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Miller-Dieker Syndrome (17p13.3 Deletion Syndrome)

Introduction Miller-Dieker syndrome (MDS) is a rare, contiguous gene deletion syndrome characterized by type I lissencephaly, facial dysmorphism, seizures, and severe mental retardation. Other associated defects including cardiac malformations, neural tube defects, omphalocele, gastrointestinal anomalies, genitourinary anomalies, and intrauterine growth restriction have also been described in relationship to this syndrome. MDS is caused by a deletion at the chromosome 17p13.3 locus and is thought to represent…

Chromosome 5p Deletion Syndrome (Cri du Chat Syndrome)

Introduction Monosomy for the distal portion of the short arm of chromosome 5 causes 5p deletion syndrome, which is also known by the currently less favored term “cri du chat” syndrome, from the French description of the monotonous high-pitched “cat-like” cry of affected infants. Initially described in 1963 by Lejeune et al., this syndrome is readily detectable by karyotype or with molecular cytogenetic methods, such as chromosomal…

Chromosome 4p Deletion Syndrome (Wolf-Hirschhorn Syndrome)

Introduction First clinically described in 1961 by Hirschhorn and subsequently in 1965 by Wolf, the 4p deletion syndrome, or Wolf-Hirschhorn Syndrome (WHS), is the first example of a classic human chromosomal deletion syndrome. This rare condition, characterized by severe prenatal findings and confirmatory genetic testing, is more limited and consists of isolated case reports and small case series. Although more than 50% of deletions are visible…

22q11.2 Deletion Syndrome

Introduction The 22q11.2 deletion syndrome is the most common human chromosomal microdeletion syndrome and one of the most common syndromes associated with prenatally detected congenital heart defects (CHDs). It has a variable phenotype, with a wide range of associated clinical findings. DiGeorge syndrome, first described in 1965, is its most severe presentation, with primary symptoms of thymus and parathyroid aplasia and severe immunologic abnormalities; CHDs were…

Mosaic Trisomies 8, 9, and 16

Introduction Trisomies can occur with any chromosome, but most often result in spontaneous abortion. For example, trisomy 16 is the most common trisomy in human pregnancies, and the majority of the time results in miscarriage. These severe trisomies are more likely to survive past the first trimester and possibly to birth if they are mosaics, in which the condition of trisomy only affects a portion of…

Turner Syndrome (Monosomy X)

Introduction Turner syndrome (monosomy X) is characterized by complete or partial loss of the second X chromosome in the female, with or without cell line mosaicism. There are three distinct phenotypes: (1) first trimester abortus (98%), (2) second trimester hydrops fetalis (often resulting in fetal demise), and least commonly (3) neonate with a cystic hygroma (thin-walled cyst containing lymphatic fluid). Turner syndrome is the only monosomy…

Trisomy 21

Introduction Trisomy 21 (Down syndrome) is the most common trisomy in live-born infants and in spontaneous abortions. British physician John Langdon Down first described the syndrome in 1866. The chromosomal abnormality was discovered in 1959 by French geneticist Jerome Lejeune, and in 1961, the name Down syndrome was proposed by the editors of The Lancet . Disorder Definition Trisomy 21, also called Down syndrome, results from…

Trisomy 18

Introduction Trisomy 18 is the second most common autosomal trisomy (after trisomy 21). Disorder Definition Trisomy 18, also called Edwards syndrome, results from the presence of an extra copy of chromosome 18. Prevalence and Epidemiology Trisomy 18 is the second most common autosomal trisomy among live-born fetuses after Down syndrome. The incidence of trisomy 18, 0.6–2.5 : 10,000, is considerably lower than that for Down syndrome. It is…

Trisomy 13

Introduction Trisomy 13, also known as Patau syndrome, is one of the three most common trisomy syndromes. It is often diagnosed prenatally by the identification of one or more congenital abnormalities seen on ultrasound (US). Trisomy 13 is associated with severe physical and mental disabilities in addition to poor long-term survival rates in live-born infants. Disorder Definition First genetically described by Patau et al. in 1960, trisomy…

Triploidy

Introduction Chromosome abnormalities are often the cause of early pregnancy loss, fetal malformations, and stillbirth. Triploidy is a lethal chromosome abnormality caused by the presence of a complete extra set of chromosomes ( Fig. 148.1 ); it can lead to spontaneous miscarriage, congenital anomalies, abnormal placental appearance, and severe intrauterine growth restriction (IUGR). A triploid karyotype is also found in most cases of partial hydatidiform mole…

Introduction to Aneuploidy

Introduction Aneuploidy is a chromosomal anomaly in which the number of one or more chromosomes is abnormal. Normal human somatic cells (i.e., nonegg or sperm cells) carry 46 chromosomes: two copies of each of the 22 autosomal chromosomes and two sex chromosomes, either XX for female or XY for male. Monosomy and trisomy conditions result from the subtraction or addition of chromosomal material, respectively. Aneuploid conditions…

VATER Association

Introduction The VATER association is a nonrandom association of congenital malformations that include v ertebral anomalies, a nal atresia, t racheo e sophageal fistula, and r enal and r adial limb anomalies. This definition has been expanded to include vascular defects as well, and some have renamed this association VACTERL, so that congenital c ardiovascular defects and l imb anomalies are represented in the name. VATER…

Smith-Lemli-Opitz Syndrome

Introduction Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by abnormal cholesterol synthesis. SLOS was originally named RSH syndrome, derived from the surnames of the first three families identified with this disorder. SLOS is characterized by growth failure, cognitive delay, behavioral disturbances, dysmorphic faces, and congenital malformations. There is marked variability in presentation of this condition among affected individuals. Although SLOS was historically divided into…

Sirenomelia

Introduction Sirenomelia is a rare congenital disorder that was previously considered a severe form of caudal regression, although it is currently considered a completely different entity. Also known as the mermaid syndrome , it is characterized by a variable degree of atrophy of the lower limbs, with the resultant appearance of a mermaid tail or fin ( Fig. 144.1 ). Because of the associated anomalies (particularly…

Tuberous Sclerosis

Introduction Tuberous sclerosis, also known as the tuberous sclerosis complex (TSC), is a disorder of cellular differentiation, proliferation, and migration in early development that variably affects multiple organ systems. First described in 1862 by Friedrich von Recklinghausen, TSC is characterized by the formation of benign, hamartomatous lesions in virtually any organ system, most commonly the central nervous system (CNS), skin, heart, lungs, kidneys, bones, and blood…

Pontocerebellar Disorders

Introduction Autosomal recessive pontocerebellar hypoplasias (PCHs) are a group of severe neurodegenerative disorders affecting the cerebellum and pons. This disease appears in fetal or neonatal life with subsequent pontocerebellar degeneration, progressive microcephaly, and atrophy of the cerebral cortex. Most affected individuals have profound motor and cognitive deficits. Life expectancy generally lasts into infancy or childhood, though there are reports of some individuals with PCH who live…

Cystic Fibrosis

Introduction Cystic fibrosis (CF) is a single-gene autosomal recessive disorder characterized by chronic airway infection, pancreatic insufficiency, gastrointestinal dysfunction, and male infertility. Symptoms typically manifest during childhood, leading to early mortality in the third and fourth decades of life. Greater than 1000 different mutations in the CF transmembrane conductance regulator (CFTR) gene have been identified with an expansive ethnic and racial distribution as well as varying…

Roberts Syndrome

Introduction Roberts syndrome, also known as Roberts-SC phocomelia syndrome or pseudothalidomide syndrome, is a rare genetic disorder characterized by prenatal growth restriction, limb reductions, and craniofacial abnormalities. The upper extremities are more severely affected than the lower extremities, with common limb abnormalities including bilateral symmetric tetraphocomelia or hypomelia. Other limb malformations, such as oligodactyly, syndactyly ( Fig. 140.1 ), clinodactyly, and elbow and knee flexion contractures,…

Prune-Belly Syndrome

Introduction Prune-belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a triad of anomalies composed of abdominal wall flaccidity, urologic abnormalities, and bilateral cryptorchidism. The typical urologic findings are distended bladder, hydronephrosis, and renal dysplasia. A patent urachus is a common finding. In some infants, urinary obstruction may lead to oligohydramnios or anhydramnios with a resulting Potter sequence (pulmonary hypoplasia, dysmorphic facies). Concomitant cardiac, orthopedic, and…

Poland Sequence

Introduction Poland sequence refers to congenital unilateral absence of the sternal costal portion of the pectoralis major muscle and ipsilateral upper limb anomalies. There is no known genetic etiology for Poland sequence. The pathogenesis of this disorder is suggested to be caused by a vascular disruptive sequence. Postpartum management usually consists of surgical correction and rehabilitation therapy for musculoskeletal defects. Disease Definition There are no formal…