Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene.

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created "matching" platforms. We describe four individuals from three unrelated families "matched" by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interprets the variants as "pathogenic." TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder.

Chromosome 1p36.22p36.21 duplications/triplication causes Setleis syndrome (focal facial dermal dysplasia type III).

Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype.

Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene.

Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. In a single case of fibrochondrogenesis, whole-genome SNP genotyping identified unknown ancestral consanguinity by detecting three autozygous regions. Because of the predominantly skeletal nature of the phenotype, the 389 genes localized to the autozygous intervals were prioritized for mutation analysis by correlation of their expression with known cartilage-selective genes via the UCLA Gene Expression Tool, UGET. The gene encoding the α1 chain of type XI collagen (COL11A1) was the only cartilage-selective gene among the three candidate intervals. Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. The parents who were carriers of missense mutations had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele, suggesting COL11A1 as a locus for mild, dominantly inherited hearing loss. These findings identify COL11A1 as a locus for fibrochondrogenesis and indicate that there might be phenotypic manifestations among carriers.

Clinical comparison of overlapping deletions of 19p13.3.

We present three patients with overlapping interstitial deletions of 19p13.3 identified by high resolution SNP microarray analysis. All three had a similar phenotype characterized by intellectual disability or developmental delay, structural heart abnormalities, large head relative to height and weight or macrocephaly, and minor facial anomalies. Deletion sizes ranged from 792 Kb to 1.0 Mb and included a common region arr [hg19] 19p13.3 (3,814,392-4,136,989), containing eight genes: ZFR2, ATCAY, NMRK2, DAPK3, EEF2, PIAS4, ZBTB7A, MAP2K2, and two non-coding RNA's MIR637 and SNORDU37. The patient phenotypes were compared with three previous single patient reports with similar interstitial 19p13.3 deletions and six additional patients from the DECIPHER and ISCA databases to determine if a common haploinsufficient phenotype for the region can be established.

Minimal evidence for a direct involvement of twisted gastrulation homolog 1 (TWSG1) gene in human holoprosencephaly.

Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Presently understood etiologies include both genetic and environmental factors, acting either alone, or more likely, in combination. The majority of patients without overt chromosomal abnormalities or recognizable associated syndromes have unidentified etiologies. A potential candidate gene, Twisted Gastrulation Homolog 1 (TWSG1), was previously suggested as a contributor to the complex genetics of human HPE based on (1) cytogenetic studies of patients with 18p deletions, (2) animal studies of TWSG1 deficient mice, and (3) the relationship of TWSG1 to bone morphogenetic protein (BMP) signaling, which modulates the primary pathway implicated in HPE, Sonic Hedgehog (SHH) signaling. Here we present the first analysis of a large cohort of patients with HPE for coding sequence variations in TWSG1. We also performed fine mapping of 18p for a subset of patients with partial 18p deletions. Surprisingly, minimal evidence for alterations of TWSG1 was found, suggesting that sequence alterations of TWSG1 are neither a common direct cause nor a frequent modifying factor for human HPE pathologies.

Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome.

OBJECTIVE: Aicardi-Goutières syndrome (AGS) is an early-onset encephalopathy resembling congenital viral infection that is characterized by basal ganglia calcifications, loss of white matter, cerebrospinal fluid (CSF) lymphocytosis, and elevated interferon-alpha levels in the CSF. Studies have shown that AGS is an autosomal-recessive disease linked to mutations in 5 genes, encoding the 3'-repair DNA exonuclease 1 (TREX1), the 3 subunits of ribonuclease H2 (RNASEH2A-C), and sterile alpha motif domain and HD domain-containing protein 1 (SAMHD1). In this study we further characterized the phenotypic spectrum of this disease. METHODS: Clinical and laboratory data were obtained from 26 patients fulfilling the clinical diagnostic criteria for AGS. Genomic DNA was screened for mutations in all 5 AGS genes by direct sequencing, and sera were analyzed for autoantibodies. RESULTS: In 20 patients with AGS, 20 mutations, 12 of which were novel, were identified in all 5 AGS genes. Clinical and laboratory investigations revealed a high prevalence of features (some not previously described in patients with AGS) that are commonly seen in patients with systemic lupus erythematosus (SLE), such as thrombocytopenia, leukocytopenia, antinuclear antibodies, erythematous lesions, oral ulcers, and arthritis, which were observed in 12 (60%) of 20 patients with AGS. Moreover, the coexistence of AGS and SLE, was for the first time, demonstrated in 2 patients with molecularly proven AGS. CONCLUSION: These findings expand the phenotypic spectrum of lupus erythematosus in AGS and provide further insight into its disease mechanisms by showing that activation of the innate immune system as a result of inherited defects in nucleic acid metabolism could lead to systemic autoimmunity.

Polyhydramnios, fetal overgrowth, and macrocephaly: prenatal ultrasound findings of Costello syndrome.

Costello syndrome is a multiple congenital anomaly syndrome consisting of dysmorphic facies, cutis laxa, short stature, developmental delay, and mental retardation. Complications include failure to thrive, hypertrophic cardiomyopathy with arrhythmias, and benign and malignant tumors. This report describes a new case of Costello syndrome in a preterm infant born at 27 weeks gestation and diagnosed with Costello syndrome at 7 weeks of life who died at 6 months of age due to cardiac and pulmonary complications. In addition, data were compiled from parent surveys including growth parameters on 16 infants who were subsequently diagnosed with Costello syndrome and had mutation confirmation. The most common prenatal findings in the literature and in this cohort were polyhydramnios and fetal overgrowth with relative macrocephaly. Based on this study, ultrasound identification of polyhydramnios in the context of prenatal overgrowth, especially with relative macrocephaly, needs to raise the possibility of a diagnosis of Costello syndrome in the fetus because of the life-threatening cardiac complications that may occur early in the newborn period.

Hardikar syndrome: new features.

Hardikar syndrome (HS) is a disorder of multiple anomalies predominantly characterized by cleft lip/palate, liver and biliary tract disease, intestinal malrotation, obstructive uropathy, and retinopathy. To date, three patients have been reported with the unusual constellation of chronic liver/biliary tract disease and obvious defects in organogenesis [Hardikar et al. (1992): Am J Med Genet 44: 13-17; Cools and Jaeken (1997): Am J Med Genet 71: 472-474]. With this report, we add another patient with this syndrome. New features, hitherto not reported, were vaginal atresia, a type 1 choledochal cyst and, owing to the progressive nature of the liver disease, the need for liver transplantation. It is intriguing to speculate, that HS could be genetically related to Alagille syndrome (AS), since both conditions share an unusual number of phenotypic abnormalities.

Neonatal upper airway obstruction in osteogenesis imperfecta: series of three cases and review of the literature.

OBJECTIVES: Osteogenesis imperfecta (OI) is a genetic disorder characterized by variable degrees of dysfunction in type I collagen formation. We sought to explore an association between OI and upper airway obstruction (UAO) in light of our recent experience. METHODS: We performed a retrospective chart audit and a review of the literature. RESULTS: Three consecutive cases of OI at our institution required otolaryngological evaluation for UAO. The first patient had the mildest mutation type and did well until he developed severe reflux-triggered laryngospasm that improved with Nissen fundoplication and gastrostomy tube placement. He had mild hypotonia on endoscopy. The second patient had severe OI and the greatest acute fracture burden at birth. He required tracheotomy after early respiratory failure, and some mild bronchomalacia was noted. The third patient had severe OI and underwent cesarean section delivery. She developed respiratory failure after 1 month, requiring tracheotomy; mild tracheomalacia and glottic narrowing were noted on endoscopy. CONCLUSIONS: The UAO consisted of mild hypotonia or malacia in 3 consecutive cases of OI, and may have contributed to pulmonary and mechanical causes of tracheotomy requirement. The greatest predictors of tracheotomy requirement appear to be the severity of the OI mutation and the fracture burden. Elective cesarean section should be considered in severe cases of OI.

Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

Further delineation of cardiac abnormalities in Costello syndrome.

We review the cardiac abnormalities in 94 patients (27 new, 67 literature) with Costello syndrome, an increasingly recognized syndrome consisting of increased birth weight, postnatal growth retardation, and distinctive facial, skin, and musculoskeletal features (MIM 218040). A cardiac abnormality was found in 59 (63%) patients, with each of three categories occurring in approximately one-third of patients. A cardiovascular malformation (CVM) was noted in 30%, typically pulmonic stenosis (46% of those with a CVM). Cardiac hypertrophy was reported in 34%, which involved the left ventricle in 50% and was usually consistent with classic hypertrophic cardiomyopathy (HCM). A variety of rhythm disturbances were reported in 33%. Most (74%) were atrial tachycardia that was reported as supraventricular, chaotic, multifocal, or ectopic. Of 31 patients with a rhythm abnormality, 22 (68%) had an additional abnormality, i.e., CVM (4), cardiac hypertrophy (12), or both (6). Nine patients had isolated dysrhythmia, five (56%) of whom died. All of the 12 (13%) patients who died had a cardiac abnormality. One patient died of embryonal rhabdomyosarcoma, but in the remainder, a cardiac cause of death could not be disproved. All patients with Costello syndrome need a baseline cardiology evaluation with echocardiography and Holter monitoring. Additional prospective evaluations, even in patients without apparent cardiac abnormalities, would be prudent, although data are insufficient to propose a specific schedule.

Advancing our understanding of the inheritance and transmission of pectus excavatum.

Pectus excavatum is the most common congenital chest wall abnormality expressed in children, yet its inheritance is poorly understood. Here we present the first comprehensive assessment of the inheritance of this disorder. After evaluating 48 pedigrees and 56 clinical traits of probands and family members, we find strong evidence of autosomal recessive, genetic control for this disorder. Additionally there is likely more than one pectus disease-associated allele, as well as a relatively large number of disease allele carriers in the human population. Some clinical traits appear important and may serve as reliable indicators for predicting the likelihood of pectus excavatum in children before severe symptoms present. Quantifying sex-ratio bias in probands demonstrates a highly significant male bias associated with pectus excavatum. When combined with pedigree data, sex-bias is indicative of sex-linked, sex-limited, and/or epigenetic control such as X-inactivation, reiterating a point made with pedigrees alone, which is that more than one mutation is likely responsible for this disorder.

Role of the pediatric otolaryngologist in diagnosis and management of children with mucopolysaccharidoses.

OBJECTIVE: Mucopolysaacharidoses (MPS) represent a spectrum of disorders characterized by the genetic deficiency of specific lysosomal enzymes occurring in as many as 1 in 10,000 live births and resulting in the accumulation of glycosaminoglycans within cells throughout the body. Children have highly variable, multi-systemic involvement that nearly always involves manifestations of the head and neck including recurrent otitis, hearing loss, upper airway obstruction, and characteristic coarse facial features. This places the otolaryngologist in a prime position for early recognition and initiation of treatment. We sought to examine our own experience in dealing with this diverse and often quite devastating clinical entity. METHODS: Retrospective chart review of children with mucopolysaccharidoses seen in our tertiary care pediatric otolaryngology clinic accompanied by review of the literature. RESULTS: Nine children were identified--five with Hurler syndrome, three with Hunter syndrome, and one with Maroteaux-Lamy syndrome. The median age of diagnosis/genetics referral was 15 months, while median age of presentation to an otolaryngologist was 12 months. Three patients were referred for genetics evaluation based upon initial evaluation/suspicion by an otolaryngologist. Two were diagnosed early because of an affected older sibling. All patients in the series had varying degrees of hearing loss, recurrent otitis, chronic effusions or abnormal facial features, and all patients required placement of at least one set of ventilation tubes. CONCLUSIONS: Otolaryngologists have an opportunity to play an increasingly integral role in the multidisciplinary approach to the diagnosis and management of many children with mucopolysaccharidoses. Clinical suspicion, early recognition, and prompt diagnosis of these challenging disorders is crucial, as outcomes of treatment in many cases appear time-sensitive, with better results being achieved when intervention is initiated at a younger age or prior to progression of the disease.

Avoiding transmitting identified mutations to offspring using preimplantation genetic diagnosis.

BACKGROUND: Preimplantation genetic diagnosis has been used to decrease or avoid the risk of transmitting identified mutations to offspring. CASE: A 29-year-old woman with spondyloepiphyseal dysplasia congenita and her 30-year-old husband with Marfan syndrome underwent in vitro fertilization with preimplantation genetic diagnosis. Two mutation-negative embryos were transferred into a gestational carrier, who became pregnant with twins and delivered two clinically normal neonates. CONCLUSION: Statistically, this couple would be predicted to have a 75% chance of producing an affected embryo. Using preimplantation genetic diagnosis, two dually unaffected embryos were selected and transferred. This experience expands the use of preimplantation genetic diagnosis to cases with multiple autosomal dominant single-gene disorders.

Enzyme replacement therapy in the home setting for mucopolysaccharidosis VI: a survey of patient characteristics and physicians' early findings in the United States.

Galsulfase, a Food and Drug Administration-approved enzyme replacement therapy for mucopolysaccharidosis VI, is administered once weekly in a hospital setting as a 4-hour intravenous infusion. To improve convenience and alleviate family responsibilities associated with clinic visits, some physicians are transitioning appropriate patients to home infusion therapy. An online survey was conducted with 3 physicians treating 4 patients with mucopolysaccharidosis VI to better understand the factors motivating the transition to home infusion therapy, identify characteristics of appropriate candidates, and evaluate the potential impact on the lives of patients and their families. Survey results showed that home infusion may offer patients and their families increased flexibility of schedule and enhanced family life.

Family study of the inheritance of pectus excavatum.

BACKGROUND: The most common congenital deformity of the chest wall is pectus excavatum, a malformation that is present in between 1 in 400 and 1 in 1000 live births and causes the body of the sternum to be displaced, producing a depression. There are many different shapes of the pectus, and multiple factors probably contribute to the final form. The etiology of pectus excavatum is uncertain, but a familial tendency has been found in clinical experience, where it may be seen in more than one sibling. Pectus excavatum is commonly associated with connective tissue disorders such as Marfan and Ehlers Danlos syndromes. Extensive literature review failed to identify articles documenting families with multiple affected members. PURPOSE: The purpose of this study was to collect evidence that pectus excavatum is familial and may be an inherited disorder. METHODS: Using the Children's Surgical Specialty Group database at Children's Hospital of The King's Daughters, families with more than one affected individual were selected. With Institutional Review Board-approved informed consent, 34 families agreed to participate. Family histories were obtained, and a 4-generation pedigree was constructed for each family. Forty questions were asked about each individual's medical history, and comprehensive systems review included features of connective tissue-related problems. Inheritance patterns for each family were determined by pedigree analysis. RESULTS: A total of 14 families suggested autosomal dominant inheritance, 4 families suggested autosomal recessive inheritance, and 6 families suggested X-linked recessive inheritance. Ten families had complex inheritance patterns. Pectus excavatum occurred more frequently in males than in females (1.8:1). Long arms, legs, and fingers; high-arched palate; mitral valve prolapse; heart arrhythmia; scoliosis; double jointedness; flexibility; flat feet; childhood myopia; poor healing; and easy bruising were commonly associated with pectus excavatum. CONCLUSIONS: Pedigree analysis of 34 families provides evidence that pectus excavatum is an inherited disorder, possibly of connective tissue. Although some families demonstrate apparent Mendelian inheritance, most appear to be multifactorial.

Classification of the dysmorphology of pectus excavatum.

BACKGROUND/PURPOSE: To describe the dysmorphology of pectus excavatum, the most common congenital chest wall anomaly. METHODS: A stratified sample of 64 patients, representative of a patient population with pectus excavatum of the Children's Hospital of King's Daughters in Norfolk, VA, was described and classified. The sample was stratified by sex to represent a 4:1 male-to-female ratio. The sample was further stratified to represent categories of age (3-10, 11-16, and 17 years and older). Preoperative photos and baseline chest computed tomography scans were examined and categorized according to the chief criteria, including asymmetry/symmetry of the depression, localized vs diffuse morphology, sternal torsion, cause of asymmetric appearance, and the length of the depression. RESULTS: Useful morphologic distinctions in pectus excavatum are localized depressions vs diffuse depressions, short and long length, symmetry, sternal torsion, slope/position of absolute depth, and unique patterns such as the horns of steer depression. CONCLUSIONS: These classifications simplify the diagnosis of pectus excavatum, aid in corrective surgery, and should improve correlation of phenotype and genotype in future genetic analysis.

Trismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8.

Trismus-pseudocamptodactyly syndrome (TPS) is a rare autosomal dominant distal arthrogryposis (DA) characterized by an inability to open the mouth fully (trismus) and an unusual camptodactyly of the fingers that is apparent only upon dorsiflexion of the wrist (i.e., pseudocamptodactyly). TPS is also known as Dutch-Kentucky syndrome because a Dutch founder mutation is presumed to be the origin of TPS cases in the Southeast US, including Kentucky. To date only a single mutation, p.R674Q, in MYH8 has been reported to cause TPS. Several individuals with this mutation also had a so-called "variant" of Carney complex, suggesting that the pathogenesis of TPS and Carney complex might be shared. We screened MYH8 in four TPS pedigrees, including the original Dutch family in which TPS was reported. All four TPS families shared the p.R674Q substitution. However, haplotype analysis revealed that this mutation has arisen independently in North American and European TPS pedigrees. None of the individuals with TPS studied had features of Carney complex, and p.R674Q was not found in 49 independent cases of Carney complex that were screened. Our findings show that distal arthrogryposis syndromes share a similar pathogenesis and are, in general, caused by disruption of the contractile complex of muscle.