New subtype of familial achondrogenesis type IA (Houston-Harris).

BACKGROUND: Achondrogenesis is a skeletal dysplasia characterized primarily by short stature, severe micromelia, short and narrow chest, prematurity, polyhydramnios, fetal hydrops, and in utero or neonatal death. Based on the radiological and histopathological findings, there are three types of achondrogenesis: type 1A (Houston-Harris), type 1B (Fraccaro) and type 2 (Langer-Saldino). CLINICAL CASE: A premature female product was studied whose clinical, radiological and histopathological characteristics were compatible with achondrogenesis Type 1A. The family information allowed us to conclude that the 4 products of the 6 previous pregnancies were affected. Statistical analysis in at least 4 families previously described, including this family case showed significant differences between expected and observed number of members, being incongruent with an autosomal recessive mode of inheritance previously reported. CONCLUSIONS: therefore, it could be considered a new subtype of achondrogenesis type 1A due to the presence of a preferential germline mutation.

INTRODUCCIÓN: La acondrogénesis es una displasia esquelética que se caracteriza principalmente por talla baja, micromelia grave, tórax corto y estrecho, prematurez, polihidramnios, hidropesía fetal y muerte fetal in utero o neonatal. Según los hallazgos radiológicos e histopatológicos existen tres tipos de acondrogénesis: tipo 1A (Houston-Harris), tipo 1B (Fraccaro) y tipo 2 (Langer-Saldino). CASO CLÍNICO: Se sometió a estudio a un producto femenino prematuro cuyas características clínicas, radiológicas e histopatológicas fueron compatibles con acondrogénesis tipo 1A. La información familiar permitió concluir que los cuatro productos de los seis embarazos previos se encontraban afectados. El análisis estadístico en por lo menos cuatro familias previamente descritas, incluyendo este caso familiar, mostró diferencias significativas entre el número de miembros esperado y el observado, siendo incongruente con el modo de herencia autosómico recesivo previamente reportado. CONCLUSIONES: Podría considerarse un nuevo subtipo de acondrogénesis tipo 1A debida a la presencia de una mutación germinal preferencial.

New subtype of familial achondrogenesis type IA (Houston-Harris). / Nuevo subtipo de acondrogénesis familiar tipo IA (Houston-Harris)

Background: Achondrogenesis is a skeletal dysplasia characterized primarily by short stature, severe micromelia, short and narrow chest, prematurity, polyhydramnios, fetal hydrops, and in utero or neonatal death. Based on the radiological and histopathological findings, there are three types of achondrogenesis: type 1A (Houston-Harris), type 1B (Fraccaro) and type 2 (Langer-Saldino). Clinical case: A premature female product was studied whose clinical, radiological and histopathological characteristics were compatible with achondrogenesis Type 1A. The family information allowed us to conclude that the 4 products of the 6 previous pregnancies were affected. Statistical analysis in at least 4 families previously described, including this family case showed significant differences between expected and observed number of members, being incongruent with an autosomal recessive mode of inheritance previously reported. Conclusions: therefore, it could be considered a new subtype of achondrogenesis type 1A due to the presence of a preferential germline mutation.

Introducción: La acondrogénesis es una displasia esquelética que se caracteriza principalmente por talla baja, micromelia grave, tórax corto y estrecho, prematurez, polihidramnios, hidropesía fetal y muerte fetal in utero o neonatal. Según los hallazgos radiológicos e histopatológicos existen tres tipos de acondrogénesis: tipo 1A (Houston-Harris), tipo 1B (Fraccaro) y tipo 2 (Langer-Saldino). Caso clínico: Se sometió a estudio a un producto femenino prematuro cuyas características clínicas, radiológicas e histopatológicas fueron compatibles con acondrogénesis tipo 1A. La información familiar permitió concluir que los cuatro productos de los seis embarazos previos se encontraban afectados. El análisis estadístico en por lo menos cuatro familias previamente descritas, incluyendo este caso familiar, mostró diferencias significativas entre el número de miembros esperado y el observado, siendo incongruente con el modo de herencia autosómico recesivo previamente reportado. Conclusiones: Podría considerarse un nuevo subtipo de acondrogénesis tipo 1A debida a la presencia de una mutación germinal preferencial.

Impact of three genetic musculoskeletal diseases: a comparative synthesis of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

Achondroplasia, Duchenne muscular dystrophy, and osteogenesis imperfecta are among the most frequent rare genetic disorders affecting the musculoskeletal system in children. Rare genetic disorders are severely disabling and can have substantial impacts on families, children, and on healthcare systems. This literature review aims to classify, summarize and compare these non-medical impacts of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

[Genetic basis for skeletal disease. Genetic defects in chondrodysplasia].

Chondrodysplasia is a subset of skeletal dysplasia caused by genetic defects affecting chondrogenesis and its development, showing abnormal shape and structure of the skeleton. Pathology of growth plate results in defective skeletal development, such as short stature, while pathology of articular cartilage predisposes degenerative skeletal disease, such as early-onset osteoarthritis. Recently identified genetic basis for chondrodysplasia contributed much in understanding the biology and pathology of cartilage. The accumulated knowledge would be a clue to develop fundamental treatment for chondrodysplasia.

Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height.

BACKGROUND: Achondroplasia is the most common short stature skeletal dysplasia, with an estimated worldwide prevalence of 250 000. Body mass index (BMI)-for-age references are required for weight management guidance for children with achondroplasia, whose body proportions are unlike those of the average stature population. OBJECTIVE: This study used weight and height data in a clinical setting to derive smoothed BMI-for-age percentile curves for children with achondroplasia and explored the relation of BMI with its components, weight and height. DESIGN: This was a longitudinal observational study of anthropometric measures of children with achondroplasia from birth through 16 y of age. RESULTS: The analysis included 1807 BMI data points from 280 children (155 boys, 125 girls) with achondroplasia. As compared with the BMI of peers of average stature, the BMI in children with achondroplasia is higher at birth, lacks a steep increase in infancy and a later nadir between 1 and 2 y of age, and remains substantially higher through 16 y of age in both sexes. Patterns of change in height and weight in children with achondroplasia are unique in that there is no overlap in the height distribution after 6 mo of age and no spike in height velocity during infancy or puberty-the 2 periods of greatest linear growth in individuals of average stature. CONCLUSIONS: Sex- and age-specific BMI curves are available for children with achondroplasia (birth to 16 y of age) for health surveillance and future research to determine associations with health outcomes (eg, cardiovascular disease, diabetes, and indication for and outcome of surgery).

Clinical hypochondroplasia in a family caused by a heterozygous double mutation in FGFR3 encoding GLY380LYS.

In classical achondroplasia (Ach), a glycine residue is replaced by an arginine at codon 380 in exon 10 of the fibroblast growth factor receptor 3 gene (FGFR3). Here we report on a mother and daughter with hypochondroplasia (Hch) caused by a new heterozygous double mutation (1138_1139GG > AA) at the same codon 380, but encoding a lysine instead of the usual arginine. Previous functional assays of these codon 380 amino acid substitutions demonstrated a lesser activation of receptor signaling by lysine compared to arginine [Webster and Donoghue, 1996; EMBO J 15:520-527]. This could explain the milder phenotype observed in our patients. Several other rare double mutations were previously described in both FGFR2 and FGFR3 and interpreted as resulting from positive selection of spermatogonial cells owing to gain-of-function in the encoded protein [Goriely et al., 2005; Proc Natl Acad Sci USA 102:6051-6056]. The present case contributes additional support for this hypothesis.

Achondrogenesis type II with normally developed extremities: a case report.

We present a case of achondrogenesis type II with normally developed extremities that was confirmed with postmortem ultrasonographic and radiographic examination. The length of the long bones may vary and the diagnosis of achondrogenesis should not be ruled out with normally developed extremities. Intrauterine sonographic examination of the vertebrae is very important and the absence of vertebral body ossification may be the unique finding of achondrogenesis type II. Axial ultrasonographic images and postmortem plain radiographs are useful to clarify the pathology.

Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are autosomal dominant osteochondrodysplasias that result in mild to severe short-limb dwarfism and early-onset osteoarthrosis. PSACH and some forms of MED result from mutations in the gene for cartilage oligomeric matrix protein (COMP; OMIM 600310 [http://www3.ncbi.nlm. nih.gov:80/htbin-post/Omim/dispmim?600310]). We report the identification of COMP mutations in an additional 14 families with PSACH or MED phenotypes. Mutations predicted to result in single-amino acid deletions or substitutions, all in the region of the COMP gene encoding the calmodulin-like repeat elements, were identified in patients with moderate to severe PSACH. We also identified within this domain a missense mutation that produced MED Fairbank. In two families, one with mild PSACH and the second with a form of MED, we identified different substitutions for a residue in the carboxyl-terminal globular region of COMP. Both the clinical presentations of these two families and the identification of COMP-gene mutations provide evidence of phenotypic overlap between PSACH and MED. These data also reveal a role for the carboxyl-terminal domain in the structure and/or function of COMP.

Achondrogenesis type II with polydactyly.

We report on a newborn male infant who presented the typical findings of achondrogenesis type II (Langer-Saldino), and who also showed postaxial polydactyly on both feet and bilateral microtia. Polydactyly is frequently part of the short-rib syndromes, but has not been reported in achondrogenesis. The hypothesis of polydactyly as part of a contiguous gene syndrome is discussed.

Cardiac malformation in two infants with hypochondrogenesis.

Autopsy records from the Women and Infants' Hospital from January 1974 through January 1994 were reviewed to identify cardiac malformations in the presence of skeletal dysplasia. Of 24 cases of lethal fetal or neonatal osteochondrodysplasias, 4 were given diagnoses in which disorders of type II collagen are regarded as causative. These 4 were categorized in the spondyloepiphyseal dysplasia (SED) spectrum of disorders; specifically two patients with hypochondrogenesis and two with spondyloepiphyseal dysplasia congenita were identified. Defects in cardiac septation were noted in the 2 patients with hypochondrogenesis. No cardiovascular abnormalities were present in the remaining cases, which included thanatophoric dysplasia, osteogenesis imperfecta, and asphyxiating thoracic dystrophy. Although cardiovascular malformations have been described in other types of osteochondrodysplasias, e.g., short rib polydactyly syndrome type II and chondroectodermal (Ellis-van Creveld) dysplasia, congenital heart disease has not been described in hypochondrogenesis. Type II collagen, which has been found to be abnormal in some patients with hypochondrogenesis, is considered to have a limited tissue distribution, and has not been detected as yet in human myocardium. The findings presented here suggest that type II collagen may function in human cardiogenesis.

Achondrogenesis type II (Langer-Saldino)--a case report.

Achondrogenesis is a lethal form of congenital chondrodystophy characterised by extreme micromelia. Definitive clinical and radiographic criteria have been established to differentiate Type II Achondrogenesis (Langer-Saldino) from type I Achondrogenesis (Parenti-Fraccaro). The mode of inheritance is autosomal recessive for both types. We are presenting a case of Type II Achondrogenesis, a still born male to consanguinous parents. The clinical features included an enlarged head, protuberant abdomen and short stubby limbs. The mother had earlier delivered two still born males presumably with similar features. Radiographic characteristics of absence of rib fractures and well ossified iliac bones with concave medial margins and absent or deficient ossification of the sacrum, ischiae, and pubic bones differentiated Type II Achondrogenesis from Type I Achondrogenesis.

The boneless neonate: a severe form of achondrogenesis type I.

We report a case of a severe form of achondrogenesis type I. Prenatal ultrasonography showed a micromelic fetus; bony structures could not be identified. Postnatal radiographs revealed some foci of ossification in the ossa ilia, the clavicles, the upper and the lower jaw and the base of the skull. The long bones, the vertebral column and the ribs were not visible. The diagnosis was established by histologic examination of the growth plates.

[Achondrogenesis. Ultrasonic diagnosis and clinical and anatomopathologic comparison]. / Achondrogénèse. Diagnostic échographique et confrontation clinique et anatomopathologique.

The authors report two cases of achondrogenesis, the first of which was diagnosed in utero. Ultrasonographic abnormalities suggested the diagnosis, which was confirmed radiographically. The diagnosis of achondrogenesis in utero made it possible to avoid a Cesarian. It is always difficult to extract the malformed fetus. The histopathology findings make it possible to codify this rare type of congenital and lethal chondrodysplasia. Achondrogenesis is probably inherited in a recessive and autosomic fashion.

[Fatal nanism: 3 different entities]. / Enanismos letales: tres entidades diferentes.

Three cases of congenital dwarfism are presented. All of them are lethal and represent the three better known nonviable nosologic entities: Achondrogenesis I, Achondrogesis II and Thanatophoric dwarfism. According to clinical features and radiologic data it is possible to approach the diagnosis accurately. We comment genetic, clinic, radiologic and histologic aspects of these processes. It is important to establish a differential diagnosis as these entities have different genetic basis, what influences genetic counsel.

A new type of achondrogenesis.

A new type of neonatal death dwarfism, resembling the achondrogenesis syndromes on clinical examination but presenting distinctive radiographic and microscopic features has been described. It presents another, new form of achondrogenesis.

Pattern recognition in bone dysplasias.

Genetically different bone dysplasias may manifest themselves in similar patterns of skeletal abnormalities. It is proposed to group these similar dysplasias in 'families' for two reasons: 1 The knowledge of developmental patterns shared by different genetic disorders cautions the diagnostician and encourages a two-step procedure: a) provisional recognition of a pattern and b) more careful analysis of the pattern to reach a final, specific diagnosis. 2 Families of bone dysplasias may be the result of similar pathogenetic mechanisms. Once the mechanism is discovered in one member of the family, a search for similar mechanisms in others may be rewarding. An example of such a pattern is dysostosis multiplex. It is found in a family of disorders caused by defects of complex carbohydrate degradation. The present study delineates four more patterns and their families: the achondroplasia pattern, spondyloepiphyseal dysplasia congenita pattern, the Larsen/OPD pattern and the Stickler/Kniest pattern.