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Craniofacial Syndromes and Malformations Marilyn T 4 Craniofacial Syndromes and Malformations Marilyn T. Miller and Anna Newlin he explosion of knowledge in the area of genetics, and a Tgreater desire by patients and their families to know the cause and risk of recurrence of genetic malformations, have resulted in greater attention to errors of morphogenesis. For physicians who do not confront these problems regularly, the vocabulary often is confusing and unclear. Increasing effort has been made to clarify definitions for better communication of ideas. Improved classification of malformations and clusters of associated anomalies will assist in better diagnosis and treat- ment and more accurate risk counseling. Spranger et al.219 Cohen,38–40 Herrmann and Opitz,100 and others have attempted to define more precisely commonly used terms. TERMINOLOGY Malformation: a morphological defect of an organ, part of an organ, or larger region resulting from an intrinsically abnor- mal developmental process. The risk of recurrence depends on the etiology of the malformation (e.g., genetic, teratogenic). Congenital anomalies: all forms of developmental defects present at birth, whether caused by genetic, chromosomal, or environmental factors. Dysmorphology: the study of congenital anomalies. The term dysmorphic describes an individual with obvious multiple and severe malformations. Sequence: pattern of multiple anomalies derived from a single structural defect or mechanical factor (e.g., Möbius sequence). 146 chapter 4: craniofacial syndromes and malformations 147 Developmental field: a group of cells or a region that responds as a coordinated unit to embryonic interaction; defects in developmental fields result in multiple malformations (e.g., formation of the lens depends on interaction with the optic cup). Many malformations are field defects.177 Syndrome: pattern of anomalies thought to be pathologically related. The term implies a single cause, not a field defect. Disruption: a morphological defect resulting from the extrinsic breakdown of, or an interference with, an originally normal developmental process (e.g., amniotic bands). As these are usually nonrecurring events, counseling will indicate low risk for future family members. Deformation: abnormal form, shape, or position of a part of the body caused by a mechanical process (e.g., intrauterine compression). Association: statistically related association of anomalies not identified as a sequence or syndrome (e.g., CHARGE association). A disturbance to a group of cells in a single developmental field may result in multiple malformations. A single structural defect or factor causing a cascade of secondary anomalies is referred to as a sequence, with a domino-type effect. A sequence implies heterogeneous causative factors. Pierre Robin syndrome (cleft palate, glossoptosis, micrognathia, and respiratory problems) may represent a sequence caused by abnormal descent of the tongue due to mandibular hypoplasia. This sequence has been reported in many syndromes, including Stickler, fetal alcohol, and chromosomal syndromes. In contrast, a syndrome implies a single cause, even if the etiological agent is not yet identified. The term syndrome is used in many ways, often utilizing a variety of definitions. It may be attached to an assortment of signs and symptoms for which the etiology is known (e.g., Down’s syndrome, Marfan syndrome, trisomy 13), or it may be used to describe a group of findings for which the cause is poorly understood. The term disease is more frequently used with a group of signs and symptoms associated with progression or deterioration (e.g., diabetes). This separation is not always precise, and there are many examples of overlapping in which the term disease is used in a way that is more consistent with the definition of syndrome and vice versa. Although the etiol- ogy is known in some syndromes, the basic defect in many mal- formation syndromes remains unknown, with the name of the 148 handbook of pediatric eye and systemic disease syndrome based on a wide variety of things, such as the physi- cian’s or patient’s name, the striking feature, and mythical designation. The number and types of abnormalities ascribed to many syndromes vary not only in the frequency with which the syndrome has been observed and reported in the literature but also in the underlying pleiotropic characteristics of the syndrome. The term phenotypic spectrum was used by Opitz et al.178 to describe the number of abnormalities reported for a given syndrome and their frequency in a controlled population. This approach helps to separate findings that are specific to the syndrome from those that are just a chance occurrence. A given anomaly may be clearly or questionably related to the syndrome or may be a chance occurrence; rarely, it may occur at a signif- icantly lower frequency than would occur in a controlled popu- lation. This latter situation would suggest that the syndrome in some way protects the organism from a given abnormality. Various malignancies show increased correlations with a syndrome, whereas a few have the opposite relationship. For example, the association of Wilm’s tumor with aniridia is well appreciated, but patients with osteogenesis imperfecta may be more resistant to cancer.143 A weak recurring pattern is described as an association. This term implies that the defects occur with more frequency than would be expected by chance but do not show a pattern that can be clearly defined as a syndrome. The CHARGE association (ocular Coloboma, Heart defects, choanal Atresia, developmen- tal or mental Retardation, and Genitourinary and Ear anomalies) is an example that may represent a variety of yet unidentified etiologies.180 If a definite etiology is established (e.g., a chromo- somal abnormality) then, more precisely, that individual has a syndrome. Cohen38–40 reported that new syndromes are described at a rate of approximately one or more per week. In a typical scenario, an infant with multiple anomalies is examined. An attempt is made to arrive at a specific diagnosis from classic textbooks.85,113,151,237 computer-based CD-ROM programs,9 London dysmorphology,142 online databases,149,176 and consulta- tions with geneticists. If these investigations do not delineate a specific syndrome, the patient is presumed to represent an unknown genesis syndrome, in which the causes are unknown but the findings are thought to represent a unique pattern. The patient is then described in the literature, and the reaction of the scientific community is awaited. chapter 4: craniofacial syndromes and malformations 149 At times, investigators have failed to recognize a previously described syndrome, and future correspondence will clarify the existing syndrome that the patient exhibits. Another possibility is that on seeing this constellation of findings, other physicians report additional cases, and this group of patients is classified into a category referred to as a recurring pattern syndrome. As more examples are observed, the validity of this new syndrome and the description of the spectrum of clinical manifestations increase. The etiology of the syndrome may not be appreciated at the time or even in the future, but if the specific cause is later described, these patients represent a known genesis syndrome and are subcategorized into such groups as (1) chromosomal defect, (2) enzyme deficiency, (3) environmental factor, (4) single gene syndrome, or (5) diseases or familial syndromes. The appre- ciation of developmental genes (e.g., Hox genes) has expanded the spectrum of possible genetic causation. The study of many cases is required to establish whether any group of patients with similar but not identical findings rep- resent different etiologies (heterogeneity) or the same cause with variable manifestations (pleiotropism). One problem confronting less experienced physicians is that textbook descriptions frequently characterize and illustrate only the classic cases or severely affected patients, and more mini- mally affected individuals may not be recognized. Figure 4-1 shows examples of mildly, moderately, and severely affected children with mandibulofacial dysostosis, a dominantly inher- ited condition with high penetrance but variable expressivity. Frequently, other family members with the syndrome are not identified until a diagnosis is made in a severely affected child. Children with congenital malformations and syndromes involving craniofacial structures are at a significant risk for ocular anomalies. The number of syndromes and isolated mal- formations is great, and the spectrum of eye problems is vast. Therefore, the development of an approach to the dysmorphic child is more productive than an attempt to memorize all ocular pathological changes reported in the literature. It is useful to consider these ocular findings in two general categories. 1. Ocular complications secondary to abnormal size, shape, or position of bony and soft tissue changes in orbital structures. These complications may occur during development (disruption or deformation) or may be acquired after birth. These derived changes can be anticipated from the malformations present in the A B C chapter 4: craniofacial syndromes and malformations 151 surrounding tissues. They are not necessarily specific to a syn- drome but are the result of a type of deformity or mechanical factors. The same anomaly may occur in separate syndromes. There are numerous common examples of secondary com- plications. Abnormalities in orbital size or position may result in many commonly listed and often severe ocular findings.
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