Reha M. Toydemir

A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7

Hereditary hemorrhagic telangiectasia (HHT) is a genetically and clinically heterogeneous multisystem vascular dysplasia. Mutations of the endoglin and ACVRL1 genes are known to cause HHT. However, existence of HHT families in which linkage to these genes has been excluded has suggested that other gene(s) can cause HHT in some families. Recently, a family was reported to be linked to chromosome 5q, the HHT3 locus. Here we report on linkage results on a family with classic features of HHT, albeit a less severe phenotype with regards to epistaxis and telangiectases, in which linkage to HHT1, HHT2, and HHT3 is ruled out. Whole genome linkage analysis and fine mapping results suggested a 7 Mb region on the short arm of chromosome 7 (7p14) between STR markers D7S2252 and D7S510. We obtained a maximum two point LOD score of 3.60 with the STR marker D7S817. This region was further confirmed by haplotype analysis. These findings suggest the presence of another gene causing HHT (HHT4). The features in this family that strongly suggest the presence of a hereditary, multisystem vascular dysplasia would be easily missed during the typical evaluation and management of a patient with an AVM. This family helps emphasize the need to obtain a very detailed, targeted medical and family history for even mild, infrequent but recurring nosebleed, subtle telangiectases. Further studies of the candidate region and the identification of the gene responsible for the vascular anomalies in this family will add to our understanding of vascular morphogenesis and related disorders.

Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome

The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosins catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders.

Expressivity of Holt-Oram Syndrome Is Not Predicted by TBX5 Genotype

Mutations in TBX5, a T-box-containing transcription factor, cause cardiac and limb malformations in individuals with Holt-Oram syndrome (HOS). Mutations that result in haploinsufficiency of TBX5 are purported to cause cardiac and limb defects of similar severity, whereas missense mutations, depending on their location in the T box, are thought to cause either more severe heart or more severe limb abnormalities. These inferences are, however, based on the analysis of a relatively small number of independent cases of HOS. To better understand the relationship between mutations in TBX5 and the variable expressivity of HOS, we screened the coding and noncoding regions of TBX5 and SALL4 for mutations in 55 probands with HOS. Seventeen mutations, including six missense mutations in TBX5 and two mutations in SALL4, were found in 19 kindreds with HOS. Fewer than 50% of individuals with nonsense or frameshift mutations in TBX5 had heart and limb defects of similar severity, and only 2 of 20 individuals had heart or limb malformations of the severity predicted by the location of their mutations in the T box. These results suggest that neither the type of mutation in TBX5 nor the location of a mutation in the T box is predictive of the expressivity of malformations in individuals with HOS.

A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome

Activating mutations of FGFR3, a negative regulator of bone growth, are well known to cause a variety of short-limbed bone dysplasias and craniosynostosis syndromes. We mapped the locus causing a novel disorder characterized by camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL syndrome) to chromosome 4p. Because this syndrome recapitulated the phenotype of the Fgfr3 knockout mouse, we screened FGFR3 and subsequently identified a heterozygous missense mutation that is predicted to cause a p.R621H substitution in the tyrosine kinase domain and partial loss of FGFR3 function. These findings indicate that abnormal FGFR3 signaling can cause human anomalies by promoting as well as inhibiting endochondral bone growth.

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.

Sheldon-Hall syndrome

Sheldon-Hall syndrome (SHS) is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face, downslanting palpebral fissures, small mouth, and high arched palate. Epidemiological data for the prevalence of SHS are not available, but less than 100 cases have been reported in the literature. Other common clinical features of SHS include prominent nasolabial folds, high arched palate, attached earlobes, mild cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. Typically, the contractures are most severe at birth and non-progressive. SHS is inherited in an autosomal dominant pattern but about half the cases are sporadic. Mutations in either MYH3, TNNI2, or TNNT3 have been found in about 50% of cases. These genes encode proteins of the contractile apparatus of fast twitch skeletal muscle fibers. The diagnosis of SHS is based on clinical criteria. Mutation analysis is useful to distinguish SHS from arthrogryposis syndromes with similar features (e.g. distal arthrogryposis 1 and Freeman-Sheldon syndrome). Prenatal diagnosis by ultrasonography is feasible at 18–24 weeks of gestation. If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible. There is no specific therapy for SHS. However, patients benefit from early intervention with occupational and physical therapy, serial casting, and/or surgery. Life expectancy and cognitive abilities are normal.

A deletion 13q34/duplication 14q32.2–14q32.33 syndrome diagnosed 50 years after neonatal presentation as infantile hypercalcemia

During infancy, this 50‐year‐old man with a previously undiagnosed multiple congenital anomalies/intellectual disability (MCA/MR) syndrome had grossly symptomatic hypercalcemia and was (briefly) thought to have Williams syndrome. Results of studies with the cytogenetic methods of the 1960s and 1970s were apparently normal. He matured late, but is high‐functioning and healthy. Over 50 years he remained a diagnostic enigma. Thus, it came as a surprise when recent high‐resolution banding methods showed an abnormality of the terminal portion of 13q, determined on array‐comparative genomic hybridization to constitute an unbalanced chromosome rearrangement with a 0.35 Mb loss of 13q34‐ter and 7.67 Mb gain of 14q32.2q32.33 translocated to 13q34. This apparently de novo genomic abnormality must be presumed as the cause of this previously undescribed MCA/MR syndrome which, however, may remain a private syndrome in this family. Williams syndrome was ruled out, and presently it is not possible to ascribe this patients severely symptomatic infantile hypercalcemia to any gene on the deleted or duplicated chromosome segments. This “case” does underscore the importance of re‐studying previously obscure but evidently genetic conditions, of long‐term follow‐up and documentation of natural history, and of providing, at last, a causal explanation to the family.

Cytogenetic and molecular characterization of double inversion 3 associated with a cryptic BCR-ABL1 rearrangement and additional genetic changes

Rearrangements of chromosome 3 involving bands 3q21 and 3q26 have been reported in about 2% of patients with acute myeloid leukemia, and rarely in myelodysplastic syndrome or chronic myelogenous leukemia (CML). To date, only six cases of inversion of both homologues have been reported. Loss of normal chromosome 3 and duplication of the inverted chromosome have been proposed as the most likely mechanism, but have not been shown experimentally. We present a 36-year-old male with an initial diagnosis of CML and resistance to imatinib mesylate. Chromosome analysis showed an inversion within the long arm of both homologues of chromosome 3 and an interstitial deletion within the long arm of one chromosome 7. The rearrangement of EVI1 locus on both homologues of chromosome 3 was confirmed by fluorescence in situ hybridization (FISH). Additional FISH studies showed a cryptic insertion of ABL1 into the BCR region, and subsequent duplication of the derivative chromosome 22. The single-nucleotide polymorphism array showed copy-neutral loss of heterozygosity on chromosomes 3 and 22, suggesting that a somatic repair mechanism is involved in the evolution of these genetic alterations. This case illustrates the complexity of genetic aberrations in neoplastic cells, and the value of array technology, used in concert with conventional cytogenetic methods, for a better understanding of the pathogenesis.

The Occurrence of Occult Acetabular Dysplasia in Relatives of Individuals With Developmental Dysplasia of the Hip.

Background: This study sought to determine the hip pathology of family members of patients with developmental dysplasia of the hip (DDH). The authors evaluated 120 people from 19 families known to have at least 1 member with surgically treated DDH. Each individual’s functional outcome scores and pelvic radiographs were assessed for hip symptoms or pathology. Methods: Using a genetic population database and a pediatric hospital patient population, 19 families with high rates of DDH were identified. All family members (n=120) underwent physical examination, radiographic assessment, and completion of outcome instruments [American Academy of Orthopedics (AAOS) Hip and Knee; Harris Hip Score (HHS); and Western Ontario and McMaster Universities Arthritis Index (WOMAC)]. Results: The 120 subjects ranged from 1 to 84 years, 34 had orthopaedically treated DDH. Of the remaining 86 supposedly normal subjects, 23 (27%) had occult acetabular dysplasia (OAD) as defined by center edge angle (CEA) <20 and/or a Severin score of III or greater. Sixty percent of the 86 individuals were less than 30 years old, 74% of the OAD group were less than 30. Outcome scores of the treated DDH patients (AAOS, HHS, and WOMAC) were worse on the involved side regardless of age. Over age 30 individuals with OAD had statistically significant decreases in their AAOS Hip and Knee and WOMAC scores on the dysplastic side, but their HHS scores were not significantly different. Conclusions: Twenty-seven percent of first-degree and second-degree relatives of patients with DDH had unsuspected radiographic acetabular dysplasia in our study. Most of the subjects with OAD were younger than 30. After age 30, many of these patients developed symptoms. Clinical Relevance: In families with a significant history of DDH, radiographic screening of siblings of patients with DDH to define OAD may be prudent. Level of Evidence: Level I—diagnostic study.

L1CAM whole gene deletion in a child with L1 syndrome

L1 syndrome is a group of overlapping, X‐linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X‐linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4‐month‐old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype–phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X‐linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2.