Chapter 128

Dysmorphology

Anne M. Slavotinek

Dysmorphology is the study of differences in human form and the mechanisms that cause them. It has been estimated that 1 in 40 newborns, or 2.5%, have a recognizable birth defect or pattern of malformations at birth; approximately half these newborns have a single, isolated malformation, whereas in the other half, multiple malformations are present. From 20–30% of infant deaths and 30–50% of deaths after the neonatal period are caused by congenital abnormalities (http://www.marchofdimes.com/peristats/ ). In 2001, birth defects accounted for 1 in 5 infant deaths in the United States, with a rate of 137.6 deaths per 100,000 live births, which was higher than other causes of mortality, such as preterm/low birthweight (109.5/100,000), sudden infant death syndrome (55.5/100,000), maternal complications of pregnancy (37.3/100,000), and respiratory distress syndrome (25.3/100,000).

Classification of Birth Defects

Birth defects can be subdivided into isolated (single) defects or multiple congenital anomalies (multiple defects) in one individual. An isolated primary defect can be classified, according to the nature of the presumed cause of the defect, as a malformation, dysplasia, deformation, or disruption (Table 128.1 and Fig. 128.1 ). Most birth defects are malformations. A malformation is a structural defect arising from a localized error in morphogenesis that results in the abnormal formation of a tissue or organ. Dysplasia refers to the abnormal organization of cells into tissues. Malformations and dysplasias can both affect intrinsic structure. In contrast, a deformation is an alteration in shape or structure of a structure or organ that has developed, or differentiated, normally. A disruption is a defect resulting from the destruction of a structure that had formed normally before the insult.

Table 128.1

Mechanisms, Terminology, and Definitions of Dysmorphology

TERMINOLOGY	DEFINITION	EXAMPLE
Sequence	Single error in morphogenesis that results in a series of subsequent defects	Pierre-Robin sequence, in which a small jaw results in glossoptosis and cleft palate DiGeorge sequence of primary 4th brachial arch and 3rd and 4th pharyngeal pouch defects, leading to aplasia or hypoplasia of the thymus and parathyroid glands, aortic arch anomalies, and micrognathia
Deformation sequence	Mechanical (uterine) force that alters structure of intrinsically normal tissue	Oligohydramnios produces deformations by in utero compression of limbs (e.g., dislocated hips, equinovarus foot deformity), crumpled ears, or small thorax
Disruption sequence	In utero tissue destruction after a period of normal morphogenesis	Amnionic membrane rupture sequence, leading to amputation of fingers/toes, tissue fibrosis, and tissue bands
Dysplasia sequence	Atypical organization of cells into tissues or organs	Neurocutaneous melanosis sequence, with atypical migration of melanocyte precursor cells from the neural crest to the periphery, manifesting as melanocytic hamartomas of skin and meninges
Malformation syndrome	Appearance of multiple malformations in unrelated tissues that have a known, unifying cause	Trisomy 21 Teratogens Numerous multiple congenital anomaly syndromes as described above

From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy , ed 2, Philadelphia, 2004, Elsevier Saunders.

Fig. 128.1 Four major types of problems in morphogenesis: malformation, deformation, disruption, and dysplasia. A, Infant with camptomelic dysplasia syndrome, which results in a multiple malformation syndrome caused by a mutation in SOX9 . B, Infant with oligohydramnios deformation sequence caused by premature rupture of membranes from 17 wk gestation until birth at 36 wk; the infant was delivered from persistent transverse lie. C, Fetus with early amnion rupture sequence with attachment of the placenta to the head and resultant disruption of craniofacial structures with distal limb contractures. D, Infant with diastrophic dysplasia caused by inherited autosomal recessive mutations in a sulfate transporter protein. (From Graham Jr JM: Smith's recognizable patterns of human deformation, ed 3, Philadelphia, 2007, Saunders, Fig 1-1, p 4.)

Most inherited human disorders with altered morphogenesis display multiple malformations rather than isolated birth defects. When several malformations coexist in a single individual, they can be classified as a syndrome, sequence, or an association. A syndrome is defined as a pattern of multiple abnormalities that are related by pathophysiology, resulting from a single, defined etiology. Sequences consist of multiple malformations that are caused by a single event, although the sequence itself can have different etiologies. An association refers to a nonrandom grouping of malformations in which there is an unclear, or unknown, relationship among the malformations, such that they do not fit the criteria for a syndrome or sequence.

Malformations and Dysplasias

Human malformations and dysplasias can be caused by gene mutations, chromosome aberrations and copy number variants, environmental factors, or interactions between genetic and environmental factors (Table 128.2 ). Some malformations are caused by deleterious sequence variants in single genes, whereas other malformations arise because of deleterious sequence variants in multiple genes acting in combination (digenic or oligogenic inheritance). In 1996 it was thought that malformations were caused by monogenic defects in 7.5% of patients; chromosomal anomalies in 6%; multigenic defects in 20%; and known environmental factors, such as maternal diseases, infections, and teratogens, in 6–7% (Table 128.3 ). In the remaining 60–70% of patients, malformations were classified as caused by unknown etiologies. Currently, the percentages have increased for all categories of known causes of malformations, the result of improved cytogenetic and molecular genetic methods for detecting small chromosomal abnormalities and next-generation sequencing studies that can screen multiple genes simultaneously and identify novel genes and deleterious sequence variants.

Table 128.2

Examples of Malformations with Distinct Causes, Clinical Features, and Pathogenesis

DISORDER	CAUSE/INHERITANCE	SELECTED CLINICAL FEATURES	PATHOGENESIS
Spondylocostal dysostosis syndrome	Mendelian; autosomal recessive	Abnormal vertebral and rib segmentation	Deleterious sequence variants in DLL3 and other genes
Rubinstein-Taybi syndrome	Autosomal dominant	Intellectual disability Broad thumbs and halluces; valgus deviation of these digits Hypoplastic maxillae Prominent nose and columella Congenital heart disease	Deleterious sequence variants in CBP and EP300
X-linked lissencephaly	X-linked	Male: severe intellectual disability, seizures Female: variable	Deleterious sequence variants in DCX
Aniridia	Autosomal dominant	Absent iris or iris/foveal hypoplasia	Deleterious sequence variants in PAX6
Waardenburg syndrome, type I	Autosomal dominant	Deafness White forelock Wide-spaced eyes Iris heterochromia and/or pale skin pigmentation	Deleterious sequence variants in PAX3
Holoprosencephaly	Loss of function or heterozygosity for multiple genes	Microcephaly	SHH, multiple other genes
		Cyclopia
		Single central incisor
Velocardiofacial syndrome	Microdeletion 22q11.2	Congenital heart disease, including conotruncal defects	TBX1 haploinsufficiency/mutations; haploinsufficiency for other genes in the deleted interval also contributes to the phenotype.
		Cleft palate
		T-cell defects
		Facial anomalies
Down syndrome	Additional copy of chromosome 21 (trisomy 21)	Intellectual disability	Increase in dosage of an estimated 250 genes on chromosome 21
		Characteristic dysmorphic features
		Congenital heart disease
		Increased risk of leukemia
		Alzheimer disease
Neural tube defects	Multifactorial	Meningomyelocele	Defects in folate sensitive enzymes or folic acid uptake
Fetal alcohol syndrome	Teratogenic	Microcephaly	Ethanol toxicity to developing brain
		Developmental delay
		Facial abnormalities
		Behavioral abnormalities
Retinoic acid embryopathy	Teratogenic	Microtia	Isotretinoin effects on neural crest and branchial arch development
		Congenital heart disease

Table 128.3

Causes of Congenital Malformations

MONOGENIC

X-linked hydrocephalus

Achondroplasia

Ectodermal dysplasia

Apert syndrome

Treacher Collins syndrome

CHROMOSOMAL ABERRATIONS and COPY NUMBER VARIANTS

Trisomy 21, 18, 13

XO, XXY

Deletions 4p−, 5p−, 7q−, 13q−, 18p−, 18q−, 22q−

Prader-Willi syndrome (70% of affected patients have deletion of chromosome 15 q11.2-q13)

MATERNAL INFECTION

Intrauterine infections (e.g., herpes simplex virus, cytomegalovirus, varicella-zoster virus, rubella virus, Zika virus, toxoplasmosis)

MATERNAL ILLNESS

Diabetes mellitus

Phenylketonuria

Hyperthermia

UTERINE ENVIRONMENT

Deformation

Uterine pressure, oligohydramnios: clubfoot, torticollis, congenital hip dislocation, pulmonary hypoplasia, 7th nerve palsy

Disruption

Amniotic bands, congenital amputations, gastroschisis, porencephaly, intestinal atresia

Twinning

ENVIRONMENTAL AGENTS

Polychlorinated biphenyls

Herbicides

Mercury

Alcohol

MEDICATIONS

Thalidomide

Diethylstilbestrol

Phenytoin

Warfarin

Cytotoxic drugs

Paroxetine

Angiotensin-converting enzyme inhibitors

Isotretinoin (vitamin A)

D -Penicillamine

Valproic acid

Mycophenolate mofetil

UNKNOWN ETIOLOGIES

Neural tube defects, such as anencephaly and spina bifida

Cleft lip/palate

Pyloric stenosis

SPORADIC SEQUENCE COMPLEXES

VATER/VACTERL sequence (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, radial and renal anomalies)

Pierre Robin sequence

NUTRITIONAL

Neural tube defects due to low folic acid

From Behrman RE, Kliegman RM, editors: Nelson's essentials of pediatrics, ed 4, Philadelphia, 2002, Saunders.

Many developmental abnormalities that are caused by deleterious sequence variants (mutations)in a single gene display characteristic, mendelian patterns of inheritance (autosomal dominant, autosomal recessive, and X-linked inheritance). Genes that cause birth defects or multiple congenital anomaly syndromes are often transcription factors, part of evolutionarily conserved signal transduction pathways, or regulatory proteins required for key developmental events (Figs. 128.2 and 128.3 ). Examples include spondylocostal dysostosis syndromes, Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, and X-linked lissencephaly (“smooth brain”) syndrome (see Table 128.2 ).

Fig. 128.2 Deleterious sequence variants in genes that function together in a developmental pathway typically have overlapping clinical manifestations. Several components of the sonic hedgehog (SHH) pathway have been identified, and their relationships elucidated (see text for further details). Mutations in several members of this pathway result in phenotypes with facial dysmorphism, as seen in holoprosencephaly, Smith-Lemli-Opitz syndrome, Gorlin syndrome, Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and Rubinstein-Taybi syndrome. CNS, Central nervous system.

Fig. 128.3 The RAS/MAPK signal transduction pathway. The MAPK signaling pathway of protein kinases is critically involved in cellular proliferation, differentiation, motility, apoptosis, and senescence. The RASopathies are medical genetic syndromes caused by mutations in genes that encode components or regulators of the Ras/MAPK pathway (indicated by dashed lines ). These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation–arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFC), and Legius syndrome. RAS/MAPK, RAS protein family/mitogen-activated protein kinase. (From Rauen KA: The RASopathies, Annu Rev Genom Hum Genet 14:355–369, 2013.)

Patients with spondylocostal dysostosis (SCD) display a characteristic pattern of vertebral segmentation defects associated with a number of other malformations, such as neural tube defects. The SCD syndromes are etiologically heterogeneous and are often caused by mutations in the gene coding for delta-like 3 (DLL3 ), a ligand of the Notch receptors. The Notch/delta pathway is conserved throughout evolution and regulates a number of developmental events. Smith-Lemli-Opitz syndrome (SLOS) results from mutations in the sterol delta-7-dehydrocholesterol reductase (DHCR7 ) gene, an enzyme critical for normal cholesterol biosynthesis. Patients with SLOS (see Fig. 128.2 ) display syndactyly (fusion of the fingers and toes), in particular affecting the 2nd and 3rd toes; postaxial polydactyly (extra digits); anteverted (upturned) nose; ptosis; cryptorchidism; and holoprosencephaly (failure of separation of the 2 cerebral hemispheres). Many of the features in SLOS are shared with those arising from deleterious sequence variants in the SHH genes, and these mutations link cholesterol biosynthesis pathogenically to the sonic hedgehog (SHH) pathway, because SHH is posttranslationally modified by cholesterol (see Chapter 97 ). Rubinstein-Taybi syndrome (see Fig. 128.2 ) typically results from heterozygous, loss-of-function deleterious sequence variants in a gene coding for a broadly acting transcriptional coactivator called CREB-binding protein (CBP) and from deleterious sequence variants in the EP300 gene. The CBP coactivator regulates the transcription of a number of genes, which is why patients with deleterious sequence variants in CBP have a pleiotropic phenotype that includes developmental delays and intellectual disability, broad and angulated thumbs and halluces (1st toes), and congenital heart disease. One of the transcription factors that binds to CBP is GLI3, a member of the SHH pathway (see Fig. 128.2 ). X-linked lissencephaly is a severe neuronal migration defect that causes a smooth brain with reduction or absence of gyri and sulci in males and that gives rise to a variable pattern of intellectual disability and seizures in females. X-linked lissencephaly is caused by deleterious sequence variants in DCX . The DCX protein regulates the activity of dynein motors that contribute to movement of the cell nucleus during neuronal migration.

Malformation syndromes can also be caused by chromosomal aberrations or copy number variants and teratogens (see Tables 128.2 and 128.3 ). Down syndrome typically results from an extra copy of an entire chromosome 21 or, less frequently, an extra copy of the Down syndrome critical region on chromosome 21. Chromosome 21 is a small chromosome that contains an estimated 250 genes, and thus individuals with Down syndrome typically have an increased dosage of the numerous genes encoded by this chromosome that causes their physical differences (see Chapter 98.2 ).

Neural tube defects (NTDs) are an example of a birth defect that displays multifactorial inheritance in most cases. NTDs and a number of other congenital malformations, such as cleft lip and palate, can recur in families, but inheritance for the majority of affected individuals does not occur in a straightforward, mendelian inheritance pattern, and in this situation, multiple genes and environmental factors together likely contribute to the pathogenesis (see Table 128.2 ). Many of the genes involved in NTDs are unknown, so one cannot predict with certainty the mode of inheritance or a precise recurrence risk in the individual case. Empirical recurrence risks can be provided on the basis of population studies and the presence of single or multiple family members with the same malformation. However, one important gene/environment interaction has been identified for NTDs (see Chapter 609.1 ). Folic acid deficiency is associated with NTDs and can result from a combination of dietary factors and increased utilization during pregnancy. A common variant in the gene for an enzyme in the folate recycling pathway, 5,10-methylene-tetrahydrofolate reductase (MTHFR ), that makes this enzyme less stable, may also be important in folic acid status. Several teratogenic causes of birth defects have been described (see Tables 128.2 and 128.3 ). Ethanol causes a recognizable malformation syndrome that is variably called fetal alcohol syndrome (FAS), fetal alcohol spectrum disorder (FASD), or fetal alcohol effects (FAE) (see Chapter 126.3 ). Children who were exposed to ethanol during the pregnancy can display microcephaly, developmental delays, hyperactivity, and facial dysmorphic features. Ethanol, which is toxic to the developing central nervous system (CNS), causes cell death in developing neurons.

Deformations

Many deformations involve the musculoskeletal system (Fig. 128.4 ). Fetal movement is required for the proper development of the musculoskeletal system, and restriction of fetal movement can cause musculoskeletal deformations such as clubfoot (talipes). Two major intrinsic causes of deformations are primary neuromuscular disorders and oligohydramnios, or decreased amniotic fluid, which can be caused by fetal renal defects. The major extrinsic causes of deformation are those that result in fetal crowding and restriction of fetal movement. Examples of extrinsic causes include oligohydramnios resulting from chronic leakage of amniotic fluid and abnormal shape of the amniotic cavity. When a fetus is in the breech position (Fig. 128.5 ), the incidence of deformations is increased 10-fold. The shape of the amniotic cavity also has a profound effect on the shape of the fetus and is influenced by many factors, including uterine shape, volume of amniotic fluid, and the size and shape of the fetus (Fig. 128.6 ).

Fig. 128.4 Deformation abnormalities resulting from uterine compression. (From Kliegman RM, Jenson HB, Marcdante KJ, et al, editors: Nelson essentials of pediatrics, ed 5, Philadelphia, 2005, Saunders.)

Fig. 128.5 Breech deformation sequence.

Fig. 128.6 A, Consequences of renal agenesis. B, Multiple deformational defects. C, Defects in amnion nodosum; brown-yellow granules from vernix have been ribbed into defects of the amniotic surface. (From Jones KL, Jones MC, Del Campo M, editors: Smith's recognizable patterns of human malformation, ed 7, Philadelphia, 2013, Elsevier, p 821.)

It is important to determine whether deformations result from intrinsic or extrinsic causes. Most children with deformations from extrinsic causes are otherwise completely normal, and their prognosis is usually excellent. Correction typically occurs spontaneously. Deformations caused by intrinsic factors, such as multiple joint contractures resulting from CNS or peripheral nervous system defects, have a different prognosis and may be much more significant for the child (Fig. 128.7 ).

Fig. 128.7 A, Diagram demonstrates the etiologically heterogeneous phenotype that results from fetal akinesia. B, Infant born with myotonic dystrophy to a mother with the same condition. He had multiple joint contractures with thin bones and respiratory insufficiency. C, Infant immobilized in a transverse lie after amnion rupture at 26 wk. D, Fetus with bilateral renal agenesis resulting in oligohydramnios. (From Graham JL. Smith's recognizable patterns of human malformation, ed 3, Philadelphia, 2007, Elsevier, Fig 47-2.)

Disruptions

Disruptions are caused by destruction of a previously normally formed organ or body part. At least 2 mechanisms are known to produce disruptions. One involves entanglement, followed by tearing apart or amputation, of a normally developed structure, usually a digit or limb, by strands of amnion floating within amniotic fluid (amniotic bands) (Fig. 128.8 ). The other mechanism involves interruption to the blood supply to a developing part, which can lead to infarction, necrosis, and resorption of structures distal to the insult. If interruption to the blood supply occurs early in gestation, the disruptive defect typically involves atresia, or absence of a body part. Genetic factors were previously considered to play a minor role in the pathogenesis of disruptions; most occur as sporadic events in otherwise healthy individuals. The prognosis for a disruptive defect is determined entirely by the extent and location of the tissue loss.

Fig. 128.8 A, Amniotic band disruption sequence. B, Bands constricting the ankle leading to deformational defects and amputations. (From Jones KJ: Smith's recognizable patterns of human malformation, ed 6, Philadelphia, 2006, Saunders.)

Multiple Anomalies: Syndromes and Sequences

The pattern of multiple anomalies that occurs when a single primary defect in early development produces multiple abnormalities because of a cascade of secondary and tertiary developmental anomalies is called a sequence (see Fig. 128.9 ). When evaluating a child with multiple congenital anomalies, the physician must differentiate between multiple anomalies that are caused by a single localized error in morphogenesis (a sequence) from syndromes with multiple malformations. In the former, recurrence risk counseling for the multiple anomalies depends entirely on the risk of recurrence for the single, localized malformation. Pierre-Robin sequence is a pattern of multiple anomalies produced by mandibular hypoplasia. Because the tongue is relatively large for the oral cavity, it drops back (glossoptosis), blocking closure of the posterior palatal shelves and causing a U -shaped cleft palate. There are numerous causes of mandibular hypoplasia, all of which can result in characteristic features of Pierre-Robin sequence.

Fig. 128.9 Holoprosencephaly sequence. A, Schematic longitudinal section of 21-day embryo. B, Developmental pathogenesis of the sequence. C, Affected individual. (From Jones KL, Jones MC, Del Campo M, editors: Smith's recognizable patterns of human malformation, ed 7, Philadelphia, 2013 Elsevier, pp 802–803.)

Molecular Mechanisms of Malformations

Inborn Errors of Development

Genes that cause malformation syndromes (as well as genes whose expression is disrupted by environmental agents or teratogens) can be part of numerous cellular processes, including evolutionarily conserved signal transduction pathways, transcription factors, or regulatory proteins required for key developmental events. When malformations are considered as alterations resulting from disturbances to important developmental pathways, this provides a molecular framework for understanding the birth defects.

Sonic Hedgehog Pathway As Model

The SHH pathway is developmentally important during embryogenesis to induce controlled proliferation in a tissue-specific manner; disruption of specific steps in this pathway results in a variety of related developmental disorders and malformations (see Fig. 128.2 ). Activation of this pathway in the adult leads to abnormal proliferation and cancer. The SHH pathway transduces an external signal, in the form of a ligand, into changes in gene transcription by binding of the ligand to specific cellular receptors. SHH is a ligand expressed in the embryo in regions important for development of the brain, face, limbs, and the gut.

Deleterious sequence variants in SHH can cause holoprosencephaly (see Fig. 128.2 ), a variably severe, midline defect associated with clinical effects ranging from cyclopia to a single maxillary incisor with hypotelorism or close spacing of the ocular orbits. The SHH protein is processed by proteolytic cleavage to an active N-terminal form, which is then further modified by the addition of cholesterol. Defects in cholesterol biosynthesis, in particular the sterol, delta-7-dehydrocholesterol reductase gene, result in SLOS , which is also associated with holoprosencephaly. The modified and active form of SHH binds to its transmembrane receptor Patched (PTCH1). SHH binding to PTCH1 inhibits the activity of the transmembrane protein Smoothened (SMO). SMO act to suppress downstream targets of the SHH pathway, the GLI family of transcription factors, so inhibition of SMO by PTCH1 results in activation of GLI1, GLI2, and GLI3, resulting in alteration of transcription of GLI targets. PTCH1 and its orthologue, PTCH2 , can act as tumor suppressors, and somatic, inactivating sequence variants can be associated with loss of tumor suppressor function, whereas activating mutations in SMO can also be oncogenic, particularly in basal cell carcinomas and medulloblastomas. Germline, inactivating mutations in PTCH1 result in Gorlin syndrome (see Fig. 128.4 ), an autosomal dominant disorder characterized by dysmorphic features (broad face, dental anomalies, rib defects, short metacarpals), basal cell nevi that can undergo malignant transformation, and an increased risk of cancers, including medulloblastomas and rhabdomyosarcomas. GLI1 amplification has been found in several human tumors, including glioblastoma, osteosarcoma, rhabdomyosarcoma, and B cell lymphomas; mutations or alterations in GLI3 have been found in Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome ( PHS), postaxial polydactyly type A (and A/B), and preaxial polydactyly type IV (see Fig. 128.2 ). GCPS consists of hypertelorism (wide-spaced eyes), syndactyly, preaxial polydactyly, and broad thumbs and halluces. PHS is an autosomal dominant disorder characterized by postaxial polydactyly, syndactyly, hypothalamic hamartomas, imperforate anus, and occasionally holoprosencephaly. GLI3 binds to CBP, the protein that is haploinsufficient in Rubinstein-Taybi syndrome .

Disorders that are caused by mutations in genes that function together in a developmental pathway typically have overlapping clinical manifestations. In this case, the overlapping features result from the expression domains of SHH that are important for development of the brain, face, limbs, and gut. Brain defects are found in holoprosencephaly (Fig. 128.9 ), SLOS, and PHS. Facial abnormalities are found in holoprosencephaly, SLOS, Gorlin syndrome, GCPS, and PHS. Limb defects are found in SLOS, Gorlin syndrome, GCPS, PHS, and the polydactyly syndromes. Overexpression, or activating mutations, affecting the SHH pathway results in cancer, including basal cell carcinomas, medulloblastomas, glioblastomas, and rhabdomyosarcomas.

The SHH pathway interaction with the primary cilium is critical to transduce the SHH extracellular signal through to the nuclear machinery. A number of disorders, including Bardet-Biedl syndrome, oral-facial-digital (OFD) syndrome type I, and Joubert syndrome, are caused by mutations in genes that function in the primary cilium. These disorders, called ciliopathies , overlap clinically with some of the phenotypic features described previously, again demonstrating that perturbations of conserved developmental pathways can cause overlapping presentations (Table 128.4 ).

Table 128.4

Childhood Diseases and Syndromes Associated with Motile and Sensory Ciliopathies

PEDIATRIC CILIOPATHY	CLINICAL MANIFESTATIONS	SELECTED GENE(S)
MOTOR
Primary ciliary dyskinesia	Chronic bronchitis, rhinosinusitis, otitis media, laterality defects, infertility, CHD	DNAI1, DNAH5, DNAH11, DNAI2, KTU, TXNDC3, LRRC50, RSPH9, RSPH4A, CCDC40, CCDC39
SENSORY
Autosomal recessive polycystic kidney disease	RFD, CHF	PKHD1
Nephronophthisis	RFD, interstitial nephritis, CHF, RP	NPHP1-8, ALMS1, CEP290
Bardet-Biedl syndrome	Obesity, polydactyly, ID, RP, renal anomalies, anosmia, CHD	BBS1-12, MKS1, MKS3, CEP290
Meckel-Gruber syndrome	RFD, polydactyly, ID, CNS anomalies, CHD, cleft lip, cleft palate	MKS1-6, CC2D2A, CEP290, TMEM216
Joubert syndrome	CNS anomalies, ID, ataxia, RP, polydactyly, cleft lip, cleft palate	NPHP1, JBTS1, JBTS3, JBTS4, CORS2, AHI1, CEP290, TMEM216
Alstrom syndrome	Obesity, RP, DM, hypothyroidism, hypogonadism, skeletal dysplasia, cardiomyopathy, pulmonary fibrosis	ALMS1
Orofaciodigital syndrome type I	Polydactyly, syndactyly, cleft lip, cleft palate, CNS anomalies, ID, RFD	OFD1
Ellis van Creveld syndrome	Chondrodystrophy, polydactyly, ectodermal dysplasia, CHD	EVC, EVC2
Jeune asphyxiating thoracic dystrophy	Narrow thorax, RFD, RP, dwarfism, polydactyly	IFT80
Sensenbrenner syndrome	Dolichocephaly, ectodermal dysplasia, dental dysplasia, narrow thorax, RFD, CHD	IFT122, IFT43, WDR35
Short rib–polydactyly syndromes	Narrow thorax, short limb dwarfism, polydactyly, renal dysplasia	WDR35, DYNC2H1, NEK1

CHD, Congenital heart disease; CHF, congenital hepatic fibrosis; CNS, central nervous system; DM, diabetes mellitus; ID, intellectual disabilities; RFD, renal fibrocystic disease; RP, retinitis pigmentosa.

From Ferkol TW, Leigh MW: Ciliopathies: the central role of cilia in a spectrum of pediatric disorders, J Pediatr 160:366–371, 2012.

Cytogenetic Aberrations and Chromosomal Imbalance

Cytogenetic imbalances resulting from an additional copy of a whole human chromosome can result in characteristic and recognizable syndromes. An additional copy of chromosome 21 results in Down syndrome (see Chapter 98.2 ); loss of one of the X chromosomes results in Turner syndrome (see Chapter 98 for discussion of syndromes with whole chromosomal imbalances). With the advent of high-resolution cytogenetic techniques, such as fluorescence in situ hybridization (FISH), array comparative genomic hybridization (array CGH), and single nucleotide polymorphism (SNP) arrays, it has become possible to identify submicroscopic chromosome deletions and duplications . A number of recurrent deletions and duplications have been identified that cause characteristic and recognizable syndromes, including Williams syndrome (deletion of chromosome 7q11.23), Miller-Dieker syndrome (deletion of chromosome 17p13.3), Smith-Magenis syndrome (deletion of chromosome 17p11.2), and 22q11 deletion syndrome (deletion of chromosome 22q11.2, also known as velocardiofacial/DiGeorge syndrome ). Array CGH and SNP arrays have also made it possible to uncover rarer microdeletions and microduplications associated with birth defects, intellectual disability, and neuropsychiatric disorders. The sensitivity and specificity chromosome microarrays have made this the technique of choice for the initial evaluation of a child with multiple congenital anomalies and/or intellectual disability, although it is important to note that all individuals may carry numerous small microdeletions and microduplications as normal or familial variation. Therefore, it is important to compare copy number variants in these children with birth defects with their parents’ chromosome analyses and with databases of normal variants detected in individuals without such birth defects.

Approach to the Dysmorphic Child

One approach to the dysmorphic child is the pattern recognition approach, which compares the manifestations in the patient against a broad and memorized (or computerized) knowledge of human pleiotropic disorders. Although this approach can be appropriate for a small number of experienced dysmorphologists, a systematic genetic mechanism approach can also be effective for clinicians who are not dysmorphology experts. By gathering and analyzing the clinical data, the general pediatrician can diagnose the patient in a straightforward case or initiate a referral to an appropriate specialist.

Medical History

The history for a patient with birth defects includes a number of elements related to etiologic factors. The pedigree or family history is necessary to assess the inheritance pattern, or lack thereof, for the disorder. For disorders that have a simple mendelian inheritance pattern, its recognition can be critical for narrowing the differential diagnosis, then prioritizing common genes with the appropriate inheritance pattern causing the patient's clinical features. A number of common birth defects have a complex or multifactorial genetic etiology, such as isolated cleft palate and spina bifida. The recognition of a close relative affected with a birth defect that is similar to that in the proband can be useful. Typically, a 3-generation pedigree is sufficient for this purpose (see Chapter 97 ).

The perinatal history is also an essential component of the history. It includes the pregnancy history of the mother (useful for recognition of recurrent miscarriages that may be indicative of a chromosomal disorder), factors that may relate to deformations or disruptions (oligohydramnios), and maternal exposures to teratogenic drugs or chemicals (isotretinoin and ethanol are potential causes of microcephaly).

Another component of the history that is often useful is the natural history of the phenotype . Malformation syndromes caused by chromosomal aberrations and single-gene disorders are frequently static, meaning that, although the patients can experience new complications over time, the phenotype is typically not progressive. In contrast, disorders that cause dysmorphic features because of metabolic perturbations (e.g., Hunter or Sanfilippo syndrome) can be mild or may not be apparent at birth, but they can progress relentlessly, causing deterioration of patient status over time.

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 and Fig. 128.10 ). By cataloging physical parameters, the clinician may be able to recognize the diagnosis.

Table 128.5

Definitions of Common Clinical Signs of Dysmorphic Syndromes

SIGN	DEFINITION
Brachycephaly	A condition in which head shape is shortened from front to back along the sagittal plane; typically the back of the skull (occiput) and face are flatter than normal.
Brachydactyly	Short digits.
Brushfield spots	Speckled white spots or rings about two thirds of the distance to the periphery of the iris of the eye.
Camptodactyly	Permanent flexion of 1 or more fingers that can be associated with missing interphalangeal crease.
Clinodactyly	A medial or lateral curving of the fingers or toes; usually refers to incurving of the 5th finger.
Hypoplastic or small nail	A small nail on a digit.
Low-set ears	This designation is made when the helix meets the cranium at a level below a horizontal plane that is an extension of a line through both inner canthi.
Melia	A suffix meaning “limb” (e.g., amelia—missing limb; brachymelia—short limb).
Ocular hypertelorism or wide-set eyes	Increased distance between the center of the pupils of the 2 eyes; also known as increased interpupillary distance (IPD).
Plagiocephaly	A condition in which head shape is asymmetric in the sagittal or coronal plane; can result from asymmetry in cranial suture closure, asymmetry of brain growth, or deformation of the skull.
Posterior hair whorl	A single hair whorl occurs to the right or left of midline and is within 2 cm anterior to the posterior fontanel in 95% of cases.
Postaxial polydactyly	Extra finger or toe present on the lateral side of the hand or foot.
Preaxial polydactyly	Extra finger or toe present on the medial side of the hand or foot.
Prominent lateral palatine ridges	Relative overgrowth of the lateral palatine ridges that can be caused by a deficit of tongue thrust into the hard palate.
Scaphocephaly	A condition in which the head is elongated from front to back in the sagittal plane; most normal skulls are scaphocephalic; also termed dolichocephaly .
Shawl scrotum	The scrotal skin joins around the superior aspect of the penis and represents a mild deficit in full migration of the labial-scrotal folds.
Short palpebral fissures	Decreased horizontal distance of the eyelid folds based on measurements from the inner canthus to the outer canthus,
Syndactyly	Incomplete separation of the fingers or toes. It most commonly occurs between the 3rd and 4th fingers and between the 2nd and 3rd toes.
Synophrys	Eyebrows that meet in the midline.
Telecanthus	Lateral displacement of the inner canthi. The inner canthal distance (ICD) is increased, but the interpupillary distance (IPD) is normal.
Widow's peak	V -shaped midline, downward projection of the scalp hair in the frontal region. It represents an upper forehead intersection of the bilateral fields of periocular hair growth suppression. It usually occurs because the fields are widely spaced, as in ocular hypertelorism.

Table 128.6

Minor Anomalies and Phenotype Variants*

CRANIOFACIAL

Large anterior fontanel

Flat or low nasal bridge

Anteverted (upturned) nose

Mild micrognathia

Cutis aplasia of scalp

EYE

Epicanthus

Telecanthus

Slanting of the palpebral fissures

Hypertelorism (widely spaced eyes)

Brushfield spots

EAR

Lack of helical folds

Posteriorly rotated pinna

Small pinnae

Auricular or preauricular pit

Atypical folding of helices

Crushed (crumpled) ear

Asymmetric ear sizes

Low-set ears

SKIN

Skin dimpling over bones

Capillary hemangioma (face, posterior neck)

Dermal melanosis (African Americans, Asians)

Sacral dimple

Pigmented nevi

Redundant skin

Cutis marmorata

HAND

Single palmar creases

Bridged palmar creases

Clinodactyly of 5th digits

Hyperextensibility of thumbs

Mild partial cutaneous syndactyly

Polydactyly

Short, broad thumb

Narrow, hyperconvex nails

Small nails

Camptodactyly

Shortened 4th digit

FOOT

Partial syndactyly of 2nd and 3rd toes

Asymmetric toe length

Clinodactyly of 2nd toe

Overlapping toes

Small nails

Wide gap between hallux and 2nd toe (wide sandal gap)

Deep plantar crease between hallux and 2nd toe

OTHER

Hydrocele

Shawl scrotum

Hypospadias

Hypoplasia of labia majora

^* Approximately 15% of newborns have 1 minor anomaly, 0.8% have 2 minor anomalies, and 0.5% have 3. If 2 minor anomalies are present, the probability of an underlying syndrome or a major anomaly (congenital heart disease, renal, central nervous system, limbic) is 5-fold that in the general population. If 3 minor anomalies are present, there is a 20–30% probability of a major anomaly.

From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy , ed 2, Philadelphia, 2004, Elsevier Saunders.

Fig. 128.10 Frequency of major malformations in relation to the number of minor anomalies detected in a given newborn baby. (From Jones KJ: Smith's recognizable patterns of human malformation, ed 6, Philadelphia, 2006, Saunders.)

Imaging Studies

Imaging studies can be critical in diagnosing an underlying genetic etiology. If short stature or disproportionate stature (e.g., long trunk and short limbs) is noted, a full skeletal survey with radiographs should be performed. The skeletal survey can detect anomalies in bone number or structure that can be used to narrow the differential diagnosis. When there are abnormal neurologic signs or symptoms, such as microcephaly or hypotonia, brain imaging can be indicated. Other studies, such as echocardiography and renal ultrasonography, can also be useful to identify additional major or minor malformations that may serve as diagnostic clues.

Diagnosis

The examining physician should gather data on the patient's pedigree and perinatal and pediatric (for older children) history and should have an appreciation for the natural history of the clinical findings. At this point, the physician has examined the child, identified atypical physical features, and obtained appropriate imaging studies.

The clinician should now attempt to organize the findings to elucidate potential developmental processes. An assessment based on specificity can be helpful for this process. If a child has multiple findings, such as a patent ductus arteriosus (PDA), mild growth restriction, mild microcephaly, and holoprosencephaly, micropenis, and ptosis, a selection of the rarer or pathognomonic findings may be prioritized. The PDA, ptosis, mild growth restriction, and mild microcephaly are considered to be largely nonspecific findings (present in many disorders or often present as isolated features that are not part of a syndrome), whereas holoprosencephaly and micropenis are present in fewer syndromes and are not considered part of normal variation. The clinician can therefore search for disorders that include both holoprosencephaly and micropenis. The search can be performed manually using the features index of a textbook such as Smith's Recognizable Patterns of Human Malformation or a computerized database such as Online Mendelian Inheritance in Man (OMIM). Searching for both holoprosencephaly and micropenis returns a list of diagnostic possibilities, and the physician can then return to the patient to examine for additional features of the leading possible candidate disorders. Appropriate genetic testing can then be undertaken to confirm the clinician's hypothesis and verify the diagnosis.

Laboratory Studies and Genetic Testing

The laboratory evaluation of the dysmorphic child can be critical to reach or confirm the correct diagnosis. Cytogenetic studies with Giemsa-banded (G-banded) chromosome analysis, or karyotyping, was the gold standard previously performed in the evaluation of a dysmorphic patient. Array CGH and SNP arrays enable copy number variant detection and, in the case of SNP arrays, evaluation of loss of heterozygosity. Chromosome deletion syndromes may also be identified with specific and sensitive FISH analysis (Table 128.7 ). These tests are the most sensitive methods for the detection of cytogenetic alterations associated with birth defects and multiple congenital anomalies.

Table 128.7

Chromosomal Deletion Syndromes

CONDITION	BRIEF DESCRIPTION	PROBE
Williams syndrome	Proportionate short stature, mild-moderate to severe intellectual disability, “cocktail patter” for conversation, stellate pattern of iris pigmentation, supravalvular aortic stenosis, recessed nasal bridge, and wide mouth with full lips	7q11
WAGR syndrome	Wilms tumor, aniridia, growth delay, intellectual disability, and genitourinary anomalies	11p13
Prader-Willi syndrome Angelman syndrome	Distinct syndromes with common or overlapping areas of deletion; phenotype depends on gender of the parent of origin of the deletion. Prader-Willi syndrome: hypotonia in infancy, short stature, obesity, mild-moderate and occasionally severe intellectual disability, small hands and feet (caused by paternal deletion of 15q11-13 or maternal uniparental disomy for chromosome 15) Angelman syndrome: severe intellectual disability, absence of speech, ataxia, tremulous movements, large mouth, frequent drooling (caused by maternal deletion of chromosome 15q11-13 or paternal uniparental disomy)	15q11
Smith-Magenis syndrome	Brachycephaly, prognathism, self-destructive behavior, wrist biting, pulling out nails, head banging, indifference to pain, severe intellectual disability, hyperactivity, social behavior problems	17p11.2
Miller-Dieker syndrome	Microcephaly, narrow temples, hypotonia/hypertonia, abnormal posturing, seizures, severe to profound intellectual disability, poor growth, lissencephaly and other brain abnormalities on CT or MRI	17p13
Velocardiofacial (VCF) syndrome (overlaps with DiGeorge syndrome)	VCF: cleft palate, congenital heart disease, learning/behavior problems, long face, prominent nose, limb hypotonia, slender hands with tapering fingers DiGeorge syndrome: T-cell deficiency, immunoglobulin deficiency	22q11

CT, Computed tomography; MRI, magnetic resonance imaging; WAGR, Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.

From Kliegman RM, Lye PS, et al, editors: Nelson pediatric symptom-based diagnosis, Philadelphia, 2018, Elsevier (Table 25-10).

Molecular testing for deleterious sequence variants that cause pleiotropic malformation syndromes is also available for many disorders as clinical or research testing. In most cases, however, such testing should not be performed indiscriminately, but instead should be ordered thoughtfully after the differential diagnosis has been considered. The introduction of next-generation sequencing has led to the identification of innumerable novel genes and revolutionized the testing that is now available for patients and families with intellectual disability, birth defects, or other suspected genetic diseases. A strong suspicion of a genetic diagnosis warrants consideration of testing to confirm the diagnosis, facilitate patient treatment and anticipatory guidance, clarify recurrence risks, and enable carrier testing for relevant inheritance patterns. Single nucleotide variants, exons, or genes are tested by Sanger sequencing targeting single or multiple exons. However, for diagnoses that have substantial genetic heterogeneity (e.g., hearing loss), panel testing, in which multiple relevant genes can be interrogated for single nucleotide variants, gene deletions, and gene duplications, is more expeditious than Sanger sequencing. Panel tests also frequently have the advantage of providing high coverage for the genes on the panel, compared to coverage for the same genes obtained by exome sequencing. However, in situations with diagnostic uncertainty, such as the investigation of a child with intellectual disability and dysmorphic features, for which there is no clinically recognizable pattern, exome sequencing may be most useful as a broad testing approach. Whole exome sequencing (WES) examines approximately 200,000 exons, or the 1–2% of the DNA that comprises the coding regions of the genome. WES is typically performed with a trio approach, in which the patient and both biological parents are tested simultaneously, so that the inheritance pattern, or segregation, of deleterious sequence variants can be determined, thus simplifying analysis. Trio sequencing has resulted in higher diagnostic yields than proband-only sequencing and can approach 30–40% for indications such as intellectual disability. In contrast, whole genome sequencing (WGS) examines all the DNA content, including noncoding regions, and includes analysis for cytogenetic rearrangements in addition to copy number loss or gain. WES and WGS are applicable to a wide range of birth defects and genetic diseases and can discover causative variants in known or novel genes associated with a particular condition.

Management and Counseling

Management of the affected patient and genetic counseling are essential aspects of the approach to the dysmorphic patient. Children with Down syndrome have a high incidence of hypothyroidism, and children with achondroplasia have a high incidence of cervicomedullary junction abnormalities. One of the many benefits of an early and accurate diagnosis is that anticipatory guidance and medical monitoring of patients for syndrome-specific medical risks can prolong and improve their quality of life. When a diagnosis is made, the treating physicians can access published information on the natural history and management of the disorder through published papers, genetics reference texts, and databases.

The 2nd major benefit of an accurate diagnosis is that it provides data for appropriate recurrence risk estimates. Genetic disorders may have direct effects on only 1 member of the family, but the diagnosis of the condition can have implications for the entire family. One or both parents may be carriers; siblings may be carriers or may want to know their genetic status when they reach their reproductive years. Recurrence risk provision is an important component of genetic counseling and should be included in all evaluations for families affected with birth defects or other inherited disorders (see Chapter 94 ).

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