Characterization and prevalence of severe primary IGF1 deficiency in a large cohort of French children with short stature.

OBJECTIVE: The prevalence of severe primary IGF1 deficiency (IGFD) is unclear. IGFD must be identified promptly as treatment with recombinant human IGF1 (rhIGF1) is now available. Our objective was to characterize and assess the prevalence of severe primary IGFD in a large cohort of patients evaluated for short stature at a pediatric endocrinology unit in France. DESIGN: Observational study in a prospective cohort. METHODS: Consecutive patients referred to our unit between 2004 and 2009 for suspected slow statural growth were included. Patients were classified into eight etiological categories. IGFD was defined by height ≤-3 SDS, serum IGF1 levels <2.5th percentile, GH sufficiency, and absence of causes of secondary IGFD. RESULTS: Out of 2546 patients included, 337 (13.5%) were born small for gestational age and 424 (16.9%) had idiopathic short stature. In these two categories, we identified 30 patients who met our criterion for IGFD (30/2546, 1.2%). In these 30 patients, we assessed the response to IGF1 generation test, time course of IGF1 levels, and efficiency of GH replacement therapy. The results indicated that only four of the 30 children were definite or possible candidates for rhIGF1 replacement therapy. CONCLUSION: The prevalence of severe primary IGFD defined using the standard criterion for rhIGF1 treatment was 1.2%, and only 0.2% of patients were eligible for rhIGF1 therapy.

Unexpected high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients.

OBJECTIVE: To assess the prevalence of skeletal dysplasias (SDs) in patients with idiopathic short stature (ISS) or small for gestational age (SGA) status. SETTING: Rare Endocrine/Growth Diseases Center in Paris, France. DESIGN: A prospective study on consecutive patients with ISS and SGA enrolled from 2004 to 2009. METHOD: We used a standardized workup to classify patients into well-established diagnostic categories. Of 713 patients with ISS (n=417) or SGA status (n=296), 50.9% underwent a skeletal survey. We chose patients labeled normal or with a prepubertal slowdown of growth as a comparison group. RESULTS: Diagnoses were ISS (16.9%), SGA (13.5%), normal growth (24.5%), transient growth rate slowing (17.3%), endocrine dysfunction (12%), genetic syndrome (8.9%), chronic disease (5.1%), and known SD (1.8%). SD was found in 20.9% of SGA and 21.8% ISS patients and in only 13.2% in our comparison group. SD prevalence was significantly higher in the ISS group than in the comparison group, especially (50%) for patients having at least one parent whose height was <-2 SDS. Dyschondrosteosis and hypochondroplasia were the most frequently identified SD, and genetic anomaly was found in 61.5 and 30% respectively. Subtle SD was found equally in the three groups and require long-term growth follow-up to evaluate the impact on final height. CONCLUSION: SD may explain more than 20% of cases of growth retardation ascribed to ISS or SGA, and this proportion is higher when parental height is <-2 SDS. A skeletal survey should be obtained in patients with delayed growth in a context of ISS or SGA.

Three-dimensional helical computed tomography in prenatal diagnosis of fetal skeletal dysplasia.

OBJECTIVES: (1) To study the use and diagnostic value, as a complement to ultrasound, of helical computed tomography (helical CT) to differentiate normal fetuses from cases of skeletal dysplasia; (2) to define the most relevant indications for helical CT; and (3) to evaluate its diagnostic performance with respect to radiological criteria considered discriminatory. METHODS: This was a retrospective study from 2005 to 2008 in 67 pregnant women who underwent helical CT after 26 weeks of gestation for suspected fetal skeletal dysplasia due to fetal shortened long bones on ultrasound (≤ 10(th) percentile), either alone or associated with other bone abnormalities. The results were compared with pediatric examinations in 41 cases and with fetal autopsy findings after elective termination of pregnancy in the others. RESULTS: Helical CT had a sensitivity of 82%, specificity of 91% and positive and negative predictive values of 90% and 83%, respectively, for diagnosis of fetal skeletal dysplasia. An etiological diagnosis that had not been suspected at ultrasound was specified in 15% of cases and diagnoses suspected at ultrasound were confirmed in 24% and discounted in 43% of cases. The prevalence of skeletal dysplasia was increased in cases of micromelia < 3(rd) percentile or if there was a combination of bone signs. Helical CT showed 69% sensitivity in identifying individual predefined pathological bone signs which were confirmed on fetal autopsy findings. CONCLUSION: Helical CT is a key examination, in combination with ultrasound, in the diagnosis of fetal skeletal dysplasia from 26 weeks of gestation. It should be reserved for cases with severe micromelia below the 3(rd) percentile and for those with micromelia ≤ 10(th) percentile associated with another bone sign. A checklist of discriminatory signs is proposed.

Slicing softly with shear.

A soft solid is more easily sliced using a combination of normal and shearing deformations rather than diced by squeezing down on it normally with the same knife. To explain why this is so, we experimentally probe the slicing and dicing of a soft agar gel with a wire, and complement this with theory and numerical simulations of cutting of a highly deformable solid. We find that purely normal deformations lead to global deformations of the soft solid, so that the blade has to penetrate deeply into the sample, well beyond the linear regime, to reach the relatively large critical stress to nucleate fracture. In contrast, a slicing motion leads to fracture nucleation with minimal deformation of the bulk and thus a much lower barrier. This transition between global and local deformations in soft solids as a function of the angle of shear explains the mechanics of the paper cut and design of guillotine blades.

Fourth case of cerebral, ocular, dental, auricular, skeletal syndrome (CODAS), description of new features and molecular analysis.

Cerebral, ocular, dental, auricular, skeletal syndrome (CODAS, OMIM 600373) is a very rare congenital malformation syndrome. This clinical entity is highly distinctive and associates mental retardation, cataract, enamel abnormalities, malformations of the helix, epiphyseal and vertebral malformations, and characteristic dysmorphic features. Since 1991, only three affected children have been reported. The etiology and pattern of inheritance of CODAS syndrome still remain unknown. We describe a new sporadic case presenting with all the characteristic features of CODAS syndrome associated with previously unreported malformations of the heart, larynx, and liver. All investigations such as karyotype, metabolic screening and array CGH were normal.

Stüve-Wiedemann syndrome: long-term follow-up and genetic heterogeneity.

Stüve-Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity.

[Genetic testing in the context of the revision of the French law on bioethics]. / Les tests génétiques à l'heure de la deuxième révision des lois de bioéthique.

This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used.

Cognitive and neuroradiological improvement in three patients with attenuated MPS I treated by laronidase.

Stem cell transplantation is not appropriate first-line treatment for attenuated phenotypes of mucopolysaccharidosis type I (MPS I). In three patients with attenuated MPSA I treated by laronidase, Patients 2 and 3 displayed significant cognitive improvement within 2years; Patients 1 and 3 displayed improvement on MRI scans of the brain.

Molecular analysis of pericentrin gene (PCNT) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPD II) families.

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II, MIM 210720) and Seckel syndrome (SCKL, MIM 210600) belong to the primordial dwarfism group characterised by intrauterine growth retardation, severe proportionate short stature, and pronounced microcephaly. MOPD II is distinct from SCKL by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Seckel syndrome is associated with defective ATR dependent DNA damage signalling. In 2008, loss-of-function mutations in the pericentrin gene (PCNT) have been identified in 28 patients, including 3 SCKL and 25 MOPDII cases. This gene encodes a centrosomal protein which plays a key role in the organisation of mitotic spindles. The aim of this study was to analyse PCNT in a large series of SCKL-MOPD II cases to further define the clinical spectrum associated with PCNT mutations. Among 18 consanguineous families (13 SCKL and 5 MOPDII) and 6 isolated cases (3 SCKL and 3 MOPD II), 13 distinct mutations were identified in 5/16 SCKL and 8/8 MOPDII including five stop mutations, five frameshift mutations, two splice site mutations, and one apparent missense mutation affecting the last base of exon 19. Moreover, we demonstrated that this latter mutation leads to an abnormal splicing with a predicted premature termination of translation. The clinical analysis of the 5 SCKL cases with PCNT mutations showed that they all presented minor skeletal changes and clinical features compatible with MOPDII diagnosis. It is therefore concluded that, despite variable severity, MOPDII is a genetically homogeneous condition due to loss-of-function of pericentrin.

Prenatal diagnosis of brachytelephalangic chondrodysplasia punctata: case report.

Brachytelephalangic chondrodysplasia punctata is a rare congenital skeletal dysplasia. Within the heterogeneous group of chondrodysplasia punctata, the brachytelephalangic type is noteworthy because it has a better prognosis than do the other types. We report a case of brachytelephalangic chondrodysplasia punctata diagnosed by ultrasound imaging at 30 weeks' gestation; it was associated with polyhydramnios and a normal cervical spinal canal. Imaging features are described and differential diagnosis with other forms of chondrodysplasia punctata is discussed.

Pamidronate treatment of children with moderate-to-severe osteogenesis imperfecta: a note of caution.

BACKGROUND/AIMS: Bisphosphonates have been reported to decrease fractures related to osteogenesis imperfecta (OI). We assessed the efficacy and long-term safety of pamidronate therapy in patients with moderate-to-severe OI. METHODS: We conducted an open-label uncontrolled study in 14 boys and 13 girls whose mean age was 6.8 years at baseline. Intravenous pamidronate, 1 mg/kg/day, was given for 3 consecutive days every 4 months for 2-6 years, with physical therapy and orthopedic surgery as appropriate. Mobility score, fracture rate, height, bone mineral density (BMD) and bone healing were evaluated throughout follow-up. RESULTS: In 24 (89%) patients, the fracture rate decreased to 6 months) occurred in 8 (29.6%) patients; their BMD gains, baseline age and treatment duration were not significantly different from those in the other patients. Tolerance was good. CONCLUSION: Pamidronate with physiotherapy and orthopedic management improved outcomes without delaying fracture healing in 19 (70%) of 27 patients. Delayed fracture healing occurred in 8/27 patients. Pamidronate should be reserved for severe OI with multiple fractures and/or flattened vertebras.

Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity.

Spondylocarpotarsal synostosis syndrome (SCT) (OMIM 272460), originally thought to be a failure of normal spine segmentation, is characterized by progressive fusion of vertebras and associates unsegmented bars, scoliosis, short stature, carpal and tarsal synostosis. Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations. Twenty-five patients have been reported. Thirteen affected individuals were siblings from six families and four of these families were consanguineous. In four of those families, Krakow et al. [Krakow et al. (2004) Nat Genet 36:405-410] found homozygosity or compound heterozygosity for mutations in the gene encoding FLNB. This confirmed autosomal recessive inheritance of the disorder. We report on two new patients (a mother and her son) representing the first case of autosomal dominant inheritance. These patients met the clinical and radiological criteria for SCT and did not present any features which could exclude this diagnosis. Molecular analysis failed to identify mutations in NOG and FLNB. SCT is therefore, genetically heterogeneous. Both dominant and autosomal recessive forms of inheritance should be considered during genetic counseling.

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.

Untreated growth hormone deficiency with extremely short stature, bone dysplasia, cleft lip--palate and severe mental retardation in a 26-year-old man with a de novo unbalanced translocation t(1;12)(q24;q24).

We report on a 26-year-old patient presenting with extremely short stature (height 72cm, weight 6.5kg, OFC 42.5cm), facial dysmorphism, cleft lip--palate, severe mental retardation and de novo 1q24.2--q25.2 and 12q24.31 interstitial deletion. He was the only child of non-consanguineous parents and his birth length was 43cm. He had severe feeding difficulties and required enteral nutrition until the age of 3 years. Standard cytogenetic analysis showed an apparently balanced de novo translocation t(1;12)(q24;q24). Endocrine studies at 11 years of age for severe growth retardation revealed multiple pituitary hormone deficiency with severe growth hormone deficiency, but the child was untreated because of associated mental retardation. At 26 years of age, he could not walk or speak and had no signs of puberty. Investigations revealed spondylo-epi-metaphyseal dysplasia with severe osteoporosis, enlarged aorta when compared to the patient's size and apparently normal pituitary development. High resolution karyotype showed a 1q24-q25 deletion, and comparative genomic hybridization studies confirmed the 1q interstitial deletion. FISH studies of both breakpoints using PACs and BACs enabled us to further characterize the 1q interstitial deletion (1q24.2-1q25.2) and also revealed a 12q24.31 interstitial microdeletion. This case is compared with previously reported patients with similar deletions, but the untreated pituitary deficiency could also be responsible in part for the severity of the growth deficiency. This observation is of interest for two reasons. First, these deletions could be a clue in the search for a gene responsible for growth hormone deficiency/midline defects. Second, it shows the importance of molecular cytogenetics in the study of de novo apparently balanced translocation with abnormal phenotype.

A gene responsible for Ghosal hemato-diaphyseal dysplasia maps to chromosome 7q33-34.

Ghosal hemato-diaphyseal dysplasia is a rare autosomal recessive disorder characterized by a progressive sclerosing diaphyseal dysplasia and refractory anemia. The pathogenesis and genetic bases of this syndrome remain hitherto unknown. We have performed a genome wide search in two inbred families originating from Algeria and Tunisia. Here, we report on the mapping of a disease gene to chromosome 7q33-34 (Zmax = 4.21 at theta = 0 at locus D7S2513) in a 3.4 Mb defined by loci D7S2560 and AC091742. Ongoing studies will hopefully lead to identification of the disease-causing gene.

Specific osseous spurs in a lethal form of hypophosphatasia correlated with 3D prenatal ultrasonographic images.

BACKGROUND: Hypophosphatasia is an osseous dysplasia with highly variable clinical expression, ranging from a recessive lethal prenatal type to late onset dominant short stature with premature shedding of teeth. Lethal forms of hypophosphatasia include short limb dwarfism with lack of ossification, especially on the vertebral bodies, very slender ribs and clavicles, and bowed, short lower extremities, with a bifid aspect of the diaphyses. Alkaline phosphatase is abnormally low in liver, bone, kidney and plasma. METHODS: We present here the prenatal images of a lethal form of hypophosphatasia, diagnosed precociously because of specific osseous spurs in a context of recurrent short limb dwarfism. RESULTS: Prenatal 3D ultrasonography has shown these spurs as early as 18 weeks. Molecular biology found compound heterozygous mutations in the gene TNSALP. CONCLUSION: In a context of short limb dwarfism, the search for these specific osseous spurs orient strongly toward the diagnosis of lethal hypophosphatasia.

Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) refer to a broader group of neurobiological conditions, pervasive developmental disorders. They are characterised by a symptomatic triad associated with qualitative changes in social interactions, defect in communication abilities, and repetitive and stereotyped interests and activities. ASD is prevalent in 1 to 3 per 1000 people. Despite several arguments for a strong genetic contribution, the molecular basis of a most cases remains unexplained. About 5% of patients with autism have a chromosome abnormality visible with cytogenetic methods. The most frequent are 15q11-q13 duplication, 2q37 and 22q13.3 deletions. Many other chromosomal imbalances have been described. However, most of them remain undetectable using routine karyotype analysis, thus impeding diagnosis and genetic counselling. METHODS AND RESULTS: 29 patients presenting with syndromic ASD were investigated using a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Eight clinically relevant rearrangements were identified in 8 (27.5%) patients: six deletions and two duplications. Altered segments ranged in size from 1.4 to 16 Mb (2-19 clones). No recurrent abnormality was identified. CONCLUSION: These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.