Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II

We present 5 cases of a short-limb dwarfism syndrome whose manifestations overlap those of atelosteogenesis and oto-palato-digital syndrome Type II. Clinical, radiographic, genetic, and histologic data are presented which demonstrate differences between our patients and previously reported cases of these other conditions. We conclude that the disorder seen in these children represents a distinct chondrodysplasia for which we propose the name atelosteogenesis Type III.     

Radiographic and morphologic findings in a previously undescribed type of mesomelic dysplasia resembling atelosteogenesis type II

The mesomelic chondrodysplasias are a heterogeneous group of dwarfing disorders characterized by shortness of the middle segments of limbs. We report on a 25-week fetus with disproportionate shortness of limbs with an apparently distinct form of mesomelic dysplasia. Radiographic findings at necropsy included ulnar deviation of hands, talipes equinovarus, distal tapering of the humeri, and hypoplastic fibulae, radii, and ulnae. Chondro-osseous morphology showed mild shortness of the physeal columns, overgrowth of perichondral bone, peripheral ingrowth of mesenchymal cells into the physis, and numerous areas of fibrillar degeneration with rings of collagen surrounding the chondrocytes. Ultrastructural findings included a degenerated territorial matrix, pericellular halos of collagen, and dilated loops of rough endoplasmic reticulum in chondrocytes. The radiographic appearance of the long bones is distinct from that of previously described mesomelic dysplasias. The chondro-osseous morphologic findings and the distal tapering of the humerus are somewhat reminiscent of atelosteogenesis type II, but the pattern of matrix degeneration and the presence of inclusion bodies in the chondrocytes distinguish it from disorders of sulfate transport. Am. J. Med. Genet. 80:247–251, 1998. © 1998 Wiley-Liss, Inc.     

A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia

Diastrophic dysplasia sulfate transporter (DTDST) is a sulfate transporter required for the synthesis of sulfated proteoglycans in the cartilage. Over 30 mutations have been described in the DTDST gene, which result in a continuous clinical spectrum of recessively inherited chondrodysplasias, including, in order of increasing severity, a recessive form of multiple epiphyseal dysplasia (rMED), diastrophic dysplasia (DTD), atelosteogenesis type II (AO-II) and achondrogenesis 1B (ACG-1B). Correlation between disease severity and residual sulfate transport activity has been reported. Here we report a patient with DTDST mutations, whose manifestations fell in a range between AO-II and DTD. The patient was a compound heterozygote for the recurrent c.835C>T (p.R279W) and novel c.1987G>A (p.G663R) mutations. Immunocytochemical analysis in HEK293 cells showed that the p.G663R mutation was localized within the cytoplasm, and not to the cell membrane, suggesting p.G663R is a loss-of-function mutation. Our case supports the previously described correlation between the severity of the phenotype and the putative level of residual transport function.     

Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis I and Boomerang dysplasia

Atelosteogenesis I (AT-I) and Boomerang dysplasia have been described as separate lethal bone dysplasias. The possibility of a common cause of both conditions was suggested by Hunter and Carpenter (Clin Genet 39(6): 471–480, 1991) in their report of a patient with apparent manifestations of both AT-I and Boomerang dysplasia. We report on a male fetus of 31 weeks gestation whose clinical, radiologic and histologic findings are compared to reported cases of AT-I, Boomerang dysplasia and the patient of Hunter and Carpenter (Clin Genet 39(6): 471–480, 1991). From the documentation of clinical and radiologic findings we demonstrate overlap of AT-I and Boomerang dysplasia in our patient, and, from histologic examination, suggest a defect of cartilage and bone formation as the basic abnormality in this lethal bone dysplasia. © 1993 Wiley-Liss, Inc.     

Spondyloepimetaphyseal dysplasia of Maroteaux (pseudo-Morquio type II syndrome): report of a new patient and review of the literature

An 11-year-old girl was seen with short stature, a head positioned in hyperextension, mild arched palate, prominent joints, limited elbow movements, hyperextensible wrists and fingers, brachydactyly, broad thorax, pectus carinatum, short trunk, a genu valgum, and flat feet. A radiographic skeletal survey revealed a generalized osteoporosis, platyspondyly, thoracic kyphoscoliosis, small and square iliac wings, short femoral necks, dysplastic epiphyses, flared metaphyses and brachydactyly with various carpal, metacarpal, and finger malformations. These features are very close to a very rare entity: the spondyloepimetaphyseal dysplasia (SEMD) of Maroteaux or "pseudo-Morquio" type II syndrome, whose specific radiological characteristics are found in this case.     

Atypical skeletal changes in otopalatodigital syndrome type II: Phenotypic overlap among otopalatodigital syndrome type II,boomerang dysplasia,atelosteogenesis type I and type III,and lethal male phenotype of Melnick-Needles syndrome

We report on 2 cases of otopalatodigital syndrome type II (OPD II) with atypical skeletal changes, overlapping those of boomerang dysplasia, atelosteogenesis type I (AO I) and type III (AO III), and the lethal male phenotype of Melnick-Needles syndrome. One patient exhibited strikingly broad, bowed femora, which resembled those of boomerang dysplasia. The other patient possessed conspicuous undertubulation of the long bones, defective ossification of the spine, and severe undermineralization of the calvaria, which may have caused diagnostic confusion with AO I, AO III, and the lethal male phenotype of Melnick-Needles syndrome. OPD II is transmitted as an X-linked recessive trait, whereas AO I, AO III, and boomerang dysplasia are considered to result from a new dominant mutation, and Melnick-Needles syndrome is inherited as an X-linked dominant trait. Accordingly, differential diagnosis is mandatory to provide the affected families with adequate genetic counseling. Awareness of these skeletal changes in OPD II will prevent the misdiagnosis of this entity as other disorders. Furthermore, the phenotypic overlap among these disorders may expand the entities that constitute the OPD-Larsen dysplasia family proposed by Spranger [1985]. Am. J. Med. Genet. 73:132–138, 1997. © 1997 Wiley-Liss, Inc.     

Attenuated familial adenomatous polyposis: a case report with mixed features and review of genotype-phenotype correlation

Familial adenomatous polyposis represents approximately 1% of all colorectal cancers and is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Most mutations are located within the first 2000 codons, and several mutational hot spots have been identified. The relative location of the mutation may be associated with the number of polyps and partially predicts specific phenotypic expression. Mutations associated with the attenuated phenotype are found predominantly in the 5' region of the gene or in the last third. We describe a patient with a mutation in codon 161 of the APC gene, which displays a phenotype most closely resembling the attenuated form of familial adenomatous polyposis, and review the literature, the implications of this mutation, and the importance of the molecular testing in the proper and more complete characterization of these patients. Differences in the APC mutation sites alone cannot completely account for intrafamilial and interfamilial variation in the polyposis phenotypes.     

Genochondromatosis type II: report of a new patient and further delineation of the phenotype

Enchondromas are common intraosseous usually benign cartilaginous tumors that develop in close proximity to growth plate cartilage. Genochondromatosis is a familial skeletal condition with autosomal dominant inheritance pattern. Genochondromatosis type I is a skeletal disorder characterized by symmetrical chondromatosis with characteristic localization: clavicle, upper end of humerus, and lower end of femur. The condition shows a benign course and is clearly different from metachondromatosis, generalized enchondromatosis, and spondyloenchondrodysplasia. In contrast, genochondromatosis type II is characterized by normal clavicles, but metaphyseal involvement of the hands, feet, knees, and wrists. To date, one family has been described with two affected individuals and possibly a second one with seven affected individuals. We report here on a boy with radiographic features of genochondromatosis type II. This report confirms that this disorder represents a separate clinical entity distinguishable for genochondromatosis type I. In addition, this report confirms the benign course of this rare disorder and will help accurate genetic counseling.     

Pure 6p22-pter trisomic patient: refined FISH characterization and genotype-phenotype correlation

First described in 1971, partial trisomy 6p is uncommon and generally secondary to a familial reciprocal translocation. The proximal breakpoint of the reported cases varies from p11 to p25. We here report on a patient with moderate mental retardation, craniofacial and pigmentary anomalies, proteinuria, and hyperglycemia who was found to have a mosaic karyotype 46,X,add(Y)(q12)/45,X. Fluorescence in situ hybridization (FISH) enabled us to identify that the additional material on Yqh derived from 6p and to define the rearrangement as der(Y)t(Y;6)(q12;p22). To the best of our knowledge, this is the first case of trisomy 6p22-pter without an associated deleted segment; the second breakpoint of the rearrangement is in Yqh. Precise mapping of the centromeric breakpoint of the trisomic 6p segment allowed a more convincing correlation between partial 6p trisomy and clinical phenotype to be addressed. In particular, the proteinuria often observed in 6p trisomic patients could be assigned to the 6p22-6pter region.     

Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family

Mutations in diastrophic dysplasia sulfate transporter (DTDST) cause a spectrum of autosomal recessive chondrodysplasias. In decreasing order of severity, they include processes designated as achondrogenesis type IB (ACG-1B), atelosteogenesis type II (AO2), diastrophic dysplasia (DTD), diastrophic dysplasia variant (DTDv), and recessively inherited multiple epiphyseal dysplasia (rMED). This is the first report of an extended family with unequivocally distinct phenotypes on the DTDST spectrum. Two siblings have DTDv and their first cousin had AO2. They all share the common Finnish mutation (IVS1?+?2C>T). The two patients with DTDv have the previously reported R279W extracellular domain missense mutation. The second mutation in the patient with AO2 is c.172delA, a deletion of one nucleotide causing a previously unreported frameshift mutation. This is the first published case of an individual with a frameshift mutation combined with the Finnish mutation. These three patients provide an opportunity, in concert with a review of previous literature, to further examine the genotype-phenotype correlation of DTDST. Analysis suggests that, while the DTDST family of disorders contains at least seven different conditions, mutations in the DTDST gene, in fact, appear to cause a phenotypic continuum. Furthermore, DTDST genotype alone is an imperfect predictor of clinical severity along this continuum.     

Spondyloepimetaphyseal dysplasia with multiple dislocations,leptodactylic type: report of a new patient and review of the literature

A 6-year-old boy with congenital hip dislocation, developmental delay, short stature, macrocephaly, low set ears, short neck, and hyperlaxity of the wrists and fingers is described. Radiographs disclosed mainly the presence of thoracic scoliosis, narrow interpedicular distances, metaphyseal vertical striations, very small irregular epiphyses, right hip dislocation, luxation of both elbows, and severe delay of ossification of the epiphyses and the carpal bones. These features are very close to the newly described entity: spondyloepimetaphyseal dysplasia and multiple dislocations. This patient brings to light the differential diagnosis and confirms the specificity of the radiological findings of this new entity.     

Metaphyseal dysplasia of Braun-Tinschert type: report of a Japanese girl

We report on a 7-year-old Japanese girl with metaphyseal dysplasia (MD) of Braun-Tinschert type, a recently recognized, autosomal dominant sclerosing bone dysplasia. All individuals with the disorder from four families in the literature originated from a small town in Bohemia or its vicinity. The occurrence of the disorder in a Japanese girl indicates that it is not restricted to Germans. The radiographic hallmarks of the disorder include metaphyseal undermodeling (Erlenmeyer-flask deformity); osteosclerosis of the chondroosseous junctions, metaphyseal cortices, and epiphyseal margins; and exostosis-like bone excrescences at the metaphyseal-diaphyseal junctions. In the girl we described, the latter two findings were conspicuous at age 4 years, but became less prominent with increasing age. The metaphyseal trabeculae were somewhat coarse. The humeri exhibited varus deformity, and the ulnae and fibulae mild bowing. The mean bone mineral density of the lumbar spine was lower than that of age-matched controls. The patient exhibited premature loss of primary teeth, likely to be a sign of increased periodontal bone resorption. Markers of bone formation and resorption were both increased, an indication of a high rate of bone turnover.     

Spondyloepiphyseal dysplasia Maroteaux type: report of three patients from two families and exclusion of type II collagen defects

Spondyloepiphyseal dysplasia (SED) Maroteaux type is an autosomal dominant skeletal dysplasia, characterized by spondylar dysplasia, mild epiphyseal dysplasia of the large joints, and type E-like brachydactyly. These manifestations overlap with those of spondyloperipheral dysplasia (SPD), in which a sporadic case with a mutation of COL2A1 has been reported. We report on three patients (an affected woman and her son and a sporadic case of an affected man) with SED Maroteaux type. The affected adults were severely short along with stubby hands and feet, and one developed myelopathy as a result of thoracolumbar gibbus. The affected child was mildly short at birth, and developed brachydactyly in early childhood. The radiological hallmarks of these patients included severe platyspondyly with square-shaped vertebral bodies, iliac hypoplasia, epiphyseal hypoplasia of the large joints, and strikingly short metacarpals and phalanges. These radiological findings appeared already apparent in early childhood. SED Maroteaux type was radiologically discriminative from SPD. Brachydactyly was much severe in the former than in the latter, and spondylar dysplasia manifestation was different between both disorders. Mutation screen by polymerase chain reaction-direct sequencing for all exons and their flanking regions of COL2A1 did not reveal any mutations in the three patients.     

Orofaciodigital syndrome type IV: report of a patient

We describe a further patient with the orofaciodigital syndrome type IV. The clinical characteristics include lobulated tongue, pseudo-cleft of lip, pre- and postaxial polydactyly of hands and feet, severe talipes equinovarus, mesomelic limb shortness associated with tibial hypoplasia, and severe bilateral deafness. Five similar cases including the present patient are now on record. Autosomal recessive inheritance is likely.     

Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a clinically and genetically heterogeneous disorder primarily characterized by susceptibility to fracture. Although OI generally results from mutations in the type I collagen genes, COL1A1 and COL1A2, the relationship between genotype and phenotype is not yet well understood. To provide additional data for genotype-phenotype analyses and to determine the proportion of mutations in the type I collagen genes among subjects with lethal forms of OI, we sequenced the coding and exon-flanking regions of COL1A1 and COL1A2 in a cohort of 63 subjects with OI type II, the perinatal lethal form of the disease. We identified 61 distinct heterozygous mutations in type I collagen, including five non-synonymous rare variants of unknown significance, of which 43 had not been seen previously. In addition, we found 60 SNPs in COL1A1, of which 17 were not reported previously, and 82 in COL1A2, of which 18 are novel. In three samples without collagen mutations, we found inactivating mutations in CRTAP and LEPRE1, suggesting a frequency of these recessive mutations of approximately 5% in OI type II. A computational model that predicts the outcome of substitutions for glycine within the triple helical domain of collagen alpha1(I) chains predicted lethality with approximately 90% accuracy. The results contribute to the understanding of the etiology of OI by providing data to evaluate and refine current models relating genotype to phenotype and by providing an unbiased indication of the relative frequency of mutations in OI-associated genes.     

Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation

Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotype-phenotype correlation has been established. In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype-phenotype correlation.