Dysmorphology

Chapter 55 Dysmorphology



Louis E. Bartoshesky, MD, MPH




Speaking Intelligently


When I am asked to see an infant with dysmorphic features or a birth defect, I realize that most likely the parents are stressed. I explain that I will ask many questions to obtain a detailed history about the infant, the pregnancy, as well as family history in search of clues to help identify the problem. After performing a complete examination, I share my impressions and make recommendations for possible laboratory testing, imaging studies, or subspecialty consultation. In some cases, a diagnosis will be possible with history and examination; in others, a definitive diagnosis will take time to elucidate; and in many instances, no specific diagnosis is made. Despite this, therapy and ongoing care will be needed to maximize the child’s health and development. Adequate time should be allotted at every step of the process for explanation of findings and answering family questions.



Medical Knowledge and Patient Care



Background and Definitions


A birth defect is an abnormality of structure, function, or metabolism present at birth. Major birth defects are those requiring medical or surgical intervention or affecting normal growth and development. Birth defects are the second leading cause of death in the first year of life and a leading cause of mortality, morbidity, and hospitalization throughout childhood. Three to five percent of newborns have a major birth defect.


Some children have a birth defect that is an isolated single anomaly; others have multiple congenital anomalies (MCA). A malformation is a primary structural birth defect arising from a local error in morphogenesis. A deformation is a structural birth defect resulting from some extrinsic effect on a developing organ or tissue with no intrinsic error in morphogenesis; for example, uterine crowding resulting in a clubfoot. Disruptions are structural defects resulting from destruction of a normally formed part, often resulting from interference with vascular supply to that structure. Dysplasias are localized or generalized abnormal organizations of cells with structural consequences. Hemangiomas can be considered to be localized dysplasias; skeletal dysplasias are generalized. A clubfoot, dislocated hips, neurogenic bladder, and Chiari type II anomaly all may result from a single neural tube defect—a lumbosacral meningomyelocele. An MCA syndrome, sometimes referred to as a sequence, is one in which there are developmental variants in more than one organ system and in which it is assumed (and sometimes proved) that there is common etiology for the multiple anomalies. An association is multiple anomalies occurring together more often than expected by chance but not with a single etiology.



Etiology


Isolated birth defects are usually argued to be multifactorial traits, that is, there are probably several variant genes along with environmental factors that are the causes for the anomaly. However, in some cases the defect may be the result of a mutation at a single gene locus. In many cases (probably 40% to 60%) the cause for multiple congenital anomalies is not clear. However, there are known environmental and genetic causes of MCA. Environmental factors that play a role in the etiology of birth defects include infectious agents (rubella, toxoplasmosis, syphilis, cytomegalovirus, varicella, and perhaps others); drugs (alcohol, certain anticonvulsants, warfarin sodium, probably cigarettes, and others); nutritional deficiencies (folic acid); radiation (but only at doses well above those of standard diagnostic studies); and maternal health (poorly controlled diabetes mellitus, maternal phenylketonuria).


MCA can be related to genetic factors. Chromosome anomalies, including aneuploidy (other than 46 chromosomes), deletions, duplications, unbalanced translocations, and inversions are all associated with MCA. Many single-gene defects are expressed as MCA. Autosomal dominant traits include many skeletal dysplasias (perhaps achondroplasia being the best known and most common), connective tissue disorders such as Marfan syndrome, neurocutaneous syndromes such as neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and others. Autosomal recessive traits presenting as MCA include lysosomal storage disorders (various categories such as mucopolysaccharidoses, oligosaccharidoses, sphingolipid disorders); peroxisomal disorders such as Zellweger syndrome; disorders of sterol metabolism such as Smith-Lemli-Opitz syndrome; disorders of metal metabolism; as well as some disorders of organic acid or amino acid metabolism and disorders of energy metabolism. Previously it had been taught that “metabolic disorders” were not associated with MCA, but it is now clear that a number of these disorders are associated with dysmorphic features and multiple anomalies. X-linked MCA syndromes include Hunter syndrome (mucopolysaccharidosis II), Menkes syndrome (disorder of copper metabolism), certain ectodermal dysplasias, and a number of syndromes associated with cognitive delay (such as fragile X syndrome). Some of the disorders of energy metabolism are related to mutations in the mitochondrial genome, and some of these present in infancy with dysmorphic features, hypotonia, hearing and vision disorders, seizures, and developmental delay. With improving chromosome technology and molecular genetic techniques made possible through the Human Genome Project, more and more causes for MCA are being determined.



Approach to the Child With Multiple Congenital Anomalies



History and Physical Examination


History includes determination of maternal risk factors such as maternal health, particularly diabetes control; maternal exposures in pregnancy—drugs, alcohol, and infections; maternal immunization status; history of maternal fever or exposure to known teratogenic infectious agents; and use of folic acid before conception. A careful three-generation family history is important with particular attention to infant and childhood death, infant and childhood disabilities, infertility, and consanguinity. Family history may be “negative,” but it is never “noncontributory.” Other pregnancy factors of possible importance to understanding a child with MCA include fetal activity (reduced in babies with certain neuromuscular disorders) and amniotic fluid quantities (elevated in certain syndromes such as Down or Turner syndromes and in the presence of fetal esophageal atresia, and reduced in cases of renal agenesis or obstructive uropathy). Reduced amniotic fluid (oligohydramnios) is a risk factor in fetal akinesia sequence—inhibited fetal movement resulting in joint contractures, flat face, flat ears, and pulmonary hypoplasia. Fetal growth is inhibited in congenital infection syndromes, in many chromosomal variant syndromes, and in many other syndromes of many different etiologies. Breech presentation may be associated with deformations such as clubfoot.


Careful examination starts with determination of length, weight, and head circumference. Measurements of interocular distances, palpebral fissure length, philtrum length, ear length, middle finger and total hand length, foot length, penile size, and testicular size are valuable in identifying a syndrome, and standards for these are available in several resources.


The presence of major anomalies is usually obvious. For example, cleft lip and palate, clubfoot, abdominal wall defects, heart malformations associated with persistent cyanosis or heart failure, tracheoesophageal fistula (TEF), diaphragmatic hernia, open neural tube defects, hypospadias, limb deficiencies, or imperforate anus are difficult to miss or at least become apparent after relatively simple evaluations—chest radiograph for diaphragmatic hernia, nasogastric tube passage for TEF and esophageal atresia, recognition of cardiac failure or cyanosis followed by echocardiography. However, major anomalies of renal structure, cataracts, deafness, and noncyanotic heart malformations require careful examination, alertness to subtle functional alterations, and awareness of important associations (such as the association of vertebral anomalies, cardiac malformations, and renal structural defects with TEF and/or anorectal anomalies—the VATER association—or of deafness, cardiac and renal anomalies with choanal atresia and iris and retinal colobomas—CHARGE syndrome).


Up to 50% of infants have a minor birth defect—one present in less than 5% of the population, but of little or no functional or cosmetic importance. However, the presence of several such minor anomalies may suggest a specific syndrome and indicate the need for further evaluation. Note should be made of color, distribution, and consistency of hair; number of hair whorls; and presence of a frontal upsweep. Size of palpebral fissures, the presence of epicanthal folds and slant or palpebral fissures, and the nature of brows and lashes may be helpful in identifying a syndrome. Ear position (low-set ears are those in which the top of the ear is below a line drawn from medial canthus of the eye) and structure, as well as presence of ear pits or preauricular tags, should be noted. Position of nose, integrity of alae nasi, and status of nasal bridge (depressed or prominent) and tip (upturned) may be helpful. Variations of length and markings of philtrum, condition of vermillion border of upper lip, symmetry of mouth movement, presence of lip pits, and defects at angle of mouth may give clues to an underlying syndrome. Cleft of soft palate may be missed on a cursory oral examination, whereas presence of a notch in the uvula or frank bifid uvula may indicate the presence of a submucus cleft.


Pits or tags on the face or neck are seen in certain oral-facial-digital syndromes. Short, broad neck or webbing is seen in children with Down syndrome, Turner syndrome, Noonan syndrome, and in the presence of cervical vertebral anomalies—including the Klippel-Feil anomaly. Inter-nipple distance is increased in Turner syndrome (a variation in chromosome number or structure) and Noonan syndrome (a disorder associated with a mutation at a single gene locus).


Hypospadias, sometimes subtle when at the corona; testicular maldescent; clitoromegaly; and labial hypoplasia or asymmetry are seen in various disorders of sexual development but also in more generalized MCA syndromes. Simple sacrococcygeal dimples are rarely of clinical importance, but when associated with a hairy patch, a hemangioma, or palpable bony defect they may indicate an underlying neural tube defect—a disorder of secondary neurulation.


Careful measurement of limb length and circumference, search for limb asymmetry, and measurement of fingers may give clues to the presence of a syndrome. Palmar and digital crease anomalies are seen in various syndromes—the transverse crease seen in children with Down syndrome being well known. The absence or underdevelopment of digital creases indicates reduced fetal movement in utero. Nail dysplasia or hypoplasia is seen in fetal alcohol and fetal phenytoin syndromes but also in ectodermal dysplasias and in other MCA syndromes. Any asymmetry of limb growth should be noted.


Hypopigmented or hyperpigmented areas of the skin may suggest a neurocutaneous disorder. There are a number of chromosomal disorders and other syndromes associated with hemangiomas and other cutaneous defects. Seborrhea-like changes and verrucous skin may be associated with certain syndromes.


Careful neurologic examination is, of course, essential in evaluating the child with MCA. Symmetry of movement, muscle tone, and deep tendon reflexes are to be observed and recorded.


Testing: A major anomaly, when isolated, does not require further laboratory study except in certain circumstances such as a child with a cleft lip and palate whose parent and grandparent also have clefts. Specific molecular DNA testing could be of value in such a child/family. A major anomaly demands a careful search for minor anomalies. There is no specific number of minor anomalies the presence of which should suggest chromosome studies. Clinical judgment is required.


High-resolution chromosome studies will detect aneuploidies and many duplications, deletions, or complex rearrangements. Children with MCA who have normal high-resolution chromosome studies may be candidates for more specific studies. Certain syndromes, when suspected, can be confirmed with specific fluorescent in situ hybridization (FISH) studies. These include Williams, velocardiofacial/DiGeorge (22q11 microdeletion syndrome), Smith Magenis, Miller-Dieker, and trichorhinophalangeal syndromes. More are likely to be added as time goes on and technology improves. Prader-Willi and Angelman syndromes are included on this list but are best ruled out by determination of methylation pattern at the appropriate loci on chromosome 15.


Comparative genomic hybridization (CGH) using microarray and other new technologies is now available. Up to 10% of children with MCA and developmental delay may have a chromosome variant (deletions, duplications, inversions, complex rearrangements) detectable by CGH that could not be detected on high-resolution studies.


When a congenital infection (rubella, cytomegalovirus [CMV], toxoplasmosis, syphilis) is suspected, specific studies for that infection should be obtained. The term TORCH was a valuable reminder of some of the infectious agents that could be associated with birth defects. However, ordering “TORCH titers” is no longer logical. If congenital toxoplasmosis is suggested, serologic studies for antibodies are indicated. If CMV is suspected, urine for CMV should be collected. Congenital rubella is very rare now, although it should not be ignored as a possibility, particularly in populations in which there might be underimmunization. Herpes, the “H” in TORCH, is a rare cause of structural congenital anomalies, although it is an important cause of serious neonatal infection. There are no antibodies for “O.”


Specialized studies are available for babies with MCA in whom lysosomal storage, peroxisomal disorders, sterol disorders, or disorders of metal metabolism are suspected. Such studies should only be obtained when there are suspicious clinical features. A “shotgun” approach of ordering everything in every baby is neither efficient nor cost effective.


Imaging studies and consultations (e.g., ophthalmology, cardiology, audiology, urology, nephrology) are ordered as indicated by information collected on history and physical examination.


In the evaluation, historical factors should be listed and major and minor anomalies described. References to texts (such as Smith’s Recognizable Patterns of Human Malformation) or databases (e.g., London Dysmorphology Data Base) and consultation with appropriate specialists may be needed to determine what syndrome is possible. Up to half of children with MCA are not assigned a diagnosis, although that figure continues to shrink as technology advances.1,2

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Jul 18, 2016 | Posted by in PEDIATRICS | Comments Off on Dysmorphology

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