The First Report of Biallelic Missense Mutations in the SFRP4 Gene Causing Pyle Disease in Two Siblings.

BACKGROUND: Pyle disease is a rare autosomal recessive bone dysplasia characterized by the broadening of metaphyses with generalized cortical thinning. Homozygous truncating mutations in secreted frizzled-related protein 4 (SFRP4) were, to date, the only known variants causative for this type of skeletal disorder. SFRP4 controls cortical and trabecular bone remodeling by differential regulation of the canonical and non-canonical WNT signaling in both bone compartments. Loss-of-function mutations in the SFRP4 gene lead to the protein deficiency causing skeletal phenotype typical for Pyle disease. RESULTS: Herein, we report on the first SFRP4 missense mutations that occurred in compound heterozygosity in two siblings affected by Pyle disease, and which we have identified using a whole-genome sequencing approach followed by a comprehensive in silico pathogenicity assessment. The variants we have found were extremely rare and evaluated to be disease-causing by several online available tools and software. CONCLUSION: With this paper, we have shown that Pyle disease may be related not only to SFRP4 truncating mutations but also to other loss-of-function alterations that possibly impair the protein capacity to bind WNT ligands. As we have expanded here, the range of deleterious variants underlying Pyle disease, we contribute to the knowledge on the pathogenesis of this rare skeletal disorder.

A 23-year follow-up of a male with Hajdu-Cheney syndrome due to NOTCH2 mutation.

We present a natural history of a 32-year-old man with Hajdu-Cheney syndrome (HJCYS), because of the de novo truncating mutation in the exon 34 of NOTCH2 (c.6424-6427delTCTG, p.Ser2142ArgfsX4), who has been followed up for a period of 23 years (between 9 and 32 years). During follow-up, we observed abnormalities of vision, hearing, voice, and progression of craniofacial features in the form of skeletal dysplasia with affected skull, dentition, spine, limbs, fingers, and toes. Low bone mineral density and history of fragility fractures also suggested primary osteoporosis being a clinical manifestation. According to Stengel-Rutkowski, Schimanek, and Wernheimer (1984; Human Genetics, 6, 272-295), systematic data acquisition has been used for quantitative analysis of anthropological, radiographic, and clinical features at childhood, adolescence, and young adulthood separately. A detailed phenotype description together with the results of reanalysis of 14 reports so far published on patients with HJCYS and NOTCH2 mutation showed similar phenotype evolution with age. The spectrum of observed features may improve diagnostic tools for HJCYS at different periods of the lifespan.

SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae.

Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal changes. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G > A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.

Exome sequencing reveals two novel compound heterozygous XYLT1 mutations in a Polish patient with Desbuquois dysplasia type 2 and growth hormone deficiency.

Desbuquois dysplasia type 2 (DBQD2) is a rare recessively inherited skeletal genetic disorder characterized by severe prenatal and postnatal growth retardation, generalized joint laxity with dislocation of large joints and facial dysmorphism. The condition was recently described to result from autosomal recessive mutations in XYLT1, encoding the enzyme xylosyltransferase-1. In this paper, we report on a Polish patient with DBQD2 who presented with severe short stature of prenatal onset, joint laxity, psychomotor retardation and multiple radiological abnormalities including short metacarpals, advanced bone age and exaggerated trochanters. Endocrinological examinations revealed that sleep-induced growth hormone (GH) release and GH peak in clonidine- and glucagon-induced provocative tests as well as insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 levels were all markedly decreased, confirming deficiency of GH secretion. Bone age, unlikely to GH deficiency, was significantly advanced. To establish the diagnosis at a molecular level, we performed whole-exome sequencing and bioinformatic analysis in the index patient, which revealed compound heterozygous XYLT1 mutations: c.595C>T(p.Gln199*) and c.1651C>T(p.Arg551Cys), both of which are novel. Sanger sequencing showed that the former mutation was inherited from the healthy mother, whereas the latter one most probably occurred de novo. Our study describes the first case of DBQD2 resulting from compound heterozygous XYLT1 mutation, expands the mutational spectrum of the disease and provides evidence that the severe growth retardation and microsomia observed in DBQD2 patients may result not only from the skeletal dysplasia itself but also from GH and IGF-1 deficiency.

Variable expressivity of the phenotype in two families with brachydactyly type E, craniofacial dysmorphism, short stature and delayed bone age caused by novel heterozygous mutations in the PTHLH gene.

Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms.

Novel mutation in the BMPR1B gene (R486L) in a Polish family and further delineation of the phenotypic features of BMPR1B-related brachydactyly.

BACKGROUND: Lehmann et al., [2003, 2006] have documented two different substitutions at position 486 of the BMPR1B gene which resulted in a phenotype of brachydactyly A2 [MIM 112600] or brachydactyly C with symphalangism [MIM 113100]. METHODS: In this article we report a family of Polish extraction with a novel mutation: c.1457G>T (R486L) which segregated with a complex brachydactyly. Clinical and radiological data are presented and details of previously reported patients with a pathogenic change of an amino acid at position 486 of the BMPR1B gene are summarized. CONCLUSION: Our data extends the previously known mutational and radiological spectrum associated with mutations in the BMPR1B gene and confirms the existence of a universal hotspot in the BMPR1B gene in this distinctive autosomal dominant brachydactyly disorder. It is of interest that an affected female in the Polish family had a severe congenital malformation of the venous system in addition to her digital anomalies. This observation raises the possibility of disturbance of embryonic angiogenesis by specific mutations in BMPR1B.

Three new patients with FATCO: fibular agenesis with ectrodactyly.

We document three new patients with fibular agenesis, tibial campomelia, and oligosyndactyly (FATCO). Two of these individuals had tetramelic manifestations while the third had bilateral abnormalities of the lower limbs. These patients and others reported as FATCO seem to belong to the phenotype "fibular aplasia with ectrodactyly." Genetic screening for CNVs and mutations in the TP63 and WNT10B genes did not show any genetic abnormalities. ©

Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia.

Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene. We tested the hypothesis that craniodiaphyseal dysplasia (CDD) (MIM 122860), an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as "leontiasis ossea", could also be caused by SOST mutations. We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST. We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.

New intermediate phenotype between MED and DD caused by compound heterozygous mutations in the DTDST gene.

DTDST mutations cause a spectrum of diastrophic dysplasia disorders characterized by defects of proteoglycans sulfation. Reduction of sulfate/chloride antiporter activity is manifested by lower sulfate uptake and depends on a combination of mutations in DTDST. We analyzed a family with an autosomal recessive form of bone dysplasia. Three affected brothers from this family are compound heterozygotes for C653S/A715V mutations. We classified their phenotype as a new intermediate form between diastrophic dysplasia and multiple epiphyseal dysplasia, manifested by shortening of stature, metatarsus adductus/club foot, mild brachydactyly, proximally placed thumbs and clinodactyly of the fifth fingers. Radiographs document platyspondyly most marked in the lower thoracic and upper lumbar spine, epiphyseal dysplasia affecting predominantly the femoral heads, widening of the metaphyses, narrow growth cartilage and multilayered patellae. Exaggerated lesser trochanters of femur, that is, "monkey wrench" sign, elevated greater trochanters, thin upper pubic rami, grossly normal carpal/tarsal bones and severe, early onset osteoarthritis were other notable features.

Ultrasound diagnosis of severe mesomelic dysplasia in two fetuses, associated with increased neck translucency and tetralogy of Fallot in one and cystic hygroma in the other.

Two stillborn male sibling fetuses born to the same parents had severe mesomelic dysplasia documented at ultrasound and confirmed by radiography and autopsy. The 17-week-old fetus with increased neck translucency had additional heart and great vessel anomalies consistent with tetralogy of Fallot. The 15-week-old fetus had a nuchal cystic hygroma. We posit that these sibs have a distinct, previously unreported skeletal dysplasia. The mode of genetic transmission could be autosomal recessive or X-linked recessive.

Osteogenesis imperfecta type V, spot diagnosis.

BACKGROUND: The first case of Osteogenesis Imperfecta Type V in the Polish literature is reported. CASE REPORT: Skeletal survey of an 8 year old girl with a history of multiple fractures and bilateral dislocation of radial heads was received for consultation. CONCLUSIONS: Generalised osteoporosis with multiple fractures, periosteal thickening and bilateral dislocation of the radial heads are characteristic signs of osteogenesis imperfecta Type V. The Nosology and Classification of Genetic Skeletal Disorders 2006 Revision classified Osteogenesis Imperfecta into 8 major types. Type V is recognizable on the basis of skeletal survey alone.

Expansion of Carraro syndrome or a new disorder?

A 6-year-old girl is described with a unique, rare type of tibial hemimelia known as Carraro syndrome (OIMI 275230). There are only two previous reports of this condition in the literature. In our patient, the tibia anomaly was associated with other skeletal abnormalities, hemivertebra and tetralogy of Fallot. This association of malformations has not previously been reported. We conclude that this girl has either a variant of Carraro syndrome or a new syndrome.

Severe neonatal spondylometaphyseal dysplasia in two siblings.

We report on two siblings with a severe neonatal form of spondylometaphyseal dysplasia (SMD). Similar cases have been reported in four publications. Analysis of pedigree data from the original and present families suggests an autosomal recessive mode of inheritance, although parental gonadal mosaicism is also possible. The similarities in the phenotype between our patients and spondyloepimetaphyseal dysplasia congenita (SEMDC) and spondyloepimetaphyseal dysplasia Strudwick (SEMDS) type, indicated that these patients could have a defect in the COL2A1 gene. Molecular analysis of genomic DNA of these patients excluded this gene. Another potential candidate gene PTHR1, was also analyzed in the selected regions and no mutation was found. This gene is probably causative in the Jansen type of SMD, which shares some phenotypic features with the siblings whom we documented. Our results indicate that a new candidate gene for the reported form of SMD should be sought.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic or Hall type: report of a case with normal face and literature review.

We have documented the clinical and radiological features of a girl with a severe form of spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic or Hall type, which is associated with marked articular hypermobility. This condition is to be differentiated clinically from generalized hypermobility syndromes specifically Ehlers-Danlos syndrome and Larsen syndrome. The radiographic differential diagnosis is with the group of spondyloepimetaphyseal dysplasias specifically spondyloepimetaphyseal dysplasia with joint laxity and sponastrime dysplasia.

A variant or a "new" postaxial acrofacial dysostosis syndrome.

In this paper, we report a boy with remarkable phenotype and noteworthy radiographic abnormalities. He presented with distinctive facies, mesomelic shortening and asymmetry of the extremities, symmetrical ulnar and fibular ray absence in the hands and feet, with unique hypoplastic/dysplastic radiographic abnormalities. His mental development was normal. We believe that he represents a previously unreported form of the postaxial acrofacial dysostosis syndrome.

A boy with severe craniodiaphyseal dysplasia and apparently normal mother.

We describe a boy and his mother affected with craniodiaphyseal dysplasia (CDD). The boy had a very severe form of the disease with extensive osteosclerosis already at birth. Facial diplegia, bilateral hearing loss and optic nerve atrophy were early, severe complications of the disease. At age 7 years progressive genu valgum and unusual epimetaphyseal radiographic appearances suggested hyperparathyroidism. This was confirmed by biochemical tests. Because of some facial similarity between the asymptomatic mother and the propositus, a limited skeletal survey of the mother was performed. It demonstrated cranial osteosclerosis and hyperostosis. It is possible that the mother has somatic mosaicism for a mutation of the genes causing CDD.

Czech dysplasia metatarsal type: another type II collagen disorder.

Czech dysplasia metatarsal type is an autosomal-dominant disorder characterized by an early-onset, progressive spondyloarthropathy with normal stature. Shortness of third and/or fourth toes is a frequently observed clinical feature. Similarities between individuals with this dysplasia and patients with an R275C mutation in the COL2A1 gene, prompted us to analyze the COL2A1 gene in the original families reported with Czech dysplasia. Targeted sequencing of exon 13 of the COL2A1 gene was performed, followed by sequencing of the remaining exons in case the R275C mutation was not identified. We identified the R275C substitution in two of the original patients reported with Czech dysplasia and three additional patients. All affected individuals had a similar phenotype characterized by normal height, spondyloarthropathy, short postaxial toes and absence of ocular and orofacial anomalies. The R275C mutation was excluded in a third patient reported with Czech dysplasia. However, the identification of the Y1391C mutation in this patient with disproportionate short stature made the diagnosis of spondyloperipheral dysplasia (SPD) more probable. The Y1391C mutation is located in the C-propeptide of the procollagen chain and has been reported before in a patient with the Torrance type of lethal platyspondylic skeletal dysplasia (PLSD-T). Our observation of the same Y1391C mutation in an additional unrelated patient with SPD further supports the evidence that PLSD-T and SPD represent a phenotypic continuum. The R275C mutation in the COL2A1 gene causes a specific type II collagen disorder that was recently delineated as Czech dysplasia.

Pachydermoperiostosis-critical analysis with report of five unusual cases.

Pachydermoperiostosis (idiopathic hypertrophic arthropathy) {MIM 167100} is an uncommon disease characterized by unique phenotype (digital clubbing and pachydermia) and distinctive radiographic appearances (periostosis). Two families are reported that, in additional to the typical phenotype and radiographic characteristics of pachydermoperiostosis, show some rare and/or unusual, not yet reported, clinical findings. In the first family, distinctive features were severe progressive arthritis with villonodular involvement of the knees. The clinical course of the disease was much more severe than usually reported. The older brother was disabled at the age of 29 years. In the second family, the clinical history was exceptional, with unique early appearance of clinical signs. Pachydermoperiostosis is usually inherited as a dominant trait, but probable autosomal recessive inheritance has been reported. Also in the present families, autosomal recessive inheritance is likely, possibly explaining the severe clinical course of the disease. Differential diagnosis and the confusing nomenclature of pachydermoperiostosis are discussed.