EDITOR'S C O L U M N
An approach to clinical dysmorphology
THE BASIC APPROACH to the patient with abnormal morphogenesis is to identify and assemble the relevant data, evaluate the observations from a developmental morphologic Viewpoint, and then by induction attempt to determine the overall diagnosis? As Sir Arthur Conan Doyle, the physician-creator of Sherlock Holmes emphasized, "It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories . instead of theories to suit facts. ''2 The gathering of data includes validation of the abnormalities, by measurement when possible, and identification of any similar abnormalities in near relatives. Thereafter the defects should be individually and collectively interpreted from the devel= opmental morphologic standpoint. 1. Does a given defect represent a deformation or a malformation? A deformation is due to extrinsic forces, there being no intrinsic problem within the developing structure? A malformation is due to an intrinsic problem within the developing structure. Deformations are most commonly secondary to late uterine constraint of the fetus as he begins to outgrow the confines of the uterus. Such constraint is more likely to occur in first-born babies, twins, those who have been in prolonged breech presentation, and/or those with oligohydramnios. The same principles that resulted in postural deformation m a y be utilized in its correction, i.e., molding via mild pressure, in this instance, toward a more desirable form?. 4 2. Can a given defect be explained as being secondary to a more primary abnormality? Table I sets forth a few examples of minor anomalies which are generally secondary to a more primary defect in morphogenesis. Though of little direct consequence to the patient, such minor anomalies can be valuable clues to the nature and timing of the problem in development. 3. In the patient with multiple defects, can some or all of them be interpreted as t h e consequence of a single more primary structural anomaly? The term anomalad has been devised to denote such an initiating anomaly in conjunction with its secondarily derived defects,' as depicted in Fig. 1. Table II presents a few of the anomalads with the presumed type of initiating localized defect for each. An anomalad, such as the Robin anoma690
The Journal of P E D I A T R I C S Vol. 91, No. 4, pp. 690-692
Single Local ized Anomaly in Morphogenesis Secondary Defects
Anomalad
Tertiary Defects Fig. 1. The concept embodied in the term anomalad: a single early anomaly which resulted in additional defects. The suffix ad derived from its usage in words such as diad and triad) (From .Smith DW: J PEDIATR87:162, 1975.)
NATUREOF PROBLEM
SINGLE LOCALIZED DEFECT I ~ MULTIPLE SECONDARY DEFECTS
MULTIPLE LOCALIZED DEFECTS inONEir MORE TISSUE
Fig. 2. Summary of the approach toward the general categorization of patients with dysmorphic problems. The rectangles represent the three general diagnostic categories. The dashed arrow simply indicates that a malformation may result in secondary deformations. For example, renal agenesis can result in oligohydramnios with a myriad of consequent features due to uterine constraint. lad, may occur in an otherwise normal individual or as a part of a broader pattern of malformation. At least 25% of patients with the Robin anomalad have this feature as a part of a known syndrome, 1~in which case the management, prognosis, and counsel are contingent on the
Volume 91 Number 4
Editor's column
69 1
Table I. Minor secondary anomalies as clues to nature and timing of problem in morphogenesis Indicated timing of problem in morphogenesis
Usually secondary to
Minor anomaly
Variable
Inner canthal folds
Low nasal bridge
Upslanting palpebral fissures
Small frontal brain region
Prominent lateral palatine ridges Aberrant scalp hair directional patterning
Deficit of tongue thrust into hard palate Defect in brain growth and/or shape
Single upper palmar crease (simian crease)
Aberrant flexional plane of palm when folded Aberrant early development of hand or foot
Unusual dermal ridge patterns (dermatoglyphics)
inclusive diagnosis. This is one of the m a n y reasons for changing the old terminology of Pierre Robin syndrome to Robin anomalad. The Pierre Robin syndrome tended to combine a variety of disorders simply because they had one feature in common, the Robin anomalad. The final category consists of patients with multiple mal/brmations in one or more tissues that are not explained on the basis of a single localized early defect in morphogenesis. These disorders comprise the malformation syndromes, of which a large n u m b e r have been recognized. For these conditions, a clinical diagnosis will often allow for the detection of a specific mode of etiology as well. The causes a n d / o r contributing factors include environmental teratogens, mutant genic disorders, and genic imbalance disorders resulting from chromosomal abnormalities. In Fig. 2 the foregoing approach to dysmorphic lesions is summarized. The following comments pertain to recurrence risk and prevention within each of the three major diagnostic categories: I. Deformation defects: The recurrence risk is low for the common postural deformities that are due to uterine constraint in an otherwise normal infant. 2. Anomaly or anomalad in an otherwise normal child: The recurrence risk for an anomalad is for the same type of initiating defect in morphogenesis. Thus, the recurrence risk for anencephaly includes both anencephaly and meningomyelocele; the recurrence risk is that for a defect of neural tube closure at either its anterior or posterior portion. The general recurrence risk for single localized anomalies in subsequent offspring is about 2 to 5% for otherwise normal parents who have one affected child. The likelihood of an affected parent having an affected child is also about 2 to 5%. These figures apply to cleft lip and palate anomalad, cleft palate alone, meningomyelocele-anencephaly anomalad, clubfoot, dislocation of the
Reference
Personal observation ? Personai observation Usually prenatal 5 Within first 11-16 wk 6 of fetal life By 11 wk of fetal life 7 By 15-20 wk of fetal life
8
Table II. Examples of anomalads and the presumed initiating defect
A nomalad Holoprosencephaly anomalad
Initiating defect
? Defect in prechordal mesoderm Anencephaly-menin- ? Defect in neural gomyelocele tube closure anomalad Cleft lip and palate Failure of lip cloanomalad sure Robin anomalad Early mandibular hypoplasia
Defkct must have occurred before gestational age qf ? 23 days
? 28 days
35 days 8-9 wk
hip, common types of cardiac malformations, hypospadias, pyloric stenosis, and distal aganglionosis of the colon (Hirschprung disease)." The enhanced liability to recurrence of these defects has been attributed to polygenic inheritance (multiple gene effects), possibly in conjunction with environmental factors. The probability of recurrence has not been determined for the Robin anomalad or for most of the other anomalads, but their recurrence risks appear to be similar or lower in magnitude in comparison with those for other localized defects of morphogenesis. The liability for each of these defects is affected by the XX versus XY genetic difference as exemplified by the fact that not one of the defects has an equal sex incidence. The recurrence risk counsel should be appropriate for the sex of the individual. This is especially important when the liability is markedly skewed, as for pyloric stenosis which is five times as likely to occur in a male and dislocation of hip which is five times as likely to occur in a female. The
692
Editor's column
severity of the anomaly or anomalad may also be taken into context. The more severe the defect, the higher the recurrence risk. For example, the recurrence risk for bilateral cleft lip (5.6%) is about twice that for unilateral cleft lip (2.7%). 11 Early fetal recognition and prevention of the birth of defective neonates by termination of pregnancy is now practical for the majority of the anencephaly-meningomyelocele anomalads. 1'-' It should be emphasized that the above data on risk of recurrence apply only to otherwise normal individuals with a single anomaly or anomalad. They do not apply when an anomaly or anomalad is only one part of a broader pattern of malformation. 3. Malformation syndromes." Genetic counsel for multiple defect syndromes is dependent on an accurate overall diagnosis and the knowledge of its cause a n d / o r recurrence risk. Such data are set forth in a book on patterns of malformation? The likelihood for recurrence of mutant gene disorders can vary from negligible for fresh mutational disorders such as achondroplasia from unaffected parents, to 25% with an autosomal recessive disorder such as the Smith-Lemli-Opitz syndrome, to 50% for a parent who has an autosomal dominant disorder such as neurofibromatosis. For chromosomal abnormalities the risk for recurrence varies from 1% or less for trisomies or fresh chromosomal breakage disorders to higher figures for disorders associated with chromosomal translocations in which the extra or missing chromosomal piece is also present in one of the parents. Early amniocentesis and chromosomal studies can obviate the birth of subsequent affected fetuses. Finally, the impact of ethanol, hydantoins, or other environmental teratogens can be obviated by discontinuing the use of such teratogenic agents "before" the occurrence of future conceptions.
The Journal of Pediatrics October 1977
The above approach to clinical dysmorphology should hopefully give rise to more rational interpretations of the problems to the parents and improve their understanding relative to recurrence risk for the same type of problem.
David IV. Smith, M.D. Dysmorphology Unit Department of Pediatrics University of Washington School of Medicine Seattle, WA 98105
REFERENCES
1. Smith DW: Recognizable patterns of human malformation, ed 2, Philadelphia, 1976, WB Saunders Company. 2. Doyle AC: Scandal of Bohemia. 3. Dunn PM: Congenital postural deformities, Br Med Bull 32:71, 1976. 4. Chapple C, and Davidson DT: A study of the relationship between fetal position and certain congenital deformities, J PEDIATR 181:483, 1941. 5. Hanson JW, Smith DW, and Cohen MM, Jr.: Prominent lateral palatine ridges: Developmental and clinical relevance, J PEDIATR89:54, 1976. 6. Smith DW, and Gong BT: Scalp hair patterning as a clue to early fetal brain development, J PEDIA~rR83:374, 1973. 7. Popich GA, and Smith DW: The genesis and significance of digital and palmar hand creases, J PEDIATR77:1017, 1970. 8. Mulvihill JJ, and Smith DW: Genesis ofdermatoglyphics, J PEDIATR 75:579, 1969. 9. Special article: Classification and nomenclature of malformation, Lancet 1:798, 1974. 10. Hanson JW, and Smith DW: U-shaped palatal defect in the Robin anomalad: Developmental and clinical relevance, J PEDIATR 87:30, 1975. 11. Carter CO: Genetics of common single malformations, Br Med Bull 32:21, 1976. 12. Brock DJH: Prenatal diagnosis-chemical methods, Br Med Bull 32:16, 1976.
An approach to clinical dysmorphology
THE BASIC APPROACH to the patient with abnormal morphogenesis is to identify and assemble the relevant data, evaluate the observations from a developmental morphologic Viewpoint, and then by induction attempt to determine the overall diagnosis? As Sir Arthur Conan Doyle, the physician-creator of Sherlock Holmes emphasized, "It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories . instead of theories to suit facts. ''2 The gathering of data includes validation of the abnormalities, by measurement when possible, and identification of any similar abnormalities in near relatives. Thereafter the defects should be individually and collectively interpreted from the devel= opmental morphologic standpoint. 1. Does a given defect represent a deformation or a malformation? A deformation is due to extrinsic forces, there being no intrinsic problem within the developing structure? A malformation is due to an intrinsic problem within the developing structure. Deformations are most commonly secondary to late uterine constraint of the fetus as he begins to outgrow the confines of the uterus. Such constraint is more likely to occur in first-born babies, twins, those who have been in prolonged breech presentation, and/or those with oligohydramnios. The same principles that resulted in postural deformation m a y be utilized in its correction, i.e., molding via mild pressure, in this instance, toward a more desirable form?. 4 2. Can a given defect be explained as being secondary to a more primary abnormality? Table I sets forth a few examples of minor anomalies which are generally secondary to a more primary defect in morphogenesis. Though of little direct consequence to the patient, such minor anomalies can be valuable clues to the nature and timing of the problem in development. 3. In the patient with multiple defects, can some or all of them be interpreted as t h e consequence of a single more primary structural anomaly? The term anomalad has been devised to denote such an initiating anomaly in conjunction with its secondarily derived defects,' as depicted in Fig. 1. Table II presents a few of the anomalads with the presumed type of initiating localized defect for each. An anomalad, such as the Robin anoma690
The Journal of P E D I A T R I C S Vol. 91, No. 4, pp. 690-692
Single Local ized Anomaly in Morphogenesis Secondary Defects
Anomalad
Tertiary Defects Fig. 1. The concept embodied in the term anomalad: a single early anomaly which resulted in additional defects. The suffix ad derived from its usage in words such as diad and triad) (From .Smith DW: J PEDIATR87:162, 1975.)
NATUREOF PROBLEM
SINGLE LOCALIZED DEFECT I ~ MULTIPLE SECONDARY DEFECTS
MULTIPLE LOCALIZED DEFECTS inONEir MORE TISSUE
Fig. 2. Summary of the approach toward the general categorization of patients with dysmorphic problems. The rectangles represent the three general diagnostic categories. The dashed arrow simply indicates that a malformation may result in secondary deformations. For example, renal agenesis can result in oligohydramnios with a myriad of consequent features due to uterine constraint. lad, may occur in an otherwise normal individual or as a part of a broader pattern of malformation. At least 25% of patients with the Robin anomalad have this feature as a part of a known syndrome, 1~in which case the management, prognosis, and counsel are contingent on the
Volume 91 Number 4
Editor's column
69 1
Table I. Minor secondary anomalies as clues to nature and timing of problem in morphogenesis Indicated timing of problem in morphogenesis
Usually secondary to
Minor anomaly
Variable
Inner canthal folds
Low nasal bridge
Upslanting palpebral fissures
Small frontal brain region
Prominent lateral palatine ridges Aberrant scalp hair directional patterning
Deficit of tongue thrust into hard palate Defect in brain growth and/or shape
Single upper palmar crease (simian crease)
Aberrant flexional plane of palm when folded Aberrant early development of hand or foot
Unusual dermal ridge patterns (dermatoglyphics)
inclusive diagnosis. This is one of the m a n y reasons for changing the old terminology of Pierre Robin syndrome to Robin anomalad. The Pierre Robin syndrome tended to combine a variety of disorders simply because they had one feature in common, the Robin anomalad. The final category consists of patients with multiple mal/brmations in one or more tissues that are not explained on the basis of a single localized early defect in morphogenesis. These disorders comprise the malformation syndromes, of which a large n u m b e r have been recognized. For these conditions, a clinical diagnosis will often allow for the detection of a specific mode of etiology as well. The causes a n d / o r contributing factors include environmental teratogens, mutant genic disorders, and genic imbalance disorders resulting from chromosomal abnormalities. In Fig. 2 the foregoing approach to dysmorphic lesions is summarized. The following comments pertain to recurrence risk and prevention within each of the three major diagnostic categories: I. Deformation defects: The recurrence risk is low for the common postural deformities that are due to uterine constraint in an otherwise normal infant. 2. Anomaly or anomalad in an otherwise normal child: The recurrence risk for an anomalad is for the same type of initiating defect in morphogenesis. Thus, the recurrence risk for anencephaly includes both anencephaly and meningomyelocele; the recurrence risk is that for a defect of neural tube closure at either its anterior or posterior portion. The general recurrence risk for single localized anomalies in subsequent offspring is about 2 to 5% for otherwise normal parents who have one affected child. The likelihood of an affected parent having an affected child is also about 2 to 5%. These figures apply to cleft lip and palate anomalad, cleft palate alone, meningomyelocele-anencephaly anomalad, clubfoot, dislocation of the
Reference
Personal observation ? Personai observation Usually prenatal 5 Within first 11-16 wk 6 of fetal life By 11 wk of fetal life 7 By 15-20 wk of fetal life
8
Table II. Examples of anomalads and the presumed initiating defect
A nomalad Holoprosencephaly anomalad
Initiating defect
? Defect in prechordal mesoderm Anencephaly-menin- ? Defect in neural gomyelocele tube closure anomalad Cleft lip and palate Failure of lip cloanomalad sure Robin anomalad Early mandibular hypoplasia
Defkct must have occurred before gestational age qf ? 23 days
? 28 days
35 days 8-9 wk
hip, common types of cardiac malformations, hypospadias, pyloric stenosis, and distal aganglionosis of the colon (Hirschprung disease)." The enhanced liability to recurrence of these defects has been attributed to polygenic inheritance (multiple gene effects), possibly in conjunction with environmental factors. The probability of recurrence has not been determined for the Robin anomalad or for most of the other anomalads, but their recurrence risks appear to be similar or lower in magnitude in comparison with those for other localized defects of morphogenesis. The liability for each of these defects is affected by the XX versus XY genetic difference as exemplified by the fact that not one of the defects has an equal sex incidence. The recurrence risk counsel should be appropriate for the sex of the individual. This is especially important when the liability is markedly skewed, as for pyloric stenosis which is five times as likely to occur in a male and dislocation of hip which is five times as likely to occur in a female. The
692
Editor's column
severity of the anomaly or anomalad may also be taken into context. The more severe the defect, the higher the recurrence risk. For example, the recurrence risk for bilateral cleft lip (5.6%) is about twice that for unilateral cleft lip (2.7%). 11 Early fetal recognition and prevention of the birth of defective neonates by termination of pregnancy is now practical for the majority of the anencephaly-meningomyelocele anomalads. 1'-' It should be emphasized that the above data on risk of recurrence apply only to otherwise normal individuals with a single anomaly or anomalad. They do not apply when an anomaly or anomalad is only one part of a broader pattern of malformation. 3. Malformation syndromes." Genetic counsel for multiple defect syndromes is dependent on an accurate overall diagnosis and the knowledge of its cause a n d / o r recurrence risk. Such data are set forth in a book on patterns of malformation? The likelihood for recurrence of mutant gene disorders can vary from negligible for fresh mutational disorders such as achondroplasia from unaffected parents, to 25% with an autosomal recessive disorder such as the Smith-Lemli-Opitz syndrome, to 50% for a parent who has an autosomal dominant disorder such as neurofibromatosis. For chromosomal abnormalities the risk for recurrence varies from 1% or less for trisomies or fresh chromosomal breakage disorders to higher figures for disorders associated with chromosomal translocations in which the extra or missing chromosomal piece is also present in one of the parents. Early amniocentesis and chromosomal studies can obviate the birth of subsequent affected fetuses. Finally, the impact of ethanol, hydantoins, or other environmental teratogens can be obviated by discontinuing the use of such teratogenic agents "before" the occurrence of future conceptions.
The Journal of Pediatrics October 1977
The above approach to clinical dysmorphology should hopefully give rise to more rational interpretations of the problems to the parents and improve their understanding relative to recurrence risk for the same type of problem.
David IV. Smith, M.D. Dysmorphology Unit Department of Pediatrics University of Washington School of Medicine Seattle, WA 98105
REFERENCES
1. Smith DW: Recognizable patterns of human malformation, ed 2, Philadelphia, 1976, WB Saunders Company. 2. Doyle AC: Scandal of Bohemia. 3. Dunn PM: Congenital postural deformities, Br Med Bull 32:71, 1976. 4. Chapple C, and Davidson DT: A study of the relationship between fetal position and certain congenital deformities, J PEDIATR 181:483, 1941. 5. Hanson JW, Smith DW, and Cohen MM, Jr.: Prominent lateral palatine ridges: Developmental and clinical relevance, J PEDIATR89:54, 1976. 6. Smith DW, and Gong BT: Scalp hair patterning as a clue to early fetal brain development, J PEDIA~rR83:374, 1973. 7. Popich GA, and Smith DW: The genesis and significance of digital and palmar hand creases, J PEDIATR77:1017, 1970. 8. Mulvihill JJ, and Smith DW: Genesis ofdermatoglyphics, J PEDIATR 75:579, 1969. 9. Special article: Classification and nomenclature of malformation, Lancet 1:798, 1974. 10. Hanson JW, and Smith DW: U-shaped palatal defect in the Robin anomalad: Developmental and clinical relevance, J PEDIATR 87:30, 1975. 11. Carter CO: Genetics of common single malformations, Br Med Bull 32:21, 1976. 12. Brock DJH: Prenatal diagnosis-chemical methods, Br Med Bull 32:16, 1976.
