Marilyn C. Jones

Evaluation of mental retardation: Recommendations of a consensus conference

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

Ethical and policy issues in genetic testing and screening of children

The genetic testing and genetic screening of children are commonplace. Decisions about whether to offer genetic testing and screening should be driven by the best interest of the child. The growing literature on the psychosocial and clinical effects of such testing and screening can help inform best practices. This policy statement represents recommendations developed collaboratively by the American Academy of Pediatrics and the American College of Medical Genetics and Genomics with respect to many of the scenarios in which genetic testing and screening can occur.

Sudden death in Williams syndrome: Report of ten cases☆☆☆★

Williams syndrome (WS) is a recognizable pattern of malformation with mental retardation, mild growth deficiency, characteristic facies and temperament, and cardiovascular disease. Sudden death is a recognized complication of WS; however, it is thought to be rare. The clinical features of 10 children with WS who died suddenly are reported here, doubling the number of unexpected deaths reported in the literature. We suggest that sudden death is a more common complication than has been assumed previously. Pathologic findings on the seven autopsy cases implicate two anatomic abnormalities that predispose individuals with WS to sudden death: coronary artery stenosis and severe biventricular outflow tract obstruction. The mechanisms for sudden death for both anatomic subgroups include myocardial ischemia, decreased cardiac output, and arrhythmia. We believe these observations warrant the development of strategies for monitoring patients with WS in an attempt to identify those at increased risk of sudden death.

Patterns of malformation in children with congenital diaphragmatic defects

The medical records of 102 live-born children with a congenital diaphragmatic defect were reviewed to determine the frequency and nature of underlying chromosomal, genetic, and nongenetic patterns of malformation. Overall, 40 children (39%) had a major nonpulmonary malformation, and 14 of these children (14%) had a previously recognized pattern of malformation. A group of 18 children (18%) with cardiac anomalies had an increased mortality rate in comparison with those children without cardiac defects (72% vs 38%). The frequency and severity of nonpulmonary abnormalities in children with congenital diaphragmatic defects suggest that examination of affected children should include cardiac evaluation, a karyotype when the defect is one feature of a broader pattern of altered development, and a careful evaluation for minor anomalies, which may provide clues to an overall diagnosis.

Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations

BACKGROUND Hereditary lymphoedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphoedema of the limbs, with variable age of onset, and extra aberrant growth of eyelashes from the Meibomian gland (distichiasis). Other major reported complications include cardiac defects, cleft palate, and extradural cysts. Photophobia, exotropia, ptosis, congenital ectropion, and congenital cataracts are additional eye findings. Recently, we reported that truncating mutations in the forkhead transcription family member FOXC2resulted in LD in two families. METHODS The clinical findings in seven additional families with LD, including the original family described by Falls and Kertesz, were determined and mutational analyses were performed. RESULTS Distichiasis was the most common clinical feature followed by age dependent lymphoedema. There is a wide variation of associated secondary features including tetralogy of Fallot and cleft palate. The mutational analyses identified truncating mutations in all of the families studied (two nonsense, one deletion, three insertion, and one insertion-deletion), which most likely result in haploinsufficiency ofFOXC2. CONCLUSIONS FOXC2mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations.

Deletions of 20p12 in Alagille syndrome: Frequency and molecular characterization

Alagille syndrome is an autosomal dominant disorder comprising cholestasis (associated with intrahepatic bile duct paucity), characteristic facial appearance, and cardiac, ocular and skeletal defects. Multiple patients have been reported with deletions or translocation involving 20p11.23-p12, providing evidence for the localization of the disease gene to this region. Fifty-six Alagille syndrome patients have been studied by cytogenetic and/or molecular analysis to determine the frequency of detectable abnormalities of 20p12. Two of fifty-six patients studied by cytogenetic analysis had abnormalities: an interstitial deletion in one patient and a translocation in another. Of forty-five patients studied by molecular analysis, three were found to have deletions of 20p, including the two patients identified with cytogenetic abnormalities. Molecular and molecular cytogenetic (FISH) analysis of the translocation (46,XX,t(2;20)(q21.3p12)) demonstrated a deletion at the translocation breakpoint. The deletions identified in the three patients are overlapping, contributing to the delineation of an Alagille syndrome critical region within 20p12. This region lies between markers D20S41 and D20S162. The frequency of detectable cytogenetic abnormalities of 20p12 in this group of Alagille patients is 2/56 (3.6%), and the frequency of molecular deletions is 3/45 (6.7%). This is considerably lower than the frequency of deletions observed in contiguous gene deletion syndromes suggesting that Alagille syndrome may be caused by the alteration of a single gene.

High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor

Malignant rhabdoid tumors are highly aggressive neoplasms found primarily in infants and young children. The majority of rhabdoid tumors arise as a result of homozygous inactivating deletions or mutations of the INI1 gene located in chromosome band 22q11.2. Germline mutations of INI1 predispose to the development of rhabdoid tumors of the brain, kidney and extra-renal tissues, consistent with its function as a tumor suppressor gene. We now describe five patients with germline deletions in chromosome band 22q11.2 that included the INI1 gene locus, leading to the development of rhabdoid tumors. Two patients had phenotypic findings that were suggestive but not diagnostic for DiGeorge/Velocardiofacial syndrome (DGS/VCFS). The other three infants had highly aggressive disease with multiple tumors at the time of presentation. The extent of the deletions was determined by fluorescence in situ hybridization and high-density oligonucleotide based single nucleotide polymorphism arrays. The deletions in the two patients with features of DGS/VCFS were distal to the region typically deleted in patients with this genetic disorder. The three infants with multiple primary tumors had smaller but overlapping deletions, primarily involving INI1. The data suggest that the mechanisms underlying the deletions in these patients may be similar to those that lead to DGS/VCFS, as they also appear to be mediated by related, low copy repeats (LCRs) in 22q11.2. These are the first reported cases in which an association has been established between recurrent, interstitial deletions mediated by LCRs in 22q11.2 and a predisposition to cancer.

Prenatal diagnosis of cleft lip and palate: detection rates, accuracy of ultrasonography, associated anomalies, and strategies for counseling.

OBJECTIVE As ultrasound becomes more widely utilized in pregnancy and imaging technology improves, cleft lip and palate will become more commonly identified in prenatal life. In efforts to meet the needs for information regarding cause and management, pregnant women and their partners are increasingly referred to cleft and craniofacial treatment programs. This group of patients provides unique challenges to professionals unfamiliar with the issues inherent to this population. Information regarding the extent of the defect and the absence of associated abnormalities is usually incomplete. Treatment teams may be uncomfortable with the possibility that couples may choose not to continue a pregnancy on the basis of what they hear. Currently between 14% and 25% of cleft lip, with or without cleft palate, is detected antenatally. About 12% of presumably isolated clefts will be one feature in a broader pattern of malformation. This article reviews the current status of ultrasound in the detection of clefts during pregnancy and outlines a strategy for counseling based on the authors experience in both a prenatal diagnosis program and a cleft-craniofacial treatment team.

Underlying Genetic Diagnosis of Pierre Robin Sequence: Retrospective Chart Review at Two Children's Hospitals and a Systematic Literature Review

OBJECTIVES To determine the underlying genetic diagnosis of Pierre Robin sequence (PRS) in 2 cohorts of individuals, assess the accuracy of genetic evaluation in young infants with PRS, and contrast the interventions provided to children with isolated and syndromic PRS. STUDY DESIGN The study involved retrospective chart reviews at 2 childrens hospitals and a systematic literature review. RESULTS Approximately 40% of the patients had isolated PRS, and 60% of the patients had additional syndromic features. The patients with PRS with syndromic features required more aggressive medical management. Stickler syndrome was the most common syndromic diagnosis in PRS. The difficulty of making an accurate genetic diagnosis during the neonatal period was demonstrated. CONCLUSION All infants with PRS should be evaluated to check for the presence of syndromic features, and a longitudinal follow-up is warranted to monitor for the development of any syndromic features.

Ring chromosome X in a child with manifestations of Kabuki syndrome

A female patient with the karyotype 45,X/46, X, r(X)(p11.2 q13) and severe developmental delay, prominent fingertip pads, long palpebral fissures, short stature, and history of hypotonia had a phenotype reminiscent of Kabuki syndrome. We hypothesized that overexpression of X chromosome-derived sequences might be associated with the Kabuki-like phenotype observed. The nature and parental origin of this small-ring X were ascertained using a combination of genotyping with microsatellite markers and quantitative Southern blotting. PCR-based genotyping demonstrated heterozygosity at X-linked loci SBMA (Xq11-q12) and DXS227 (Xq13.1). Hemizygosity was observed at several loci: DMD STR-49 (Xp21.2), DXS1003 (Xp11.23), DXS988 (Xp11.21), DXS101 (Xq21.3), FMR-1 (Xq27.3), and DXYS64 (Xq28). This ring X chromosome is paternally derived since only maternal alleles are inherited at three informative microsatellite loci. Results of FISH and RT-PCR experiments indicate that the XIST locus is missing in the ring X chromosome and not expressed. These data indicated a large deletion of the X chromosome consistent with a small-ring X chromosome with approximate breakpoints near p11.2 and q13. These results are comparable to the observation of others where an atypically severe phenotype has been associated with the presence of an r(X), or small mar(X).