The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA.

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.

Penile biometry on prenatal magnetic resonance imaging.

OBJECTIVE: In view of the implementation of magnetic resonance imaging (MRI) as an adjunct to ultrasonography in prenatal diagnosis, this study sought to demonstrate normal penile growth on prenatal MRI. METHODS: This was a retrospective study of MRI of 194 male fetuses (18-34 weeks' gestation) with normal anatomy or minor abnormalities. On sagittal T2-weighted MRI sequences, we measured penile length from the glans tip to the scrotal edge (outer length) and from the glans tip to the symphyseal border (total length). Descriptive statistics, as well as correlation and regression analysis, were used to evaluate penile length in relation to gestation. T-tests were calculated to compare mean outer/total length on MRI with published ultrasound data. RESULTS: Mean length values, including 95% CIs and percentiles, were defined. Penile length as a function of gestational age was expressed by the following regression equations: outer mean length = - 5.514 + 0.622 × gestational age in weeks; total mean length = - 8.865 + 1.312× gestational age in weeks. The correlation coefficients, r = 0.532 and r = 0.751, respectively, were statistically significant (P < 0.001). Comparison of outer penile length on MRI with published ultrasound penile length data showed no significant differences, while total penile length on MRI was significantly greater than ultrasound penile length (P < 0.001). CONCLUSION: Our MRI results provide a reference range of fetal penile length, which, in addition to ultrasonography, may be helpful in the identification of genital anomalies. Outer penile length on MRI is equivalent to penile length measured on ultrasound, whereas total length is significantly greater.

Female external genitalia on fetal magnetic resonance imaging.

OBJECTIVES: To characterize the normal development of the female external genitalia on fetal magnetic resonance imaging (MRI). METHODS: This retrospective study included MRI examinations of 191 female fetuses (20-36 gestational weeks) with normal anatomy or minor abnormalities, following suspicion of anomalies on prenatal ultrasound examination. Using a 1.5-Tesla unit, the bilabial diameter was measured on T2-weighted sequences. Statistical description, as well as correlation and regression analyses, was used to evaluate bilabial diameter in relation to gestational age. MRI measurements were compared with published ultrasound data. The morphological appearance and signal intensities of the external genitalia were also assessed. RESULTS: Mean bilabial diameters, with 95% CIs and percentiles, were defined. The bilabial diameter as a function of gestational age was expressed by the regression equation: bilabial diameter = - 11.336 + 0.836 × (gestational age in weeks). The correlation coefficient, r = 0.782, was statistically significant (P < 0.001). Bilabial diameter on MRI was not significantly different from that on ultrasound (P < 0.001). In addition, on MRI we observed changes in morphology of the external genitalia and in signal intensities with increasing gestational age. CONCLUSIONS: We have provided a reference range of fetal bilabial diameter on MRI, which, in addition to ultrasound findings, may be helpful in the identification of genital anomalies.

Male sexual development in utero: testicular descent on prenatal magnetic resonance imaging.

OBJECTIVE: To visualize in utero male fetal testicular descent on magnetic resonance imaging (MRI) and to correlate it with gestational age. METHODS: This retrospective study included 202 MRI examination results of 199 male fetuses (17-39 gestational weeks) with normal anatomy or minor congenital abnormalities, following suspicion of anomalies on prenatal ultrasound examination. Using a 1.5-Tesla unit, multiplanar T2-weighted sequences were applied using a standard protocol to image and identify the scrotal content. The relative frequencies of unilateral and bilateral testicular descent were calculated and correlated with gestational age. RESULTS: Between 17 and 25 gestational weeks, neither unilateral nor bilateral testicular descent was visualized on MRI. Testicular descent was first observed at 25 + 4 weeks, in 7.7% of cases. 12.5% of 27-week fetuses showed unilateral descent and 50% showed bilateral descent. Bilateral descent was observed in 95.7% of cases, on average, from 30 to 39 weeks. CONCLUSIONS: Our results chart the time course of testicular descent on prenatal MRI, which may be helpful in the identification of normal male sexual development and in the diagnosis of congenital abnormalities, including the early detection of cryptorchidism.

Abnormalities of the upper extremities on fetal magnetic resonance imaging.

OBJECTIVE: In view of the increasing use of fetal magnetic resonance imaging (MRI) as an adjunct to prenatal ultrasonography, we sought to demonstrate the visualization of upper extremity abnormalities and associated defects on MRI, with regard to fetal outcomes and compared with ultrasound imaging. METHODS: This retrospective study included 29 fetuses with upper extremity abnormalities visualized with fetal MRI following suspicious ultrasound findings and confirmed by postnatal assessment or autopsy. On a 1.5-Tesla unit, dedicated sequences were applied to image the extremities. Central nervous system (CNS) and extra-CNS anomalies were assessed to define extremity abnormalities as isolated or as complex, with associated defects. Fetal outcome was identified from medical records. MRI and ultrasound findings, when available, were compared. RESULTS: Isolated upper extremity abnormalities were found in three (10.3%) fetuses. In 26 (89.7%) fetuses complex abnormalities, including postural extremity disorders (21/26) and structural extremity abnormalities (15/26), were demonstrated. Associated defects involved: face (15/26); musculoskeletal system (14/26); thorax and cardio/pulmonary system (12/26); lower extremities (12/26); brain and skull (10/26); and abdomen (8/26). Of the 29 cases, 18 (62.1%) pregnancies were delivered and 11 (37.9%) were terminated. MRI and US findings were compared in 27/29 cases: the diagnosis was concordant in 14 (51.9%) of these cases, and additional findings were made on MRI in 13/27 (48.1%) cases. CONCLUSIONS: Visualization of upper extremity abnormalities on fetal MRI enables differentiation between isolated defects and complex ones, which may be related to poor fetal prognosis. MRI generally confirms the ultrasound diagnosis, and may provide additional findings in certain cases.

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene.

BACKGROUND: The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate. OBJECTIVE: To investigate in more detail the phenotype resulting from arginine to cysteine mutations in the COL2A1 gene. METHODS: The clinical and radiographic phenotype of all patients in whom an arginine to cysteine mutation in the COL2A1 gene was identified in our laboratory, was studied and correlated with the abnormal genotype. The COL2A1 genotyping involved DHPLC analysis with subsequent sequencing of the abnormal fragments. RESULTS: Six different mutations (R75C, R365C, R519C, R704C, R789C, R1076C) were found in 11 unrelated probands. Each mutation resulted in a rather constant and site-specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C, R519C, or R1076C mutation. Short third and/or fourth toes was a distinguishing feature of the R75C mutation and brachydactyly with enlarged finger joints a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C mutation. The R365C and R789C mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita (SEDC), respectively. CONCLUSIONS: Arginine to cysteine mutations are rather infrequent COL2A1 mutations which cause a spectrum of phenotypes including classic SEDC and Stickler dysplasia, but also some unusual entities that have not yet been recognised and described as type II collagenopathies.

Pachydermoperiostosis: an update.

Pachydermoperiostosis (PDP) is a rare genodermatosis, characterized by pachydermia, digital clubbing, periostosis and an excess of affected males. Although an autosomal dominant model with incomplete penetrance and variable expression has been proved, both autosomal recessive and X-linked inheritance have been suggested. However, at present, genetic heterogeneity is not fully supported. The aim of this study is to review the clinical and pedigree data of 68 published PDP families, including 204 patients. This analysis has confirmed an autosomal dominant mutation in 37 families and suggested the existence of an autosomal recessive form in the remaining families. The two forms may differ in clinical severity, intrafamilial variability and prevalence of some features. Additionally, the marked skewed sex ratio could not be easily explained by an X-linked mutation, but alternative explanations (i.e. testosterone promoting proliferation) are discussed.

Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias.

OBJECTIVE: Recognition of prenatal-onset skeletal dysplasias has improved with advances in ultrasound imaging. Skeletal abnormalities can be recognized by two-dimensional (2D) ultrasound, but generating a precise diagnosis can be challenging. We aimed to determine whether three-dimensional (3D) imaging conferred any advantages over 2D imaging in these cases. METHODS: We studied five women with fetuses of 16-28 gestational weeks referred for abnormal ultrasound skeletal findings. First 2D and then 3D sonography was performed and the results compared. RESULTS: The pregnancies resulted in the following skeletal dysplasias: thanatophoric dysplasia, achondrogenesis II/hypochondrogenesis, achondroplasia, chondrodysplasia punctata (rhizomelic form) and Apert's syndrome. For all five fetuses, the correct diagnosis was made in the prenatal period by analysis of the 2D images. In each case the 3D images confirmed the preliminary diagnosis and for many findings it improved the visualization of the abnormalities. CONCLUSION: The 3D imaging had advantages over the 2D imaging when it came to evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements and the hands and feet. Most importantly, the patient and referring physician appreciated the 3D images of the abnormal findings more readily which aided in counseling and management of the pregnancy.

Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita.

Pseudoachondroplasia (PSACH) and spondyloepiphyseal dysplasia congenita (SEDC) are autosomal dominant forms of short-limb short stature caused by mutations in genes that encode structural components of the cartilage extracellular matrix. PSACH results from mutations in the cartilage oligomeric matrix protein (COMP) gene, while SEDC is caused by mutations in the gene for type II procollagen (COL2A1). We report a child with a distinct skeletal dysplasia due to the combined phenotypes of PSACH and SEDC. The proband's mother had PSACH and his father had SEDC. The child was suspected of having both phenotypes on the basis of the severity of his clinical and radiographic findings, and this was confirmed by molecular analysis. The COMP gene mutation (C348R), while not previously published, is typical of those in PSACH patients, whereas the COL2A1 mutation (T1370M) is somewhat atypical, as it predicts an amino acid change within the carboxyl-terminal region of the protein. Both mutations segregated with their respective phenotypes within this family. The description and natural history of the double heterozygote phenotype may be useful in counseling families regarding risk and prognosis.

"Baby rattle" pelvis dysplasia.

We report an apparently previously undescribed lethal skeletal dysplasia, clinically resembling achondrogenesis, but with distinct radiologic and chondro-osseous morphologic features. These comprise bifid distal ends of the long bones of the limbs, absent vertebral body ossification, a unique "baby rattle" pelvic configuration with tall and broad ilia, absent endochondral ossification, regions of mesenchymal cells within the resting cartilage, and abnormal mesenchymal ossification.

The molecular basis of X-linked spondyloepiphyseal dysplasia tarda.

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2-7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G-->A, 157-158delAT, 191-192delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.

Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype.

Multiple epiphyseal dysplasia (MED) is an osteochondrodysplasia characterized clinically by mild short stature and early-onset degenerative joint disease and radiographically by epiphyseal hypoplasia/dysplasia. MED is genetically heterogeneous, with autosomal dominant cases resulting from mutations in at least three genes: the cartilage oligomeric matrix protein (COMP) gene (EDM1) and the COL9A2 (EDM2) and COL9A3 (EDM3) genes of type IX procollagen. We present here a comparison of the radiographic phenotypes of MED patients with type IX collagen gene mutations and those with COMP gene mutations. We reviewed radiographs from two patients with MED produced by COMP mutations, two families with COL9A2 mutations, and one family with a mutation in COL9A3. The data demonstrated that the patients with type IX collagen defects had more severe joint involvement at the knees and relative hip sparing, while the patients with COMP mutations had significant involvement at the capital femoral epiphyses and irregular acetabuli. This pattern of joint involvement was consistent regardless of overall degree of severity of the phenotype.

"Duplicate calcaneus": a rare developmental defect observed in several skeletal dysplasias.

Duplication of the calcaneus is a rarely observed radiographic finding that probably results from delayed coalescence of two primary calcaneal centers of ossification. We performed a review of 2,500 computerized cases of skeletal dysplasias and syndromes with bone involvement in the International Skeletal Dysplasia Registry, searching for those cases in which a duplicate calcaneus had been recorded. We found that it was a non-random feature of three skeletal dysplasias and groups comprising thanatophoric dysplasia and the chondrodysplasia punctata and short rib (polydactyly) groups. We conclude that duplication of the calcaneus should be considered a consistent feature of these entities and may reflect a more generalized developmental defect.

Molecular-pathogenetic classification of genetic disorders of the skeleton.

Genetic disorders of the skeleton (skeletal dysplasias and dysostoses) are a large and disparate group of diseases whose unifying features are malformation, disproportionate growth, and deformation of the skeleton or of individual bones or groups of bones. To cope with the large number of different disorders, the "Nosology and Classification of the Osteochondrodysplasias," based on clinical and radiographic features, has been designed and revised periodically. Biochemical and molecular features have been partially implemented in the Nosology, but the rapid accumulation of knowledge on genes and proteins cannot be easily merged into the clinical-radiographic classification. We present here, as a complement to the existing Nosology, a classification of genetic disorders of the skeleton based on the structure and function of the causative genes and proteins. This molecular-pathogenetic classification should be helpful in recognizing metabolic and signaling pathways relevant to skeletal development, in pointing out candidate genes and possible therapeutic targets, and more generally in bringing the clinic closer to the basic science laboratory and in promoting research in this field.

Oto-palato-digital syndrome, type II: report of three cases with further delineation of the chondro-osseous morphology.

Oto-palato-digital syndrome type II (OPD II) is a lethal X-linked skeletal dysplasia with pleiotropic manifestations. The basic defect is not known. There has been only one detailed report of the chondro-osseous abnormalities in this condition describing abnormal periosteal ossification in a single case [1990: Am J Med Genet 36:226-231]. We report on three cases of OPD II emphasizing the chondro-osseous morphology. Although endochondral ossification was normal, periosteal ossification was defective with islands of cortical bone aplasia and hyperplasia of the periosteum. The trabecular bone was also extremely poorly formed and markedly hypercellular. Both membranous ossification and bone remodeling appear to be defective in OPD II and should account for part of the observed phenotype. The biglycan gene maps to Xq28 and is involved in bone formation, but was excluded as a candidate by direct sequencing of cDNA in one case.

New mesomelic dysplasia with absent fibulae and triangular tibiae.

We report on two unrelated, sporadic cases of a mesomelic dysplasia characterized by absence of fibulae and severely hypoplastic, triangular-shaped tibiae. Moderate mesomelic shortness was present in the upper limbs with proximal widening of the ulnae. There was also axial skeletal involvement in both cases, characterized radiographically by an abnormal pelvis and marked bilateral glenoid hypoplasia. These cases appear to represent a new form of mesomelic dysplasia distinct from those previously delineated.

Schmid type metaphyseal chondrodysplasia: a spondylometaphyseal dysplasia identical to the "Japanese" type.

BACKGROUND: Schmid-type metaphyseal chondrodysplasia (Schmid MCD) is an autosomal dominant chondrodysplasia resulting from various mutations in the COL10A1 gene. This disorder has been well delineated at a clinical level and has been classified radiographically as a pure metaphyseal chondrodysplasia. A missense mutation in the COL10A1 gene has also been shown to cause a rare spondylo-metaphyseal chondrodysplasia (SMD) named the "Japanese" type which, apart from exhibiting a mild spinal phenotype, shares striking clinical and radiographic similarities to Schmid MCD. OBJECTIVE: The clinical, radiographic and molecular similarities between Schmid MCD and Japanese SMD led to the hypothesis that these conditions could be identical type X collagenopathies. MATERIALS AND METHODS: We analyzed 33 cases of typical Schmid MCD from the International Skeletal Dysplasia Registry, looking specifically for any radiographic evidence of spinal involvement. RESULTS: We found that in 9.1% (3/33) of cases reviewed there was definite radiographic evidence of spinal involvement comprising mild platyspondyly, vertebral body abnormalities, and end-plate irregularity. CONCLUSION: These data indicate that spinal changes are an uncommon but variable component of Schmid MCD and that this condition and "Japanese" SMD are identical collagen type X disorders. Furthermore, the fact that the specific mutation reported in the family with Japanese type SMD, resulting in the substitution of a glutamic acid residue for a glycine at codon 595 (G595 E), has also been reported in a patient with Schmid MCD strongly supports this conclusion.

Exclusion of the Ellis-van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes.

Ellis-van Creveld syndrome (EVC) is a relatively rare, usually non-lethal, autosomal recessive skeletal dysplasia characterized by short stature, polydactyly, cardiac and renal anomalies. Linkage analysis has localized the disease gene to chromosome 4p16, with the markers at loci D4S827 and D4S3135 defining the centromeric and telomeric limits of the linked interval, respectively. There has been long-term speculation that asphyxiating thoracic dystrophy (ATD) and the short-rib polydactyly syndromes (SRP) represent the severe end of the EVC disease spectrum. We performed linkage analysis using markers from the EVC region in seven families manifesting either ATD or SRP type III. In two of the families, one segregating ATD and one SRP kindred, linkage of the phenotype to the EVC region was excluded. In the other five families linkage of the phenotype to the EVC region could not be excluded, but the families were too small for linkage to the region to be established. The exclusion of the EVC region in ATD and SRP III families suggests that locus heterogeneity exists within the short-rib dysplasia (with and without polydactyly) group of disorders.

Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder.

Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strategy of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases. Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five cases, analysis of cartilage type II collagen suggested incorporation of the abnormal alpha1(II) chain in the extracellular collagen trimers. The G943S mutation has been reported previously in another unrelated patient with a strikingly similar phenotype, illustrating the possible specific effect of the mutation. The radiographically less severely affected patient was heterozygous for a 4 bp deletion in the splice donor site of intron 35, likely to result in aberrant splicing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of the proalpha1(II) collagen chain. Study of the clinical, radiographic, and morphological features of the seven cases supports evidence for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype.