Laterality Sequences In addition to reversal of the sides, with partial to complete situs inversus, there can be bilateral left- or right-sidedness. The primary defect in both is a failure of normal asymmetry in morphogenesis. The basic problem would presumably be present before 30 days of development. Figure 1 sets forth the differences as well as the similarities between the patterns predominantly caused by left-sided bilaterality…

Coffin-Siris Syndrome Hypoplastic to Absent Fifth Finger and Toenails, Coarse Facies Coffin and Siris reported three patients with this disorder in 1970. Coffin-Siris syndrome (CSS) and Nicolaides Baraitser syndrome are the most recognizable BAFopathies. The causal genes affecting chromatin remodeling also cause less-specific phenotypes of nonsyndromic intellectual disability. Abnormalities Growth. Prenatal onset of mild-to-moderate growth deficiency, delayed bone age. Performance. Moderate-to-severe intellectual disability, severe speech impairment,…

Fetal Alcohol Spectrum Disorders Prenatal Onset of Growth Deficiency, Microcephaly, Short Palpebral Fissures In 1968, Lemoine of Nantes, France, recognized the multiple effects that alcohol can have on the developing fetus. Lemoine’s report was not well accepted, and the disorder was independently rediscovered in 1973 by Jones and colleagues and was referred to as fetal alcohol syndrome (FAS). In 1996, an Institute of Medicine (IOM) report…

Hypohidrotic Ectodermal Dysplasia Defect in Sweating, Alopecia, Hypodontia There are a number of ectodermal dysplasia (ED) syndromes, only a few of which are represented in this text. The division into hypohidrotic ectodermal dysplasia (HED) and hidrotic categories based on the extent of the deficit of sweat glands is in no way absolute. Just as there is variable hypoplasia of hair follicles, there is variable hypoplasia of…

Sturge-Weber Syndrome Flat Facial Hemangiomata, Meningeal Hemangiomata with Seizures The association and localization of aberrant vasculature in the facial skin, eyes, and meninges are compatible with a defect arising in a limited part of the cephalic neural crest, cells of which migrate to the supraocular dermis, choroid, and pia mater. Abnormalities Performance. Seizures, paresis, intellectual disability. Craniofacial. Port-wine capillary malformation, most commonly in a trigeminal facial…

Marfan Syndrome Arachnodactyly with Hyperextensibility, Lens Subluxation, Aortic Dilatation Described as dolichostenomelia in the initial report by Marfan, this disorder was extensively studied and recognized as an autosomal dominant connective tissue disorder by McKusick. In 2010, an international expert panel established a revised Ghent nosology, which puts more emphasis on the cardiovascular and ocular manifestations, as well as in mutation studies, than in the 1996 Ghent…

Mucolipidosis II (Leroy I-Cell disease) Early Alveolar Ridge Hypertrophy, Joint Limitation, Thick Tight Skin in Early Infancy This disorder was recognized by Leroy and DeMars when they noted unusual cytoplasmic inclusions in the cultured fibroblasts of a girl considered to have the Hurler syndrome despite the fact that she did not have cloudy corneas or excessive acid mucopolysaccharide in the urine. Mucolipidosis II (ML II) is…

Multiple Synostosis Syndrome (Symphalangism Syndrome) Symphalangism, Hypoplasia of Alae Nasi In the past this disorder was generally termed symphalangism (synostosis of finger joints), a nonspecific anomaly. The multiple synostosis character of this disorder was emphasized by Maroteaux and colleagues, based on the presence of characteristic facial features and more severe and widespread joint involvement, especially in the vertebrae and hips. Abnormalities Craniofacial. Sloping forehead, prominent supraorbital…

Saethre-Chotzen Syndrome (Acrocephalosyndactyly Type III) Brachycephaly with Maxillary Hypoplasia, Prominent Ear Crus, Syndactyly Originally described by Saethre and by Chotzen in the early 1930s, this disorder has an estimated prevalence of 1 in 25,000 to 1 in 50,000 live births. Abnormalities Craniofacial. Craniosynostosis, most commonly coronal, but also sagittal, lambdoidal, metopic, or multiple sutures; late closing fontanels; brachycephaly with high flat forehead; low frontal hairline; shallow…

Osteopetrosis: Autosomal Recessive—Lethal (Infantile Malignant Osteopetrosis) Dense, Thick, Fragile Bone; Secondary Pancytopenia; Cranial Nerve Compression More than 100 cases of this genetically heterogeneous and commonly lethal group of disorders have been reported since the first cases were described. Two different subsets of patients are recognized based on bone morphology: (1) osteoclast-rich, associated with a high number of mature but nonfunctional osteoclasts; and (2) osteoclast-poor, in which…

Achondrogenesis Types IA and IB Low Nasal Bridge, Very Short Limbs, Incomplete Ossification of Lower Spine This early lethal disorder was described in 1925 by Donath and Vogl and termed achondrogenesis by Fraccaro in 1952. More than 20 cases have been reported. Studies by Borochowitz and colleagues indicate that achondrogenesis type I (previously referred to as Parenti-Fraccaro type) represents two radiographically and histopathologically distinct disorders, referred…

Poland Sequence Unilateral Defect of Pectoralis Muscle, Syndactyly of Hand In 1841, Poland reported unilateral absence of the pectoralis minor and the sternal portion of the pectoralis major muscles in an individual who also had cutaneous syndactyly of the hand on the same side. This unique pattern of defects has been noted subsequently in numerous cases and has an incidence of approximately 1 in 20,000. It…

Miller Syndrome (Genee-Wiedemann syndrome, Postaxial Acrofacial Dysostosis Syndrome) Treacher Collins–Like Facies; Limb Deficiency, Especially Postaxial In 1979, Miller and colleagues brought together six cases, four of which were from the literature, and recognized this disorder as a concise entity. The facial appearance is similar to that of Treacher Collins syndrome and, in combination with limb defects, resembles Nager syndrome. The severity of the postaxial deficiencies distinguishes…

Moebius Sequence Sixth and Seventh Nerve Palsy The basic features of Moebius sequence are mask-like facies with sixth and seventh cranial nerve palsy, usually bilaterally. Minimal diagnostic criteria include congenital nonprogressive facial palsy, abduction deficits, and full vertical motility. Necropsy cases implicate at least four modes of developmental pathology in the genesis of the problem. These are (1) hypoplasia to absence of the central brain nuclei,…

Amyoplasia Congenita Disruptive Sequence Arms Extended with Flexion of Hands and Wrists, Shoulders Internally Rotated with Decreased Muscle Mass, Bilateral Equinovarus, Variable Contractures of Other Major Joints Initially described by Paré in 1840, this disorder is the most frequent form of arthrogryposis occurring in 20% to 30% of cases. A complete review of the literature, including diagnosis, etiology, and management was published by Hall and colleagues…

Fragile X Syndrome (FXS, Martin-Bell Syndrome, Marker X Syndrome) Intellectual Disability, Mild Connective Tissue Dysplasia, Macroorchidism In 1943, Martin and Bell published the first pedigree documenting an X-linked form of intellectual disability. Lubs, in 1969, showed the presence of a fragile site on the long arm of the X chromosome in affected males and some carrier females in one family. Macroorchidism without endocrinologic abnormalities was described…

Progeria Syndrome (Hutchinson-Gilford Syndrome) Early Aging with Alopecia, Atrophy of Subcutaneous Fat, Skeletal Hypoplasia and Dysplasia The following entry was recorded in the St. James Gazette in 1754: “March 19, 1754 died in Glamorganshire of mere old age and a gradual decay of nature at seventeen years and two months, Hopkins Hopkins, the little Welshman, lately shown in London. He never weighed more than 17 pounds…

Smith-Lemli-Opitz Syndrome Anteverted Nostrils, Ptosis of Eyelids, or Both; Syndactyly of Second and Third Toes; Hypospadias and Cryptorchidism in Male Four patients with this disorder were described by Smith and colleagues in 1964. Tint and colleagues in 1993 identified an abnormality in cholesterol biosynthesis in patients with this disorder that appears to explain much of the clinical phenotype. The incidence of Smith-Lemli-Opitz syndrome (SLOS) in the…

Cornelia de Lange syndrome (Brachmann–De Lange Syndrome) Synophrys, Thin Downturning Upper Lip, Micromelia The syndrome was originally reported in 1933 by Cornelia de Lange, although Brachmann described a child with similar features at autopsy in 1916. As the molecular etiology of this condition has been elucidated, both a classic as well as nonclassic phenotypes are recognized. The disorder is now known to be caused by variants…

1p36 Deletion Syndrome (Monosomy 1p36 Deletion Syndrome) Large Anterior Fontanel, Deep-Set Eyes, Pointed Chin First delineated in 1997 as a recognizable pattern of malformation, monosomy 1p36 is the most commonly observed terminal deletion in the human population with an estimated prevalence of 1 in 5000. Abnormalities Growth. Postnatal onset of growth deficiency, obesity. Performance. Intellectual disability, severe in the majority of cases, although mild in a…