Campomelic dysplasia (CMD) is a rare skeletal disorder that is usually lethal. It is characterised by bowing of the lower limbs, severe respiratory distress, and many of the chromosomal (XY) males show sex reversal. Because of a number of reports of familial campomelic dysplasia it is considered to be inherited in an autosomal recessive manner. In this study, details of 36 patients with campomelic dysplasia were collected from genetic centres, radiologists, and pathologists in the United Kingdom. The chromosomal sex ratio was approximately 1:1. There was a preponderance of phenotypic females owing to sex reversal. Three quarters of the chromosomal males were sex reversed or had ambiguous genitalia. Three cases are still alive, two with chromosomal rearrangements involving chromosome 17q. The majority of the others died in the neonatal period. The 36 index cases had 41 sibs of whom only two were affected. Formal segregation analysis gave a segregation ratio of 0.05 (95% CI approximately 0.00 to 0.11). This excludes an autosomal recessive mode of inheritance. The data suggest a sporadic, autosomal dominant mode of inheritance. Patients with a chromosomal rearrangement involving 17q (q23.3-q25.1) show a milder phenotype. The molecular mechanism for the difference is still unknown.

https://jmg.bmj.com/content/jmedgenet/32/6/415.full.pdf

A clinical and genetic study of campomelic dysplasia.

Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality. Clinical overlap with Schwartz-Jampel type 2 syndrome (SJS2) has suggested that SWS and SJS2 could be allelic disorders. Through studying a series of 19 families with SWS/SJS2, we have mapped the disease gene to chromosome 5p13.1 at locus D5S418 (Zmax=10.66 at θ=0) and have identified null mutations in the leukemia inhibitory factor receptor (LIFR or gp190 chain) gene. A total of 14 distinct mutations were identified in the 19 families. An identical frameshift insertion (653_654insT) was identified in families from the United Arab Emirates, suggesting a founder effect in that region. It is interesting that 12/14 mutations predicted premature termination of translation. Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells. We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13.

https://www.cell.com/ajhg/pdf/S0002-9297(07)61840-0.pdf

Null Leukemia Inhibitory Factor Receptor (LIFR) Mutations in Stüve-Wiedemann/Schwartz-Jampel Type 2 Syndrome

At a meeting of the international working group on bone dysplasias in Bad Honnef , June 26-28, 1991, the 1972 Paris classification of constitutional disorders of bone 1 has been subjected to its 2nd revision. There are some major changes from earlier versions. First, the present classification is exclusively based on radiodiagnostic criteria, grouping morphologically similar disorders. The majority of the working group felt that this stratification would facilitate the recognition of specific entities. The former mixture of clinical, pathogenetic and radiological criteria led to many inconsistencies and was of lesser diagnostic assistence. Clinical criteria such as age of onset and natural course are no longer used because of

International classification of osteochondrodysplasias

Considerable progress has been made in the delineation of the genetic skeletal dysplasias, a heterogeneous group of disorders, that consist of over 80 distinct conditions. Morphologic studies have added a further dimension to the delineation of these conditions, their diagnosis, and the investigation of their pathogenetic mechanisms. In certain diseases, the morphologic alterations are characteristic and pathognomonic. In others only nonspecific alterations are observed, whereas in still other disorders growth-plate structure is essentially normal. Histologic, histochemical, and electronmicroscopic studies of growth-plate cartilage have provided new insights into the complexity of morphogenetic events in normal growth through the demonstration of morphologic defects in the genetic disorders of skeletal growth. As yet, very little is known of the biochemical abnormalities underlying the morphologic abnormalities. However, the great variety of morphologic findings points to a number of different pathogenetic defects in the synthesis, release, and assembly of connective tissue macromolecules and in the cells involved in growth-plate metabolism.

A. Stüve

Papers

Congenital bowing of the long bones in two sisters.