Audiological phenotyping evaluation in KBG syndrome: Description of a multicenter review.

OBJECTIVES: Our objective was to reinforce clinical knowledge of hearing impairment in KBG syndrome. KBG syndrome is a rare genetic disorder due to monoallelic pathogenic variations of ANKRD11.The typical phenotype includes facial dysmorphism, costal and spinal malformation and developmental delay. Hearing loss in KBG patients has been reported for many years, but no study has evaluated audiological phenotyping from a clinical and an anatomical point of view. METHODS: This French multicenter study included 32 KBG patients with retrospective collection of data on audiological features, ear imaging and genetic investigations. RESULTS: We identified a typical audiological profil in KBG syndrome: conductive (71%), bilateral (81%), mild to moderate (84%) and stable (69%) hearing loss, with some audiological heterogeneity. Among patients with an abnormality on CT imaging (55%), ossicular chain impairment (67%), fixation of the stapes footplate (33%) and inner-ear malformations (33%) were the most common abnormalities. CONCLUSION: We recommend a complete audiological and radiological evaluation and an ENT-follow up in all patients presenting with KBG Syndrome. Imaging evaluation is necessary to determine the nature of lesions in the middle and inner ear.

Unequal Impact of COL1A1 and COL1A2 Variants on Dentinogenesis Imperfecta.

Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype-genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions-MLRB2 in α1(I) and MLBR 3 in α2(I)-could significantly predict DI (P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.

Craniosynostosis and metabolic bone disorder. A review.

INTRODUCTION: Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder. MATERIAL AND METHODS: A review of the literature on metabolic forms of craniosynostosis was performed. RESULTS: The most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe. CONCLUSION: The impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.

Gnathodiaphyseal dysplasia with a novel R597I mutation of ANO5: Mandibular reconstruction strategies.

Gnathodiaphyseal Dysplasia (GDD) is a rare, often misdiagnosed, autosomal-dominant disorder due to point mutations in the ANO5 gene. GDD combines craniofacial fibro-osseous lesions, dental loss and progressive curvature and cortical thickening of long bones and vertebra, causing pathological fractures. Diagnosis is based on bone pathology and mutation screening. Here we report three GDD cases within a single family with a novel ANO5 mutation: c.1790 G > T (p.Arg597Ile, i.e. R597I) on exon 16. Microsurgical mandibular reconstructions were performed in the three cases. We reviewed the literature on jaw reconstruction in this condition and discussed the challenges of craniofacial reconstruction in GDD due to the diffuse bone anomalies affecting potential flap donor zones and a specific risk for jawbone osteomyelitis.

Enzyme-replacement therapy in perinatal hypophosphatasia: Case report and review of the literature.

Hypophosphatasia (HPP) is a rare disease resulting from alterations of the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Perinatal HPP is mainly characterized by bone hypomineralization and severe respiratory insufficiency. We describe a full-term boy diagnosed with perinatal HPP after birth, showing dramatic improvement after treatment with Asfotase Alfa, an enzyme-replacement therapy (ERT) prescribed in HPP cases. He initially presented with respiratory insufficiency due to bone hypomineralization, and severe pulmonary hypoplasia that required tracheostomy and invasive ventilation for 8 months. He was taken off ventilation at 41 weeks of age. He also presented complications including hypercalcemia, craniosynostosis, nephrocalcinosis, hypotonia, and a severe feeding disorder. He is still alive at 30 months of age, and his respiratory status and tonus is steadily improving. This case reflects the progression of HPP patients with specific therapy added to symptomatic management. Some aspects of the disease are now well known, such as nephrocalcinosis and craniosynostosis, related to the natural course of the disease, which persisted despite the ERT. The long-term prognosis and outcome for this newborn child remain unknown.

IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences.

By describing 10 new patients recruited in centres for Human Genetics, we further delineate the clinical spectrum of a Crouzon-like craniosynostosis disorder, officially termed craniosynostosis and dental anomalies (MIM614188). Singularly, it is inherited according to an autosomal recessive mode of inheritance. We identified six missense mutations in IL11RA, a gene encoding the alpha subunit of interleukin 11 receptor, 4 of them being novel, including 2 in the Ig-like C2-type domain. A subset of patients had an associated connective tissue disorder with joint hypermobility and intervertebral discs fragility. A smaller number of teeth anomalies than that previously reported in the two large series of patients evaluated in dental institutes points toward an ascertainment bias.

[Transverse reductional anomaly and atypical fibrodysplasia ossificans progressiva: A case diagnosed late]. / Anomalie réductionnelle transverse et fibrodysplasie ossifiante progressive atypique, à propos d'un cas de diagnostic tardif.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by the association of congenital bone abnormalities and extraskeletal ossification flare-ups occurring in muscles and fasciae. Early diagnosis is important to prevent ossification flare-ups, but some atypical presentations can lead to errors in diagnosis and therefore delay. Here, we report on a case of an atypical presentation of FOP in a girl, in whom prominent transverse reductional abnormalities delayed diagnosis. The patient developed extraskeletal ossifications and progressive fibrosis that led to motor restrictions. Since early diagnosis is important, we discuss the clinical presentations of FOP and the differential diagnoses.

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.

Perinatal and infantile hypophosphatasia: clinical features and treatment.

Hypophosphatasia (HPP) is a rare hereditary disease characterized by defective skeletal mineralization, and with a broad severity spectrum. The perinatal forms, lethal and non-lethal, are associated with severe neonatal respiratory distress, potential seizures, hypotrophy and marked hypotonia. The diagnosis is rapidly suggested by a combination of typical radiological signs, hypercalcemia, hyperphosphatemia and low alkaline phosphatase (ALP) activity. In the infantile form, the clinical signs appear before the age of six months, but the patients usually have no or very mild signs at birth. The diagnosis should be considered in the event of early deformation of the pectus, feeding difficulties, hypotonia, frequent respiratory tract infections, hypercalcemia, and even early constitution of craniosynostosis. Radiological signs may be less obvious characterized by irregular metaphyses and generalized hypomineralization. Management is initially symptomatic, and adjusted to the symptoms. Care should be provided by a multidisciplinary team, in close collaboration with Reference Centers experts for the disease. Currently, recombinant enzyme replacement therapy (ERT) is under development for the severe form of HPP. The course of the disease, depending on the degree of severity and the various types of management, requires long-term evaluation through joint prospective follow-up to assess the long-term outcomes of these patients. Multidisciplinary follow up is needed to identify the medical and socio-economic outcomes of children and adults affected by HPP.

Craniosynostosis and hypophosphatasia.

Hypophosphatasia (HPP) when diagnosed at a young age may induce premature fusion of one or several cranial sutures, resulting in a craniocerebral disproportion. The main forms of craniosynostosis associated with HPP are loss of the sagittal suture (scaphocephaly), alone or associated with loss of the coronal sutures (oxycephaly) or associated with loss of the coronal and lambdoid sutures (pansynostosis). Craniosynostosis is accompanied by putatively functional consequences. Diagnosis must thus be early and lead to management by a specialized team.

[Craniofacial strategy for syndromic craniosynostosis]. / Stratégie craniofaciale pour les faciocraniosténoses.

The complexity of treatment of faciocraniosynostosis justifies the treatment in a reference center for rare diseases. The growth disturbances in the skull and face being variable according to the type of mutation in the FGFr (Crouzon, Pfeiffer, Apert), the strategy is adapted to the phenotype according to the following principles: posterior expansion with or without distraction around 6 months to limit the descent of the cerebellum tonsils and to prevent the turricephalic development; fronto-facial monobloc advancement with internal distraction around the age of 18 months in case of severe exorbitism or breathing impairment. The dissociated strategy (fronto-orbital advancement first, followed by facial osteotomy of Le Fort 3 type). The growing evolution dictates the sequence of subsequent surgeries according to the monitoring of intracranial pressure by fundus examination and of the respiration by polysomnography. Le Fort 3 and transversal maxillary distraction may be repeated if necessary. Orthognathic surgery is almost always compulsory after the age of 14, before the aesthetic refinements which can be undertaken ultimately (rhinoplasty, genioplasty, canthopexies, fat grafting…).

Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

[Natural history of Morquio A disease]. / Histoire naturelle de la mucopolysaccharidose IV de type A (maladie de Morquio A).

Type IV mucopolysaccharidosis (Morquio A syndrome; MPS IVA; OMIM 253000), is a multisystemic, severe and very disabling disease, also life-threatening; MPS IVA is due to a deficiency of the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme responsible for the degradation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The disease is characterized by respiratory, pulmonary manifestations and also causes bone involvement with progressive spondyloepimetaphyseal degradation and mild and late-onset ophthalmologic, hearing and cardiac complications. These manifestations progressively impair the patients' physical mobility. Severe forms of the disease, diagnosed before the age of 1 year, can be distinguished from intermediary (diagnosed between 1 and 5 years old) and attenuated disease, diagnosed after the age of 5 years (occasionally far later). The main signs are bone deformities namely pectus carinatum, kyphoscoliosis and genu valgum, with early flattening of the growth curve, leading rapidly to almost complete growth arrest. Patients have normal cognitive development. The radiological signs are relatively specific with, in particular, platyspondyly, shortening of the long bones and characteristic pelvic changes. The diagnosis is suggested by elevated urinary GAGs level and profile, and is confirmed by GALNS enzymatic studies on molecular testing. Genetic counseling is important in this autosomal recessive disorder and enzymatic and/or molecular testing can be offered for prenatal diagnosis. Management is mostly symptomatic, based on early detection and orthopedic correction of spine and lower limb deformities, ENT and respiratory management and psychological, social and educational support for the child and his/her family.

[GACI syndrome: a case report with a neonatal beginning]. / Le syndrome GACI : à propos d'une observation à début néonatal.

GACI (generalized arterial calcification of infancy) is a rare autosomal recessive disorder characterized by arterial and periarticular calcifications. Most children die in the first months of life of cardiovascular complications. Hypophosphatemic rickets (HR) resistant to medical treatment may complete the phenotype and is associated with a milder phenotype. This report discusses the case of a girl who presented neonatal ectopic periarticular calcifications with spontaneous regression, and then at the age of 3 years developed HR. There was no clinical improvement after treatment with calcitriol and phosphate, and correction of alkaline phosphatase induced the recurrence of periarticular and tissular calcifications : the treatment was reduced and the bone distortion treated by surgery. GACI diagnosis was confirmed by genetic analysis. At the age of 4.5 years, she developed a retinal abnormality and decreased radial pulse: these clinical signs are usually observed in pseudoxanthoma elasticum (PXE). It is now established that GACI and PXE belong to the same entity characterized by arterial and tissular calcifications of which this original case report is an illustration.

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.

Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: report of 13 new families.

Split hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.

Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the WTX locus.

Osteopathia striata congenita with cranial sclerosis (OSCS) is a skeletal dysplasia caused by germline deletions of or truncating point mutations in the X-linked gene WTX (FAM123B, AMER1). Females present with longitudinal striations of sclerotic bone along the long axis of long bones and cranial sclerosis, with a high prevalence of cleft palate and hearing loss. Intellectual disability or neurodevelopmental delay is not observed in females with point mutations in WTX leading to OSCS. One female has been described with a deletion spanning multiple neighbouring genes suggesting that deletion of some neighbouring loci may result in abnormal neurodevelopment. In this cohort of 13 females with OSCS resulting from deletions of WTX, a relationship is observed where deletion of ARHGEF9 and/or MTMR8 in conjunction with WTX results in an additional neurodevelopmental phenotype whereas deletion of ASB12 along with WTX is associated with a good neurodevelopmental prognosis.