BASIC DYSMORPHOLOGY
In addition to reviewing a patient's family, medical and developmental history, observations made during a clinical evaluation might also lead you to conclude that your patient should be referred for a genetic consultation. While major malformations are obvious at birth and often result in an immediate referral for a genetic evaluation, minor malformations may go unnoticed as they have no clinical consequence. However, it is the recognition of these minor malformations that might lead to the early detection of a genetic condition and prompt intervention for the child and family.
Assessing a person's body proportion (the length of the arms and legs relative to the trunk) may provide important information. The midpoint of the body is at about the level of the umbilicus in the newborn. As a child grows, this shifts downwards so that by maturity the midpoint is at the upper border of the symphysis pubis. The ratio of the upper segment (head to symphysis pubis) to the lower segment (symphysis pubis to floor) is about .92, indicating that the legs are slightly longer than the trunk. The arm span is usually equal to the standing height.
Achondroplasia (a-absence, chondro-cartilage, plasia-growth) is a common form of dwarfism. Since achondroplasia affects mainly cartilaginous bones (arms and legs), the sitting height is normal while the standing height is short. Associated features include trident fingers, prominent forehead, a large skull, and saddle-shaped nose (on side view). This is an autosomal dominant disorder. Another form of dwarfism that was formerly included in the spectrum of achondroplasia is diastrophic (twisted limb) dwarfism. However, this is now recognized as a distinct entity with associated clubfeet, "cauliflower" ears and "hitchhiker" thumbs. Diastrophic dwarfism is an autosomal recessive disorder.
As discussed in the previous section on Mendelian inheritance, an autosomal dominant disorder due to a new mutation can mimic an autosomal recessive disorder (in both cases an affected child would have normal parents). If a child has achondroplasia secondary to a new mutation, the risk of recurrence in future sibs would be negligible. In diastrophic dwarfism, the risk of recurrence for a couple would be 25%. This difference in risk recurrence clearly illustrates the importance of an accurate diagnosis (made possible by the different minor malformations associated with each disorder) in risk counseling.
The converse of short stature is tall stature, a clinical feature seen in patients with Marfan syndrome. Individuals with this condition are taller than average, with long arms and legs relative to trunk. Affected individuals may also have lax joints, arachnodactyly (spider-like long fingers), cardiovascular abnormalities, including aneurysm (ballooning or dilatation) of the aorta and aortic insufficiency (dilatation of the ring at the base of the aortic valve allowing a backflow of blood), and dislocated lens. When all three cardinal features are present, the diagnosis is relatively easy to make. A family history showing first or second degree relatives with features of this condition is also helpful in making the diagnosis in the proband. Problems in diagnosis arise in young children who do not have a family history of Marfan syndrome, as the syndrome is not yet fully developed or expressed. This points to the importance of follow-up. As more clinical features develop with age, the diagnosis becomes definitive over time.
Facial features provide important clues to diagnosis. Measurements are taken of the inner canthal distance, outer canthal distance and interpupillary distance (between the inner corners of the eye, the outer corners of the eye and the pupils, respectively). These measurements are then compared with established norms. The palpebral fissures (eye slits) should be on a horizontal plane rather than upslanting or downslanting. The length of the palpebral fissure is usually equal to the distance between the inner corners of the eyes. Hypotelorism refers to eyes that are close together. Hypertelorism refers to eyes that are far apart. Epicanthic fold refers to a fold of skin that overlies the inner corner of the eye. The nose can be variously described as short or long (from root to tip) with a high, low or wide nasal bridge, or upturned nares. Measuring from the nasal bridge to the upper lip, the nose should equal 2/3 to 3/4 of this length. The ears may be low-set, posteriorly rotated or prominent. Normally, the ear should be transected by an imaginary horizontal line drawn from the outer corner of the eye. The lips can have a full or thin vermilion border, a tented shape, down-turned corners or a cleft. The philtrum, on the upper lip, is bounded by ridges that run from under each nostril marking the fusion of the premaxilla and the lateral maxillary processes. The philtrum may be flat. The palate can be intact, high arched, or cleft. The chin can be prominent (prognathic) or small (micrognathia).
There are also established norms for head size as it increases with age. Microcephaly refers to a head circumference less than the 2nd percentile. Macrocephaly refers to a head circumference greater than the 98th percentile. The head shape can also be abnormal because of craniosynostosis (early closure of the skull sutures). The head shapes include brachycephaly (short front to back), scaphocephaly (long front to back), and trigonocephaly (triangular shape). These are best assessed by looking directly downwards at the top of the head.
The diagnosis of fetal alcohol syndrome is partly based on craniofacial features which include microcephaly, telecanthus, narrow palpebral fissures, thin lips and a flat philtrum, with or without cleft lip or palate. Facial abnormalities figure prominently in the diagnosis of malformation syndromes because the modeling of the face (and for that matter, the hands and the feet) is a complicated process that occurs over time, is governed by numerous genes, and is subject to extraneous influences.
Abnormalities of the hands (and feet) include brachydactyly (short fingers, the length of the third finger is normally equal to the width of the palm), arachnodactyly (long fingers), clinodactyly (incurved digits, usually the fifth), syndactyly (fusion of digits, usually third and fourth for the fingers and second and third for the toes), polydactyly (extra digits), and other asymmetric abnormalities of the fingers and toes with or without dysplastic nails. All fingers have two creases except for the thumb which has one. Occasionally the fifth digit has only one crease because of a small middle phalanx. The palm has two horizontal creases and an oblique crease created by thumb to finger apposition. These creases are usually present by the twelfth week in utero. In Down syndrome, because of short hand and finger bones, it is not uncommon to have a single flexion crease on the palm (simian line) and the fifth fingers along with brachydactyly and clinodactyly of the fifth fingers.
Skin and hair abnormalities are important. Pigmentary abnormalities such as hemangioma (strawberry birthmarks), cafe-au-lait spots (brown spots), and streaks or whorl-like pigmentation need to be noted. Hair abnormalities such as localized areas of alopecia (absent hair on the scalp), synophrys (fused eyebrows), a low posterior hairline on the nape of the neck, a white forelock or hirsutism (excess hair) over the face, shoulders or lower back can serve as important diagnostic clues.
Abnormalities of the spine are usually major malformations that are readily apparent at birth such as anencephaly (absent skull and brain), encephalocele (cranial defect with the brain extruding into an external sac), and myelomeningocele (spine defect with the spinal cord and membranes extruding into an external sac). A milder form of spine abnormality, spina bifida occulta, refers to a hidden spine defect apparent only because a tuft of hair is present on the overlying skin along with a waddling or abnormal gait. This belongs to a group of conditions referred to as neural tube defects which has been discussed previously in the section on multifactorial traits and prenatal diagnosis.
The shape, size and symmetry of the chest and breast bone is often altered in skeletal dysplasias. Pectus carinatum (forward projection of the sternum resembling the keel of a boat) or pectus excavatum (an indention at the lower part of the chest) are two common alterations. The position of the nipple is normally directly below the mid-point of the collar bone. Widely spaced nipples and a broad chest are features seen in Turner syndrome. Breast development in males or the lack of development in females may be useful clues to an underlying genetic syndrome.
The abdomen may show abdominal wall defects including omphalocele (a dilated umbilical ring with intestine herniating into the cord), and gastroschisis (a muscle and skin defect with the intestine externalized and the umbilical cord to one side). Should these abnormalities be noted on an ultrasound examination in pregnancy, it is important to know that an omphalocele is often associated with a fetal chromosome abnormality and an amniocentesis is recommended. Umbilical or inguinal hernias are associated with a number of known genetic conditions. Hepatosplenomegaly is a common finding in children with storage diseases.
The genitalia should be definitively male or female. Large testes are seen in males with fragile X syndrome, and small testes are common in Prader-Willi syndrome. Delayed development of the secondary sexual characteristics is common in both Turner syndrome and Klinefelter syndrome. Ambiguous genitalia is observed in children with a number of different genetic disorders. It should result in a genetics referral in the newborn period to rule out life threatening congenital adrenal hyperplasia (CAH).
It is important to emphasize that a solitary minor malformation should not cause undue concern. Single minor malformations are seen in 13.4% of newborns, and only 3% of these children will have a major malformation. However, two minor malformations are seen in 0.8% of newborns and are associated with an 11% chance of a major malformation, and three or more minor malformations are seen in 0.5% of newborns and are associated with a 90% chance of a major malformation. The presence of a number of major and minor malformations in a child with failure to thrive, short stature, microcephaly or developmental delay is highly suggestive of a chromosomal disorder or a malformation syndrome and should result in a genetic consultation.
In addition to noting minor malformations, it is also important to assess an individual's psychomotor development during a physical examination by careful observation or the use of formal assessment tools. If a delay is noted, it is important to document whether a skill was acquired then lost. The loss of ability may be associated with a number of inborn errors of metabolism or adult onset neurodegenerative disorders.
Syndrome describes a group of major and minor abnormalities that are associated frequently enough to be clinically recognizable as a specific entity. When attempting to understand the relationship between a diverse set of major and minor abnormalities, it often helps to consider the underlying developmental pathology. These include malformation, deformation and disruption.
Malformation refers to a primary defect in the cells or tissue forming an organ or organ system. The defect may be caused by an abnormality in a gene, a group of genes, or a chromosome. A number of syndromes fall into this category: chromosomal abnormalities such as Down syndrome, trisomy 18, cri-du-chat syndrome; single gene disorders such as Apert syndrome and Marfan syndrome; and multifactorial traits such as congenital heart defects and cleft lip and palate.
Deformation refers to intrinsic or extrinsic biomechanical forces acting on the fetus to cause a structural abnormality. A prolonged breech presentation can cause congenital dislocation of the hip, clubfeet and a flattened, elongated "breech head". These are usually benign and, with the constraints removed, can be corrected. Realize that a primary malformation can lead to a secondary deformation. An obstructed urethra causing oligohydramnios (deficient amount of amniotic fluid which is mainly fetal urine) leads to flattened facial features and arthrogryposis (fixed joints). The risk of recurrence will depend upon the initiating event.
Disruption refers to the breakdown of a normally formed tissue or structure. Limbs can be amputated by an amniotic band. Porencephalic cysts (fluid filled cavities within the brain) can follow a blood clot within a cerebral blood vessel.
When a cascade of effects can be shown to occur as the result of a primary defect the term sequence has been used. An example is the oligohydramnios sequence just described which can lead to dilated ureters and enlarged cystic kidneys. Another example is the Robin sequence, where a very small jaw leads to the upward displacement of the tongue which prevents the palate from closing, leading to micrognathia, cleft palate, and glossoptosis (posteriorly displaced tongue that can fall back and obstruct respiration and swallowing).
SUMMARY
This section is not meant to be an exhaustive review of congenital malformations. Rather, it focuses on surface physical features that should be apparent to the careful observer. Again, a single minor malformation should not cause concern, especially if it is a feature shared with a normal parent. However, three or more minor malformations, especially if associated with short stature or failure to thrive, microcephaly or developmental delay, should engender further investigation.
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