Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome.

Rieger syndrome (RIEG) is an autosomal-dominant human disorder that includes anomalies of the anterior chamber of the eye, dental hypoplasia and a protuberant umbilicus. We report the human cDNA and genomic characterization of a new homeobox gene, RIEG, causing this disorder. Six mutations in RIEG were found in individuals with the disorder. The cDNA sequence of Rieg, the murine homologue of RIEG, has also been isolated and shows strong homology with the human sequence. In mouse embryos Rieg mRNA localized in the periocular mesenchyme, maxillary and mandibular epithelia, and umbilicus, all consistent with RIEG abnormalities. The gene is also expressed in Rathke's pouch, vitelline vessels and the limb mesenchyme. RIEG characterization provides opportunities for understanding ocular, dental and umbilical development and the pleiotropic interactions of pituitary and limb morphogenesis.

A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD.

We report here the identification of a new human homeobox gene, PITX3, and its involvement in anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts in humans. The PITX3 gene is the human homologue of the mouse Pitx3 gene and is a member of the RIEG/PITX homeobox gene family. The protein encoded by PITX3 shows 99% amino-acid identity to the mouse protein, with 100% identity in the homeodomain and approximately 70% overall identity to other members of this family. We mapped the human PITX3 gene to 10q25 using a radiation-hybrid panel. A collection of 80 DNA samples from individuals with various eye anomalies was screened for mutations in the PITX3 gene. We identified two mutations in independent patients. A 17-bp insertion in the 3'-end of the coding sequence, resulting in a frame shift, occurred in a patient with ASMD and cataracts, and a G-->A substitution, changing a codon for serine into a codon for asparagine, in the 5'-end of the gene occurred in a patient with congenital cataracts. Both mutations cosegregate with the disease phenotype in families, and neither were found in up to 300 control individuals studied. Further expression analysis of Pitx3 in the mouse supports a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae and limbs. These data strongly suggest a role for PITX3 in ASMD and cataracts and provide new evidence of the contribution of the RIEG/PITX gene family to the developmental program underpinning normal eye formation.

Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy.

INTRODUCTION: Autosomal dominant optic atrophy (ADOA) is considered as the most common form of hereditary optic neuropathy. Although genetic linkage studies point to the OPA1 locus on chromosome 3q28-q29 as by far the most common gene locus, previous screening studies-based on sequencing of the coding exons-detected OPA1 mutations in only 32-70% of ADOA patients. We therefore hypothesised that larger deletions or duplications that remained undetected in previous screening approaches may substantially contribute to the prevalence of OPA1 mutations in ADOA. METHODS: 42 independent ADOA patients were analysed for the presence of genomic rearrangements in OPA1 by means of multiplex ligation probe amplification (MLPA). Deletions or duplications were confirmed either by long distance polymerase chain reaction (PCR) and breakpoint sequencing or loss of heterozygosity analyses with flanking microsatellite markers. Patients underwent ophthalmological examination including visual acuity, colour vision testings, perimetry and funduscopy. RESULTS: We identified genomic rearrangements in 8 of 42 patients, including single exon deletions of exon 9 and exon 24, respectively, a deletion of exons 1-5, two different deletions of the complete OPA1 gene as well as a duplication of the exons 7-9, with the latter being present in three unrelated families. Patients' phenotypes were highly variable, similar to patients with point mutation in OPA1. DISCUSSION: Our findings show that gross genomic aberrations at the OPA1 gene locus are frequent in ADOA and substantially contribute to the spectrum and prevalence of OPA1 mutations in ADOA patients. They further strengthen the hypothesis that haploinsufficiency is a major pathomechanism in OPA1 associated ADOA.

Genotype phenotype correlation of 30 patients with Smith-Magenis syndrome (SMS) using comparative genome hybridisation array: cleft palate in SMS is associated with larger deletions.

BACKGROUND: Smith-Magenis syndrome (SMS) is rare (prevalence 1 in 25 000) and is associated with psychomotor delay, a particular behavioural pattern and congenital anomalies. SMS is often due to a chromosomal deletion of <4 Mb at the 17p11.2 locus, leading to haploinsufficiency of numerous genes. Mutations of one of these gemes, RAI1, seems to be responsible for the main features found with heterozygous 17p11.2 deletions. METHODS: We studied DNA from 30 patients with SMS using a 300 bp amplimers comparative genome hybridisation array encompassing 75 loci from a 22 Mb section from the short arm of chromosome 17. RESULTS: Three patients had large deletions (10%). Genotype-phenotype correlation showed that two of them had cleft palate, which was not found in any of the other patients with SMS (p<0.007, Fisher's exact test). The smallest extra-deleted region associated with cleft palate in SMS is 1.4 Mb, contains <16 genes and is located at 17p11.2-17p12. Gene expression array data showed that the ubiquitin B precursor (UBB) is significantly expressed in the first branchial arch in the fourth and fifth weeks of human development. CONCLUSION: These data support UBB as a good candidate gene for isolated cleft palate.

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 theta=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.

Somatic mosaicism for partial paternal isodisomy in Wiedemann-Beckwith syndrome: a post-fertilization event.

Genomic imprinting has been implicated in the aetiology of an overgrowth cancer-prone syndrome, the Wiedemann-Beck-with syndrome (WBS). We have demonstrated uniparental disomy (UPD) for paternal chromosome 11p markers in 5 out of 25 sporadic cases (20%). Delineation of the extent of the disomy region may help in understanding the mechanism and the stage, meiotic or mitotic, of disomy formation in this disease and in associated tumours. Our current studies in WBS patients with seventeen 11p and one 11q markers reveal paternal isodisomy, not heterodisomy, in the five cases. For one case we demonstrate unambiguously that partial isodisomy for 11p and somatic mosaicism for UPD resulted from a post-fertilization event. The restriction of isodisomy to part of 11p in another case, and somatic mosaicism for UPD in three other cases, suggest a mitotic recombinational event that must have occurred after fertilization. Mosaic phenotypes reflect the timing of their origin and the fate of the cells involved, as well as the cell-specific pattern of imprinting. Somatic mosaicism for UPD in four cases may thus explain the incomplete forms of WBS. The association of hemihypertrophy in sporadic WBS and even some cases of isolated hemihypertrophy. This is in agreement with a recent report of paternal isodisomy for 11p markers in a patient with hemihypertrophy, Wilms' tumour and adrenocortical carcinoma. Moreover, the risk of developing a tumour seems higher (50%) for patients with paternal 11p UPD than for WBS patients in general (7.5%).

Wolfram syndrome. A report of four cases and review of the literature.

This is a report of four new cases of Wolfram syndrome in three families and a review of the literature. The ophthalmologic, urologic, otologic, psychiatric and endocrine findings of the syndrome are discussed as well as their pathophysiology. Two recent reports with features atypical of the Wolfram syndrome are discussed. The genetics of this syndrome are also discussed.

Glaucoma with a Larsen-like syndrome.

A 12-year-old girl with a history of intrauterine growth delay, hip dysplasia, dislocated elbows and knees, dislocatable knuckles, bifid thumb, joint laxity and short stature is presented. She developed glaucoma at age four and was operated at age 14. Her sister had similar dislocations and died of complications of an atrioventricular canal at age three months. Clinical and genetic features of these two patients are discussed as well as their similarity and differences with the Larsen syndrome.

Kabuki syndrome - report of six cases and review of the literature with emphasis on ocular features.

Six cases of Kabuki syndrome (KS) with ocular anomalies are reported and the variety of ocular features reported in the literature for this syndrome is described. Routine ocular examinations are recommended for every patient with KS because of the high proportion of ocular anomalies found in these patients, the presence of which can hamper development if not adequately addressed.

The Wiedemann-Rautenstrauch neonatal progeroid syndrome: a case report and review of the literature.

We present the case of a post-term newborn with intrauterine growth retardation, pseudohydrocephalus, a tiny face and mouth, thin wrinkled skin, an aged appearance, lipoatrophy and a normal cranial CT scan, suggestive of the Wiedemann-Rautenstrauch neonatal progeroid syndrome. He developed hypothyroidism on day 18 due to a partial organification disorder as did a later born sib. His mental development remains normal at age 2 with delayed growth at -2.5 SD. The case is presented and discussed and the literature is reviewed.

A hereditary syndrome with retinopathy and ataxia or deafness in two consanguineous brothers.

Of two brothers born of Sephardic first cousin parents one presented with congenital neural deafness, nyctalopia, visual field loss, flat ERG, unintelligible speech and a shuffling gait, and the other with severe ataxia, severe decreased visual acuity, mild field loss, decreased ERG, dysarthric speech and high grade myopia. The diagnosis of Usher syndrome type 1 or 2 is discussed as well as the possibility that both brothers have different genetic disorders.

Optic atrophy, microcephaly, mental retardation and mosaic variegated aneuploidy: a human mitotic mutation.

A 12-year-old girl presents with optic atrophy, pale papilla, amblyopia and microcephaly (-3 s.d.) with mild mental retardation and facial dysmorphism. She had mitral insufficiency with mitral prolapse and moderate short stature (-2.5 d.s.). She had normal flash visual evoked potentials, normal electroretinograms and electrooculograms and normal cranial CT scan as well as other lab tests to rule out malformations, tumors or multiple sclerosis. Her lymphocyte karyotype showed a variegated mosaicism with: 2 cells with 49, XX, +mar,+mar,+mar; 21 cells with 48, XX, +mar,+mar; 57 cells, with 47, XX,+mar; 20 cells with 46,XX; while parental karyotypes were normal. This syndrome therefore associates optic atrophy, mental retardation and microcephaly and short stature with chromosomal instability in the form of variegated mosaicism.

A new look at the management of the oculo-mandibulo-facial syndrome.

The authors review the literature on the oculo-mandibulo-facial syndrome and present the case of a six-year-old boy with congenital cataracts, microphthalmos, nystagmus, failure to thrive, dysmorphic features with a tiny pinched nose, mandibular hypoplasia, microstomia, double chin, chronic snoring, recurrent respiratory infections and dental problems. Chronic obstructive sleep apnoea with decreased oxygen saturation was present. Optimal medical management of OMFS-patients is described.

Incontinentia pigmenti (type 1) and X;5 translocation.

The authors present a 5-year-old girl with total absence of speech, dysmorphic features, pigmented lesions on the legs, an abnormal EEG and otherwise normal intelligence representing a mild form of type 1 Incontinentia pigmenti associated with an (X;5) (p11.2;q35.2) apparently balanced translocation prenatally diagnosed. The seven previous translocation type 1 IP patients are reviewed and all have the same Xp11 breakpoint. Somatic cell hybrids have been made to further study this breakpoint and further define the putative type 1 IP gene.

Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet-Biedl and McKusick-Kaufman syndromes.

McKusick-Kaufman syndrome (MKKS) is a rare, recessively inherited syndrome reported mainly in young children and is characterised by vaginal atresia with hydrometrocolpos, postaxial polydactyly, and congenital heart defect. Bardet-Biedl syndrome (BBS) is the generic name for a genetically heterogeneous group of autosomal recessive disorders characterised by retinal dystrophy or retinitis pigmentosa (appearing usually between 10 and 20 years of age), postaxial polydactyly, obesity, nephropathy, and mental disturbances, or, occasionally, mental retardation. Typically, MKKS is diagnosed (and reported) in very young children, whereas the diagnosis of BBS often is delayed to the teenage years. We report here a series of nine patients diagnosed in infancy with MKKS because of the presence of vaginal atresia and postaxial polydactyly, who later developed obesity and retinal dystrophy, thus turning out to be instances of BBS. The overlap of BBS and MKKS is a real diagnostic pitfall and its importance has to be stressed, for genetic counselling, for clinical management and follow up, and for molecular approaches. The diagnosis of MKKS should be considered with caution in all published cases described exclusively in the neonatal period and in those with mental retardation. We strongly recommend all children seen in infancy with a diagnosis of MKKS to be re-evaluated for RP and other signs of BBS.