Pediatric Annals

The Face in the Diagnosis of Dysmorphogenesis

Robert J Gorlin, DDS; Heddie O Sedano, DDS; William S Boggs, DDS

Abstract

1 . Thompson. D.W. On Growth and Form. New York: Cambridge University Press, 1942.

2. Pashayan, H., and Fraser, F.C. Facial features associated with predisposition to facial cleft. Birth DeC. Orig. Art. Ser. 7:7 (1971), 58-61.

3. Johnston, M.C. A radioautographic study of the migration and fate of cranial neural crest cells in the chick embryo. Anat. flee, i 56 (1966), 143-155.

4. Le Douarin, N. A biological cell labeling technique and its use in experimental embryology. Dev. Bioi. 30 (1973). 217-222.

5. Johnston,M.C..and Listgarten, M. A. Histochemical and electron microscopic observation on the mesenchyme and muscle plates of the visceral arches. Anat. Ree. 154 (1966). 363.

6. Aarskog, D. A familial syndrome of short stature associaled with facial dysplasia and genital anomalies. J. Pediat. 77 (1970), 856-861; Birth Dei. Orig. Art. Ser. 7:6 (1971), 235-239.

7. Scott, C. I., Jr. Unusual facies, joint hypermobility, genital anomaly and short stature. A new dysmorphic syndrome. Birth Dei. Orig. Art. Ser. 7:6 (1971). 240-246.

8. Langer, L. O., et al. Achondroplasla. Amer. J. Roentgenol. 100 (1967), 12-26.

9. Silverman, F. N. A differential diagnosis of achondroplasia. Radio!. Clin. N. Amer. 6 (1968), 223-237.

10. Bergstrom, L., étal. Otologie manifestations of acrocephalosyndactyly, Arch. Otûlaryngol. 96 (1972), 117-123.

11. Dodson, W. E., et al. Acrocephalosyndactylia associated with a chromosomal îranslocation. Amer. J. Dis. Child. 120 (1970), 360-362.

12. Cash, R., and Berger, C. K. Acrodermatitis enteropathica: Defective metabolism of unsaturated fatty acids. J. Pediat. 74 (1969), 717-729.

13. Schulze, R. R., and Winkelmann, R. K. Acrodermatitis enteropathica. Mayo CHn. Proc. 41 (1966), 331-341.

14. Newcombe, D.S., and Keats, T. E. Roentgenographic manifestations of hereditary peripheral dysostoses. Amer. J. Roentgenol. íD6(1969). 178189,

15. Robinow, M., et al. Acrodysostosis: A syndrome of peripheral dysostosis, nasal hypopiasia and mental retardation. Amer. J. Dis. Child. 121 (1971), 195-203.

16. Bloom. D. The syndrome of congenital telangiectatic erythema and stunted growth. J. Pediat. 68 (1966), 103-113.

17. Sawitsky, A., et al. Chromosomal breakage and acute leukemia in congenital telangiectatlc erythema and stunted growth. Ann Intern. Med. 65 (1966), 487-495.

18. Sakat, N., et al. A new syndrome with acrocepfialopolysyndactyly. cardiac disease and distinctive defects of the ear, skin and lower limbs. J. Pediat. 79(1971), 104-109.

19. Temtamy, S.A. Carpenter's syndrome: Acrocephalopolysyndactyly. An autosomal recessive syndrome. J. Pediat. 69 (1966). 111-120.

20. McKusick. V. A. Cartilage-hair hypoplasia. TheThird Conference on the Clinical Delineation of Birth Defects, the Johns Hopkins Hospital, June, 1970.

21. Ray, H. C., and Dorsi, J. P. Cartilage-hair hypoplasia. Prog. Pediat. fiadiol. 4 (1973), 270298.

22. Sedano. H. O. . et al. B group short-arm deletion syndromes. Birth Dei. Orig. Art. Ser. 7:7 (1971). 89-97.

23. Breg, W. R., et al. The cri du chat syndrome in adolescents and adults: Clinical findings in 13 older patients with partial deletion of the short arms of chromosome No. 5 (Sp-). J. Pediat. 77 (1970), 782-791 .

24. Jan, J. E., et al. Cerebro-hepato- renal syndrome of Zellweger. Amer. J. Dis. Child. 119 (1970), 274-277.

25. Poznanski, A. K., et al. The cerebro-hepatorenal syndrome (CHRS): Zellweger's syndrome. Amer. J. Roentgen. 109 (1970), 313-322.

26. Khosla, V.M., and Korobkin, M. Cherubism. Amer. J. Dis. Child. 120 (1970), 458. Hammer, J. E., Ill, and Ketcham. A. S. Cherubism and analysis of treatment. Cancer 23 (1969), 1133.

27. Gorlin, R, J., and Goldman. H. M. Thoma's Oral Pathology. St. Louis: The C.V. Mosby Company, 1970.

28. Spranger. J.W. , et al. Heterogeneity of chondrodysplasia punciafa. Humangenetik. J) (1971), 190-212.

29. Spranger, J. W., et al. Chondrodysplasia punctata (Chondrodystrophia calcificans). I: Typ Conradi-Hünermann. Fortschr. Roentgenstrahl. 113 (1970), 717-726.

30. Biggerstaff, R.H., and Mazaheri. M,…

"I shouldn't know you again If we did meet," Humpty Dumpty replied In a discontented tone, giving her one of his fingers to shake: "you're so exactly like other people."

"The face is what one goes by, generally," Alice remarked In a thoughtful tone.

"That's just what I complain of," said Humpty Dumpty. "Your face is the same as everybody has- the two eyes, so-" (marking their places in the air with his thumb) "nose in the middle, mouth under. It's always the same. Now if you had the two eyes on the same side of the nose, for instance- or the mouth at the top- that would be some help."

"It wouldn't look nice," Alice objected. But Humpty Dumpty only shut his eyes, and said "Wait till you've tried."

Through the Looking Glass, Lewis Carroll

M uch of the current pediatrie literature has been devoted to "funny-looking kid" syndromes. This term disturbs us for personal as well as for scientific reasons. The use of the term "funnylooking" is certainly pejorative. We strongly suspect that the clinician who would use such a term would not be flattered were he to be referred to as a "funny-looking doctor." Furthermore, we are disquieted because there is no precision in describing a child with manifold anomalies as being "funnylooking." This has not been something we alone have felt, but it has been the concern of many people all over the world.

The face is an area of interest for many disciplines: medicine, dentistry, physical anthropology, biomathematics, genetics, radiology, developmental biology, photography, and the arts. The face of man is observed by all about him. It is the part that manifests most clearly a person's reactions.

What is it that distinguishes the unusual-looking child from the range of variation that constitutes the norm? Since this discussion is going to be limited largely to the face, we must consider various aspects. Do facial characteristics present at birth in various genetic disorders remain characteristic throughout life? Or do they change as the child grows older? Does age either accentuate or minimize the stigmas that one considers characteristic for a given clinical entity? What specific measurements do we have for appraising the norm?

Various fanciful terms have been employed to describe the facies of infants, viz., elfin, leprechaunlike, etc. Precision is obviously not the forte of this technique, since, we suspect, few can be consonant with the appearance of imaginary creatures. The statement that a patient has ocular hypertelorism when, in fact, no measurement of interocular distance was ever attempted is often erroneous. It is easy to be misled by clinical impression, since the distance between the eyes may appear to be abnormal, depending on the width of the face, the form of the glabellar area, the presence of epicanthal folds, the shape and width of the nose, etc . Moreover, one must accurately define "ocular hypertelorism." Does one refer to bony interorbital distance, interpupillary distance, or inter-inner-canthal distance? How accurate is the last of these if the patient has marked epicanthal folds? How accurate is measurement of interpupillary distance in an uncooperative patient? While few would question the accuracy of bony interorbital distance as measured in an infant cephalostat, how many clinicians have one at their disposal?

Partly because of the lack of precise standards, accurate description of the face has been deficient.

Some of these measurements - such as head circumference, ear length, palatal dimensions, interpupillary distance, and especially cephalometric distances and angles ascertained from radiographs - are no doubt easy to duplicate. Other measurements, such as philtrum length and the intercommissural (interangular) length of the oral aperture, are less reliable, since these represent soft-tissue measurements that require the mouth to be completely at rest.

Nasal and auricular form and variations, as well as the morphology of the normal eye and ear, have been studied. In spite of all the data, one commonly reads that a patient has "low-set ears," "high palatal vault," "wide-spaced eyes," or "funny-looking nose" when, in fact, none of these findings were actually documented. In part, the difficulties inherent in such sloppy verbal description can be neutralized by excellent clinical photographs. Nevertheless, the impression received by a photograph, or even by clinical examination of the patient, can be misleading. Posterior rotation, for example, can make the pinna look lowset. Abnormal palatal form may give the observer the impression of an abnormally high palate. Sunken nasal bridge and epicanthal folds cause the child with Down's syndrome to have "wide-spaced" eyes when, in fact, one usually finds ocular hypotelorism (often as much as 5 mm. below the norm).

With all the sophisticated techniques at hand during this age of computerization, how can we approach the problem of abnormal facial form? While description of an object in nearly all fields is initiated by simple words, the end point is analytic - that is, defined in the precise language of mathematics. This concept was voiced most eloquently over 30 years ago by D'Arcy Thompson, who stated: "If the difficulties and representation could be overcome, it is by means of such coordinates in space that we should at last obtain an adequate and satisfying picture of the process of deformation and direction of growth."1

As a means of assessment of both shape and growth, computerization of cephalometric roentgenograms can be quite rapid and accurate. Conceivably, by means of grenz ray (soft x-ray) or other techniques, soft-tissue form may also be analyzed.

Biostereometrics, which is essentially contour mapping of various forms, is another technique that employs spatial and spatiotemporal analysis of biologic form and function based on principles of analytic geometry. When exposed under carefully controlled conditions, photographs, holographs, radiographs, infra-red radiographs, and other forms of imagery can provide convenient, noncontact means of measuring organic form in three dimensions and changes in form, such as movement or growth. Thereby the shape of the structure, be it the face or one of its component parts, can be characterized digitally, using Cartesian or other coordinate systems, and analogically by contour maps, cross sections, or physical replicas. A modification of this technique was employed by Pashayan and Fraser,2 who projected a grid onto the face of parents of a child with facial clefting, comparing their photographs with parents of normal children.

Finally it is not beyond the realm of possibility to establish an International Commission for Classification and Nomenclature of Facial Phenotype under the sponsorship of the World Health Organization. For a decade, WHO has been engaged in such activities with regard to various groups of neoplasms . Furthermore, cy togeneticists have had several international meetings to establish and then to update chromosome nomenclature. These have been eminently successful endeavors. Alterations in form may be subtle, but they are certainly not beyond the bounds of quantification.

Classification of orofacial anomalies would be greatly abetted were the morphogenesis of this area completely understood. While giant steps have been made in this area by Johnston and co-workers3 and Le Douarin*- such as the discovery that all connective tissue, bone, and cartilage in the facial area are derived from ectomesenchyme, a neural crest derivative - the precise timing of various "mesenchymal flows" has not been determined in man, and consequently many questions related to the morphogenesis of craniofacial anomalies need to be answered. To some degree, this has been attempted by Johnston and Listgarten5 in their efforts to explain such anomalies as cyclopia (and other holoprosencephalic states) and otocephaly as the result of deficient or maltimed flow of ectomesenchyme. For example, otocephaly, a condition in which the mandible is deficient and the ears are fused at the midline, is explained by the failure of ectomesenchyme to flow to the point farthest from its origin. In cyclopia, ectomesenchyme fausto flow over the prosencephalon and into the frontonasal process, allowing the eyes to join in the midline while trapping the olfactory placodes above the eye. There the placodes differentiate into a blindended proboscis. These theories are admittedly conjectural and, we suspect, somewhat simplistic, since there are several examples of infants with bilateral supraorbital probóscides and widely separated eyes. Even the pathogenesis of the "simpler" anomaly of unilateral nasal proboscis remains unknown .

That mammals do not differ appreciably from amphibians or birds in embryologie development of the head and orofacial structure has been well demonstrated. Consequently, there is ample opportunity for experimental production of craniofacial anomalies utilizing a number of models. Several Veratrum alkaloids have been employed teratogenically, but the pathogenetic mechanisms at work have not been elucidated. There is good evidence that various holoprosencephalic states come about by more than one mechanism, viz., trisomy 13, deletion of the short arm of a chromosome 18, and possibly even from the homozygotic state of an autosomal-recessive gene. Whether the embryologie paths to the same end product are identical regardless of cause is, of course, not known.

Another problem that concerns the dysmorphologist is the constancy of clinical aspects of a syndrome. Do the features of the disorder alter with time? In infants with cri-du-chat syndrome, the mewing cry and the full round face disappear within the first year of life. With the disappearance of these hallmarks, the clinician is faced with a mentally retarded, microcephalic child who exhibits ocular hypertelorism and who "vanishes in the crowd" of undeciphered mental retardates unless described on the basis of karyotypic screening.

Conversely, we have other lacunae of ignorance. Is a facies that is as striking as that of the supravalvular aortic stenosis-idiopathic hypercalcemia syndrome one that is invariant with time? All pictures of this disorder that we had seen had been of children ranging in age from a year or so to adolescence; we had not seen any adults. We became curious whether the overlong philtrum and retrousse" role with anteverted nostrils, so characteristic in the child, metamorphose into far less subtle changes in the older patient. A short trip to an institution for the mentally retarded demonstrated that the facies does, in fact, remain constant with age, since we were able to obtain childhood pictures of these subjects.

The variability of expression of traits, however, is destined not to be conquered. For example, if one chooses to consider disorders in which one facet is a "thin nose," it should become apparent that not all thin noses are thin in the same way. Some are "thin" because of a markedly narrow dorsum, others because of hypoplasia of the nasal alae or extension of the nasal tip far below the columellar base. To further illustrate how complex the situation can become take, as a specific example, the nasal alar hypoplasia in Waardenburg's syndrome; this may be quite variable in its expression. Thus, while there may be a typical "Waardenburg's nose," not all patients with the syndrome possess this attribute or, if they do, they do not- have it to the same degree.

The group of conditions presented in this article were chosen because it was thought that their facial components were such as to warrant inclusion.

Some of these conditions present only facial anomalies, while others are accompanied by a plethora of associated clinical alterations that are present in practically every system. Some are inherited, others are known to be nonfamilial, a third group may be druginduced, and many others are of unknown origin.

All these preclude the idea that classification of dysmorphogenic syndromes is a task that can, at this point, be undertaken. Many divisions or classifications have been proposed, but without pedantry we believe that the degrees of clinical and etiologic variations present in these conditions give rise to an enormous number of combinations impossible to classify in any simple manner. We still prefer the alphabetic order in which we shall present them in this article.

Figure 1. Aarskog's syndrome.

Figure 1. Aarskog's syndrome.

AARSKOG'S SYNDROME

This disorder6-7 is characterized by (1) short stature, (2) genital anomalies, and (3) unusual facies. The syndrome is inherited as an X-linked trait. The female heterozygote tends to be short.

The forehead is broad, with prominent ridging of the metopic suture. Commonly there is a widow's peak. Ocular hypertelorism with ptosis of the upper eyelids - combined with a short, broad, somewhat stubby nose with anteverted nostrils and a broad but not depressed nasal bridge- characterizes the face (Figure 1). The philtrum may be long and the pinnae poorly modeled and rotated. The ear lobes are thick.

Although birth size is normal, growth retardation usually becomes evident between two and four years of age. Most patients are below the third percentile in height, adults rarely exceeding 160 cm. Muscle tone usually remains poor throughout life. Small hands and feet, short fifth fingers, mild cubitus valgus, internal tibial torsion, metatarsus varus, pigeon-toed gait, pes planus, pectus excavatum, and hyperextensibility of interphalangeal joints have been noted. Inguinal hernia is a common feature.

Striking changes observed radiographically are generally limited to the cervical spine and hands. We have seen a patient with fusion of C2 and C3. The terminal phalanges of the fingers and the middle phalanx of the fifth finger are hypoplastic.

The scrotum appears bifid, with the scrotal fold extended ventrally around the base of the penis, somewhat resembling a shawl thrown about the neck. Presumably this results from failure of caudal shift of the fused labioscrotal folds. In some patients one or both testes are undescended. Fertility has been experienced, although it may be reduced.

Bilateral simian creases and clinodactyly of the fifth fingers are frequent.

ACHONDROPLASIA

Achondroplasia8'9 has been known since antiquity, but Parrot, in 1878, was the first to coin the name. The disorder is inherited as an autosomaldominant trait. About 80 per cent of patients are considered to be spontaneous mutations. Achondroplasia has an estimated frequency of 1 in 10,000 live births, but, owing to confusion with various other types of dwarfism, this is not a reliable figure. The majority of patients are of northern European descent.

Figure 2. Achondroplasia.

Figure 2. Achondroplasia.

Achondroplasia is probably the most common of the chondrodysplasias. It is characterized by shortlimbed dwarfism, detectable at birth. Patients are short, with a large head, a relatively long trunk, and stubby limbs. Proximal arms and legs are shorter than the distal segments.

Only endochondral bone is affected. In the skull the endochrondral bone of the base is severely affected, but the membranous bone of the vault is practically normal. This difference in growth results in a large head with frontal bossing, a small foramen magnum, a "scooped-out" face with relative nasal depression, and a retroussé nose (Figure 2).

Patients have an unusual walk, owing to lumbar lordosis and associated bowed legs. A high incidence of spinal cord compression due to anteriorly wedged vertebral bodies has been noted. A trident hand is a constant finding, since patients are unable to completely approximate their finger tips. There is a marked space between the third and fourth fingers. Fingers are moderately short. The rest of the clinical picture is accentuated by a flat thoracic cage and a protuberant abdomen.

A number of affected children die from compression of the brain stem during the newborn period and up to one year of age. Pneumoencephalographic studies show mild to moderate ventricular dilatation . Self-limiting hydrocephalus has also been noted. Mild hypotonia with early slow motor progress is noted. Intelligence is normal.

ACROCEPHALOSYNDACTYLY (Apert's Syndrome)

Acrocephalosyndactyly10,11 is a rare variant among the craniostenoses, characterized by (1) turribrachycephaly and (2) syndactyly of hands and feet. The incidence is estimated to be 1 in 160,000 live births, with an equal distribution between sexes. Because of the high infant mortality, the frequency decreases to about 1 in 2,000,000 in the general population.

Most cases of acrocephalosyndactyly are sporadic. The syndrome may be transmitted as an autosomal-dominant trait. An advanced paternal age effect has been demonstrated.

The middle third of the face appears flat and underdeveloped, producing a relative prognathism. Hypertelorism and strabismus are often noted. The orbits are flattened, and the eyes tend to be proptosed. In infancy a horizontal groove may extend across the forehead just above the supraorbital ridges (Figure 3). Intelligence is usually below normal.

The cranium is brachycephalic with a high, prominent, steep forehead. The frontal and temporal areas bulge. The apex of the cranium is located near or in front of the bregma, the occipital region being flat and in the same vertical plane as the neck. A number of patients possess an open anterior fontanel, which at times continues to an open metopic suture. There is irregular early obliteration of cranial sutures. Fusion of the coronal suture is often found, alone or together with fusion of the sagittal suture. Accentuation of digital markings is usually observed.

Figure 3. Acrocephalosyndactyly.

Figure 3. Acrocephalosyndactyly.

The symmetric syndactyly varies in degree. Often there is true progressive osseous syndactyly of metacarpale, metatarsals, and phalanges. When the three middle fingers are completely fused, there is usually a common nail that gives the hand the appearance of a mitten ("middigital hand mass").

Other skeletal abnormalities - such as aplasia or ankylosis of several joints, especially elbow, shoulder, and hip; ankylosis of vertebrae; and spina bifida - have been noted.

High-arched palate, occasionally with a marked median furrow, is frequently observed. Posterior clef t palate or bifid uvula is found in at least 25 per cent of these patients. Associated with hypoplastic maxilla is relative mandibular prognathism and compression of the upper arcade, which becomes V-shaped, leading to an irregular positioning of the teeth. Crowding of the teeth may lead to a marked thickening of the alveolar process.

ACRODERMATITIS ENTEROPATHICA

Acrodermatitis enteropathica12-13 is a rare childhood syndrome whose primary signs are (1) skin lesions, (2) hair loss, (3) nail changes, and (4) gastrointestinal disturbances.

In 65 per cent of the reported cases, there is a history of familial occurrence. Autosomal-recessive transmission is likely.

Acrodermatitis usually begins between the ages of three weeks and 10 years, with an average age at onset of nine months in reported cases. Occasionally the syndrome is reported in - adults. It seems to improve by the time of puberty. The onset is insidious and follows an intermittent course, often with spontaneous, partial remissions, succeeded by increasingly severe exacerbations. Most cases end fatally.

Children suffering from acrodermatitis enteropathica exhibit a striking uniformity of appearance, mainly because of the alopecia and the orificial location of lesions. Alopecia is found in 98 per cent of reported cases; in most patients it is total.

The syndrome usually starts with small, erythematous, moist skin eruptions localized around the natural orifices.

The perioral area is always affected. Because of the pustular eruptions, weeping bilateral erosions at the angle of the mouth are often seen, at times with severe fissuring. Conjunctivitis, blepharitis, and photophobia have occasionally been found. The affected child usually holds his head at an angle, with face downward (Figure 4) . The oral changes are sometimes described as "stomatitis" or "glossitis." Undoubtedly, a large number of children with the syndrome suffer from thrush. The buccal mucosa (less often the palate, gingiva, and tonsils) contains reddish and white spots or edema with erosions, ulcérations, and desquamation.

Body growth has been found retarded in 80 per cent of the patients, and 40 per cent show mental changes, often in the form of schizoid features associated with the exacerbations.

Other skin lesions are found symmetrically on the buttocks, elbows, knees, hands, and feet, especially between the fingers and toes and around the nails. The trunk is only slightly affected. In most cases the rash is of vesiculobullous type. After a short time the vesicular lesions begin to dry and crust, subsequently turning into sharply marginated lesions. When the lesions heal, they leave no scars.

In over 50 per cent of the cases reported, Candida albicans is found in lesions of skin or mucous membranes or in stools, leading to the assumption that the syndrome is the result of a monilial infection. Most investigators, however, agree that the monilial infection is a secondary phenomenon. It may be that acrodermatitis enteropathica is associated with an increased susceptibility to yeast infection.

The gastrointestinal disturbances consist of bouts of diarrhea, with increased excretion of fat. Diarrhea has been found in 90 per cent of reported cases. The stools are often large, foul, foamy, and green, indicating maladsorption. In some cases the only intestinal symptom is occasional loose stools.

Paronychia with nail dystrophy was observed in 95 per cent of reported cases, with prolonged involvement resuiting in complete loss of nails.

Figure 4. Acrodermatitis enteropathica.

Figure 4. Acrodermatitis enteropathica.

ACRODYSOSTOSIS

(Peripheral Dysostosis, Nasal Hypoplasia, and Mental Retardation)

This syndrome14-15 consists of (1) peripheral dysostosis, (2) nasal and midface hypoplasia, (3) mental retardation, and (4) growth failure.

All cases reported to date have been sporadic. Paternal age at time of conception has been increased in a number of cases. It may be a dominant disorder, each patient representing a new mutation.

Patients have an unusual facies (Figure 5). Most common is marked hypopJasia of the nose. The entire nose is flat and short, with a broad, sometimes dimpled tip and anteverted nostrils. The bridge is low, and in some cases the bony framework may be missing. The center of the nasal tip is more severely reduced than the sides, so that the alae extend below the columella. The philtrum is usually long. Apparent hypertelorism, as well as epicanthus, has been noted. Brachycephaly and occasionally mild microcephaly are evident. Nasal bones are hypoplastic or even missing.

Figure 5. Acrodysostosis.

Figure 5. Acrodysostosis.

Maxillary hypoplasia, producing a peculiar flattening of the cheeks, is frequently associated with the hypopfastic nose. In contrast, the upper alveolar process is usually prominent. Open bite is common, and relative mandibular prognathism may be conspicuous. The mandibular angle is often increased.

Most patients have intellectual deficit, with I. Q. s ranging from 35 to 85. Associated neurologic defects have included internal hydrocephaly, optic atrophy, seizures, choreoathetosis, and strabismus. Hearing loss, delayed puberty, and numerous pigmented nevi have also been noted.

Intrauterine growth retardation and short stature are almost constant findings. Birth weight at normal term has ranged from 1,800 to 3,000 gm., and birth length from 44 to 48 cm.; growth failure is progressive.

Short hands with stubby fingers and very short and broad fingernails, somewhat resembling the hands of achondroplasia patients, are a cardinal feature. The feet are similarly affected. These deformities may be obvious at birth, or they may become apparent during the first year or not until some years later. Skin and subcutaneous tissues gradually outgrow the skeleton to form bulges and folds over the dorsal aspects of the hands and fingers. Because of premature arrest of metacarpal and phalangeal growth, the relative shortness of the fingers becomes more pronounced with age. Arthritic changes supervene early in hands and feet and may be generalized.

The most striking radiographie finding is severe shortening of metacarpals and phalanges. In most cases involvement is most severe in metacarpals. Epiphyses are deformed and fuse prematurely. Phalanges have cone-shaped epiphyses, which also fuse prematurely . Continued remodeling broadens and deforms the bones into even more grotesque shapes.

Forearm shortening seems to become more severe with age. In standing adults, the hands barely reach the trochanters. Epiphyses of the elbow region appear and fuse prematurely. The distal radius and ulna are often malformed. Hypoplastic ulna with a poorly developed or absent styloid process is common.

The foot changes are comparable with those in the hands. The metatarsal and phalanges of the hallux are usually large and broad, sometimes accompanied by hallux valgus. The first cuneiform and navicular participate in relative hyperplasia of the first ray. The remaining metatarsals and phalanges are disproportionately small.

Partially collapsed vertebral bodies and irregularly deformed end plates in the thoracic and lumbar spine, with resultant dorsolumbar kyphosis, have suggested juvenile spondylitis in several cases.

BLOOM'S SYNDROME

This syndrome16'17 consists of (1) telangiectatic erythema appearing in infancy and principally affecting the face, (2) sunlight sensitivity, and (3) stunted growth. The syndrome is inherited as an autosomal-recessive trait. It has an increased incidence among Jews of eastern European extraction.

Parental consanguinity is higher among non-Jews, indicating the rarity of the gene among that group. Cy togenetic studies have demonstrated a consistent tendency to chromosomal breakage and rearrangement in cells cultured in vitro and, consequently, a high incidence of aneuploidy,

Birth weight is low, rarely exceeding 2,300 gm. at normal term. The mean birth length is 44 cm. (mean normal: 50 cm.) without signs of prematurity. Maximum adult height rarely exceeds 145 cm. for the male and 130 cm. for the female.

The telangiectatic erythema principally affects the butterfly area of the face, nose, lips, dorsa of hands, nape, and ears (Figure 6). The eyelashes are commonly lost, and although acute skin involvement and sensitivity to sunlight lessen with age, resultant scarring, depigmentation and atrophy are permanently disfiguring. Cafe-aulait spots are noted in more than half of the cases.

A host of minor anomalies have been described, including high-pitched voice, sacral dimple, testicular atrophy or hypoplasia, and urethral stricture. Diminished immunoglobulin levels have been noted.

As with ataxia-telangiectasia and Fanconi's anemia, Bloom's syndrome is associated with a high incidence of leukemia and lymphoma. In all three conditions there is an increase in chromosomal rearrangements in cultured lymphocytes. Half of the patients with Bloom's syndrome who have survived to 21 years of age have subsequently died of malignant neoplasia.

Figura 8. Bloom's syndrome. (From German, J. L. Ame J. Human Genet. 21 [l969], 196.)

Figura 8. Bloom's syndrome. (From German, J. L. Ame J. Human Genet. 21 [l969], 196.)

CARPENTER'S SYNDROME

(Acrocephalopolysyndactyly)

The syndrome originally described by Carpenter18'" consists of (1) acrocephaly; (2) soft-tissue syndactyly, especially of the third and fourth fingers, and brachymesophalangia; (3) preaxial polydactyly and syndactyly of the toes; (4) coxa valga and pes varus; (5) congenital heart disease; (6) mental retardation; (7) hypogenitalism; (8) mild obesity; and (9) hernia. Less commonly there is (10) postminimal polydactyly of the hands.

The skull is usually tower-shaped. Premature synostosis of all cranial sutures often occurs asymmetrically, producing distorted calvaria. Flat nasal bridge and dystopia canthorum are also constant features. The sagittal and lambdoid sutures often fuse first, and the coronal last. Wormian bones can be found in the anterior fontanel.

Dystopia canthorum is nearly a constant feature; i.e., the medial intercanthal distance is increased, but the interpupillary and bony interorbital distances are normal. Often this is combined with epicanthal folds and depressed nasal bridge, giving the eyes a "down-thrust" appearance (Figure 7) . Maldeveloped cornea or microcornea and corneal opacity have been noted, as have slight optic atrophy and blurring of disk margins. The ears are usually low-set, and the neck is short.

The obesity mainly affects the trunk, the proximal portion of the limbs, the face, and the back of the neck. Height is usually below the 25th percentile, but weight is often above average.

The hands are short with stubby fingers. Marked soft-tissue syndactyly may be present between the third and fourth fingers, with less marked syndactyly between other fingers. The proximal phalanx of the thumb has two ossification centers. A tongueshaped projection may extend from the radial side of the epiphysis for the proximal phalanx of the index finger. Often there is brachymesophalangia of all digits or agenesis of some middle phalanges of the second to fifth digits.

Usually there are bilateral varus deformities of the feet and preaxial polydactyly with duplication of the second toes. In many cases toes exhibit softtissue syndactyly. Radiography shows metatarsus varus and replication of the second toe and, to a lesser extent, the second metatarsal. The first metatarsal is short and remarkably broad. Only two phalanges are present in each toe. The proximal phalanx of the hallux has two rounded and a triangular distal ossification center.

Figure 7. Carpenter's syndrome. (Courtesy of M. M. Cohen, Jr., Seattle, Wash.)

Figure 7. Carpenter's syndrome. (Courtesy of M. M. Cohen, Jr., Seattle, Wash.)

In nearly all cases there has been genua valga and lateral displacement of the patellae. Hip joint mobility may be reduced.

Congenital heart disease - such as ventricular septaJ defect, atrial septal defect, patent ductus arteriosus, pulmonary stenosis, and tetralogy of Fallot- has been reported. A relatively low level of intelligence is achieved by those who do not succumb to congenital heart disease.

Miscellaneous findings include spina bifida occulta, absent coccyx, flaring of the ilia and poor development of acetabula, coxa valga, postminimus digits of hands, scoliosis, vertically oriented orbits, omphalocele, accessory spleen, hydronephrosis and /or hydroureter, inguinal hernia, and undescended testes.

CARTILAGE-HAIR HYPOPLASIA SYNDROME

(McKusick's Syndrome)

This syndrome, 20<" first seen in 1964 by McKusick et al. among isolated Old Order Amish, comprises (1) dwarfism, (2) fine hair with eventual baldness, (3) sparse eyebrows and eyelashes, and (4) short and pudgy hands.

The disorder is inherited as an autosomal-recessive trait with reduced penetrance, Approximately 80 cases have been found among the Amish, but the syndrome has been reported from non-Amish groups as well.

The head is normal in size. The hair, when present, is of small caliber, sparse, silky, and light in color, becoming darker with age. Eyelashes and eyebrows are occasionally sparse, as is the beard in males (Figure 8). Body hair is similarly affected.

The dwarfism is of the short-limbed variety, the height of patients ranging from 100 to 150 cm. The chest is of normal size, but occasionally there are sternal deformities. The hands are short and pudgy, but the fingers can be brought together. The nails are short.

Fingers, feet, and wrists are hyperextensible, but patients are unable to fully.extend their elbows. Flat foot on weight-bearing is a constant finding. Mild bowing of legs is present.

Normal epiphyses but irregular and fragmented metaphyses in long bones, especially at the knee joints, can be observed radiographically.

Absorptive intestinal defect, as well as megacolon and increased susceptibility to viral infections, especially chickenpox, has been described in several cases.

Chronic neutropenia and abnormal cellular immunity have been recently reported as part of the syndrome.

Figure 8. Cartilage-hair hypoplasia syndrome.

Figure 8. Cartilage-hair hypoplasia syndrome.

CAT-CRY (5p-) and WOLF-HIRSCHHORN (4p-) SYNDROMES

In 1963, Lejeune and co-workers reported the first three cases of the "cat-cry" syndrome, which is due to short-arm deletion of a chromosome, No. 5 (Sp-). In 1965, Wolf and Hirschhorn independently described patients with multiple congenital anomalies. Karyotypes revealed short-arm deletion of a chromosome of the B group. Autoradiographic studies demonstrated this to be chromosome No. 4 (4p-). Patients with either syndrome22'23 are mentally retarded, with an I. Q. of 30 or less. Although both disorders share some similar clinical features, differential diagnosis can be established by careful clinical studies and by means of chromosomal banding techniques.

Cat-cry (Sp-) syndrome (Figure 9 ). Features include catlike cry, present only during the first year of life, (2) microcephaly, (3) mental retardation, (4) apparent ocular hypertelorism due to broad nasal root and/or bilateral epicanthal folds, (5) antimongoloid obliquity of palpebrai fissures, (6) micro- or retrognathia, (7) low-set ears, and (8) abnormal derma t oglyphics.

In 13 per cent of reported cases of 5p- syndrome, one parent had a balanced translocation, indicating increased inheritance risk. Consequently, chromosome analysis of parents and siblings of a given proband should be carried out routinely in order to rule out balanced translocation. Data based on 102 cases of 5p- syndrome showed 63 affected females and 39 affected males, a ratio significantly different from the 50-50 expectation. This could suggest a higher mortality (pre- or postnatal) of males with the 5p- syndrome.

The dermatoglyphic abnormalities found in patients with the 5p- syndrome are distally placed axial triradius, simian crease, and low total ridge count.

Other associated anomalies are low birth weight, growth retardation, hypotonicity, clinodactyly, talipes equinovarus, strabismus, broad nasal root, high palatal vault, and congenital heart defect.

Wolf -Hirschhorn (4 p-) syndrome (Figure 10) consists of (1) microcephaly, (2) seizures, (3) mental retardation, (4) ocular hypertelorism, (5) coloboma of iris and/or retina, (6) antimongoloid obliquity of palpebrai fissures, (7) lowset and malformed ears, (8) clefting of lip and/or palate, and (9) hypospadias. Associated facial findings are prominent glabella and beaked nose.

Life expectancy of 4p- patients appears to be much lower than for those with 5p- syndrome. About 35 per cent of infants with this syndrome die before the age of three years. Associated anomalies are low birth weight, muscular hypotonia, sacral dimple, preauricular dimple, and congenital heart defect.

The main differences between the two syndromes are the presence or absence of the catlike cry and of seizures and cleft lip-palate.

Figure 9.Cal-cry (Sp-) syndrome. (From Gordon, R. R.. and Cooke, P. Develop. Med. child Neurol 10 [1968], 69

Figure 9.Cal-cry (Sp-) syndrome. (From Gordon, R. R.. and Cooke, P. Develop. Med. child Neurol 10 [1968], 69

CEREBROHEPATORENALSYNDROME

(Zellweger's Syndrome}

This syndrome 24·" consists of (1) hypotonia, (2} high forehead and other craniofacial anomalies, (3) flexion contractures, (4) hypoprothrombinemia, (5) hepatomegaly, (6) renal cortical cysts, and (7) developmental abnormalities of the brain. It is inherited as an autosomal-recessive trait with female predilection. Failure to thrive and early death (neonatal to six months of age) are characteristic.

The forehead is high. The skull may be pear-shaped, with flattened occiput in about half of the cases. The facies, especially the supraorbital ridges, is flat. Puffy eyelids, ocular hypertelorism, mild mongoloid obliquity of the palpebrai fissures, epicanthal folds, Brushfield spots, cataracts, and nystagmus may be observed, as may full cheeks, anteverted nostrils, micrognathia, and redundant skin on the neck. The ears may be posteriorly rotated (Figure 11).

Figure 10. Wolf-Hirschhorn syndrome (4p-). (From Carter, R., Baker. E., and Hayman, D. J. Meo. Genet. 6[1969], 224.)

Figure 10. Wolf-Hirschhorn syndrome (4p-). (From Carter, R., Baker. E., and Hayman, D. J. Meo. Genet. 6[1969], 224.)

Severe hypotonia, seizures, abnormal electroencephalographic findings, dilated ventricles, a tendency toward megalencephaly, macrogyria, polymicrogyria, pachygyria, lissencephaly, olfactory hypoplasia, absent corpus callosum, histologie leukoencephalomyelopathic changes, and disorganized histologie elements in the cerebellum have been reported.

Camptodactyly of one or more fingers, simian or transitional simian creases, ulnar deviation of hands, cubitus valgus, flexion at knees and hips, talipes equinovarus, metatarsus adductus, rocker-bottom feet, and dorsiflexion of fourth toes have also been reported.

Fontanels and sutures are widely patent. Bone age may be retarded, and hypomineralization and Wormian bones have been noted. Calcific stippling has been observed, especially in the acetabular cartilages and along the inferior medial margin of the patellas. Stippled epiphyses are present in long bones in about half of the cases. Calcification of the hyoid bone and thyroid cartilage has been noted. Metaphyseal radiolucencies have also been described.

Figure 11. Cerebrohepatorenal syndrome. (From Passarge, E.. and McAdams. A. J. J. Pedlat. 71 [1967], 691.1

Figure 11. Cerebrohepatorenal syndrome. (From Passarge, E.. and McAdams. A. J. J. Pedlat. 71 [1967], 691.1

Hepatomegaly, intrahepatic biliary dysgenesis, small cysts, disturbances of lobular architecture, diffuse fibrosis, and iron pigment deposition, renal cortical cysts, and, less frequently, foci of renal dysgenesis may be found.

Cardiac anomalies include patent ductus arteriosus and patent foramen ovale. Widely spaced nipples, deep sacral dimple, hypoplastic dermal ridges, small penis, hypospadias, cryptorchidism, prominent clitoris, umbilical hernia, diastasis recti, hypertrophied pylorus, partial malrotation of colon, splenomegaly, extramedullary hematopoiesis, pancreatic islet cell hyperplasia, and absence of thoracic lobes of the thymus gland have also been described.

CHERUBISM

This syndrome 26'27 was first described by Jones in 1933 as a familial multilocular bone disease that almost exclusively affects the jaws.

The disorder is inherited as an autosomal-dominant trait with variable expression and incomplete penetrance in females. Cherubism should not be considered a form of fibrous dysplasia of the jaws.

The disorder first becomes manifest as a painless swelling between the ages of 18 months and four years. Generally involvement is bilateral, but unilateral cases have occasionally been reported. Maxilla and mandible can be affected at the same time, but the maxilla is less often involved.

The jaws increase rapidly in size until about puberty, when the swelling tends to remain stationary and then progressively disappears. After the age of 20 years, scattered areas of slightly increased bone density are the only remaining radiographie evidence.

The bone is replaced by fibrous connective tissue with scattered multinucleated giant cells. This produces displacement of primary teeth, as well as abortive formation or absence of permanent molar teeth.

The face is characterized by bilateral swelling, giving a cherubic appearance. Ocular hypertelorism is an almost constant feature. Involvement of the orbital floor produces upward displacement of the eye, exposing a characteristic rim of sclera beneath the iris (Figure 12).

A "soap bubble" appearance, generally extending bilaterally from the molar region to the angle and ramus of the mandible, is observed radiographically. The condyle is never affected. Severe cases may evince total involvement of the mandible. The maxilla is most frequently affected in the area of the tuberosity and antrum.

Severe cases exhibit a grotesque appearance, and there are complications in mastication, deglutition, respiration, and speech. Occasionally, extraoral lesions have been reported to occur in the humerus, ribs, femur, etc. Submandibular and cervical lymphadenopathy can sometimes be observed during the active phase of the condition.

Figure 12. Cherubism.

Figure 12. Cherubism.

CHONDRODYSPLASIA PUNCTATA

(Stippled Epiphyses)

Chondrodysplasia punctata (chondrodystrophia calcificans congenita)"'29 is inherited as either an autosomal-recessive or dominant trait. It is extremely rare, the estimated frequency being about two to three cases per million births. At least 50 per cent of affected children die before the end of the first year of life. Presumably, most of them are of the autosomalrecessive (rhizomelic) type. The dominant (Conradi-Hiinermann) type has a much milder course.

The face has deficient nasal bones, resulting in a severe saddle-nose deformity and congenital cataracts (Figure 13). Other clinical findings are micromelia, rhizomelia, short neck, short stature, dislocated hips, flexion contractures, optic atrophy, and mental retardation.

Figure 13. Chondrodysplasia punctata.

Figure 13. Chondrodysplasia punctata.

Patients with the rhizomelic form may have an associated cleft palate, and common neurologic alterations are cerebral atrophy, spastic diplegia, and optic atrophy.

The most pronounced changes occur in the skeleton, and numerous punctate opacities in the unossified epiphyseal cartilages may be noted on radiographic examination. The stippled appearance of the epiphyses is due to areas of premature ossification and hyaline mineral deposition. The hip, knee, shoulder, and wrist joints are especially prone to involvement. This usually disappears by four years of age, and hence radiographie studies of the older child are of limited diagnostic value.

CHONDROECTODERMAL DYSPLASIA

(Ellis and van Creveld Syndrome)

Typically this syndrome30,31 consists of (1) bilateral manual ulnar polydactyly; (2) chondrodysplasia of long bones, resulting in acromelic dwarfism; (3) hidrotic ectodermal dysplasia, principally affecting the nails and teeth; and, in half of the cases, (4) congenital heart malformations.

The syndrome is inherited as an autosomal-recessive trait . We found that the consanguinity rate among the parents of affected patients was 30 per cent. McKusick found 50 cases in 31 families of an Amish community.

Oral manifestations are quite characteristic and constant, comprising fusion of the anterior portion of the upper lip to the maxillary gingival margin, so that no mucobuccal fold exists anteriorly. Because of this fusion, the middle portion of the upper lip has a slight V notch, resembling a lip that has undergone cheiloplasty (Figure 14). Teeth tend to be somewhat conical and, at times, to have hypoplastic enamel. The anterior portion of the lower alveolar ridge is often serrated. In more than 50 per cent of reported cases, teeth have been present at birth.

Dwarfism is due to shortening of the extremities, which progresses distalward. Tubular bones are shortened and thickened, with plump diaphyseal ends. Manual polydactyly is almost constant, the extra digit being on the ulnar side. Occasionally, extra toes are seen. Other skeletal anomalies - such as genua valga, talipes equinovarus and calcaneo valgus, pigeon breast, and curvature of the humérus - have occasionally been reported. Usually there is a marked koilonychia and hypoplasia of fingernails and toenails. Affected males may show cryptorchidism, epispadias, or hypospadias. One-third of the patients are mildly mentally retarded.

Congenital heart anomalies of the nature of interseptal defect, cor triloculare, or cor biloculare have been noted in 50 per cent of patients.

Figura 14. Ellis and van Creveld syndrome.

Figura 14. Ellis and van Creveld syndrome.

CLEFT LIP AND/OR PALATE ANDCONGENITAL LIPFISTULAS

The syndrome of cleft lip-palate and congenital Up fistulas32-33 has been recognized for over 100 years. It is transmitted as an autosomal-dominant trait with 80 per cent penetrance of any component of the syndrome, but there is a possibility that the type of cleft present is influenced by modifying genes. The syndrome is seen with a frequency of about 1:75,000 to 1: 100,000 live births and affects both sexes equally.

Usually bilateral, symmetrically located depressions are observed on the vermilion portion of the lower lip (Figure 15). The fistulas may be as large as 3 mm. or more in diameter or so small that they barely permit the introduction of a hair probe. The dimple may be circular or may present as a transverse slit. In rare instances, they may be located at the apex of nipplelike elevations. The depressions represent blind sinuses that descend through the orbicularis oris muscles to a depth of 0.5-2.5 cm. and communicate with underlying minor salivary glands through excretory ducts. These fistulas often transport a viscid saliva to the surface, either spontaneously or upon pressure.

Figure 15. Cleft lip and/or cleft palate with congenital lip fistulas.

Figure 15. Cleft lip and/or cleft palate with congenital lip fistulas.

The pits may be an isolated finding (in about 35 per cent) or associated with cleft lip-palate (about 75 per cent). When they are associated with cleft lippalate, the clefts are bilateral in over 80 per cent of the patients.

A few cases have been reported in which there has been but a single pit. Adhesions between maxilla and mandible and filiform adhesions between the eyelids have also been noted. Congenital lip pits have also been seen occasionally in association with the oral-facial-digital syndrome and with the syndrome of popliteal pterygia.

CLEFTPALATE, FLATTENED FACIES, AND MULTIPLE CONGENITAL DISLOCATIONS

(Larsen's Syndrome)

First recognized as a distinct entity by Larsen in 1950, this syndrome34'33 includes the following components: (1) peculiar facies, (2) multiple congenital dislocations, (3) foot deformities, and (4) cleft palate. Consanguinity has been noted in a few cases. Autosomalrecessive transmission appears likely.

The face is typically flattened, with a depressed nasal bridge. Frontal bossing may be marked. The eyes appear widely spaced (Figure 16).

The skeletal anomalies are bilateral and include anterior dislocation of the tibia on the femora, antenatal elbow and hip dislocations, and talipes equinovarus or equinovalgus deformities of the feet. The fingers are long and cylindrical, with extra finger creases, and the thumb is spatulate, without normal taper. The metacarpale are relatively short. Abnormal segmentation of vertebrae or multiple vertebrae have also been seen. A juxtacalcaneal accessory bone or bifid calcaneus has been noted.

Inter-ventricular septal defect has been described in a few cases.

Figurais. Cleft palate, flattened facies, and multiple congenital dislocations (Courtesy of R. K. Greenlaw, Shriners Hospital, San Francisco.)

Figurais. Cleft palate, flattened facies, and multiple congenital dislocations (Courtesy of R. K. Greenlaw, Shriners Hospital, San Francisco.)

Oral changes seem to be essentially limited to cleft palate. This is rarely complete and apparently never combined with cieft lip.

CLEFT PALATE, MICROGNATHIA, AND GLOSSOPTOSIS

(Robin's Anomaly)

This well-recognized syndrome of micrognathia, glossoptosis, and cleft palate,36-37 ordinarily known as Robin's syndrome, was described in 1822 by St. Hilaire. We prefer to think of the disorder as a nonspecific anomaly that may occur as an isolated finding or together with a number of other disorders.

Figure 17. Cleft palate, micrognathia, and glossoptosis. (From Ortlepp. J., and Brandt. H. P. Klin. Mol. Augenheilk-148 [1966], 46.)

Figure 17. Cleft palate, micrognathia, and glossoptosis. (From Ortlepp. J., and Brandt. H. P. Klin. Mol. Augenheilk-148 [1966], 46.)

There is no apparent genetic pattern, although several familial examples have been described. The syndrome is more frequent in the offspring of elderly mothers: about 25 per cent have a history of intrauterine disturbance in early pregnancy. It seems probable that the pathogenesis of this syndrome is based on arrested development. Presumably the primary defect lies in the dysplastic growth of the mandible, from whatever cause. This prevents the normal descent of the tongue from between the palatal shelves. The disparity becomes quite apparent by the fourth or fifth month, the embryo being micrognathic during this stage. The growth of the jaws will progress so that an essentially normal profile is achieved by four to six years of age.

The facies is striking at birth (Figure 17). The mandible is small and symmetrically receded, producing an "Andy Gump" appearance. Commonly the base of the nose is flattened.

Difficulty in the inspiratory phase of respiration is apparent, being attested to by periodic cyanotic attacks, usually evident at birth in labored breathing and recession of the sternum and ribs. This becomes especially apparent when the child is supine.

Congenital murmurs and/or patent ductus arteriosus and foramen ovale, atrial and/or ventricular septal defect, ventricular hypertrophy, cor triloculare with coarctation of the aorta, biventricular aorta, and dextrocardia have been observed in about 15 to 25 per cent of patients who die in early infancy.

Congenital amputations, bilateral talipes equinovarus, hip dislocation, syndactyly, and sternal anomalies have been described. Ocular findings have included esotropia, congenital cataract, glaucoma, and microphthalmia. Low-set ears, deformed pinna, and deafness are less frequently observed. About 20 per cent of patients have exhibited major mental retardation.

The mandible has been described as having a foreshortened body, with a characteristic ratio of ramus to mandibular body length. The tongue has been said by some investigators to be small, by others to be normal, and by still others to be large. Ankyloglossia is a commonly associated complication.

The palatal defect may vary widely, from cleft uvula to clefting that involves two-thirds of the hard palate. The majority have a defect of intermediate degree. Cleft lip does not occur in combination with cleft palate in this disorder. We believe that cleft palate is an essential element of the anomaly.

CLEIDOCRANIAL DYSPLASIA

Cleidocranial dysplasia38'39 is transmitted as an autosomal-dominant trait. Patients are short in stature, with long necks and narrow shoulders. The face appears small (Figure 18), the nasal bridge is depressed, and the nose is broad at the base.

The skull is brachy cephalic, with marked frontal, parietal, and occipital bossing. Fontanels and sutures remain open, often for life. Wormian bones are formed through secondary centers of ossification in the suture lines. The paranasal sinuses are often underdeveloped or absent. Because of altered function of the sternocleidomastoid muscles, the mastoids are usually not pneumatized.

Several oral manifestations, such as supernumerary teeth and submucous or complete cleft palate, are present in the syndrome. The so-called pseudoanodontia is due to delayed eruption and impaction of deciduous, permanent, and supernumerary teeth. Probably the most prominent oral manifestation is the number of supernumerary teeth present; at times a third dentition is simulated.

The clavicles may be unilaterally or bilaterally aplastic or hypoplastic, generally at their acromial end. Because of this bony defect, patients with the disorder are able to approximate their shoulders in front of the chest.

Other observed bony anomalies include congenital dislocation of hip, late development of pubic symphysis, coxa vara or coxa valga, genua valga, scoliosis, kyphosis, and cervical ribs.

Figura 18. Cleidocranial dysplasia.

Figura 18. Cleidocranial dysplasia.

COCKAYNE'S SYNDROME

Cockayne's syndrome40'41 is characterized by (1) cachectic dwarfism, (2) premature aging, (3) mental deficiency, (4) microcephaly, (5) intracranial calcifications, (6) neurologic deficits, (7) retinal pigmentary abnormalities, (8} sensorineural deafness, and (9) photosensitivity. About 50 patients have been described, and autosomal-recessive inheritance has been established. Most patients have been of British origin.

Lack of subcutaneous fat of the face, particularly of the cheeks, gives prominence to the facial veins. This feature - combined with the microcephaly, sunken eyes, thin, often beaklike nose, large ears, and prognathism - gives a birdlike appearance to the patient Figure 19).

In nearly all patients there is enophthalmos. The retina is studded with fine, speckled pigment of the salt-andpepper type, with the greatest concentration in the macular area. Optic atrophy and arteriolar narrowing are also present. Cataracts develop by adolescence.

Figure 19. Cockayne's syndrome. (Courtesy of H. J. Grossman, University of Illinois College of Medicine, Chicago.)

Figure 19. Cockayne's syndrome. (Courtesy of H. J. Grossman, University of Illinois College of Medicine, Chicago.)

The progressive neurologic signs include cerebellar ataxia, choreoathetosis, moderate to severe mental deficiency, sensorineural deafness, and blindness. Neuropathologic studies of the brain have shown microcephaly; widespread mineralization in the cortex, basal ganglia, and cerebellum; and patchy demyelinization, often severe, in the subcortical white matter.

Photosensitivity is a prominent feature. The dermatitis appears on the sun-exposed parts of the body by the second year of life, with a butterfly arrangement on the face. The forehead is spared, but the pinnae and chin are affected. The photodermatitis may resuit in scarring and pigmentary changes in older patients. Subcutaneous fat appears to be decreased throughout the body except in suprapubic area.

Dwarfism is a prominent feature this disorder. Growth retardation comes evident during the second of life after a normal gestation, weight, and infancy. Kyphosis ankylosis are frequent. The limbs disproportionately large. Flexion tractures may involve the ankles, knees, and elbows, and the langeal joints of the hands and feet show periarticular thickening.

CONGENITAL DEAFNESS, WHITE FORELOCK, DYSTOPIA CANTHORUM, AND HETEROCHROMIA IRIDES

(Waardenburg's Syndrome)

This syndrome42'43 consists tially of (1) congenital deafness; (2) lateral displacement of medial canthi and lacrima! punctae, with broad nasal root; 3) white lock or poliosis; (4) irides; and (5) hyperplasia of the al portion of the eyebrows.

The disorder is inherited as an somal-dominant trait. It is that about 2 per cent of all deaf persons have the syndrome.

Although the interpupillary outer canthal distances are normal, there is an increased distance the inner canthi (dystopia canthorum), resulting in blepharophimosis. This pears to be the most constant (Figure 20). Little or no sclera may visible on the medial side, giving impression of convergent squint.

The inferior lacrimal points are ally displaced, being situated even far laterally as the cornea. In half of the patients, the eyebrows confluent in the midline and the medial ends are hyperplastic, characteristic may be less evident women because of their tendency to pluck these hairs.

Heterochromia irides or, more accurately, hypoplasia of the irides is seen in about 25 per cent of persons with the syndrome. It may be partial or total, both irides being completely blue. Especially striking is the presence of one blue and one brown eye or of two pale-blue eyes in a Negro. Commonly there is a peculiar pigmentary mottling at the periphery of the fundi.

There is minimal alar flare, resulting in narrow nostrils. The tip of the nose tends to be rounded and slightly upturned, revealing the columella.

A white forelock is present in fewer than one-fifth of affected persons, but when it is present, its effect is dramatic. Detection of this trait in females may be difficult because of their tendency to mask it by coloring the hair or because of a fashion for the creation of white forelocks. Premature graying of the eyebrows and lashes may also occur. Vitíligo is infrequent but may occur in this syndrome.

Figure 20. Congenital deafness, white forelock, dystopia canthorum. and heterochromia !rides.

Figure 20. Congenital deafness, white forelock, dystopia canthorum. and heterochromia !rides.

Congenital sensorineural deafness is present in about 20 per cent of patients. The degree is variable, ranging from mild to moderate bilaterally. Some patients have profound unilateral impairment. The deafness has been shown to be due to absence of the organ of Corti.

CONGENITAL INDIFFERENCE TO PAIN

(Congenital Insensitivity to Pain)

Dearborn described a syndrome in which there was complete congenital indifference to pain,44'45 resulting in injury to both soft and hard tissues and subsequent severe scarring. Trauma to bones causes aseptic necrosis, osteomyelitis, or fractures. The disorder is inherited as an autosomal-recessive trait.

Figure 21. Congenital indifference to pain.

Figure 21. Congenital indifference to pain.

There is total absence of reaction to painful stimuli. Deep tendon reflexes as well as the corneal reflex are often absent or diminished, but the thermal reflex is generally normal or mildly diminished.

Intelligence has ranged from dull to normal. Patients with severe mental retardation represent examples of other syndromes associated with indifference to pain.

Lack of pain sensation results in severe oral and paraoral mutilation. The tongue and lips are especially subject to injury, with resultant scarring. The characteristic facies will show mutilated lips, especially the lower. Scars and burns are also quite frequent. All these clinical findings should be conducive to the diagnosis of any of a group of disorders associated with indifference to pain (Figure 21). This becomes apparent as soon as the teeth appear, and may lead to early diagnosis. Extensive decay is not accompanied by toothache, and teeth may be lost early on this account. Some patients painlessly extract their own teeth.

Osteomyelitis, aseptic necrosis, fracture, Charcot's joint, and distal necrosis with spontaneous resorption of toes and fingers are virtually constant features. These complications have been ascribed to lack of pain sensation, the patient being unable to recognize trauma.

CRANIOCARPOTARSAL DYSPLASIA

(The Whistling Face Syndrome)

This syndrome46'*7 was originally described in 1938 by Freeman and Sheldon. Unaware of the earlier report, Burian in 1963 coined the term "whistling face syndrome." The syndrome is inherited as an autosomal-dominant trait.

The characteristic facies (Figure 22) presents deeply sunken eyes with true ocular hypertelorism. Convergent strabismus is common, as is a mild degree of blepharophimosis and ptosis. Antimongoloid obliquity of the lids is due to hypoplasia of the malar bones. The nose is small, with narrow nostrils and a long philtrum. The nasal alae are often bent, simulating nostril colobomas. Near the nasal tip the alae are of normal thickness, but they thin out backwards to be inserted close to the columella. The naso labial folds are seen only near the sides of the nose.

Since the central parts of the cheeks bulge excessively when the patient is whistling, a muscle deficiency is suspected. Microstomia is nearly always present, the intercommisural (interangular) distance being about twothirds that in a normal child of the same age. The lips are held as if whistling. The palate is high-arched, and the mandible is generally smaller than normal.

A typical finding is that of a fibrous band, demarcated by two paramedian grooves extending from the middle of the lower lip to the chin. This scarlike structure often presents an H or V shape.

Height is generally below the third percentile. Flexion contractures of the fingers have been present in all patients, the thumbs generally being affected at the metacarpophalangeal joint. Dinar deviation of fingers without bone anomalies and talipes equinovarus, generally bilateral, are constant features.

Less frequent anomalies include kyphoscoliosis, mild pectus excavatum, mild pterygium colli, asymmetric pinnae, and spina bifida occulta.

Figure 22.Craniocarpotarsal dysplasia. (From Weinstein, S., and Gorlin. R.J. Amer. J. Dis. Child-117[1969], 427.)

Figure 22.Craniocarpotarsal dysplasia. (From Weinstein, S., and Gorlin. R.J. Amer. J. Dis. Child-117[1969], 427.)

CRANIOFACIAL DYSOSTOSlS

(Crouzoris Syndrome)

Crouzoji's syndrome48,49 is characterized by (1) cranial synostosis, (2) bilateral exophthalmos with external strabismus, (3) parrot-beaked nose, and (4) relative mandibular prognathism with drooping lower lip.

The syndrome is inherited as an autosomal-dominant trait without complete penetrance. Not uncommonly, sporadic cases have been reported, representing new mutations.

The facies is easily recognized and is characterized by marked exophthalmos, ocular hyper tel or ism, and hypoplastic maxilla. This last feature produces a marked relative mandibular prognathism and short upper lip (Figure 23 ) . The cranium is brachycephalic, with frontal bossing and riding of the sagittal suture. The coronal, sagittal, and lambdoid sutures are prematurely synostosed. Increased digital markings are almost always present.

Exophthalmos is a constant feature, and is probably due to shallow orbits. At times there is spontaneous luxation of the eyes. Eighty per cent of patients have optic nerve damage. Nystagmus and mental retardation are occasionally seen.

Oral manifestations include hypoplastic maxilla, a V-shaped palatal arch in contrast to the normal U shape, dental malocciusion, and partial clefting of the palate.

Figure 23. Craniofacial dysostosis.

Figure 23. Craniofacial dysostosis.

CRANIOMETAPHYSEAL DYSOSTOSIS AND CRANIODIAPHYSEAL DYSOSTOSIS

Buried under various designations, such as leontiasis ossea and osteopetrosis, craniometaphyseal dysostosis80'51 consists of (1) alterations in the metaphyses of long bones - i.e., increased diaphyseal density and reduced metaphyseal modeling - and (2) bony overgrowth of the face and jaws, especially evident in the paranasal areas.

The disorder, usually transmitted as an autosomal-dominant trait, may also be inherited as a recessive trait.

A head that appears rather largewith an extremely broad and flat nasal bridge, ocular hypertelorism, and open mouth - gives the patient a vacuous expression (Figure 24). The open mouth is due to nasal blockage. Blindness, resulting from optic atrophy in early infancy, is not uncommon, and ocular hypertelorism has been a relatively constant finding. Facial nerve paralysis and deafness, presumably due to overgrowth of the foramina, have been common features.

Figure 24. Craniometaphyseal dysostosis.

Figure 24. Craniometaphyseal dysostosis.

Soon after birth the skull exhibits marked thickening and increased density of the vault with elimination of the diploë, especially in the frontal and occipital areas. The paranasal sinuses are similarly obliterated. The bones of the skull base, the maxilla, and the mandible also become enlarged, thickened, and increased in density.

Figure 25. Craniodiaphyseal dysostosis. (Courtesy of R. Lachman. Harbor General Hospital. Torrance, Calif.)

Figure 25. Craniodiaphyseal dysostosis. (Courtesy of R. Lachman. Harbor General Hospital. Torrance, Calif.)

Generalized late motor development is typical. Several patients have shown marked mental retardation, headache, vomiting, and irritability.

The long bones, especially the femurs, assume an "Erlenmeyer flask" shape in the metaphyseal area, with decreased density. The diaphyseal area is increased in density, the medullary bone being porotic and lacking the usually trabecular pattern. Similar changes are seen in the epiphyseal ends of the metacarpals and phalanges.

The blood count and serum calcium, phosphorus, and alkaline phosphatase are normal and may be used to rule out several entities.

What appears to be a different disease, yet has several facets in common with craniometaphyseal dysostosis, is craniodiaphyseal dysostosis (Figure 25). It is much more severe, producing marked facial distortion and severe mental retardation. The disorder is probably inherited as an autosomalrecessive trait. Consanguinity has been reported. Nasal obstruction and facial alteration are noticeable within the first few years. Vision fails by the seventh or eighth year.

Figure 26. Cryptophthalmia syndrome. (From lde, C. H., and Wollschlaeger, P. B. Arch. Ophthal. 81 [1969], 638.)

Figure 26. Cryptophthalmia syndrome. (From lde, C. H., and Wollschlaeger, P. B. Arch. Ophthal. 81 [1969], 638.)

There is marked sclerosis of the calvaria and facial bones, and the paranasal sinuses are overgrown. The ribs are widened and extremely dense, the clavicles being most severely affected and thickened in the midportions. The vertebrae, for the most part, are unaffected. The long bones are straight, with a thin cortex and a remarkably uniform thickness of the shaft. Similar changes are seen in the metacarpals and metatarsals. There is some degree of ballooning of the midportion of the shaft. Except in the first metacarpal, which shows some osteosclerosis, the cortex is thinner than normal.

CRYPTOPHTHALMIA SYNDROME

This syndrome 5Z. « consists of (1) extension of the skin of the forehead to completely cover one or both eyes, (2) total or partial soft-tissue syndactyly of fingers and/or toes, (3) coloboma of the alae nasi, (4) abnormal hairline, and (5) various urogenital abnormalities. The syndrome is inherited as an autosomal-recessive trait.

The eyebrows may be completely or partly missing. The globes can be seen and felt beneath the skin covering. In about 60 per cent of the cases, the cryptophthalmos is bilateral (Figure 26). Exposure to strong light may induce reflex wrinkling of the skin due to contraction of the orbicularis muscles. In case of unilateral cryptophthalmos, the opposite eye may exhibit lid coloboma, micr ophthalmia, or epibulbar dermoid. The conjunctival sac is partly or completely obliterated. The cornea has been shown to be differentiated from the sclera. The lens may be absent, hypoplastic, or calcified and displaced. Orbicularis and levator palpebrae muscles are normal, however.

Often the hairline is bizarre, extending over the entire temple area and tapering to a point in the skin of the forehead overlying the eyes.

The pinnae tend to be small. Not uncommonly, the skin of the upper part of the helix is continuous with that of the scalp. The external auditory meatuses are narrow. There is usually conduction loss, and malformed ossicles have also been noted.

In about 25 per cent of patients, there are mild colobomas of the nostrils. These may be unilateral or bilateral. Cleft lip and palate and ankyloglossia have been noted in 10 per cent of the cases. Laryngeal atresia or hypoplasia has been present in about 10 per cent.

Syndactyly has been noted in about 40 per cent of the cases. It may affect both the hands and feet.

Umbilical hernia occurs in about 20 per cent, and there has been a vast array of urogenital abnormalities observed, including cryptorchidism, hypospadias, male and female pseudohermaphroditism, chordee, micropenis, and agenesis of a kidney. Meningoencephalocele has been noted in about 10 per cent of the cases.

CUTIS LAXA SYNDROME

(Generalized Elastolysis)

The cutis laxa syndrome54-55 is characterized by (1) skin that hangs in loose folds, (2) emphysema, (3) hernia, and often (4) diverticulae of various organs.

Although the term "cutis laxa" was used initially to refer to Ehlers-Danlos syndrome or cutis hyperelastica, within the past two decades the name has been restricted to a condition in which the skin hangs in folds. Although it may occur later in life (acquired form) as a postinflammatory cutaneous phenomenon, we shall limit our discussion largely to the congenital forms.

There appear to be two congenital forms, the more common being a severe autosomal-recessive type. Parental consanguinity has been noted in several instances, and there have been affected sibs. Less common is a relatively benign autosomal-dominant form. Patients with the latter form seldom have more than sagging skin; a deep, resonant voice; and inguinal hernia.

Most manifestations of the syndrome can be explained on the basis of generalized elastolysis.

The drooping and ectropion of the eyelids, together with the sagging facial skin (jowls) and accentuation of the nasolabial and other facial folds, produce a "bloodhound" or aged appearance (Figure 27). An affected pubertal. child may look older than his parents!

The skin of the entire body appears too large, often hanging in folds. It is not hyperelastic, and there is no fragility or difficulty in healing.

Figure 27. Cutis laxa syndrome.

Figure 27. Cutis laxa syndrome.

A few children have exhibited late closure of the anterior fontanel. In some, somatic growth has been retarded and muscles have been hypotonic. Hip dislocation and joint hyperextensibility - as well as inguinal, diaphragmatic, and umbilical hernias - are not uncommon in the disorder.

Emphysema, a result of the generalized elastolysis, has been one of the most common features. This causes right- ventricular enlargement, bundlebranch block, cor pulmonale, and often death at an early age. Pulmonary stenosis and extremely tortuous blood vessels have been noted.

Diverticulae of the gastrointestinal tract, prolapse of the gastric and rectal mucosa, and bladder diverticulae have been described by several authors.

DE LANGE'S SYNDROME

The most characteristic features of this syndrome56'57 are (1) severe primordial growth failure, (2) mental retardation, (3) skeletal anomalies, (4) characteristic facies, and (5) hirsutism.

Most reported cases are isolated examples. Some familial cases have also been observed. The cause is still unknown, but we believe that it is multifactoral.

The facies is characterized by synophrys (fusion of eyebrows in the midline), low hairline at the forehead, hirsutism, long upper Hp, anteverted nostrils, depressed nasal bridge, long, profuse lashes, bilateral epicanthal folds, and ocular hypertelorism (Figure 28). During infancy a low-pitched, growling cry is present. The neck is short, and the ears are low-set.

Patients are generally mentally retarded, with an I. Q. of 50 or below. Height and weight are below the third percentile. Microcephaly is a constant feature. Hirsutism is also a common feature. The hair, of lanugo type, is especially evident on the shoulders, lower back, and extremities.

The most frequent skeletal anomaly is hypoplasia of the arm bones. These malformations range from peromelia to hypoplasia of a single digit. Other characteristic skeletal anomalies are short first metacarpal, hypoplastic middle phalanx of a curved fifth finger, and proximally placed thumb. Other bony anomalies include postaxial oligodactyly, syndactyly of second and third toes, short upper and lower extremities, narrow ribs, reduced number of sternal ossification centers, and abnormal sternal angle.

Cutis marmorata is frequently present.

Other associated anomalies have included congenital heart defect (12 per cent), cleft palate (10 per cent), and hypoplastic genitalia usually manifested as cryptorchidism. The female genitalia are generally normal. The umbilicus is usually very small.

Figure 28. De Lange's syndrome.

Figure 28. De Lange's syndrome.

DIASTROPHIC DWARFISM

In 1960, Lamy and Maroteaux defined a new syndrome that they designated "diastrophic dwarfism"58'59 to emphasize the progressive kyphoscotiosis that became evident during the first year of life.

The syndrome consists of (1) micromelic dwarfism, (2) talipes equinovarus with limited dorsiflexion, (3) anomalies of the pinna, (4) restricted joint motion, (5) progressive kyphoscoliosis, (6) adduction of thumbs and halluces, (7) severe epimetaphyseal ossification defects, and (8) cleft palate.

Diastrophic dwarfism is clearly inherited as an autosomal-recessive trait. Most commonly the disorder is erroneously considered to be atypical achondroplasia - a grievous mistake if genetic counseling is to be given.

The facies is not especially remarkable, although the cystic ears, if viewed in the florid hemorrhagic stage, can be quite striking. This process soon resolves, and plates of calcium can then be felt in the helices. Some patients have had a mildly depressed nasal bridge (Figure 29). At least 40 per cent have cleft palate.

The disproportionate dwarfism is especially marked. The limbs are severely shortened. The trunk is also foreshortened, but less so proportionately, as a result of the severe kyphoscoliosis that may be present at birth and progresses over the first few years of life. The feet are usually supinated and adducted. Attempts at correction have been doomed to failure. The hallux and thumb are often widely opposed and hypermobile ("hitchhiker's thumb"). The fingers are short, with extension contractures of the interphalangeal joints. The hands may be ulnar-deviated at the wrists. Most peripheral joints are markedly restricted in motion, and posterior dislocation of the ulna and subluxation of the knees are common. Progressive degeneration of the hips is a frequent finding, and ambulation becomes difficult.

Severe alterations in the metaphyses of long tubular bones may be seen roentgenographically. The epiphyses appear late and are severely flattened or deformed. The phalanges, metacarpale, and metatarsals are plump; their metaphyses are broad, and their epiphyses deformed. The first metacarpals are broad and have widened distal ends. The second, third, and fourth cervical vertebrae are often keel-shaped and produce a severe cervical kyphosis and subluxation, and the cervical spine appears to slide under the base of the skull. The thoracic and lumbar vertebrae are of normal height. The interpediculate distance in the lumbar area is essentially normal, a finding that clearly distinguishes this disorder from achondroplasia.

Figure 29. Diastrophic dwarfism. (From Spranger. J., and Gerken, H. Z. Kind. 98 [1967], 227.)

Figure 29. Diastrophic dwarfism. (From Spranger. J., and Gerken, H. Z. Kind. 98 [1967], 227.)

DOUBLE LIP, BLEPHAROCHALASIS, AND NONTOXIC THYROID ENLARGEMENT

(Ascher's Syndrome)

The syndrome of blepharochalasis, double Hp, and thyroid struma60'61 is of unknown origin, although vasomotor instability, hormonal dysfunction, and autosomal-dominant inheritance have been suggested.

An abnormal facies is produced by the combination of the sagging eyelids and the abnormal lip (Figure 30).

The upper lids, rarely the lower, are characterized by relaxation of the supratarsal fold, which allows the tissue between the eyebrows and the edge of the lid to hang slack over the palpebrai fissure. The Hd skin is markedly thin and atrophie. The atrophy and drooping of the Hd often follow repeated angioneurotic edemalike episodes. The swelling of the lids and the enlargement of the lips may occur simultaneously .

Figure 30. Double Mp1 blepharochalasis, and nontoxic thyroid enlargement. (Courtesy of K. S'tehr. Munich, West Germany.)

Figure 30. Double Mp1 blepharochalasis, and nontoxic thyroid enlargement. (Courtesy of K. S'tehr. Munich, West Germany.)

The upper lip is almost always the site of a horizontally running duplication located between the inner and outer parts. The fold cannot be seen when the lips are closed; it can be seen only when the patient is smiling or talking. The enlargement of the lip may exist from childhood. In rare cases the lower lip is also enlarged.

Thyroid gland enlargement is variable and not associated with toxic symptoms. It may appear several years after eyelid involvement but usually appears during the second decade.

DOWN'S SYNDROME

Down's syndrome (trisomy 21, trisomy GI, mongolism)62'63 was named for Dr. J. Langdon Down, who described the disorder in 1866.

The syndrome is due to the trisomie state for the 21st chromosome, produced by chromosomal nondisjunction, translocation, and chromosomal mosaicism. Down's syndrome due to nondisjunction comprises over 95 per cent of cases and is age-dependent; i.e., a mother of 45 years has about a onein-40 chance of producing a child with trisomy G1, while a mother of 20 years has perhaps a one-in-3,000 chance. Translocation is not age-dependent; while it comprises only 3 per cent of cases, genetic counseling is extremely important and amniocentesis may play a significant role. The frequency of trisomy GI is about 1.5 per 1,000 births.

The phenotype is characterized by an almost inordinate number of physical alterations, only the most common of which can be considered here.

The child with Down's syndrome is often born before term with low birth weight. Height is retarded throughout life: males rarely exceed 155 cm., while females are seldom taller than 145 cm.

The facies is usually quite distinctive (Figure 31). The head is brachycephalic, with the occiput flat and the neck short and broad. The tongue tends to protrude and exhibits papillary hypertrophy and furrowing. The palate is short. Cleft lip and/or palate occurs in about one of 200 children with Down's syndrome. Tooth eruption is often delayed.

The palpebrai fissures are oblique, sloping downward nasally; there are prominent epicanthal folds. The shape of the nasal bridge and epicanthal folds tends to give the impression that the eyes are farther apart than normal when in fact, in adults, they are about 5 mm. nearer one another than normal. The iris is often speckled (Brushfield's spots), the spots being arranged in a ring concentric with the pupil. Lens opacities and convergent strabismus are seen in at least a third of cases.

The pinnae are often bizarre; the helix is often angular and overlapping, the antihelix prominent, and the lobe absent or hypoplastic.

Cardiac anomalies are frequent in about 20 per cent), the most common being atrioventricular canal and ventricular septal defects. They frequently result in death within the first year of life. There is also an increase in the incidence of isolated aberrant subclavian artery. An association between acute leukemia and mongolism has been noted.

The newborn 21-trisomic is hypotonic, and motor development is retarded, although most sit by the age of one year and learn to walk between two and three years of age. The abdomen tends to be prominent. Umbilical hernia and diastasis recti occur in about 10 per cent, and duodenal atresia has increased frequency. The pubic hair is invariably straight. The beard and axillary hair are scanty. Libido is markedly diminished, and no proven case exists of a 21-trisomic's fathering a child,

Roentgenographic alteration also may be noted. The hands are short and broad, and there is flattening of the lower edges of the iliac bones and widening and flaring of the iliac wings.

Although the vast majority (in spite of the term "mongoloid idiocy") are imbeciles - i.e., having an LQ. of 25-49 - there have been children with trisomy Gi with an LQ. as high as 75. It has been demonstrated that children with Down's syndrome reared at home have I. Q. s higher on the average than those raised in institutions. The social age of the child with trisomy G1 is ordinarily advanced by several years over his mental age.

Dermatoglyphic alterations are many, but the most constant are distal axial triradii, decreased thenar patterns, increased hypothenar patterns, and fingerprint ulnar loops. A radial loop, if it occurs, tends to be on the fourth or fifth finger. Clinodactyly (in over 50 per cent), a single flexion crease (in about 25 per cent) on the fifth finger, and a characteristic transverse fold (four-finger line, simian crease), seen in 30 to 60 per cent, aid in diagnosis. Hallucal dermatoglyphic patterns common in trisomy G1 are the tibial arch (in about 50 per cent) and small distal loop (in about 35 per cent).

Figure 31. Down's syndrome. (From Goodman, R. M., and Gorlin, R. J. The Face in Genetic Disorders. St. Louis: The C.V. Mosby Company, 1970.)

Figure 31. Down's syndrome. (From Goodman, R. M., and Gorlin, R. J. The Face in Genetic Disorders. St. Louis: The C.V. Mosby Company, 1970.)

Dq- AND Dr SYNDROMES

Over 30 case reports have been published in which the patient had deficiency of part of the long arm of a D-group chromosome (Dq-) or in which a D-group chromosome was replaced by a ring (Dr).64'65 Although these cases may represent a heterogeneity, there is good evidence to suggest that most have to do with chromosome No. 13.

Mean survival has been 39 months for Dq- cases and 89 months for Dr examples.

All patients have exhibited mental and somatic retardation, and many have been hypotonie. Microcephaly has been present in 60 to 80 per cent of the cases, with some exhibiting various degrees of holoprosencephaly.

Unilateral or bilateral retinoblastoma has been documented in over one-quarter of the Dq- cases but in only one example of Dr syndrome. Other eye defects, present in almost half of the cases, include microphthalmia, iris and/or retinal coloboma, and apparent hypertelorism (Figure 32). Cleft palate has been noted in several examples of the Dq- syndrome.

Ventricular septal defect or malformation of the aorta has been reported in about 50 per cent.

Musculoskeletal abnormalities have included bilateral hip dislocation, focal lumbar vertebral agenesis, inguinal hernia, coxa valga, and synostosis of the fourth and fifth metacarpale. Absent or hypoplastic thumbs have been described in about 70 per cent of the Dq- cases but in less than 30 per cent of the Dr cases.

Genitourinary anomalies- hypospadias, cryptorchidism, cleft or hypoplastic scrotum, micropenis, and pelvic kidney - have been frequent. Anal atresia has also been described.

Dermatoglyphic alterations, other than increased frequency of simian creases, have not been remarkable.

DYKE-DAVlDOFF SYNDROME

The syndrome first described in 1933 by Dyke, Davidoff, and Masson66'67 consists of (1) mental retardation, (2) seizures, (3) facial asymmetry, and (4) contralateral hemiplegia. A triad of roentgenographic findings in the skull consisting of (1) homolateral thickening of the calvaria, (2) hypertrophy of the frontal sinuses, and (3) elevation of the sphenoid wings must be present to confirm the diagnosis.

The syndrome is not inherited. Neonatal injury and severe neonatal disease affecting one side of the brain are possible causative factors. Some degree of mental retardation is a consistent finding.

Figure 32. Dq- syndrome- (From DePra, M., GiIIi. G.. and Vianello. M. G. Minerva Peaiatr. 21 [1969], 1009.)

Figure 32. Dq- syndrome- (From DePra, M., GiIIi. G.. and Vianello. M. G. Minerva Peaiatr. 21 [1969], 1009.)

The characteristic facies is a normal full side with the eye appearing wider than normal (Figure 33). Some degree of visual disturbance is often found on the affected side, but blindness is unusual. The smile is asymmetrical. There may be varying degrees of hemiplegia, neurologic impairment, and atrophy of the contralateral side of the body. A mixed seizure disorder is a consistent finding but may be absent in the younger child.

There is lack of development of the brain on the affected side. This hemiatrophy accounts for the roentgenographic findings and the facial asymmetry that becomes increasingly apparent as the child grows older.

Chromosomal analysis and amino acid studies have been normal.

Figure 33. Dyke-Davidoff syndrome.

Figure 33. Dyke-Davidoff syndrome.

DYSCEPHALY, SAETHRE-CHOTZEN TYPE

(Acrocephalosyndactyly Type 3, Chotzen's Syndrome)

This syndrome,68'69 first described by Saethre in 1931 and Chotzen in 1932, has been referred to as "pseudoCrouzon" syndrome, familial craniostenosis, or oxycephaly.

The syndrome is inherited as an autosomal-dominant trait with marked penetrance and variable expressivity. Isolated cases probably represent new mutations.

The crani ostenosis is of varying degree but with asymmetric facies characterized by protruding forehead, depressed nasal bridge, large parrotshaped nose with septum deviation, and low-set hairline (Figure 34).

Figura 34. Dyscephaly, Saethre-Chotzen type.

Figura 34. Dyscephaly, Saethre-Chotzen type.

Early closure of cranial sutures may result in increased intracranial pressure with associated microcephaly, mental retardation, and visual problems.

Ptosis of the eyelids, tear-duct anomalies, and strabismus are common findings. Some patients have mild sensorineural deafness and others small deformed pinnae.

High arched palate is a frequent finding. In addition, cleft palate and pegging of the maxillary lateral incisor are occasionally seen.

The hands tend to be small. Occasionally, clinodactyly of the fifth finger may be observed, Syndactyly, if present, will be manifest as a webbing between proximal phalanges 2-3 or 3-4 in the hands and 2-3 in the feet, Hallux valgus may also be present. Simian creases are observed in most patients.

EHLERS-DANLOS SYNDROME

In 1901, Ehlers described the association of (1) hyperelastic skin, (2) skin hemorrhages, and (3) loose jointedness. In 1908, Danlos added (4) cutaneous pseudotumors. Several varieties of the syndrome70'71 are now recognized, most having autosomal-dominant inheritance. Another variety is X-Iinked. Another type, apparently autosomalrecessive, is characterized by severe ocular complications leading to blindness.

The basic defect in the syndrome seems to be an abnormality in the organization of the collagen bundles, with consequent increase in elastic fibers.

Frontal bossing, "lop ears," and bilateral epicanthal folds with an apparent broad nasal root are frequent facial findings (Figure 35). Ocular manifestations that occur less often than bilateral epicanthal folds are blue sclera and angioid streaks.

Figure 35. Ehlers-Danlos syndrome. (From Gorlin, R. J.. and Pindborg, J. J. Syndromes of ihe Head and Neck. New York: McGraw-Hill Book Co.. Blakiston Division. 1964.)

Figure 35. Ehlers-Danlos syndrome. (From Gorlin, R. J.. and Pindborg, J. J. Syndromes of ihe Head and Neck. New York: McGraw-Hill Book Co.. Blakiston Division. 1964.)

The skin, especially over the joints, is hyperelastic and has a velvety feel. After being stretched, it returns to its normal position. Skin fragility is responsible for gaping wounds and easy bruising, with marked subcutaneous bleeding. Healing of the skin results in papyraceous scars. Molluscoid pseudotumors and calcified subcutaneous spheroids over bony prominences of the forearms and shins are commonly observed.

Joint hyperextensibility is perhaps the most outstanding feature of the syndrome. Habitual dislocation of the joints, pes planus, and genu recurvatum are usually seen. Scoliosis and kyphoscoliosis, when present, are not severe. Osteoarthritic changes, probably due to recurrent dislocation, occur in the weight-bearing joints of most affected adults. Thoracic asymmetry, hernia, and mild muscular hypotonicity also may be seen.

Diverticula of almost every part of the gastrointestinal tract have been reported. Several patients have died of spontaneous rupture of main arteries or dissection of the aorta.

1Sq-SYNDROME

This disorder72 was first described by de Grouchy in 1964. Birth weight is generally below 2,700 gm. Maternal age is not elevated. In some cases the disorder is due to translocation.

Mental retardation is profound, and few patients have an I. Q. over 30.

Midfacial hypoplasia and mild microencephaly (Figure 36) are characteristic. The eyes are deep-set, and there are frequent ophthalmologic defects: glaucoma, strabismus, nystagmus, tapetoretinal degeneration, optic atrophy. The nose is short. A small subcutaneous nodule may be present at the site of cheek dimples. The mouth is carp-shaped in 75 per cent of patients. The pinnae are somewhat unusual, the antitragus and antihelix being especially prominent. The ear canals are atresic in over 50 per cent. In several cases, cleft lip and/or cleft palate has been noted.

Figure 36. 18q- syndrome (Courtesy ol J. Stewart, University of Colorado School of Medicine, Denver.)

Figure 36. 18q- syndrome (Courtesy ol J. Stewart, University of Colorado School of Medicine, Denver.)

IgA has been diminished in some cases.

Fingerprint whorls characteristically exceed five, and there may be a high frequency of large composite patterns.

Somatic growth is also retarded. Hypotonia and seizures are frequent. The voice is often low-pitched. Skin dimples may be present over the subacromion and epitrochlear areas, lateral to the patellae, and over the knuckles. The fingers are long and tapering. Skeletal anomalies are limited to supernumerary ribs. Congenital heart anomalies are present in over 65 per cent. The genitalia are hypoplastic in both sexes, the labia, clitoris, and penis being small.

ENCEPHALOFACIAL ANGIOMATOSIS

(Sturge-Weber Syndrome)

This syndrome73'74 is characterized by (1) venous angiomas of the leptomeninges overlying the cerebral cortex, with ipsilateral angiomatous lesions of the face; (2) ipsilateral gyriform calcifications of the brain; (3) epilepsy; (4) mental retardation; (5) ocular impairment; and (6) contralateral hemiplegia.

The cause of the syndrome is unknown. Neither sex preponderance nor predilection for affliction to either side of the face is present.

The presence of an angioma of the leptomeninges over the posterior parietal and occipital lobes is characteristic. This angiomatosis is formed by thin-walled venous vessels that calcify after the second year of life. Radiographically, the intracraneal calcifications show a convolutional and gyriform pattern with peripheral doublecontoured ("tram-line") lines.

Figure 37. Encephalolacial angiomatosis. (From Gorlin, R. J., and Pindborg, J. J. Syndromes of the Head and Neck. New York: McGraw-HIII Book Co., Blakiston Division, 1964.)

Figure 37. Encephalolacial angiomatosis. (From Gorlin, R. J., and Pindborg, J. J. Syndromes of the Head and Neck. New York: McGraw-HIII Book Co., Blakiston Division, 1964.)

Ipsilateral to the cerebral angiomatosis, a nevus flammeus (port-wine nevus) frequently occurs on the face (Figure 37). Over 85 per cent of patients have the facial nevus present at birth. It is generally unilateral. The color varies from pink to purplish red and often decreases in intensity with age.

Choroidal angioma, buphthalmos, and glaucoma are the most frequent ocular findings. The glaucoma may be due to an associated abnormality of the anterior chamber angle.

About 90 per cent of the patients have epilepsy, with their symptoms appearing in infancy. Seizures are contralateral to the angiomatosis, commonly focal, although generalized convulsions may be seen.

One-third of children with the syndrome are mentally retarded. Intelligence may improve, however, after surgical excision of the diseased portions of the brain. In some cases vascular abnormalities affect the extremities, lungs, gastrointestinal tract, trunk, and ovaries.

The most frequent oral sign is the presence of vascular hyperplasia of cheek, lips, and gingiva. The palate is less frequently affected. The tongue may present either telangiectasia or hemihypertrophy. The gingiva exhibits a characteristic enlargement, ranging from slight vascular hyperplasia to monstrous masses, making closure of the mouth impossible. The gingival mass is soft and purple, and the decoloration usually stops at the midline of the palate. The facial nevus generally stops at the outer margin of the philtrum. In some cases the hyperplasia of the gingiva is due to a combination of vascular and collagen hyperplasia, the latter due to diphenylhydantoin medication used in many of these patients.

ERYTHEMA MULTIFORME EXUDATIVUM

(Stevens-Johnson Syndrome)

This syndrome75'76 is seen mainly in young adults, predominantly males. It is a self-limited, frequently recurrent disease with an acute onset and may last from one to several weeks. The initial manifestation is usually an upper respiratory infection (tonsillitis, rhinitis, pharyngitis, bronchitis) associated with headache, nausea, malaise, and/ or arthralgia. Fever may be present in the early stage.

In some cases there may be a history of allergy or drug idiosyncrasy, but most cases are idiopathic.

The face shows congested conjunctivas with fibrinomembranous exudate. Marked photophobia is almost always present. The lips have shallow erosions covered by a hemorrhagic and necrotic pseudomembrane. This process develops into extensive crust formations, giving a typical red-brown appearance to the lip (Figure 38) .

Skin lesions may occur anywhere, but they are predominantly on the dorsum of hands and feet. The basic skin lesion shows an annular pattern that may vary in size and form from maculopapular to vesiculobullous. The lesions are usually symmetrically distributed.

Oral lesions usually appear after the skin involvement. In some cases, however, the sequence is reversed. Occasionally one can see oral involvement without cutaneous manifestations. Intraoral lesions occur on the buccal and gingival mucosa, tongue, and hard and soft palate. The ruptured oral vesicles become confluent and are covered by a necrotic pseudomembrane. The lesions are secondarily infected, complicating the clinical picture. Other mucous membranes may also be involved, penis and vulva being most frequently affected. Bronchitis, bronchopneumonia, and ulcération of the gastrointestinal tract also occur.

Figura 38. Erythema multiforme exudativum.

Figura 38. Erythema multiforme exudativum.

FAMILIAL DYSAUTONOMIA

(Riley-Day Syndrome)

This disorder"-7* was first recognized in 1949 by Riley et al. It is transmitted as an autosomal-recessive trait and is virtually limited to persons of Ashkenazi-Jewish extraction. An estimation of the frequency of dysautonomia among American Jews is approximately 1 in 10,000. A similar finding was noted in Israeli Jews of Ashkenazic extraction. No specific enzyme defect has been demonstrated.

Figure 39. Familial dysautonomia.

Figure 39. Familial dysautonomia.

The syndrome becomes evident soon after birth with difficulty in swallowing and by régurgitation. Absence of tears and corneal anesthesia, with resultant corneal ulcération, skin blotching, insensitivity to pain (which may result in Charcot's joints as the child grows older), motor incoordination, excessive sweating, high fever of unknown cause, diminished gag reflex, frequent vomiting and breath-holding spells that may result in loss of consciousness, and a mild degree of retardation are the most frequent findings during the first three years. There may also be ataxia and scanning nasal speech (dysarthria).

The facies quite characteristically exhibits a transverse elongated mouth with symmetrical facial drooping (Figure 39). The tongue shows an almost complete absence of fungiform and circumvallate papillae. Associated with this is a decreased sensitivity to sweet and bitter tastes. This is a consistent pathognomonic feature of the RileyDay syndrome.

Postural hypotension and paroxysmal hypertension may develop later in life. Stature is small, and physical growth and psychomotor development are delayed. Severe progressive kyphoscoliosis commonly appears around the eighth or ninth year of life.

There is a marked tendency to recurrent bronchopneumonia, probably owing to the frequent aspiration of food. Twenty-five per cent of patients succumb from pulmonary infection by the end of the first decade. Males seem to have a significantly poorer chance of survival up to the sixth year of age.

FETAL FACE SYNDROME

(Robinow-Silverman Syndrome)

Described initially by Robinow et al. in 1969, this syndrome7,80 consists of characteristic facies, forearm brachymelia, and hypoplastic genitalia. It is inherited as an au toso mal-dominant trait.

The facies (Figure 40) resembles that of the fetus at eight weeks - i.e., there is disproportionately large neurocranium, bulging forehead, ocular hypertelorism, S-shaped lower eyelids, short upturned nose with anteverted nostrils, and triangular mouth with downturned angles.

Figure 40. Fetal tace syndrome. (Courtesy of M. Robinow, Yellow Springs, Ohio.)

Figure 40. Fetal tace syndrome. (Courtesy of M. Robinow, Yellow Springs, Ohio.)

Growth is at the lower level of normal at birth and during the neonatal period but falls below the third percentile by the third year of life.

Forearm brachymelia is a constant feature, and the ratios of the upper to lower arm and height to span are excessive. Hemivertebrae and minor anomalies of the radius, ulna, metacarpale, and phalanges have been noted.

The penis may not be apparent at birth. With time it becomes less hypoplastic. The scrotum and testicles are normal. The clitoris and labia minora are hypoplastic.

FOCAL DERMAL HYPOPLASIA SYNDROME

This syndrome,81'82 originally described by Goltz et al. in 1962, consists of (1) atrophy and linear pigmentation of the skin, (2) localized superficial fatty deposits in the skin, (3) multiple papillomas of mucous membranes or periorificial skin, and (4) anomalies of the extremities, including syndactyly, oligodactyly, and adactyly.

The face exhibits varied eye anomalies, such as strabismus, coloboma of the iris and/or choroid, and microphthalmia. The most striking finding is the presence of multiple papillomas of the lip (Figure 41).

Streaky pigmentation, atrophy, and telangiectasia are usually present at birth over the trunk and extremities. Reddish-yellow nodules of subcutaneous fat, arborescent papillomatosis of the skin or mucosa of the oral, anal, or genital regions, and paper-thin nails have been associated with the syndrome.

Figure 41. Focal dermal hypoplasia syndrome. (From Gorlin, RJ., et al. Acta Derm. 43 [1963], 421.)

Figure 41. Focal dermal hypoplasia syndrome. (From Gorlin, RJ., et al. Acta Derm. 43 [1963], 421.)

Bilateral syndactyly of variable degree between digits, polydactyly, absence or hypoplasia of a digit or hand bone, clinodactyly, scoliosis, spina bifida, and hypoplasia of the right clavicle are frequent findings.

Umbilical and/or inguinal hernia, joint hypermobility, microcephaly, and mental retardation also have been noted.

Several oral anomalies, such as hypoplasia of enamel and hypodontia, have been reported. Papillomas of the gingiva and buccal mucosa are less frequently seen.

FRONTOMETAPHYSEAL DYSPLASIA

Frontometaphyseal dysplasia"'84 was recognized as an entity by Gorlin and Cohen in 1969. Inheritance is autosomal-dominant .

The facies is quite striking, presenting a pronounced supraorbital ridge, mild facial asymmetry, wide nasal bridge, slight antimongoloid obliquity of palpebrai fissures, hirsutism above the eyebrows, and a small pointed chin (Figure 42).

Radiographie alterations include thick frontal ridge, absence of frontal sinuses, defects of the supraorbital rims, antegonial notching of the lower mandibular border, as well as hypoplasia of the angle and condyloid process. The occiput has an abnormal relationship to the first cervical vertebra, with the foramen magnum being distally placed.

Figure 42. Frontometaphyseal dysplasia. (From Gorlin, R. J. Birth Def. OrIg. Art. Ser. 5:2 1969], 65.)

Figure 42. Frontometaphyseal dysplasia. (From Gorlin, R. J. Birth Def. OrIg. Art. Ser. 5:2 1969], 65.)

Conductive deafness due to bony changes appears to be part of the syndrome.

The long bones present an increased density in the diaphyseal region, with lack of modeling of the metaphyseal region, producing an Erlenmeyer flasktype deformity. With the exception of the pisiform, carpal bones are fused into a conglomerate mass.

Marked flaring of the iliac bones and coxa valga are also present. Associated anomalies may include pectus carinatum; generalized body hirsutism; arachnodactyly and camptodactyly of the fingers; clinodactyly of the toes; ankylosis and diminished motion of the elbows, wrists, knees, and ankles; keloid formation; and dental malocclusion.

Differential diagnosis should include Pyle's disease and craniometaphyseal dysplasia.

FRONTONASAL DYSPLASIA

Frontonasal dysplasia85-86 is a nongenetic, congenital disorder whose manifestations are limited to the head. The syndrome consists of (1) ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose or both the nose and upper lip and, at times, the palate; (4) uni- or bilateral clefting of the ala nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum; and (7) V-shaped hair prolongation into the forehead, generally over the area of ihe cranium bifidum. The disorder presents variable clinical combinations. DeMyer called the disorder the median cleft face syndrome.

The anomaly is probably produced by interference with the normal embryologie development of the face, especially the nose. This interference takes place at different stages of development, producing four closely related clinical types that are identified as follows:

Figure 43. Frontonasal dysplasia - facies A. (Courtesy ol F. Burian, Prague.)

Figure 43. Frontonasal dysplasia - facies A. (Courtesy ol F. Burian, Prague.)

Figure 44. Frontonasal dysplasia - facies B. (From DeMyer, W. Neurology 17 [1967], 961.)

Figure 44. Frontonasal dysplasia - facies B. (From DeMyer, W. Neurology 17 [1967], 961.)

Figure 45. Frontonasal dysplasia - facies C. (From Sedano, H. O., et al. J. Peöiaf. 76 [1970], 906.)

Figure 45. Frontonasal dysplasia - facies C. (From Sedano, H. O., et al. J. Peöiaf. 76 [1970], 906.)

Figure 46. Frontonasal dysplasia - facies D. (From Sedano, H. O., et al. J. Pediat 76 [1970], 906.)

Figure 46. Frontonasal dysplasia - facies D. (From Sedano, H. O., et al. J. Pediat 76 [1970], 906.)

Facies A. Ocular hypertelorism, broad nasal root, and median nasal groove with absence of the nasal tip. True clefting of the midline is not present (Figure 43).

Facies B. Ocular hypertelorism, broad nasal root, and deep median facial groove or true cleft affecting the nose or both the nose and the upper lip. The palate may also be cleft (Figure 44).

Facies C. Ocular hypertelorism, broad nasal root, and uni- or bilateral notching of the ala nasi (Figure 45).

Facies D. Combination of facies B and C (Figure 46).

Anterior cranium bifidum occultum can be present in all four types. The varied and sporadic associated anomalies reported in some cases are probably adventitious findings unrelated to the condition.

Cleft lip and/or cleft palate is associated with facies B and D.

Frontonasal dysplasia should be differentiated from nasal glioma. The latter presents a normal configuration of the tip and alae of the nose, and true ocular hypertelorism is not present.

Figure 47. Hereditary progressive arthroophthalmopathy. (From Gortin. R. J., and Knobloch, W. H. Z. Kinderheilk 113 [1972], 81.)

Figure 47. Hereditary progressive arthroophthalmopathy. (From Gortin. R. J., and Knobloch, W. H. Z. Kinderheilk 113 [1972], 81.)

HEREDITARY PROGRESSIVE ARTHROOPHTHALMOPATHY

(Stickler's Syndrome)

Stickler et al. first described five generations of a family with a syndrome87-88 composed of (1) progressive myopia and (2) arthropathy. The disorder is inherited as an autosomaldominant trait with complete penetrance and variable expression.

Patients have a facies characterized by depressed nasal bridge, maxillary hypoplasia, and long philtrum (Figure 47). Progressive myopia (to -18 diopters) is frequently associated with lattice degeneration and retinal detachment, especially in childhood, accompanied by glaucoma and amblyopia.

Joint impairment is characterized by irregularly shaped articular surfaces and enlargement of the joints with marked stiffness, progressive impairment of locomotion, and pain. Occasionally, subluxation of the hip joints is observed. The spine shows narrow intervertebral spaces and flattened vertebral bodies, sometimes leading to kyphosis and, occasionally, to scoliosis. Thoracic kyphosis and mild flexion in the hips, knees, and ankles constitute the typical body posture. Abnormal development of the epiphyseal plates in the vertebrae and long bones appears to be causally related to the skeletal defects.

Cleft palate or submucous palate and bifid uvula is a common finding. Progressive sensorineural hearing loss also has been seen associated with the syndrome.

juvenile retinal detachment, cleft palate, and maxillary hypoplasia without severe arthropathy but with a similar facies to that seen in Stickler's syndrome have been referred to as Wagner's or Cervenka's syndrome, which is also inherited as an autosomaldominant trait.

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