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Background: Dental complications of Ehlers-Danlos syndrome (EDS) include periodontitis with gum fragility and inflammation, enamel hypoplasia with frequent caries, high palate with dental crowding, TMJ instability, sutural dehiscence or scarring, and insensitivity to anesthetics. Objective: Determine if EDS dental complications always define a specific type and genetic cause or if they can arise as a general consequence of altered inflammatory response in EDS. Method: We compared findings of a 58-year-old female with complement component 1R (C1R) gene mutation (c.1553A > T, p.Asp518Val) found by whole exome sequencing to 43 patients with C1R gene mutations ascertained because of periodontal disease and to 710 EDS patients conventially ascertained because of joint and skin laxity. Result: Female patients ascertained as periodontal EDS showed the expected higher frequency of periodontitis (96% versus 14%) but had similar frequencies of hypermobility (81% versus 90%) and some skin findings (84% versus 92% with skin fragility) as the general group and our female patient who shared their C1R gene change. Her oromandibular bone loss rather than gum disease may reflect the more carboxy-terminal position of her C1R gene mutation compared to those in the patients identified as periodontal EDS. Conclusion: While mutation of the C1R gene may predict more frequent periodontal, skin, and vascular complications, focus on an articulo-autonomic dysplasia process that includes mast-cell activation and altered inflammatory response rather than extreme EDS types will help dentists and other subspecialists identify all EDS patients and anticipate their frequent oral manifestations.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

A novel medical approach for qualifying DNA variants found by whole exome sequencing (WES) facilitates discovery of new gene-disease relationships and emphasizes that DNA change must be correlated with clinical findings before having utility for diagnosis. Delineation of an arthritis-adrenaline disorder (AAD) process qualified variants in 23 genes as diagnostically useful in 727 patients having WES among 1656 with Ehlers-Danlos syndrome (EDS); these results distinguished them from 102 patients who had qualified gene variants among 728 with developmental disability. Excess maternal transmission of AAD by pedigree analysis plus 167 maternally versus 111 paternally transmitted DNA variants and 75 patients with only mitochondrial DNA variants suggest maternal influence on inheritance of AAD and its subsumed EDS types. Genes grouped by impact on different connective tissue elements showed variation in similar numbers of patients with hypermobile or classical EDS, benign joint hypermobility, or predominant dysautonomia: COL7A1, FLG acting on skin in 21 patients; SCN9A/10A/11A, POLG on nerve in 24; COL6A1/A2/A3, COL12 on muscle in 19; COL5A1/A2, FBN1, TGFB2/3, TGFBR1/2 on tissue matrix in 51; COL3A1, VWF on vessel in 18; COL1A1/A2, COL11A1/A2 acting on bone in 15 patients. Each gene group acts through a postulated articulo-autonomic dysplasia cycle to produce reciprocal tissue laxity and dysautonomia findings that transcend EDS types. This same tissue laxity-dysautonomia cycle acts to produce secondary complications in disorders ranging from distinctive connective tissue dysplasias to developmental disorders with hypotonia and acquired conditions with autonomic imbalance. Several altered genes were previously associated with neuromuscular disorders, foreshadowing a large myopathic EDS category that will incorporate many patients with hypermobility. The importance of muscle for joint constraint supports present exercise and future mesenchymal stem cell therapies, whether AAD is genetic or epigenetic from trauma, surgery, inflammation, or aging.

Findings in 1656 patients referred for evaluation of Ehlers-Danlos syndrome, 710 evaluated systematically using novel history and physical forms, defined a characteristic clinical pattern termed arthritis-adrenaline disorder, a genus that provides immediate therapy while delineation of particular tissue laxity/dysautonomia species is underway. Preliminary diagnoses, clinical findings, and laboratory results were entered into an MS Excel© database with IRB approval and correlations or statistical significance analyzed using Excel© functions. Frequencies of 80 findings by history and 40 on physical were similar among EDS groups, females paralleling males with more total history (35 versus 23) and physical (18 versus 15) findings. Finding frequencies in joint-skeletal (6.2 of 15) and dysautonomia (11 of 20) subcategories were substantial regardless of age, EDS diagnosis, or referral source, the latter was shown by 6.4 and 13 average findings for cardiology, 5.3 and 8.3 for orthopedic referrals. Early affliction evidenced by history findings averaging 19.5 in those under 12 increased dramatically to 25 for teens and 32 for adults with plateauing at older ages arguing against degenerative disease. Frequent neuromuscular symptoms in females emphasize surrounding muscle support and protection of joint-connective tissue as a key factor in decreased male severity. The congruent clinical profile suggests operation of an articulo-autonomic dysplasia cycle where lax vessels and lower body pooling elicit sympathetic response, autonomic imbalance in turn affecting small nerve fibers and enhancing connective tissue laxity. Recognition of this arthritis-adrenalin disorder can guide management strategies while underlying causes are pursued, among them, physical therapy, exercise, and vitamin D to build muscle/bone strength; lower gluten/dairy and antihistamine protocols for low bowel motility/mast-cell activation; hydration, salt, and exercise for postural orthostatic tachycardia syndrome.

A female patient with substantial history and physical findings of Ehlers-Danlos syndrome by systematic evaluation had a variant in the gene encoding the sixth subunit of mitochondrial ATP synthetase gene that produced a change from glycine to aspartic acid at position 132 of the MT-ATP6 protein (MT-ATP6 m.8921G>A, p.Gly132Asp). The mutation was heteroplasmic, affecting 32% of the mitochondria in blood leucocytes, was qualified as a pathogenic variant because of its significant molecular change, but was not detected in the maternal blood sample as might be expected for its low degree of heteroplasmy. The patient was shown to have typical findings of Ehlers-Danlos syndrome by comparison of 48 history and physical findings in her and a peer group of 32 teenage females with that diagnosis. None of the classical neurosensory or developmental symptoms of mitochondrial disease were present in mother or daughter, but the patient had symptoms, metabolite alterations during rest or exercise, and muscle biopsy changes that suggested mild mitochondrial dysfunction. She also had heterozygous variants of uncertain significance in the nuclear PLOD1, FLNA, and ATP2A genes by concomitant whole exome sequencing that could also contribute to her arthritis-adrenaline disorder. Mitochondrial dysfunction is proposed to influence neuromuscular components of connective tissue, acting through an articulo-autonomic dysplasia cycle to cause the typical joint-skin laxity and dysautonomia of Ehlers-Danlos syndrome.

Background/Purpose The increasing prevalence of abdominal wall defects prompted analysis of anomalies associated with gastroschisis and omphalocele in the Texas Birth Defects Registry (TDBR). Methods Cases of gastroschisis (ICD9 code 756.71), omphalocele (756.70), and/or unspecified anomalies of the abdominal wall (756.79) were obtained from the TDBR after IRB approval and analyzed using Microsoft Access© and Excel© databases. Results Analysis began with 2825 cases including 1831 of gastroschisis, 814 of omphalocele, and 180 of unspecified abdominal wall defects plus 9680 associated anomalies that were classified according to system. The overall prevalence of abdominal wall defects among 3,806,299 Texas births from 1999 to 2008 was 7.4 per 10,000 with 4.8 per 10,000 for gastroschisis and 2.1 for omphalocele. After excluding ambiguous cases (8.5% possibly misclassified), anomaly spectra were similar for the two AWD with musculoskeletal (limb contractures or defects), cardiovascular, gastrointestinal, urogenital, and central nervous system defects being most common. Of 1831 cases with gastroschisis, 594 (32%) had associated anomalies compared to 654 (80%) of 814 omphalocele cases. Conclusions Gastroschisis as well as omphalocele has significant associated anomalies that are important to appreciate during pre- and postnatal management.

A 13-year-old male presented with new onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs. Laboratory investigation demonstrated combined deficiency of protein C, protein S, and antithrombin III. He and his 17-year-old sister had a mental retardation-multiple anomaly syndrome associated with microcephaly, unusual facies, and lax connective tissue. Their dysmorphology included elongated faces with narrow forehead, arched eyebrows, large mouth with down-turned corners, malformed teeth, and furrowed tongue. Both had Marfanoid habitus with lax joints, pectus excavatum, kyphoscoliosis, and flat narrow feet. The most likely diagnosis for these siblings is the autosomal recessive Cohen syndrome of mental retardation, congenital hypotonia with Marfanoid habitus, microcephaly, pleasant affect, micrognathia, and open mouth with prominent incisors. The sagittal sinus thrombosis, left frontal intracranial hemorrhage, carotid aneurysm, tortuous descending aorta, and deep venous thrombosis suffered by the male sibling adds the Cohen syndrome to genetic vasculopathies that may be associated with stroke.

Background The objective of the study was to describe a novel Xp13.2 chromosome microduplication in a child with some features of Turner syndrome but with menorrhagia after normal menarche. We used clinical evaluation and high resolution chromosome (microarray) analysis. Case A 15-year-old girl with typical (short stature, pulmonic stenosis, widely-spaced nipples) and atypical (Madelung deformity, menorrhagia) manifestations of Turner syndrome had a novel chromosome constitution with extra material (microduplication) at band Xq13.2 that contained the X-inactive-specific-transcript locus. She also had connective tissue laxity, suggestive of vessel fragility as a contributor to her menorrhagia as well as her diagnosis of von Willebrand disease. This first case of selective X-inactive-specific-transcript locus duplication suggests a role for gene repression in Turner syndrome and other disorders that affect ovarian function. Conclusion High-resolution chromosome (microarray) analysis, now a standard of care, will provide new insights into adolescents with abnormal growth and reproductive tract symptoms, especially when accompanied by congenital anomalies.

Nine thousand two hundred eighty abnormalities associated with 2,943 abdominal wall defects (AWD) encoded from 1999 to 2008 by the Texas Birth Defects Registry (TBDR) were classified and analyzed for mechanism, beginning with 1,831 gastroschisis cases, 774 (41%) with 2,368 associated anomalies (AA) and 814 of omphalocele, 727 (89%) with 4,092 AA. Typical AA profiles for Trisomy 18 (23% of omphalocele cases) and Beckwith–Wiedemann syndrome (15%) validated registry AA descriptors, chromosome disorders surprisingly accounting for 24% of known conditions with gastroschisis followed by expected amniotic band (ADAM) complex (23%) and amyoplasia/arthrogryposis (16%). Separation of known diagnoses, fetal-stillbirth cases, and transitional or secondary AA left 330 cases of gastroschisis with 594 AA (452 major, 142 minor) and 295 cases of omphalocele with 956 AA (683 major, 273 minor). Anomalies suggestive of vascular origin (intestinal atresias, amyoplasia, bands) were more frequent with gastroschisis and those of defective lateral folding (exstrophies, limb-body wall defects) with omphalocele. Most AA favoring omphalocele had parallel frequencies with gastroschisis, whether by system/region—for example, cardiac AA (10% of cases), contractures (4.7%), limb (3.7%), CNS (3.2%) for gastroschisis versus cardiac (35%), contractures (14%), digestive-excretory-trunk-axial (all ∼11%), CNS (9.9%) for omphalocele—or for particular minor/major AA—for example, micrognathia (0.72% versus 3.3%), spina bifida (0.59% versus 3.9%), anal atresia (0.73% versus 6.4%), two-vessel cord (0.22% versus 5.6%). Similar frequencies of many AA reflective of early patterning support common AWD origin within early developmental fields and reinforce the use of large birth defect numbers from suitably qualified registries to define anomaly mechanism as well as prevalence. © 2015 Wiley Periodicals, Inc.

Wilson disease or hepatolenticular degeneration has a prevalence of 1 in 33,000 and presents with cirrhosis, neuropsychiatric symptoms, and, more rarely, multisystem disease due to abnormal copper accumulation. Initial hepatic disease is seen in 40% including children in the second decade, while neurologic (40%), psychiatric (20%), or mixed presentations are more typical of adults in the third or fourth decade. Hepatic symptoms range from chronic hepatitis to acute liver failure; neuropsychiatric symptoms from personality changes to tremors, dystonia, choreoathetosis, or even psychosis. The triad of low ceruloplasmin, high urine copper, and Kayser–Fleischer ring differentiates Wilson disease from other copper accumulation states, the diagnosis confirmed by DNA test showing mutation of ATP7B membrane ATPase that transports copper into the Golgi apparatus. Therapy with penicillamine, trientine, zinc, or liver transplant for refractory disease is very effective and underlines the importance of early diagnosis in affected patients and their at-risk siblings.

Here we report on a 39-year-old woman with severe mental retardation, short stature, unusual face with prominent nose, broad thumbs, and broad first toes diagnostic of the Rubinstein-Taybi syndrome. Following admission because of headache and anorexia, a bifrontal lobe neoplasm was excised and diagnosed as an angioblastic meningioma. The unusual tumor and aged appearance of the patient add 2 facets to the natural history of Rubinstein-Taybi syndrome.

Two hundred and sixteen infant evaluations were selected for analysis from those of 669 outpatients (930 total visits) at a weekly Down syndrome clinic. Each record contained perinatal history and physical examination results, and 191 of the 216 included a systematic interview regarding parental experiences with diagnosis and counseling. Gastrointestinal problems (77% of neonates), cardiac anomalies (38%), and hematologic problems (11%) were the most common complications; cited problems included anal stenosis (11%), which is described as a newly recognized cause of constipation in early infancy. Counseling experiences were positive in 66 (34%) of the 191 parent interviews, with counselor knowledge, timing, setting, and attitudes being cited as key factors. Appropriate counseling and surveillance for gastrointestinal problems can greatly facilitate parental adjustment to the neonate with Down syndrome.

Eight new and five previously illustrated patients with Niikawa-Kuroki syndrome (NKS) are compared to those in the literature, providing data on 183 cases. Eight patients had disproportionate microcephaly and in one autopsied patient there was frontal lobe atrophy, focal polymicrogyria, and a hypoplastic fourth ventricle. The metacarpophalangeal pattern profiles of three Caucasian patients with NKS were similar to that of a prior case report, but those of two Hispanic patients were more variable. NKS was eliminated by follow-up in nine suspect cases, highlighting the diagnostic value of findings such as arched eyebrows, long palpebral fissures, flat nasal tip, and prominent finger pads. One patient suspected of having NKS had a very different metacarpophalangeal pattern profile, supporting its diagnostic utility in selected cases. Higher frequencies of neonatal complications, abnormal dentition, hypotonia, and microcephaly were noted in non-Asian patients with NKS, while a higher frequency of skeletal anomalies was seen in Japanese patients. Complications affecting cognitive, visual, hearing, cardiac, renal, skeletal, immune, and endocrinologic functions are translated into a program for preventive management. X chromosome anomalies are the most compelling of diverse genetic changes seen in NKS, and this report adds another case to several possible instances of vertical transmission. The 108 non-Asian patients now reported emphasize the worldwide significance of NKS recognition.

Exome results are reported for two patients with connective tissue dysplasia, one refining a clinical diagnosis of Ehlers–Danlos to Marfan syndrome, the other suggesting arthrogryposis derived from maternofetal Stickler syndrome. Patient 1 had mutations in transthyretin (TTR), fibrillin (FBN1), and a calcium channel (CACNA1A) gene suggesting diagnoses of transthyretin amyloidosis, Marfan syndrome, and familial hemiplegic migraines, respectively. Patient 2 presented with arthrogryposis that was correlated with his mother's habitus and arthritis once COL2A1 mutations suggestive of Stickler syndrome were defined. Although DNA results often defy prediction by the best of clinicians, these patients illustrate needs for ongoing clinical scholarship (e.g., to delineate guidelines for management of mutations like that for hyperekplexia in Patient 2) and for interpretation of polygenic change that is optimized by clinical genetic/syndromology experience (e.g., suggesting acetazolamide therapy for Patient 1 and explaining arthrogryposis in Patient 2). © 2014 Wiley Periodicals, Inc.

It was suggested that a "fetal cocaine syndrome" exists. The objective of this study was to systematically investigate whether or not a "cocaine syndrome" exists. The setting was Parkland Memorial Hospital, a large urban public hospital in Dallas, TX, where approximately 15,000 infants are delivered annually. Infants who tested positive by urinalysis for cocaine (n = 25) were included in this study. Controls negative for cocaine (n = 25) were matched to cocaine-exposed infants for estimated gestational age, sex, and race. A standardized dysmorphology examination (135 features) and a series of anthropometric measures (n = 22) were done for each cocaine-exposed and control infant by an observer blinded to drug-exposure status. Fetal growth retardation characterized cocaine-exposed infants. No characteristic pattern of minor dysmorphic or anthropometric features of the face, limbs, or torso was observed among cocaine-exposed infants. Cocaine-exposed infants lack a facial gestalt or torso/limb features that would characterize a syndrome. If a "cocaine syndrome" that can be characterized dysmorphologically and/or anthropometrically exists, its occurrence seems infrequent.

New mechanisms of inheritance are described and illustrated in neurologic disorders such as Duchenne muscular dystrophy, Charcot-Marie-Tooth disease, Prader-Willi syndrome, fragile X syndrome, Steinert myotonic dystrophy, and Zellweger syndrome. Novel genetic mechanisms include contiguous gene deletion, somatic mosaicism, genomic imprinting, triplet repeat expansion, and assembly disorders that violate the one-gene-one- enzyme hypothesis.

We describe a boy with short stature, developmental delay, unusual face, right iris coloboma, malformed ears, micrognathia, and skeletal anomalies including hyperphalangy of the index fingers, bilateral fifth finger clinodactyly, short halluces, and scoliosis. Internal anomalies included asymmetric and dilated cerebral ventricles and ventricular septal defect. The neonatal history of small jaw with feeding and respiratory difficulties suggested a Pierre Robin sequence, but there was no cleft palate. Two maternal uncles with similar anomalies had died at ages 13 months and 5 years, respectively. RFLP studies with the DNA probes DXS72 and F8C were consistent with but not diagnostic of X-linked recessive inheritance. The pattern of anomalies was compatible with a diagnosis of Catel-Manzke syndrome, but a novel dysostosis syndrome must also be considered.

A 14-year-old girl with ichthyosis and severe liver disease is compared to 35 reported cases of KID or Senter syndrome. Common manifestations such as ichthyosis (35/35 patients), sensorineural deafness (33/34), "ectodermal dysplasia" (25/28), corneal abnormality (26/31) were present in the proposita, while less common manifestations such as chronic infections (15/20) and neuromuscular disease (12/35) were absent. Two families with vertical transmission and 28 sporadic cases are compatible with an autosomal dominant form of KID syndrome, while one inbred sibship with liver disease suggests the existence of an autosomal recessive form. The proposita was similar to the latter patients in having progressive cirrhosis necessitating liver transplantation; she also had short stature (10/35 patients) and mental retardation (3/35). Hepatic findings included micronodular cirrhosis, cholestasis, hyperplastic Kupffer cells, abundant Mallory's hyaline, copper accumulation without steatosis, and normal peroxisomes.

The frequency of abortion following chorionic villus sampling (CVS) is similar to that following amniocentesis. However, there is no information on long-term effects, such as malformations in liveborn children exposed to CVS. We evaluated 189 infants whose mothers had either CVS or amniocentesis as participants in the Canadian Collaborative Randomized Trial, a prospective assessment of the safety of CVS compared with amniocentesis. The participation rate of children who could be contacted was 95%. Ninety-five of the 189 infants (50.2%) had been exposed to CVS, 87 (46%) to amniocentesis, and 7 (3.8%) to both. (The latter group was excluded from calculations.) One hundred twenty-eight (128) children had greater than or equal to one minor anomalies but no major abnormalities: 58 of 95 (60%) in the CVS and 70 of 87 (80%) in the amniocentesis group. Twenty-six children had malformations: 17 (17.8%) in the CVS and 9 (10.3%) in the amniocentesis group. Only one anomaly, Sturge-Weber dysplasia (amniocentesis group), was potentially severe and none were life-threatening. Superficial cavernous hemangiomas (strawberry nevi) were noted more frequently in children in the CVS group (12.6%) than in the amniocentesis group (3.4%), but only slightly higher than in the general public. We conclude that exposure to CVS is not associated with an increased frequency of malformations or minor anomalies in infants compared with amniocentesis although we observed a higher frequency of superficial cavernous (strawberry) hemangiomas in the children in the CVS group.

Knowledge of a few disease categories and their associated laboratory tests can award the pediatrician full partnership in the management of genetic disease. The provision of a DNA test for cystic fibrosis is a recent example of the important advances occurring in genetics. Only the enlightened practitioner can ensure that patients have full and proper access to such advances.

Health care providers in the primary care medical home are uniquely positioned to identify and initially evaluate developmental differences in young children. They are familiar with aspects of the family history and with psychosocial factors that may place a child at higher risk for developmental delay. Primary health care providers are aware of birth events and usually provide for the care of newborns. For those developmental disabilities that are identifiable prenatally or at birth or that result from perinatal complications, early detection is possible. Finally, and most important, the primary care medical home provides a headquarters for longitudinal anticipatory care during which alterations in developmental course can be recognized, investigated, and managed. For most parents, the primary care physician is the first and most trusted respondent to their worries or concerns about their young child's development. It is important that all primary care physicians feel comfortable with this responsibility, confident in their skills at developmental surveillance and screening, clear about the resources for intervention and further evaluation, and knowledgeable about management, care coordination and advocacy. This chapter provides an overview of the approach to the child with a developmental delay or disability from the perspective of the primary care medical home. Taking a generic approach that is intended to complement the specific guidelines of other chapters, we review the epidemiology of developmental disabilities. Developmental screening in the medical home is discussed, with guidelines for referral to community-based agencies and for further medical evaluation.

Stature or length, limb segments, and head circumference are proportionate in symmetrical or harmonic growth failure, and disproportionate in asymmetrical or dysharmonic dwarfism. Disproportion of the head, thorax, or limbs often suggests a skeletal dysplasia as will be discussed in Chapter 11. Proportionate growth failure of stature and limbs may be accompanied by a slightly larger head circumference in nutritional deficiencies (“head-sparing”) or by a slightly smaller head circumference in some congenital syndromes. Table 10.1 summarizes various syndromes with proportionate growth failure, classifying them by time of onset (prenatal and/or postnatal) and by accompanying changes in head circumference (with or without microcephaly). Syndromes with symmetrical intrauterine growth retardation include many chromosomal and teratogenic syndromes discussed in Chapters 5–7. Intrauterine growth retardation is a harbinger for congenital disease, and a thorough investigation of maternal health, gestational history, and the fetal karyotype is often indicated. Once disorders such as fetal alcohol syndrome, Cri-du-Chat syndrome, and trisomy 13/18 are excluded by physical and laboratory findings, the clinician should begin considering syndromes with primary growth failure. Since isolated fetal disease (e.g., cardiac anomaly, renal anomaly) rarely produces intrauterine growth failure, a more global process must be suspected. Table 10.1 lists the more common syndromes with growth failure that do not involve obvious karyotypic changes. These disorders will exhibit proportionately small birth measurements and/or symmetrical failure to thrive. Any clinician concerned about shortened limbs, small thorax, frontal bossing with a shallow nasal bridge, or certain skeletal anomalies should obtain a skeletal radiographic survey to evaluate the possibility of a skeletal dysplasia (dwarfism – see Chapter 11).

Medical genetics is a harlequin specialty. One side is bright with the power of DNA diagnosis and genotyping; the other is darkened by ignorance of complex phenotypes. Fortunately, the molecular revolution is proceeding so rapidly that even complex syndromes are being drawn into the light of genetic analysis. For a growing number of developmental and/or metabolic disorders, proper recognition and referral can lead to definitive diagnostic testing. It is thus extremely important for practitioners to be familiar with common presentations of genetic and developmental diseases, allowing affected children and their families to receive the benefits of informed management and genetic counseling. A correct diagnosis is the gateway to anticipatory guidance and case management. Although the primary care physician may not be the first practitioner to establish the correct diagnosis, it is essential that he or she be able to incorporate specialty opinions and laboratory data into a comprehensive care plan. It is not necessary for practitioners to know long lists of eponymic disorders, but it is necessary that they recognize the possibility of genetic or congenital disease so that appropriate referrals and information can be obtained.Computerized databases such as Online Mendelian Inheritance in Man (OMIM – www.ncbi.nlm.nih.gov/entrez) with links to genome and literature databases of the National Institutes of Health, Recognizable Patterns of Human Malformation (Jones, 1997), Syndromes of the Head and Neck (Gorlin et al., 2001), and The Metabolic and Molecular Bases of Inherited Disease (Scriver et al., 2001) are available to provide details on particular diseases.

Improvements in chromosome banding allowed detection of small deletions and duplications, beginning with missing small bands on chromosome 13 in certain children with retinoblastoma and on chromosome 15 in certain children with Prader–Willi syndrome. These subtle deletions, called microdeletions, were sometimes not reproducible because banding techniques could vary according to the specimen and laboratory conditions. Fluorescent in situ hybridization (FISH) and chromosome painting technologies, using fluorescent DNA probes to highlight specific chromosome regions, improved the characterization of microdeletions and complex rearrangements, revealing a new class of submicroscopic deletions that were not visible by the best-banding techniques. If targeted DNA segment is deleted, then the probe will not yield a fluorescent signal on that chromosome. Chromosome microscopic and submicroscopic deletions cause half (haploid) dosage of autosomal genes within the deleted area, or complete deficiency of genes within deleted regions of the X chromosome in males. The phenotypes of submicroscopic deletions are more easily explained by their haploid or missing genes than are aneuploidies of larger chromosome segments described in Chapters 7 and 8. Schmickel (1986) coined the term “contiguous gene deletion” to denote composite phenotypes that result when neighboring deleted genes are associated with standard Mendelian diseases. Several examples of these aggregate phenotypes are found with small X chromosome deletions like that causing Duchenne muscular dystrophy, glycerol kinase, and adrenal hypoplasia. Each of these disorders had been described as a separate X-linked-recessive disease, so their concurrence in one patient is caused by deletion of the contiguous genes.

We describe a female infant with morphologic features of Rutledge multiple-congenital-anomaly syndrome (RM-CAS) and biochemical features of Smith-Lemli-Opitz syndrome (SLOS). She had microcephaly with hypoplastic cerebral frontal lobes and cerebellum, agenesis of the splenium of corpus callosum, abnormal facies including hypertelorism with bilateral inner epicanthal folds, a broad nasal bridge with slightly anteverted nares and patent choanae, low set ears and complex conchal formation, high-arched palate and thick maxillary alveolar ridges, and micrognathia. Her chest was broad, genitalia were ambiguous, and uterus was bicornuate. Skeletal abnormalities included a hypoplastic appendicular skeleton, post-axial hexadactyly of the right hand and the left foot, syndactyly of bilateral 2nd–3rd toes and left 5th–6th toes, right talipes varus and left talipes valgus, and fused L5–S1 vertebrae. Congenital heart disease consisted of hypoplastic left heart, coronary sinus agenesis, ostium secundum and ostium primum defects, and a thickened septum primum. The lungs were hypolobated and the kidneys manifested oligopapillary hypoplasia. Total colonic Hirschsprung disease was noted microscopically. Analysis of liver tissue taken at postmortem examination revealed the ratio of 7-dehydrocholesterol and cholesterol to be 143 (expected, 0.28 ± 0.28). Although initially described as a distinct syndrome, RMCAS was merged with the severe form of SLOS, because of significantly overlapping features [Online Mendelian Inheritance in Man (OMIM) #268670]. The biochemical data showing an excess of 7-dehydrocholesterol and low cholesterol in the liver tissue of our case supports this viewpoint.