What genetic term refers to a recognized pattern of malformations with a single specific cause?

Physical Examination

The physical examination is very important for the diagnosis of a dysmorphic syndrome. The essential element of the physical evaluation is an objective assessment of the patient's clinical findings. The clinician needs to perform an organized evaluation of the size and formation of various body structures. Familiarity with the nomenclature of dysmorphic signs is helpful (Table 128.5). The size and shape of the head is relevant; for example, many children with Down syndrome have mild microcephaly and brachycephaly (shortened anteroposterior dimension of skull). Eye position and shape are useful signs for many disorders. Reference standards are available with which physical measurements (e.g., interpupillary distance) can also be compared. It is also useful to categorize abnormalities as “major” or “minor” birth defects. Major defects either cause significant dysfunction (e.g., absence of a digit) or require surgical correction (e.g., polydactyly), and minor defects neither cause significant dysfunction nor require surgical correction (e.g, mild clinodactyly) (Table 128.6 andFig. 128.10). By cataloging physical parameters, the clinician may be able to recognize the diagnosis.

Introduction

Dysmorphology refers to alternations of ‘normal’ or typical morphology that can be observed and/or measured in a population. Traditionally, the study of dysmorphology is concerned with the description and categorization of birth defects, diagnosis of syndromes, and investigation and counseling of affected individuals and their families. Though the discipline grew out of the study and characterization of human disease phenotypes, the availability of mouse and other animal models for many genetic disorders has broadened the scope of dysmorphology to include the study of the development of phenotypes expressed in animal models. This has enabled more precise scrutiny of the molecular, cellular, and developmental bases of dysmorphology across pre- and postnatal time.

D Work-up

1.

Imaging to evaluate for major anomalies

Head ultrasound (US) or brain magnetic resonance imaging (MRI)

Echocardiogram

Complete abdominal US

Skeletal survey with radiographs composed of: AP views of skull, chest/ribs, upper extremities and hands, lower extremities and feet; lateral views of skull, complete spine, chest, and odontoid view.

Dilated eye exam

Hearing evaluation

Genetic testing: SeeFig. 13.4 andTable 13.8. The patient should be referred to genetics for a dysmorphology evaluation and appropriate testing.

Introduction

Dysmorphology refers to alterations of “normal” or typical morphology that can be observed and/or measured in a population. Traditionally, the study of dysmorphology is concerned with the description and categorization of birth defects, diagnosis of syndromes, and investigation and counseling of affected individuals and their families. Current clinical protocols stress the use of the term “difference” to replace “dysmorphology” or “deformity” to underscore the idea that these morphologies exist at the extremes of a normal distribution of the phenotype in question. Though the discipline grew out of the study and characterization of human disease phenotypes, the availability of mouse and other animal models for many genetic disorders has broadened the scope of dysmorphology to include the study of the development of phenotypes expressed in animal models. This has enabled more precise scrutiny of the molecular, cellular, and developmental bases of dysmorphology across pre- and postnatal time.

Associated Dysmorphology

A thorough physical examination should be done to identify any other dysmorphic features. Genital abnormalities are often part of dysmorphic syndromes and are frequently associated with midline defects.45 Examples include the presence of the Turner phenotype in gonadal dysgenesis and campomelic dwarfism (bowing and angulation of the lower limbs, flat facies, shortened vertebrae) in XY gonadal dysgenesis. Some DSD patients appear phenotypically normal at birth, including many (but not all) cases of gonadal dysgenesis, XX male, 46,XY male with persistent Müllerian ducts, and complete androgen insensitivity syndrome (cAIS).

Dysmorphology—Past and Present

Dysmorphology, the study of human congenital malformations and syndromes, is quite a young discipline in clinical genetics. Dysmorphic syndrome (DS) includes a particular set of developmental anomalies that create a recognizable and consistent pattern of abnormalities. DS has a known or assumed single etiology. The term dysmorphic is used to describe children whose physical features, particularly facial features, and also features of the entire body (stature, neck, limbs, hands, feet, trunk, and genitalia) are not usually found in children of the same age and/or ethnic group. Dysmorphology attempts to interpret the patterns of human growth and structural defects. These include malformation, disruption, deformation, and dysplasia [1–3]. Many dysmorphic children have significant internal or external malformations or developmental delay or some combination of these.

Congenital malformations represent one of the most frequent and important reasons for genetic counseling. Children with a congenital defect and/or DS represent 2–3% of live births [4]. Many multidefect syndromes and DSs are very rare (even 1:50,000 to 1:200,000 live births), but with a large number of individual syndromes (about 7000 currently recognized syndromes described by OMIM and Orphanet) [5–7], they are collectively frequent, affecting millions of people worldwide, accounting for a major proportion of serious disorders, disability, hospitalizations, and early deaths in children [8–12]. Moreover, they account for rising costs of health care in every country and society [9–11].

Dr David Smith, a pediatrician, was the founder of clinical dysmorphology. He formed, in 1960, in the United States (Madison, WI, and Seattle, WA), a clinical and scientific group of specialists devoted to the study of congenital malformations [13]. A few years later, Dr Jon Aase, a former student of Dr Smith, elaborated a detailed concept of dysmorphology, which “as a scientific discipline combines concepts, knowledge, and techniques from the fields of embryology, clinical genetics and pediatrics. As a medical subspecialty, dysmorphology deals with people who have congenital abnormalities and with their families” [3,13].

From 1968 to 1974, Victor A. McKusick organized annual conferences on birth defects and subsequently published new discoveries in this field. Victor McKusick understood that congenital malformations overlapped with a wider group of genetic disorders that were progressively becoming clinically and scientifically defined. In the 1970s and after, clinical dysmorphology rapidly developed owing to the common efforts of numerous researchers, including Robert Gorlin, Michael M. Cohen, John Opitz, Judith Hall, Jon Aase, David Rimoin, Robin Winter, Dian Donnai, John Carey, Giovanni Neri, and many others [13]. At that time, clinicians and dysmorphologists attempted to interpret the patterns of human structural defects based on their own knowledge and experience. Owing to the difficulties in providing a definitive diagnosis, further frustrating the family of the affected child, some criticism arose toward dysmorphology as a discipline. However, around 1990, clinical dysmorphology began rapidly advancing in parallel with the enormous progress in cytogenetics and molecular genetics [1,2]. The accurate delineation of DS at the molecular level increases the possibilities for patient management and is essential to provide genetic counseling to the families [1–3].

11 Geneticists and pediatricians use the terms malformation, deformation, and disruption. What do they mean?

The dysmorphology approach to congenital anomalies divides defects into one of three sequences, which are defined as problems that lead to a cascade of events:

In a malformation sequence, poor formation of tissue within the fetus initiates the chain of defects, which may range from minimal to severe. All gradations of radial dysplasia, ranging from absence of the thenar muscles to complete absence of the radius resulting in the club hand posture, are examples. Occurrence rate is in the 5% range. Radial dysplasias also are associated with malformation in other organ systems, such as the VATER association (vertebral anomalies, anal atresia, tracheoesophageal fistula, renal anomalies, and radial dysplasia) and Holt-Oram syndrome (radial dysplasia and congenital heart disease).

The deformation sequence involves no intrinsic problem with the fetus or embryo; instead, abnormal external mechanical or structural forces cause secondary distortion or deformation. Tethering or constriction of limb parts by anular bands in the constriction ring syndrome is a prime example. The occurrence rate is very low.

In the disruption sequence, the normal fetus or embryo is subjected to tissue breakdown or injury, which may be vascular, infectious, mechanical, or metabolic in origin. The hand deformities associated with maternal ingestion of thalidomide or alcohol are good examples.

Often the patient's problem cannot be explained by a single initiating factor. When the cause of a defect is unknown, the term malformation is preferred. Multiple defects are usually referred to as a malformation syndrome.

9 ZP Defects and Female Factor Infertility: Clinical Significance

ZP dysmorphology like dark ZP, large perivitelline space, oval, or irregular shaped ZP has been shown to be associated with reduced implantation and pregnancy rates following IVF as compared to normal oocytes (Sauerbrun-Cutler et al., 2015). However, multiple ZP dysmorphological features do not affect pregnancy rates by intracytoplasmic sperm injection (ICSI; Rienzi, Vajta, & Ubaldi, 2011). Predictive potential of the ZP/oocyte morphology in pregnancy outcome remains to be established. In addition to several studies pertaining to ZP morphology and its implications in fertility, few studies have also been undertaken to investigate the role of mutations in the genes encoding human zona proteins as factor(s) for female infertility. Analysis of Zp1, Zp2, Zp3, and Zp4 genes in women whose eggs fail to fertilize using IVF as compared to those with successful fertilization following IVF as well as women with proven fertility show 1.5-fold increase in sequence variation in Zp1 and Zp3 genes (Männikkö et al., 2005). Two single-base substitutions in the sequence of the Zp3 gene are found to exist with increased frequency as compared to the control fertile groups. One of these mapped to a conserved motif in the upstream regulatory region (element IIA) of the gene, suggesting that changes in the expression levels of the ZP genes may lead to altered matrix formation with adverse consequences for fertility. Another independent study in infertile women enrolled in the infertility clinic reveals sequence variations in genes encoding Zp2 and Zp3 that might be associated with most frequent morphological anomalies observed in the ZP (Pökkylä, Lakkakorpi, Nuojua-Huttunen, & Tapanainen, 2011). Sequencing of human Zp1, Zp2, Zp3, Zp4 and regulatory element for the Zp3 gene from three infertile women with abnormal oocyte ZP appearance reveal eight synonymous and nonsynonymous previously reported polymorphisms only in Zp1, Zp2, and Zp3, suggesting that genetic changes may not be responsible for abnormal oocyte ZP appearance (Margalit et al., 2012). In another study, mutations in the genes encoding four ZP glycoproteins in six members of the family were studied. There was no ZP in any of the eggs collected from the index patient. A homozygous transcript deletion of 8 bp encompassing nucleotides 1169–1176 in Zp1 in all the six members of the family is observed. It results in the production of truncated form of ZP1 (404 aa residues). Defective ZP1 protein and normal ZP3 protein are colocalized throughout the oocytes and are not expressed on the oocyte cell surface. These observations suggest that aberrant ZP1 prevents the formation of the ZP around oocyte (Huang et al., 2014). However, additional studies are needed to further delineate the role of mutations in the genes encoding human zona proteins leading to either abnormal morphology of the ZP or failure of fertilization during IVF.

6.1.1 Limitations of “clinical” dysmorphology and the newer dysmorphology tools

Diagnosing a rare dysmorphology syndrome is an integral part of a typical clinical genetics practice. Pattern recognition is a key skill in clinical dysmorphology aided by finding a match to the findings under consideration in the published literature. However, absence of a previously described alike may not necessarily indicate the novelty of the syndrome because the matching process remains largely subjective [2]. Dysmorphology alone might be misleading as it is also subjective to experience of the geneticist, variability of phenotype, and phenocopies [3]. Academic forums examining such cases included dysmorphology meetings; peer-reviewed literature seeks to establish whether a particular syndrome is truly novel. This process lacks throughput, and it may take a long time before a novel recognizable syndrome is designated. Tools such as dysmorphology databases and computerized dysmorphology analysis may aid clinicians in reaching a diagnosis.

Dysmorphology databases are useful tools that require accurate identification of clinical signs as a handle to reach a diagnosis. These are typically equipped with patient photographs, characteristic radiological images, and allow filtering for essential and additional features, inheritance patterns, which might help in narrowing down on a smaller number of differentials. Since features are prelisted, a clinician can be reminded of other clinical features that are not so well-known and are missed. However, just keying some features in databases may not always lead to a diagnosis as there could be hundreds of syndromes with those features. It is not easy to identify an accurate diagnosis from background noise of other syndromes bearing the same clinical features and knowledge of genetic syndromes, which is often necessary to sieve out the conditions of interest.

Computerized dysmorphology analysis: There is an increasing recognition of use of 3D facial image analysis in identifying facial dysmorphology and related genetic disorders. Recent advances in computational models of facial dysmorphology can assist early recognition of characteristic face shape presented as frontal and supine photographs. Patients and control subjects are matched for gender and age. Software with specific mathematical programs have been developed, which extract and analyze information from certain landmarks (a grid of nodes placed on relevant facial structures) on these photographs and categorize them using a classification algorithm. An unknown subject is classified by assessing his/her similarity to case/control group within the database [4]. Although such efforts contribute to making the hazy field of subjective dysmorphology assessment more objective and user friendly, there is a lot of scope for improvement in computational dysmorphology. Faces might appear different in different ethnicities depending on their “normal” pattern, and they keep changing over time in both normal and syndromic individuals. Studies using subjective and objective statistical approaches have revealed contrasting age-related changes that either render the phenotype subtler or make it more apparent with age, making a clinical diagnosis challenging in older and younger individuals, respectively [5].

It is speculated that such advanced facial analysis might in future inform the strategy for molecular analysis and confirmation of a clinical diagnosis. Studies combining morphological and molecular analyses of atypical patients with a genetic condition can help identify the role of individual genes in different facets of the associated clinical pathologies.

98.8.4 Clinical Features

The characteristic dysmorphology includes the following: wide slack mouth, malocclusion, prominent upper lip, underdeveloped mandible, depressed nasal bridge, hypertelorism, epicanthic folds, low-set ears, increased bone density, craniostenosis, and osteosclerosis, especially at the base of the skull. Neurologic manifestations include hypotonia, hyperreflexia, and motor retardation. Children are unusually friendly and have been described as having “cocktail party” personalities. Renal involvement is common in Williams syndrome, including nephrocalcinosis and anatomic defects. A variety of clinical manifestations can occur including renovascular hypertension, proteinuria, and an elevated plasma creatinine concentration.

Cardiovasuclar abnormalities involve local or diffuse stenosis of the medium-sized or large-sized arteries, most commonly in the ascending aorta above the aortic valves (i.e. supravalvular aortic stenosis) or in the pulmonary arteries. Nonetheless, stenosis of the descending aorta, intracranial arteries, and renal arteries has been reported. Overall, unexpected death is rare but is 25-fold to 100-fold higher than in age-matched control subjects. Factors implicated in sudden death have included supravalvular aortic stenosis, severe pulmonary stenosis, and myocardial ischemia secondary to either coronary insufficiency or biventricular outflow tract obstruction with ventricular hypertrophy. Coronary insufficiency appears most likely because of stenosis that results from intimal fibrosis and muscular hypertrophy. Stroke and hypertension occur at younger-than-expected ages. Cases showing portions of the phenotype have sometimes been collected within this syndrome without implying identical pathophysiology for all cases (302). Early studies showed elevated serum and urine levels of calcium during the first year of life and a tendency to develop nephrocalcinosis. Hypercalcemia rarely persists after the first year of life, but persistent hypercalciuria is not uncommon. Although many reports of children with Williams syndrome have failed to document a high frequencyof hypercalcemia, in a report of 50 cases from Greece, three had hypercalcemia (303) . Serum 25(OH)D and 24,25(OH)2D are normal (304), but circulating levels of 25(OH)D show excessive increases after administration of vitamin D (305). Serum 1α,25(OH)2D levels have been reported to be elevated (306), or suppressed (304,307,308), suggesting more than one mechanism for the hypercalcemia (309).