clear (blue) sclerae are the most constant feature of the syndrome (Figure 75). The intensity of blueness varies from family to family and from case to case. The blue color is apparently due, in part, to thinning of the sclerae, allowing the choroid color to be transmitted, and also to increased translucency related to a thinner fibrous coat, a deficiency in collagen fibers, or an increase in mucopolysaccharide content.
Deafness, one of the most frequent findings, usually begins in the third decade, increases progressively with time, and is conductive. Fewer than half of the patients with the heritable form of osteogenesis imperfecta are deaf, while only 20 per cent of those without a family history of the disorder are so affected. Rarely is complete deafness observed, but hearing appears to be more severely impaired in patients with serious bone involvement. In some patients the tympanic membrane has been found to be thinned and bluish.
The deciduous teeth are affected in about 80 per cent of patients, the permanent teeth in only about 35 per cent. There does not appear to be any relationship of dentin impairment to the degree of bone involvement.
The crown of the tooth is usually shorter than normal. Upon eruption, the teeth are noted to be translucent or opalescent. The color darkens with age, becoming gray, pink, amber, or bluish. The enamel, although it is clinically normal, usually breaks off.
Figure 75. Osteogenesis imperfecta and dentinogenesis imperfecta (blue sclera). (From Gorlin. R. J.. and Goldman. H. M. Thoma's Oral Pathology. St. Louis: The C. V. Mosby Company. 1970.)
Roentgenography shows the roots to be thin, fine, and disproportionately shortened. The pulp chamber and canal are greatly diminished in size or even totally absent.
The skull is large, especially in the anteroposterior direction. The forehead is broad, and a temporal bulge and an overhanging occiput give the skull a mushroom appearance. Roentgenography also reveals remarkably thin calvaría and the presence of numerous Wormian bones in the occipital area.
The long bones, especially those of the legs, are bowed. Subperiosteal fractures of the shaft and multiple microfractures at the epiphyses are often seen, as are kyphoscoliosis and pectus carinatum and excavatum. Laxity of ligaments, resulting in habitual dislocations of joints, and flatfoot are seen in at least 25 per cent of patients.
In 1962, Taybi reported a case of "generalized skeletal dysplasia with multiple anomalies," suggesting that this possibly represented a new entity. In 1967, Dudding, Gorlin, and Langer presented three new cases, collected data from other unreported cases, and proposed the name otopalatodigital (OPD) syndrome.143·144 The disorder comprises (1) conductive deafness, (2) cleft palate, (3) generalized bone dysplasia, and (4) characteristic facies.
Figure 78. Otopalatodigital syndrome. (From Langer. L. 0.. Jr. Amer. J. Roentgen. 100 , 63.)
The syndrome has X-linked inheritance. Only males have the full-blown syndrome. Female carriers present less severe manifestations in accordance with the Lyon hypothesis. Cleft palate has never been reported in an affected girl, but it is present in all affected males.
The facies of the affected male has a characteristic pugilistic appearance, with prominent supraorbital ridges, frontal bossing, apparent ocular hypertelorism, and antimongoloid obliquity of the palpebral fissures (Figure 76). The nose is flat and has a broad, flat nasal bridge. The mouth is generally small and, when open, has a "fish mouth" appearance. The lateral supraorbital ridges are prominent in the female carrier.
Bilateral conductive hearing loss is noted early in life. Abnormally shaped ossicles have been reported. All patients have been mildly retarded, with slow speech development, but this may be related to the hearing loss and palatal clef ting.
Skeletal findings include a large variety of malformations, such as small mandible with obtuse angle, moderate pectus excavatum, coxa valga, lateral bowing of the femur, and hypoplasia of the proximal radius with posterior dislocation. The hands show clinodactyly; short, broad distal phalanges of all fingers; shortening of the thumb; a second ossification center at proximal of the second metacarpal; and teardropshaped lesser multangulum. The feet also present distinctive findings, such as short phalanges and metacarpal of great toe; long, abnormally shaped second and third metatarsals; and absence of normal modeling in the metaphyseal regions of tubular bones. Feet bear a marked resemblance to those of a tree frog. In general, skeletal growth is retarded, below the 10th percentile.
POPLITEAL PTERYGIUM SYNDROME
The popliteal pterygium syndrome,145,146 inherited as an autosomal-dominant trait, is one of perhaps 40 or more syndromes of facial clefting.
The facies is characterized by cleft lip-palate, congenital lower lip pits, and occasionally filiform adhesions that may join the eyelids (Figure 77).
The most striking feature is a pterygium or skin web, nearly always bilateral, which extends from the heel to the ischial tuberosity. This limits extension and abduction as well as rotation of the leg. Along its free edge is a hard, inelastic fibrous band. Beneath this is the sciatic nerve. Awareness of this is important to the surgeon correcting the defect.
Figure 77. Popliteal pterygium syndrome. (From Dahmen. G. Z. Orthop. 95 , 112.)
Hypoplasia or agenesis of digits, talipes equinovarus, and syndactyly of hands or feet are often associated. A pyramidal skin fold may be present on the hallux. Some toenails may be absent.
Cryptorchidism, absent or cleft scrotum, inguinal hernia, absence of labia majora, infantile uterus, and in* tercrural pterygium are frequently evident.
This syndrome147,148 was first described in 1956 by Prader and coworkers. The major components are (1) mental retardation, (2) muscular hypotonia, (3) obesity, (4) short stature, (5) hypogonadism, (6) diabetes mellitus, and (7) acromicria.
The cause of the disorder is unknown; according to recent reviews, evidence for hereditary transmission is lacking. Chromosomal abnormalities have been described in some cases, but they appear to be incidental. There is a preponderance of affected males (3:1).
Generalized obesity is consistently seen and becomes apparent during the second or third year of life.
Marked obesity is present around the cheeks and under the chin, giving a characteristic facies (Figure 78). Almond-shaped eye sockets with slightly overhanging lids, retroussé nose, and a fishlike mouth with a triangular-shaped upper lip are also constant and typical findings. Oral manifestations include micrognathia, high-arched palate, and malocclusion.
Hypotonia is present at birth, while poor sucking and swallowing reflexes, a weak cry, and, at times, episodes of asphyxia are seen in the first months of life. Psychomotor retardation and oligophrenia are constant findings.
Short stature, retarded bone age, and acromicria are usual. Such other anomalies as clinodactyly, syndactyly, and genua valga are less frequently seen.
The penis is small, the testes are not palpable, and the scrotum is rudimentary. In males, pubertal changes are both delayed and diminished. In females, no genital abnormalities have been observed.
Diabetes mellitus frequently develops during childhood and adolescence, but it differs from the usual childhood type by the absence of weight loss and acidosis, the presence of insulin resistance, and the good response to oral hypoglycemic drugs. The diabetes associated with Prader-Willi syndrome is probably not related to growth hormone.
Figure 78. Prader-Willi syndrome.
PROGERIA (Hutchinson-Gilford Syndrome)
Progeria149,150 is characterized by dwarfism, immaturity, and pseudosenility. Persons afflicted with the syndrome have a peculiar form of hypermetabolism and generally die during their midteens of coronary heart disease.
Figure 79. Progeria. (From Rosenthal, I. M., at al. Ped. 18 , 565.)
Progeria affects both sexes. The evidence that it is inherited as an autosomal-recessive trait is sparse.
Scalp hair, eyebrows, and eyelashes are completely lost by the end of the second year of life. The face is small. The head, although 2 to 4 cm. less than the norm in circumference, appears to be hydrocephalic because of lack of hair. Frontal and parietal bossing is notable. Small ears and thin nose are also typical (Figure 79).
The skin is atrophic and occasionally pigmented. The veins are prominent, especially over the skull and thighs. The nails are thin and atrophic.
The facial skeleton is reduced in size, and the mandible and maxilla are hypoplastic. Extremely thin calvaria and an open anterior frontal are roentgenographically apparent. Frequently there are no frontal sinuses. Mastoid processes are poorly developed. Maxillary and other paranasal sinuses are hypoplastic.
Bones are generally osteoporotic, and the joints of the extremities undergo periarticular fibrosis that limits extension. Coxa valga is a constant finding. There is premature arteriosclerosis, and cerebrovascular accidents can occur as early as seven years of age.
Pyknodysostosis151,152 has been defined as a syndrome consisting of (1) dwarfism; (2) increased bone density; (3) osteolysis of the terminal digits of the hand and feet; (4) cranial anomalies, such as persistence of fontanels and failure of closure of cranial sutures; (5) frontal and occipital bossing; and (6) hypoplasia of the angle of the mandible.
In a recent survey of the literature, we found a total of 75 cases in 53 families. The disorder is inherited as an autosomal-recessive trait. The consanguinity rate among the parents of affected patients was 36 per cent. There is good evidence to suggest that Toulouse-Lautrec had this disease.
The face is characterized by parrotlike nose and receded chin. Agenesis of the angle of the mandible is a pathognomonic alteration. Facial bones are usually underdeveloped with pseudoprognathism (Figure 80).
Figure 80. Pyknodysostosis. (Courtesy of B. Weisskopf, Child Evaluation Center, Louisville, Ky.)
The skull is dolichocephalic with frontal and occipital bossing. Most cranial sutures and fontanels are open, especially the parietooccipital. Wormian bones are commonly observed.
The frontal sinuses are consistently absent, and the other paranasal sinuses are hypoplastic or missing. The mastoid air cells are often not pneumatized.
The adult height is reduced, being 53 to 60 inches in most cases. The terminal digits of the fingers and toes have a characteristic drumstick appearance.
Increased bone density is responsible for multiple fractures in these patients, but this peculiarity tends to disappear after puberty.
There is an increased radiopacity of all bones, but especially of the long bones, spine, and skull base. The terminal digits of the fingers and toes are markedly osteolytic, exhibiting fragmentation of the heads with preservation of the bases, underdevelopment of the unguiculate processes, or narrowing of the ends of otherwise normal terminal phalanges.
Rothmund and Thomson delineated a syndrome153,154 consisting of (1) poikiloderma, appearing from the third to the sixth month of life; (2) bilateral cataracts, which appear from the fourth to the seventh year; and (3) hypogonadism.
The syndrome has autosomalrecessive inheritance, although over 70 per cent of patients have been female.
About the third to sixth month of life, the skin of the cheeks and ears becomes red and swollen. This inflammatory phase soon subsides and leaves areas that appear to be varying combinations of pigmentation, depigmentation, atrophy, and telangiectasia. The eyebrows and lashes have frequently been absent or severely diminished (Figure 81). The cataracts are bilateral and usually appear between the fourth and seventh years, though they may appear earlier. A few authors have noted a large head with frontal bossing, sparse hair, and a broad, depressed nasal bridge. Microcephaly has also been mentioned.
Sensitivity to sunlight in the form of blister production is seen in at least 35 per cent of patients; it is more severe in early life. The extensor surfaces of the hands, forearms, legs, thighs, and buttocks become involved, but usually to a lesser degree: the exposed surfaces are more severely affected.
Pubic and axillary hair is often somewhat sparse; in some patients it is almost absent.
Figure 81. Rothmund-Thomson syndrome. (Courtesy of J. M. Moragas, Barcelona, Spain, through W. B. Reed, Burbank, Calif.)
Warty hyperkeratoses, especially over joints and with late development of squamous cell carcinoma, and palmoplantar keratoses have been found. Nail dystrophy has been noted in at least one-quarter of the cases.
Hypogonadism is present in about one of four patients. Scanty menstruation is common, and few affected women have borne children.
Over half of the patients have been of markedly small stature, with short terminal phalanges. Dwarfism has been proportional. The limbs are often slender or delicate, and acrocyanosis may be severe.
Absence of thumbs and rudimentary ulna and radius, bipartite patella, and bone sclerosis have been noted in some patients. Cystic areas similar to fibrous dysplasia have been described, and anterior subcapsular, perinuclear, and posterior stellate cataracts are present in over 50 per cent of the cases.
RUBINSTEIN-TAYBI OR BROAD THUMBGREAT TOE SYNDROME In 1963, Rubinstein and Taybi described a syndrome155·156 consisting of (1) mental retardation, (2) characteristic facies, and (3) broad terminal phalanges of thumbs and great toes.
The syndrome is relatively rare: fewer than 125 cases have been described. The prevalence in the general population is not known, but frequency in institutions for the mentally retarded is approximately 1 in 500 patients. There is no sex predilection. The syndrome is apparently rare in Negroes. There is no evidence that the syndrome is genetically transmitted. Nor is parental age related.
The facies can be quite distinctive, but not in all persons with the syndrome. The forehead is often prominent, the nasal bridge is broad and beaked, and the septum often extends below the alae (Figure 82). The palate is characteristically highly arched, with prominent palatine shelves ("Byzantine arch palate"). The mandible tends to be somewhat small. The palpebral fissures have an antimongoloid slant, strabismus is common (in about 75 per cent), and nasolacrimal duct obstruction occurs with increased frequency.
Figure 82. Rubinstein-Taybi syndrome.
Head circumference is below the 10th percentile, and I. Q. is less than 50 in 80 per cent of the patients. Electroencephalographic abnormalities have been described in about twothirds of the cases. Deep tendon reflexes are hyperactive in perhaps half of the patients.
Superficial hemangioma of the forehead, nape, or back has been noted in about half of the patients, and hirsutism of the trunk and limbs is common.
Neonatal distress, recurrent respiratory infections, and feeding difficulties have been noted in over 70 per cent of these children. Stature is reduced below the third percentile in 80 per cent. Weight, however, is often far less depressed, and many are relatively obese. The gait is commonly stiff, and the joints are hyperextensible. Constipation is noted in about 40 per cent.
The thumbs are spatulate - i.e., broad and flattened, with shortening of the distal phalanx. In about onethird of the cases, because of an abnormal interphalangeal angle, the thumbs appear curved radially. The other fingers also often appear broad, and the terminal phalanges are somewhat shortened and wide. A simian crease and fifth-finger clinodactyly have been noted in approximately half of the patients. The great toe is broadened and occasionally (in 20 per cent) medially deviated. In rare instances, there is postaxial Polydactyly of toes.
A large foramen magnum has been noted roentgenographically in over 60 per cent. Less frequently, the anterior fontanel is delayed in closure. Parietal foramina have been observed in over one-third of the cases. The terminal phalanx of the thumbs is short and wide. When extreme radial curvature of the thumb is present, the proximal phalanx is triangular, with the epiphysis set along the radial aspect rather than at the tip. The distal phalanx of the hallux is greatly enlarged, and there are occasional (in 15 per cent) segmentation abnormalities of the proximal or distal phalanx. Other skeletal anomalies include flaring of the ilia and flat acetabular angle, sternal and rib anomalies, and scoliosis.
An azygous lobe of the lung or other anomaly of lung lobation has been seen in about half of the cases.
The syndrome of short stature, significant asymmetry, low birth weight at full term, and variations in the pattern of sexual development was independently described by Silver in 1953 and by Russell in 1954. 157,158 Debate exists, however, as to whether the conditions described by these two authors are identical, since not all of Russell's patients manifested congenital asymmetry.
There is no evidence that the syndrome is hereditary. No sex or racial predilection has been found.
Birth weight is usually less than 2,200 gm. at full term. Short stature, usually below the third percentile level, is maintained throughout childhood.
Figure 83. Russell-Silver syndrome.
The facies is characterized by pseudohydrocephalus. This is due to the relative smallness of the face, the normal-size calvaría appearing large. The forehead is prominent and sometimes bossed, the face is triangular, and the chin is small and pointed. The corners of the mouth may be turned down (Figure 83).
Congenital asymmetry has been noted in about 80 per cent of patients. While it may be total, it may involve only the head, trunk, or limbs. In some cases, asymmetry becomes evident only with growth. The child also tends to have poorly developed musculature.
Delayed closure of the anterior fontanel of the skull is common. Bone age is usually retarded in relation to sexual development and chronologic age. For example, at the age of five to 10 years, there is usually a two-year disparity.
The humeri may be somewhat shortened. The fifth fingers are short and exhibit clinodactyly in over 75 per cent.
Roentgenography demonstrates that there is hypoplasia of the middle phalanges of the fifth fingers. Pseudoepiphyses are found more often at the base Of the second metacarpal than in the normal population. Soft-tissue syndactyly between the second and third toes is seen in about one-third of the cases.
Variation in sexual development has been found in over 30 per cent of patients. There may be premature puberty or cryptorchidism. Urinary gonadotropins have been elevated in about 10 per cent. In some cases there has been premature estrogenation of the urethral or vaginal mucosa.
Café-au-lait spots have been noted in about 45 per cent.
In 1964, Smith, Lemli, and Opitz first described patients having multiple skeletal and urogenital anomalies and a characteristic facies.159,160
The syndrome, having autosomalrecessive inheritance, comprises fetal hypoactivity and intrauterine growth retardation. Thus, at birth, affected infants are moderately small and hypotonic. Failure to thrive, observed during the first years of life, progressively changes to spasticity in later years. Microcephaly, associated with mild to severe mental retardation, is a constant finding. The facies (Figure 84) is characterized by bilateral blepharoptosis, short nose with broad bridge and anteverted nostrils, and micrognathia. Occasional findings are low-set ears, strabismus, epicanthal folds, and cataracts.
Figure 84. Smith-Lemli-Opitz syndrome. (Rom Schumacher, H. P. Z. Kinderheilk. 105 , 88.)
Intraorally, a broad maxillary anterior alveolar ridge has been associated with the syndrome.
Patients are generally of short stature, with narrow shoulders and short neck. Irritable behavior - with typical shrill screaming, as if the patient were in constant pain - is also observed. Frequent vomiting with regurgitation may result in secondary pneumonia.
Marked soft-tissue syndactyly of second and third toes is a constant finding. Urogenital anomalies, present only in affected males, comprise hypospadias, cryptorchidism, and cleft scrotum.
Patients present abnormal dermatoglyphics characterized by palmar simian creases, high number of digital whorls, and arch tibial pattern.
Chromosome studies have shown no abnormalities.
Less frequent findings have included stippled epiphyses, cleft palate, Polydactyly, sacral dimples, pyloric stenosis, and abnormal EEG and ECG.
THALASSEMIA MAJOR (Mediterranean Anemia, Cooley's Anemia)
Thalassemia161,162 was first described as an entity in 1925 by Cooley.
Thalassemia major is the homozygous form of thalassemia - where both parents have the recessive form, thalassemia minor.
It is a hypochromic and microcytic anemia due to a deficient synthesis of adult hemoglobin. The anemia is progressive and marked unless treated by transfusions.
Figure 85. Thalassemia major.
In reaction to the severe anemia and hemolysis, there is a great increase in the medullary and extramedullary hematopoietic tissue. The massive increase in the medullary tissue of the malar and cranial bones and an overgrowth of the overlying bones cause the typical mongoloid facies with high cheek bones (Figure 85). There is usually dental malocclusion, with protrusion of the upper teeth.
The skin is pallid and often shows some mild icterus.
Growth is impaired, and puberty is delayed.
The overactivity and overgrowth of the bone marrow produce osteoporosis, with widening of the medullary spaces, thinning of the cortex, trabecular atrophy, and coarse reticulation of the bones.
Collapsed vertebrae and increased disposition to pathologic fractures from minor trauma are common.
Cardiac failure, diabetes mellitus, and cirrhosis are frequently found in these children.
In 1966, Giedion described a syndrome163,164 comprising (1) coneshaped epiphyses; (2) sparse, fine hair; (3) a somewhat pear-shaped nose; and (4) growth retardation.
Giedion has suggested that trichorhinophalangeal syndrome may have genetic heterogeneity. He describes autosomal-dominant and recessive forms and separates those cases in which there are associated cartilaginous exostoses, since these patients tend to be somewhat mentally retarded and have mild microcephaly.
Scalp hair is sparse from the time of birth. Its texture is fine and its growth is slow. The hair is especially sparse in the trontotemporai areas, somewhat simulating male-pattern baldness. The medial part of the eyebrows is broad, but the lateral portion is narrow and thin. The cilia may be scant. The nose is rather broad and pear-shaped. The philtrum appears to be overly long. The appearance is not grotesque, however, and is easily overlooked (Figure 86).
The fingers tend to become progressively deformed from the age of six years. These changes tend to level off at puberty. Characteristically, there is swelling of the middle phalangeal joints and axial deviation of the fingers distal to this point. There is also brachyphalangy. The distal phalanx of the thumb and the hallux are usually short and, not uncommonly, one or more fingers or toes are abbreviated. Nails are thin. Pes planus was noted in several cases.
Scoliosis or lordosis has been described by several authors. The scapulae are often winged. Usually there is retardation in height between the third and 10th percentiles. Bone age is often several years behind chronologic age.
On roentgenography, the middle phalanges of the second, third, and fourth fingers are seen to be the sites of cone-shaped epiphyses. One or more metacarpals, usually the fourth or fifth, are commonly shortened. Multiple cone-shaped epiphyses are also noted in the toes. Cartilaginous exostoses of long bones have been noted in the Langer-Giedion variant.
Figure 86. Trichorhinophalangeal syndrome.
Increased susceptibility to upperrespiratory tract infections has also been observed.
TRISOMY 13 SYNDROME
Possibly first described by Bartholin in 1657, trisomy 13 165,166 occurs about once per 5,000-15,000 live births. As with other trisomies, this disorder can arise either from nondisjunction or from translocation. Increased maternal age is noted in cases of nondisjunction but not with translocation. In the latter, cardiac anomalies are less severe but otherwise do not differ markedly from those in cases of nondisjunction.
Although the average time of survival is about 100 days, one-half succumb within the first month, twothirds before the fourth month, and 19/20 before the fourth year.
Figure 87. Trisomy 13 syndrome.
The average birth weight is about 2,500 gm. A host of anomalies occur, but only the most striking can be discussed here. Jitteriness, apneic spells, and developmental retardation are almost constant features. About 75 per cent of patients have cleft lip and/or cleft palate and microcephaly with or without scalp defect.
Eye defects range from microphthalmia to iris coloboma. The ears are nearly always poorly modeled and deformed, and deafness is nearly a constant feature. A capillary hemangioma commonly graces the forehead (Figure 87).
At least one-half, probably more, are microcephalic and arhinencephalic, although no more than 10 per cent have alobar holoprosencephaly. (A few known examples of cyclopia and cebocephaly patients and a considerably greater number with premaxillary agenesis have had trisomy 13.)
Postaxial Polydactyly (more often of the hands) and hyperconvex nails occur in 75 per cent, and at least one-half have flexion deformity of the fingers with retroflexible thumbs.
Congenital cardiac defects - ventricular septal defect (60 per cent), atrial septal defect (45 per cent), patent ductus arteriosus (50 per cent), and dextroposition of the heart (65 per cent) - are common and are usually responsible for the death of the child.
Genitourinary abnormalities, also common, include undescended testes (100 per cent), biseptate uterus (70 per cent), and polycystic renal cortex (55 per cent).
Infants with trisomy 13 characteristically manifest abnormal elevation of fetal hemoglobin F. The polymorphonuclear leukocytes often have nuclear projections.
The dermatoglyphics are characterized by single palmar creases, distal axial triradius, and fibular S-shaped hallucal arch.
TRISOMY 18 SYNDROME
First described by Edwards in 1960, the 18 trisomy syndrome165,166 is due to the presence of an extra chromosome in the E group. The syndrome is correlated with increased maternal age, the average being about 32 years at time of birth. Few infants survive the first six months of life. The affected male lives only two weeks on the average - as opposed to the female, who survives for a mean of 19 weeks. This, in large part, is no doubt responsible for the fact that 75 per cent of the diagnosed cases are in females. The difference cannot be accounted for by a higher abortion rate of trisomy 18 male fetuses, for this has been shown not to be true. The average birth weight is 2,250 gm.
Numerous anomalies occur, but only the more common ones will be discussed here. Developmental retardation, feeding difficulties, and failure to thrive are constant features.
Elongated skull - with occipital bulge, micrognathia, and low-set malformed ears - is almost always present (Figure 88). A meningomyelocele has been noted in about 10 per cent. Cleft lip or cleft palate is present in about 15 per cent of cases.
Virtually all cases have flexion deformity of the fingers and hypertonia. Shield chest and/or short sternum are present in 85 per cent of the cases, as is limited hip abduction.
Other abnormalities include prominent calcaneus (75 per cent), talipes calcaneovalgus (50 per cent), short dorsiflexed hallux (75 per cent), renal anomaly (60 per cent), Meckel's diverticulum (40 per cent), and eventration or thinning of diaphragm (40 per cent).
All affected males have cryptorchidism. Congenital cardiac defects are present in 85 per cent of cases and are usually responsible for the death of the child. These defects include ventricular or major atrial septal defects and persistent ductus arteriosus. In about 15 per cent, dextroposition of the heart is seen.
The dermatoglyphics are characterized by an increased number of arches on the fingertips.
Figure 88. Trisomy 18 syndrome.
(Bourneville-Pringle Syndrome, Epiloia)
Tuberous sclerosis167,168 is one of the neurocutaneous syndromes. Its most important facets are (1) epilepsy, (2) mental deficiency, and (3) adenoma sebaceum. The components of the triad may appear in any order. Some patients may manifest signs at birth, but in most cases the seizures and skin changes first appear in the two- to six- year-old.
The syndrome is found in about 0.1 to 0.6 per cent of persons institutionalized for epilepsy and mental retardation and in about 1 in 300,000 to 500,000 in the general population. The syndrome is inherited as an autosomal-dominant trait.
Most patients die before they are 20 years old, but some survive into middle age. The usual cause of death is pneumonia, cachexia, status epilepticus, or acute heart failure.
The skin lesions are of several types. Most common are the small, reddish, flat or rounded seedlike masses composed of hyperplastic connective and vascular tissues that are symmetrically located over the nose, cheeks, nasolabial furrows, and chin. The number seems to increase at puberty. Round, flat plaques (shagreen patches) also may be seen on the face (Figure 89).
Figure 89. Tuberous sclerosis.
Although it is present in only about 20 per cent of patients, the most interesting ocular finding is unilateral or bilateral retinal tumor, or "phakoma," which may be large and nodular or, more commonly, flat and oval. These tumors are gray or yellowish gray and are composed of glial cells, nerve cells, and vascular tissue.
In about one-half of the cases, the skull exhibits thickened calvaría with an irregular outer table, and exostoses are often seen on the inner table of the frontal bone. Areas of increased density appear throughout the skull, especially in the parietal region after puberty.
Less common findings are soft polypoid fibromatous masses over the dorsal trunk or scalp, or beneath or along the nail beds (subungual fibromas). The presence of ovoid areas of depigmentation on the trunk is especially helpful in diagnosis of the syndrome in the infant with epilepsy.
The name "tuberous sclerosis" is derived from the numerous smooth, hard, "potatolike" masses of proliferated glial elements and ganglion cells located throughout the cerebral cortex, ependymal lining of the ventricles, and other areas of the brain. About 60 per cent of those affected manifest intracranial calcification.
Only about one-half of the patients with adenoma sebaceum are mentally retarded, but when the mind is affected, these patients are often idiots or low-grade imbeciles. Seizures of petit mal, grand mal, or Jacksonian-type epilepsy usually begin within the first two years of life and occur with variable frequency. The degree of severity seems to increase with time.
About two-thirds of patients have cystlike areas in the phalanges and irregular periosteal new bone formation along the shafts of the metacarpals and metatarsals.
Approximately 80 per cent of patients have renal tumors of the mixed type. Rarely is there a malignant change. Rhabdomyomas of the heart and cystic defects ("honeycomb") of the lungs, as well as hepatic and pancreatic hamartomas, are common.
In over 10 per cent, the oral mucosa may be the site of fibrous growths. Most frequently they are located in the anterior gingiva. They are usually the color of normal oral mucosa but occasionally are bluish red or yellow; they range in size from that of a pinpoint to that of a small pea. They seem to appear first either from four to 10 years of age or at puberty.
Figure 90. Turner's syndrome. (From Gorlin, R. J.. and Pindborg, J. J. Syndromes of the Head and Neck. New York: McGraw-Hill Book Co., Blakiston Division, 1964.)
The syndrome originally described in 1938 by Turner169,170 consists of (1) short stature; (2) ovarian dysgenesis with primary amenorrhea; (3) infantile uterus, vagina, and breasts; (4) pterygium colli; (5) cubitus valgus; and (6) low hairline at the back of the neck. It occurs in about 1 per 2,500 births.
In 60 per cent of the cases, the syndrome is produced by complete absence of an X-chromosome. In these individuals - owing to absence of Barr bodies, which would normally be formed by the missing X-chromosome - buccal mucosal cells exhibit a so-called chromatin-negative pattern. Some patients are mosaic with an XOiXX karyotype. In them, anomalies tend to be less severe. Other types include X-isochromosome, X-short arm deletion, and X- ring chromosome.
Bilateral epicanthal folds are present in 20 per cent. Other ocular findings may include myopia, strabismus, nystagmus, and ptosis of the eyelids (Figure 90).
A striking clinical feature of the syndrome is webbing of the neck, which extends bilaterally from the mastoid to the acromion process. Surgical attempt at correction may result in keloid formation.
Low implantation of hair in the back of the neck is also frequent. Numerous pigmented nevi are scattered over the body in about 20 per cent of patients.
Hearing impairment is seen in at least two-thirds of affected individuals. Intelligence is usually normal, although the patient may have a cognitive defect.
During infancy, edema of the hands and feet is present in most cases. This results from underdeveloped lymph vessels. It is usually resolved by the third year of life.
Primary amenorrhea is characteristic. The breasts are underdeveloped, and the nipples appear widely spaced. The pubic and axillary hair is very sparse, and the vagina and uterus remain infantile. The ovaries consist of narrow fihrotic streaks in the broad ligaments. In postpubertal patients, the concentration of urinary gonadotropins is elevated and 17-ketosteroid levels are lower than normal.
Renal anomalies are present in over 60 per cent and include horseshoe kidney, unilateral renal agenesis, duplication of renal pelvis, and cleft renal pelvis. Cardiac abnormalities, present in 35 per cent, include coarctation of the aorta and, less often, ventricular septal defect, dextrocardia, and anomalous return of a pulmonary vein to the superior vena cava.
Skeletal anomalies include osteoporosis, shortening of the fourth metacarpal and metatarsal, abnormalities of the knee, and elbow joint epiphyses. Cubitus valgus is often noted.
WILUAMS ELFIN FACIES SYNDROME
This syndrome171,172 was first recognized as an entity in 1961 by Williams, Barratt-Boyes, and Lowe. There is no inherited basis for the syndrome. Results of chromosome studies have been within normal limits.
The fades is quite characteristic, and unrelated patients look remarkably alike (Figure 91). They have a broad forehead; a depressed nasal bridge with apparent ocular hypertelorism; strabismus; wide, fishlike mouth with protruding lips; long philtrum; full, heavy cheeks; low-set ears; and pointed chin. A peculiar metallic voice quality has been noted.
Figure 91. Williams elfin face syndrome.
One component of the syndrome is supravalvular aortic stenosis, which may be mild or severe and has been found in about one-third of the patients. The stenosis is generally located just above the sinuses of Valsalva and is represented by narrowing of a few millimeters. Aortic regurgitation may also be present. The heart is usually normal or slightly enlarged. Multiple peripheral pulmonary artery stenoses may also be a component of the syndrome.
A few weeks after birth, a systolic thrill and murmur, grade 3 or 4-6, can be detected; it is more pronounced in the first right intercostal space and just below the clavicle. Electrocardiograms generally give normal results or exhibit left or biventricular hypertrophy. Patients are below the third percentile in height. Intelligence has varied from severe mental retardation with inability to speak to almost normal.
Other findings have included valvular pulmonic stenosis, persistent left superior vena cava, artrial septal defect, hypoplastic thoracic aorta, subaortic stenosis, bicuspid aortic valve, and narrowing of the ascending aorta.
Skeletal anomalies - such as kyphoscoliosis, talipes equinovarus, camptodactyly, and prognathism - have also been reported.
Because of some clinical similarities, an association with hypercalcemia was suggested. Recent studies, however, have demonstrated that patients - as well as parents, sibs, and unrelated normal controls - have no changes in serum calcium, phosphorus, or cholesterol following administration of high doses of vitamin D. Hypercalcemia has been present in only one reported patient with this syndrome.
Another syndrome of supravalvular aortic stenosis, inherited as an autosomal-dominant trait with incomplete penetrance in the male, has been described recently. This entity is not associated with either mental retardation or the characteristic facies.
XERODERMA PIGMENTOSUM SYNDROME
The association of xeroderma pigmentosum with mental deficiency, microcephaly, dwarfism, gonadal hypoplasia, and various neurologic complications was first pointed out by deSanctis and Cacchione in 1932.173,174
Figure 92. Xeroderma pigmentosum syndrome. (From Gorlin. R. J.( and Goldman. H. M. Thome's Oral Pathology. St. Louis: The C. V. Mosby Company, 1970.)
The frequent occurrence of the syndrome in siblings and the increased rate of parental consanguinity suggest autosomal-recessive inheritance. The mothers of affected children often present a history of increased incidence of spontaneous abortion. The syndrome appears to have a higher frequency in Arab countries.
Marked sensitivity to sunlight (especially wavelengths from 2,800 to 3,100 Angstroms) is noted early in life. Many of these children experience severe sunburn reactions and subsequent freckling of exposed skin areas between the sixth month and the first birthday. Within the first few years, the condition rapidly progresses to development of cutaneous malignancies of both ectodermal and mesodermal origin. Keratoacanthoma, squamous cell carcinoma, basal cell carcinoma, melanoma, and/or fibrosarcoma often involve the facial skin or other sun-exposed areas. All these findings occur as well on the face, giving a typical appearance as seen in Figure 92. Leukemia has also been noted. Early death resulting from a malignancy or from poor resistance to infection is common.
Mental retardation is usually evident within the first year of life and is progressive. Microcephaly, premature closure of cranial sutures, retarded growth and sexual development, choreoathetosis, cerebellar ataxia, and other signs of spinocerebellar disease are frequent. Sensorineural deafness has been noted in several cases.
Reports by some authors of increased serum copper, decreased blood glutathione and increased globulin, aminoaciduria, and reduced 17-ketosteroid and 17-hydroxycorticosteroid levels have been denied by other investigators. Complete porphyrin studies have given normal results. Necropsy has revealed cerebral and olivopontocerebellar atrophy. Nuclear atypia of pancreatic islet cells and liver cells has been noted.
The repair mechanism of DNA following visible and ultraviolet light exposure appears to be defective in this disorder. A functional form of UV-specific endonuclease is lacking. Fibroblasts from patients with the xeroderma pigmentosum syndrome have 10 to 20 per cent of the normal ability to repair. Increased chromosomal breakage has been found in fibroblasts from these patients but not in lymphocyte culture.
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