Pierre Maroteaux

Common mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases, our series seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder.

Mazabraud syndrome in two patients: Clinical overlap with McCune‐Albright syndrome

Mazabraud syndrome is a rare sporadic disorder, mainly characterized by bone fibrous dysplasia and intramuscular myxomas. We report here two new cases of Mazabraud syndrome. One of our patients (Patient 1) also had café-au-lait spots and multinodular goiter suggestive of McCune-Albright syndrome. We review the 37 previously reported cases with Mazabraud syndrome and discuss the 6/37 patients with criteria of Mazabraud and McCune-Albright syndromes. Based on the clinical overlap between the two syndromes, we tested the GNAS1 gene in blood leukocytes and skin fibroblasts of Patient 1, but found no evidence of an activating mutation in the GNAS1 gene.

Langer-Giedion syndrome with and without del 8q. Assignment of critical segment to 8q23

SummaryTwo patients with typical Langer-Giedion or trichorhino-phalangeal type II syndrome are reported. One had an apparently normal karyotype. The second had an intercalary del 8q23. Attention is drawn to the severe bone defects seen in the latter and observations from the literature are discussed. The critical segment is assigned to band 8q23. The syndrome may result in a number of cases from a visible deletion, and in other instances from a more conventional gene mutation, although the molecular mechanism is uncertain.

Desbuquois dysplasia, a reevaluation with abnormal and “normal” hands: Radiographic manifestations

Radiological features of 35 patients with the diagnosis of Desbuquois dysplasia were analyzed. The diagnosis of Desbuquois dysplasia was based on the association of specific facial alterations, markedly short stature of prenatal onset, joint laxity, ‘Swedish key’ appearance of the proximal femur, and advanced carpal and tarsal bone age. Patients were divided into two groups, depending on whether or not typical hands with an extra ossification center distal to the second metacarpal and/or a delta phalanx of the thumb were present (group 1, 46%) or absent (group 2, 54%). In this study, beside the ‘Swedish key’ appearance of the proximal femur and advanced carpal and tarsal ossification, we were able to define three additional major radiographic criteria for the diagnosis of Desbuquois dysplasia, including flat acetabular roof, elevated greater trochanter, and proximal fibular overgrowth. Other manifestations included wide metaphyses, flat epiphyses, coxa valga, coronal and saggital clefts of the vertebrae, wide anterior rib portions, medial deviation of the foot, and enlarged first metatarsal. We conclude that characteristic hand abnormalities are not mandatory for the diagnosis of Desbuquois dysplasia.

An interstitial deletion in Xp22.3 in a family with X-linked recessive chondrodysplasia punctata and short stature

SummaryIn a four-generation family, chondrodysplasia punctata was found in a boy and one of his maternal uncles. These two patients also have short stature, as do all female members of the family. DNA molecular analysis of the pseudoautosomal and Xp22.3-specific loci revealed the presence of an interstitial deletion that cosegregates with the phenotypic abnormalities. The proximal breakpoint of this deletion was located distal to the DXS31 locus and the distal breakpoint in the pseudoautosomal region between DXYS59 and DXYS17. This maps the recessive X-linked form of chondrodysplasia punctata between the proximal boundary of the pseudoautosomal region and DXS31, and an Xp gene controlling growth between DXYS59 and DXS31.

Mutations in three subdomains of the carboxy-terminal region of collagen type X account for most of the Schmid metaphyseal dysplasias.

We have used the polymerase chain reaction and single strand conformation polymorphism (SSCP) methods to analyse the COL10A1 gene, which encodes collagen type X, in DNA samples from patients with metaphyseal dysplasia type Schmid (SMCD) and other related forms of metaphyseal dysplasia. Five cases of SMCD were sporadic and three others were familial. Abnormal SSCP profiles were observed in six instances. In two families, the altered pattern segregated with the phenotype. The heterozygous mutations corresponded to a glycine substitution by glutamic acid at position 595 and to an asparagine substitution by lysine at position 617. In one sporadic case, the sequence studies demonstrated that the individual was heterozygous for a single base deletion (del T 1908) that produced a premature stop codon. Three additional mutations were single base substitutions that affected highly conserved residues at positions 597, 644 and 648. In two additional individuals with SMCD, in two patients with unclassifiable forms of metaphyseal dysplasia, and in one family with epiphyso-metaphyseal dysplasia, SSCP analysis detected neutral polymorphisms in the entire coding sequence of the gene but no mutations. Our results demonstrate that mutations in the carboxy-terminal region of collagen X are specific for the SMCD phenotype. Mutations appear to be clustered into three small subdomains: one of them is rich an aromatic residues, the second includes the putative N-linked oligosaccharide attachment site and the third contains mostly hydrophilic residues. The absence of clinical variability between patients carrying heterozygous single base substitutions or small deletions suggests that, in both instances, the mutant collagen chains either fail to be incorporated into stable trimers or disturb type X collagen assembly.

Dominant mutations in familial lethal and severe osteogenesis imperfecta

SummaryFour families presenting with familial osteogenesis imperfecta (OI) have been studied: 2 with the lethal type II and 2 with the severe type III form. Fibroblasts of the patients, all issue from non-consanguineous parents, produced normal and abnormal α(I) chains. These heterozygous mutations differentiate the recurrent forms from homozygous mutations characteristic of autosomal recessive forms. Although the identity of the mutations could not be determined, such recurrence of autosomal dominant OI is probably the result of germinal mosaicism in one of the parents. Biochemical results were consistent with a somatic mosaicism in the fathers fibroblasts in one family. Moreover, our studies show that not only OI type II but also severe OI type III can arise from gonadal mosaicism. We discuss the importance of such a phenomenon for genetic counseling.

Linkage study in a large pedigree with Stickler syndrome : exclusion of COL2A1 as the mutant gene

SummaryA three generation family with Stickler syndrome is reported. Affected patients exhibited myopia with frequent retinal detachment or glaucoma. Most of them had characteristic facial dysmorphism, the Pierre-Robin sequence being observed in four individuals. Neonatal radiological signs of the Weissenbacher-Zweymüller syndrome were also noticed but early arthopathy was not reported in adults. Restriction fragment length polymorphism studies with the type II collagen gene (COL2A1) showed a recombination event between the disease locus and COL2A1, thus excluding collagen type II as the candidate gene. Although the calculation of the likelihood of genetic heterogeneity versus homogeneity based on 10 families was not statistically significant, we suggest that a second locus is probably involved in this highly variable syndrome.

Revisiting metatropic dysplasia: Presentation of a series of 19 novel patients and review of the literature†

Metatropic dysplasia (MD—OMIM: 156530 and 250600) is a rare chondrodysplasia characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis, first described in 1893. Up until now, 81 other patients have been reported. The phenotypic variability of MD has led to a classification based on radiological anomalies dividing into three different types: a lethal autosomal recessive form, an autosomal recessive non‐lethal form and a non‐lethal autosomal dominant form with less severe radiographs manifestations and a better clinical outcome. Here, we report on clinical and radiological features of 19 novel MD patients. We describe new radiological features, including precocious calcification of hyoid and cricoid cartilage, irregular and squared‐off calcaneal bones and severe hypoplasia of the anterior portion of first cervical vertebrae. In addition, the observation of an overlap between the autosomal recessive non‐lethal form and the non‐lethal autosomal dominant form, the rarity of sibship recurrences and the observation of vertical transmissions of MD in the literature argue in favor of an autosomal dominant mode of inheritance for all MD types. This hypothesis is reinforced by the use of the statistical single ascertainment method that rejects the hypothesis of an autosomal recessive mode of inheritance responsible for MD. Therefore, we propose that recurrence in sibs is due to gonadal mosaicism.

Homozygosity mapping of a Desbuquois dysplasia locus to chromosome 17q25.3

Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia characterised by short stature, joint laxity, facial dysmorphism, a “Swedish key” appearance of the proximal femur, advanced carpal and tarsal bone age, and hand anomalies consisting of phalangeal dislocations and an extra ossification centre distal to the second metacarpal. However, the latter changes are not consistently observed in all Desbuquois patients, defining two distinct groups, based on the presence or absence of hand anomalies. We have performed a genome wide search in four inbred Desbuquois families with typical hand anomalies originating from France, Sri-Lanka, the United Arab Emirates, and Morocco. Here, we report on the mapping of a disease gene to chromosome 17q25.3 (Zmax=4.61 at θ=0 at locus D17S1806) in the 9.5 cM interval defined by loci D17S802 and D17S1822. The present study supports the genetic homogeneity of the clinical subtype with hand anomalies and will hopefully help in identifying the Desbuquois dysplasia gene.