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In this paper, the etiology of monostotic fibrous dysplasia and McCune-Albright syndrome is explained. Both monostotic fibrous dysplasia and McCune-Albright syndrome are sporadically occurring disorders in which a mutation in the GNAS1 gene occurs postzygotically in a somatic cell. All cells descended from the mutated cell can manifest features of McCune-Albright syndrome or fibrous dysplasia. Cells descended from non-mutated cells develop into normal tissues. Thus, the clinical pattern is variable in distribution and appearance. More generalized vs more localized expression depend on (a) how small or how large the cell mass is during embryogenesis when the mutation occurs and (b) where in the cell mass the mutation occurs. Topics discussed include G proteins and their receptors, cycling of stimulatory G protein between active and inactive forms, and specific mutations in GNAS1. We also discuss four possibilities: (a) Are there masked mutations? (b) Are there effects of imprinting? (c) Are there non-classical mutations? and (d) Is fibrous dysplasia a neoplasm?

To understand the molecular biology of the nevoid basal cell carcinoma syndrome, the hedgehog signaling network is explained. The syndrome is caused by mutations in patched, a tumor suppressor gene. A single point mutation in one patched allele may be responsible for the malformations found in the syndrome. Inactivation of both patched alleles results in the formation of tumors and cysts (basal cell carcinomas, odontogenic keratocysts, and medulloblastomas). Several new hypotheses are proposed to account for a minority of nevoid basal cell carcinoma syndrome patients. Evidence is provided to suggest that these hypotheses deserve to be investigated.

This is the second of three articles on modern genetic concepts of a number of syndromes and disorders. Three short limb skeletal dysplasias with additional abnormalities of the skull are discussed. All are caused by mutations on fibroblast growth factor receptor 3 (FGFR3). A pathogenetic hypothesis is proposed to explain differences in the severity of short stature, midface deficiency, and craniosynostosis.

This is the first of three articles on modern genetic concepts of a number of syndromes and disorders. About 1% of cancer mutations arise in the germline and produce a variety of neoplasms and hamartomatous syndromes. However, upward of 10-15% of all cancers have a major inherited component, although many of these are still enigmatic. The genetic basis is presented and following a review of many neoplasms and hamartomatous syndromes, the RET proto-oncogene is discussed as an example.

Twenty-one patients with frontonasal dysplasia were studied. A 2:1 male-to-female sex ratio and increased paternal and maternal ages at the time of conception were found. The significance is uncertain because of small sample size and lack of normal mean values for parental age in Brazil. Apparently, our series is the first to report macrocephaly (six cases). Our series also had a high frequency of patients with agenesis of the corpus callosum (12 cases), basal encephalocele (10 cases), lipoma of the corpus callosum (four cases), and mental deficiency (11 cases). Three patients had the combination of agenesis of the corpus callosum, mental deficiency, and micropenis. It is concluded that frontonasal dysplasia is pathogenetically heterogeneous, representing a regional defect which may not be a single developmental field or sequence. Causal genesis includes a dominantly inherited form, dup(2q), and autosomal recessive Shanske syndrome. Of unknown genesis are two subsets of frontonasal dysplasia patients: 1) the combination of agenesis of the corpus callosum, tibial hypoplasia, and hallucal duplication and 2) ophthalmofrontonasal dysplasia or oculoauriculofrontonasal dysplasia with associated ear tags and epibulbar dermoids.

A clinical study of the craniofacial features in Apert syndrome is based on our experience with 136 cases. Characteristics included hyperacrobrachycephaly, steep wide forehead, flat occiput, common craniofacial asymmetry, ocular hypertelorism and proptosis, downslanting palpebral fissures, divergent upgaze and esotropic downgaze, a tendency towards large ears, and marked depression of the nasal bridge. The nose is short and wide with a bulbous tip, and the anterior facial height is reduced. Common features during infancy included horizontal grooves above the supraorbital ridges that disappear with age, a break in the continuity of the eyebrows, and a trapezoidal-shaped mouth at rest. Radiographic aspects of Apert syndrome were also assessed. Tables are provided which compare the craniofacial features of Apert and Crouzon syndromes.

Normal pre- and post-natal changes in the interorbital distance are described. Causes of illusory hypertelorism include flat nasal bridge, epicanthic folds, exotropia, widely-spaced eyebrows, narrow palpebral fissures, and dystopia canthorum. Measurements of hypertelorism may involve soft tissues or bone, and a number of indices have also been proposed. Various types of measurements are evaluated and recommendations suggested. Possible pathogenetic mechanisms for hypertelorism include: early ossification of the lesser wings of the sphenoid; failure in nasal capsule development allowing the primitive brain vesicle to protrude into the space normally occupied by the capsule resulting in morphokinetic arrest in the position of the eyes; and disturbances of the cranial base in Apert syndrome. Associations with increased interorbital distance are also discussed: orofacial clefting, nonprotruding lipomas of the corpus callosum, calcification of the falx cerebri, duplication of the crista galli, wrinkling of the nose, and tissue tags of the nose. Finally, experimental models of hypertelorism in animals are discussed.

The craniosynostoses are both etiologically and pathogenetically heterogeneous and many syndromes have been delineated. The present paper highlights well-known craniosynostoses that can present asymmetrically. These include plagiocephaly resulting from premature unilateral synostosis of the coronal or lambdoid sutures. Apert syndrome, and Saethre-Chotzen syndrome.

The hamartoses are a large group of disorders with autosomal dominant inheritance or sporadic occurrence. The genes responsible for some have been localized to specific chromosomes and in several instances, genetic heterogeneity has been established. Thus neurofibromatosis and tuberous sclerosis are no longer single entities. For example, the gene for Type I neurofibromatosis is on chromosome 17 and the gene for Type II is on chromosome 22. In this paper, genetic aspects of the hamartoses are updated and asymmetry is discussed in Sturge-Weber angiomatosis, epidermal nevus syndrome, Gardner syndrome, neurofibromatosis, and Proteus syndrome.

Hemi-asymmetries discussed here include: 1) hemihyperplasia which may affect either one tissue such as bone with secondary regional consequences or multiple tissues on a primary basis such as "hemihypertrophy"; 2) hemihypoplasia which may also affect one tissue such as bone with secondary regional consequences or multiple tissues on a primary basis such as in hemifacial microsomia; 3) hemiatrophy, the quintessential craniofacial disorder being Romberg syndrome; and 4) miscellaneous conditions such as Bencze syndrome and hemimaxillofacial dysplasia.

Mandibular asymmetry may be caused by infection or trauma. Unilateral facial paralysis has many causes and Bell's palsy, which is idiopathic, is the most common type. Asymmetric muscle involvement is discussed, including the masseter, temporalis, depressor anguli oris, extraocular, and sternocleidomastoid muscles. Tumors that present asymmetrically are also considered, including the juvenile hemangioma, lymphangioma, osteoma, embryonal rhabdomyosarcoma, and Burkitt's lymphoma. Finally, some miscellaneous conditions are discussed, including fibrous dysplasia, mucus retention phenomenon, electrical burns of the mouth, and cancrum oris.

Part I introduces the survey and presents a topic outline of the six parts that make up this series of articles on craniofacial asymmetry. The discussion in Part I considers normal variation, normal and abnormal laterality, types of anomalies that may be asymmetric, and finally, some well-known causes of craniofacial asymmetry.

Asymmetric embryopathies--severe malformations and disruptions--that affect the craniofacial region are discussed, including anomalies of the eye, nose, mouth, and ear. Asymmetric Tessier clefts are also discussed.

An indirect method for estimating the birth prevalence of the Apert syndrome is presented. The fraction of Apert syndrome patients in large clinical surveys of all cases of craniosynostosis is calculated and the fractional component obtained is multiplied by the known birth prevalence of craniosynostosis in general. Apert syndrome makes up approximately 4% of all cases of craniosynostosis. Using a weighted average estimate, birth prevalence was calculated to be 13.7/1,000,000. The results of the indirect method compare favorably with those obtained by the direct method. Nevertheless, because the indirect method is based on a number of assumptions that are easily violated, we cannot recommend its general use except under special conditions.

The effects of intravenous cocaine (2 mg/kg) were tested on several indices of cardiac electrical activity in sedated dogs. These included sinus rate, PR, AH, and HV intervals; AV nodal effective refractory period (AVNERP); ventricular effective refractory period; QRS duration; and the QT interval. Cocaine induced significant changes in six control animals with an intact-functioning autonomic nervous systems. After pharmacologic autonomic blockade with propranolol plus propantheline, cocaine increased the PR interval (+ 11 +/- 4.0 ms, p less than 0.05), primarily by slowing conduction at the AV nodal level. However, with constant atrial pacing at a rate above the sinus cycle length, prolongation of both the AH and the HV intervals (+ 15 +/- 2.5 and 6.7 +/- 1.7 ms, respectively) occurred. There was also a significant increase in the AVNERP (+ 29 +/- 5.9 ms, p less than 0.05). Consistent with the observed rate-dependent HV prolongation, cocaine decreased the rate of rise of phase 0 of the transmembrane action potential of Purkinje fibers. These data indicate that cocaine impairs cardiac conduction by direct actions on AV nodal and His-Purkinje cells.

The role of minor anomalies in dysmorphology is discussed followed by consideration of facial measurements. Photographic documentation, facial change with time, and facial gestalt are emphasized in the process of syndrome diagnosis. Finally, several recent techniques for craniofacial evaluation are presented including facial anthropometry, cephalometrics, laser scanning, three-dimensional craniofacial surface imaging from CT scans, and magnetic resonance imaging.

Part X is the reference section for Parts I through VIII which appeared in the four previous issues of the journal and Part IX which appears in this issue. The reference section itself is divided into two parts. The first part provides general references of selected topics for the interested reader. The second part consists of an alphabetical listing of all references cited in Parts I through IX.

Principles of teratogenesis are reviewed, including adverse environmental factors and the genotype, timing of exposure, mechanisms and pathogenesis, the nature of teratogenic agents, manifestations of deviant development, and dosage. Human teratogenic conditions are summarized with special emphasis on the fetal alcohol syndrome, fetal hydantoin syndrome, fetal trimethadione syndrome, fetal valproate syndrome, warfarin embryopathy, retinoic acid embryopathy, congenital rubella syndrome, radiation effects, and diabetic embryopathy.

A deformation is an abnormal form or position of the body caused by nondisruptive mechanical forces. Clubfoot, congenital hip dislocation, and infantile mandibular asymmetry (not based on mandibular malformation) serve as examples. The musculoskeletal system is involved in almost all deformations. Various disturbances of intrauterine movement are the usual causes and commonly occur during the fetal period. Causes may be mechanical or malformational. The former includes first pregnancies, small maternal size, uterine malformations and tumors, and amnionic rupture leading to oligohydramnios. Malformational causes usually involve the urogenital system and the central nervous system. A disruption is a morphologic defect of an organ, part of an organ, or a larger region of the body resulting from a breakdown of, or interference with, an originally normal developmental process. Amnionic band disruptions with digital amputations serve as an example. The most recent studies of disruptions and their suggested mechanisms are discussed. Finally, the interrelationships between malformations, deformations, and disruptions are explained.

In Part IV, the terms sequence and syndrome are defined and the difference between them is emphasized. Malformations and sequences are non-specific; each may occur as an isolated defect and each may occur as a component part of various syndromes. True malformation syndromes are characterized by embryonic pleiotropy in which a pattern of developmentally unrelated malformations occurs, that is, the malformations that make up the syndrome occur in embryonically non-contiguous areas. It is emphasized that syndrome diagnosis is never made from obligatory anomalies, but from the overall pattern of defects. Finally, the relationships among etiology, pathogenesis, and the phenotype are discussed.

The effect of oral plain aspirin tablets (ASA) on gastric mucosal endoscopic appearance and histology and on the prostaglandin E (PGE) content of the gastric juice and gastroduodenal mucosa was determined in ten healthy young adults. In all subjects the initial endoscopic appearances and microscopy of biopsies from antrum and duodenum were entirely normal. After ASA (2.6 g/day for 5 days) all subjects showed obvious endoscopic damage and 6 showed a histological gastric lesion consisting of loss of mucus and an alteration in nuclear appearance. In addition there was a significant reduction (p less than 0.01) in the PGE content of the gastric juice and of the antral and duodenal mucosa. There was no correlation between the severity of the mucosal damage and the degree of reduction in PGE. It is concluded that aspirin damages the human gastric mucosa by at least two distinct mechanisms one of which is inhibition of protective prostaglandins.

Part I introduces the survey and presents a topic outline of the 10 parts that make up this overview of syndromology in this and the next four issues. The discussion in Part I considers various concepts and definitions of the term "syndrome" and different ways of applying syndrome designations. A population definition of a syndrome is then developed to show the meaning of common, less common, and occasional anomalies in various syndromes. The differences between a true multiple anomaly syndrome and a variant familial pattern are discussed. Finally, two types of weak recurrent patterns--chance patterns and association patterns--are explained.

Various aspects of aneuploidy are discussed including growth disturbance, developmental buffering and variable expression, generalized features of aneuploidy, and microdeletion syndromes.

In Part III, the process of syndrome delineation is unfolded and its significance discussed. Unknown genesis syndrome categories include provisionally unique pattern syndromes and recurrent pattern syndromes. As more information becomes available, it is often possible to establish a Mendelian, chromosomal, teratogenic, or biochemical basis for the disorder in question. It has been estimated that newly recognized syndromes are being described at the rate of one or more per week. The process of syndrome delineation is not an academic exercise but actually fosters good patient care. As an unknown syndrome becomes delineated, its phenotypic spectrum, its natural history, and its recurrence risk become known, allowing for better patient care and family counseling.

Rats were dosed with the cathartics cascara, phenolphthalein, senna or ricinoleic acid with or without a 3 day pretreatment with indomethacin. Jejunum, proximal and distal ileum and colon were assayed for prostaglandin E (PGE) content by RIA. While indomethacin significantly reduced the PGE content of all tissue in all treatment groups it did not completely prevent the increase in PGE content induced by phenolphthalein, senna and ricinoleic acid. It is concluded that the contact cathartics increase PGE synthesis by the gastro-intestinal tract and this could in part explain their action. Ricinoleic acid did not appear to act as a PG precursor.

The role of chance using a stochastic single gene model has been shown to generate a continuous liability curve resembling that obtained from a multifactorial threshold model. Segregation of some malformations may be explained by a single defective gene that predisposes to, but does not necessarily result in, the malformation. Low penetrance and remarkably variable expressivity that characterize a number of presumed autosomal dominant malformation syndromes are possibly reflections of specific stochastic influences that are intrinsic to the embryonic process itself. Gene analysis is discussed and illustrated. Using polymorphic DNA probes to study cleft palate and ankyloglossia in males and ankyloglossia only in females in a large Icelandic family, the responsible gene was found to be located on the long arm of the X chromosome in the Xq21.1 region. In addition to gene analysis, some of the implications of transgenic analysis using mice are discussed. Among disorders of collagen metabolism, both the osteogenesis imperfectas and the Ehlers-Danlos syndromes are shown to represent genetically heterogeneous groups of connective tissue disorders. The days of thinking about osteogenesis imperfecta as one disorder and the Ehlers-Danlos syndrome as another are a thing of the past; persistence of such thinking is erroneous and misleading. Of the many disorders affecting bone mineral, the complexities of hypophosphatasia and pseudohypoparathyroidism are singled out for discussion. For lysosomal storage disorders, an overview of the mucopolysaccharidoses is provided. Finally, the recently delineated peroxisomal disorders--hyperpipecolic acidemia, rhizomelic chondrodysplasia, neonatal adrenoleukodystrophy, Zellweger syndrome, and infantile Refsum disease--are known to share a distinctive biochemical phenotype, although fibroblast complementation analysis suggests that some of these disorders are etiologically distinct.